Polycyclic compound, preparation method therefor, and pharmaceutical use thereof

Abstract

The present disclosure relates to a polycyclic compound, a preparation method therefor, and the pharmaceutical use thereof. Specifically, the present disclosure relates to a polycyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, in particular, the use as an RAS inhibitor and the use in the preparation of a drug for treating and / or preventing RAS-mediated or dependent diseases or conditions, wherein each group in general formula (I) is as defined in the description.

Description

Polycyclic compounds, processes for their preparation and their use in medicine TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a polycyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the polycyclic compound, and the use of the polycyclic compound as a therapeutic agent, in particular, the use as a RAS inhibitor and in the preparation of a medicament for treating and / or preventing a disease or disorder mediated or dependent on RAS mutant protein. BACKGROUND

[0002] RAS is one of the most common oncogenes in tumors, accounting for about 30% of tumors, including KRAS, HRAS and NRAS. The most frequently mutated sites in RAS are codons 12, 13 and 61, of which the mutation of codon 12 is the most common. Under normal conditions, RAS protein is converted between the inactive state of GDP binding and the activated state of GTP binding. After RAS mutation, the GTPase-activating proteins (GAPs) dependent or endogenous GTP hydrolysis enzyme activity of RAS is destroyed, so that the RAS protein is always in the activated state of GTP binding, continuously activating the downstream MAPK, PI3K and other signaling pathways, promoting the occurrence and progression of tumors.

[0003] Due to the lack of traditional small molecule binding sites on the surface of RAS protein and the pM affinity with GTP, it is extremely difficult for compounds to inhibit RAS, and for a long time, RAS has been considered as an undruggable drug target. Although KRAS G12C inhibitors have been marketed, drugs directly targeting the activated state of GTP-bound RAS have not been approved, and therefore there is still a need to develop such inhibitors for the treatment of RAS mutant tumors. SUMMARY

[0004] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0005] wherein:

[0006] represents that the ring is an aromatic ring or a non-aromatic ring;

[0007] X, Y and Z are the same or different, and each is independently selected from -(CR 4a R 4b ) m -, -NR 5 (CR 4c R 4d ) r’ -, -C(O)NR 5 -, -NR5 C(O)-, -C(O)- and -O(CR) 4e R 4f ) n -;

[0008] m can be 0, 1, 2, 3, or 4;

[0009] n is 0, 1, 2, 3 or 4;

[0010] r' can be 0, 1, 2, 3 or 4;

[0011] R 4a R 4b R 4c R 4d R 4e and R 4f The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more R*;

[0012] R 5 and R R The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more R*; or

[0013] R 4a R 4b R 4c R 4d R 4e R 4f and R 5 The two atoms in the group together with the attached atoms form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R*.

[0014] G 1 G 2 Whether the CR is the same as or different from G, and each is independent of the other. 6 CR 66 R 67 C(O), NR 68 N = O or N;

[0015] Ring A is a heterocyclic group;

[0016] The ring carbons may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl groups;

[0017] RA R B R C R 66 R 67 R 68 R 6 R 7a R 7b R 7a R 7b R 7a R 7b R 7c R 7a R 7b R 8 R 8 R 7a R 7b R w R 8 R 61 R 62 R 63 R 64 R 9a R 9b R

[0018] R A R AA R

[0019] R D R 7a R 7b R 7a R 7b R 7a R 7b R 7c R 7a R 7b R 8-C(O)OR 8 -C(O)NR 7a R 7b -S(O) w R 8 -S(=O)(=N-R 64 )R 8 -alkyl-NR 7a R 7b -alkenyl-NR 7a R 7b -alkynyl-NR 7a R 7b -O-alkyl-cycloalkyl, -O-alkyl-heterocyclyl, heterocyclyl(alkylene) 0-6 heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkenyl, heterocyclylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, heterocyclylalkynyl, arylalkynyl, and heteroarylalkynyl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, -alkyl-NR 7a R 7b -alkenyl-NR 7a R 7b -alkynyl-NR 7a R 7b -O-alkyl-cycloalkyl, -O-alkyl-heterocyclyl, heterocyclyl(alkylene) 0-6 heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkenyl, heterocyclylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, heterocyclylalkynyl, arylalkynyl, and heteroarylalkynyl, each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =S, =N-R 64 , alkyl optionally substituted with one or more R*, alkenyl optionally substituted with one or more R*, alkynyl optionally substituted with one or more R*, alkoxy optionally substituted with one or more R*, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b , hydroxy, hydroxyalkyl, cycloalkyl optionally substituted with one or more R*, heterocyclyl optionally substituted with one or more R*, aryl optionally substituted with one or more R*, heteroaryl optionally substituted with one or more R*, cycloalkylalkyl optionally substituted with one or more R*, heterocyclylalkyl optionally substituted with one or more R*, arylalkyl optionally substituted with one or more R*, and heteroarylalkyl optionally substituted with one or more R*;

[0020] R 2 is selected from the group consisting of O, NH, and N-alkyl;

[0021] L 2 The alkylene group is optionally alkylene oxide (R0) or alkylene oxide (R0) by one or more R0. L2 replace;

[0022] R L2 Same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =NOR 61 =CR 62 R 63 =NR 64 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R* groups; or

[0023] Two Rs L2 Together with the attached atoms, it forms a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. LL2 replace;

[0024] L 1 It is an alkylene or cycloalkyl group, wherein the alkylene or cycloalkyl group is optionally surrounded by one or more R groups. L1 replace;

[0025] L is R 10 or

[0026] R 11 and R 12 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more R E replace;

[0027] L 3 For key or -N(R) L3 )C(O)-;

[0028] L 4 For bonds or -(alkylene) y -N(R L4 )C(=O)-;

[0029] R 10 Selected from alkyl, cycloalkyl, heterocyclic and NR 101 R 102 The alkyl, cycloalkyl, and heterocyclic groups are each independently and optionally influenced by one or more R groups. F replace;

[0030] Each R F They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b hydroxyl group, oxo group, =S, =NOR 61 =CR 62 R 63 =NR 64 cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R F1 -C(O)OR F1 -C(O)NR F2 R F3 -S(O) w R F1 and -S(O) w OR F1 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. FF replace;

[0031] R 7a R 7b R 7c R 9a R 9b R L3 R L4 R 101 R 102 R F2 and R F3 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, heteroalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0032] Or R 7a and R 7b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 9a and R 9b Together with the attached nitrogen atom, it forms a heterocyclic group, or R 101 and R 102 Together with the attached nitrogen atom, it forms a heterocyclic group, or R F2 and R F3 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally selected from halogens, oxo groups, =S, =NR. 64one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0033] R 8 R F1 R 61 R 62 R 63 R 64 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclyl is independently optionally substituted with one or more R # ; or

[0034] R 62 R 63 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R FF ;

[0035] each R AA R DD R LL2 R L1 R E R FF R #the same or different, and each is independently selected from the group consisting of oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amido, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy, each of said =N-alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy being independently optionally substituted with one or more substituents selected from the group consisting of oxo, =S, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amido, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy;

[0036] w is 0, 1, or 2;

[0037] n is 0, 1, 2, 3, 4, 5, or 6;

[0038] p is 0, 1, 2, 3, 4, 5, or 6;

[0039] q is 0, 1, 2, or 3; and

[0040] y is 0, 1, 2, 3, 4, 5, or 6.

[0041] In some embodiments of the disclosure, R 2 is O.

[0042] In some embodiments of the disclosure, R R is a hydrogen atom or C 1-6 alkyl; in some embodiments, R R is a hydrogen atom.

[0043] In some embodiments of the disclosure, ring A is a 5- to 8-membered heterocyclyl; in some embodiments, ring A is a 6-membered heterocyclyl.

[0044] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof.

[0045] in:

[0046] Dashed lines indicate single or double bonds;

[0047] R B , q, G 1 G 2 G, X, Y, Z, R D L 1 L 2 R A , n, ring C, R C p and L are as defined in general formula (I).

[0048] In some embodiments of this disclosure, X is -(CR 4a R 4b ) m -、-NR 5 C(O)- or -C(O)-; where R 4a R 5 R 4b And m as defined in general formula (I); in some embodiments, X is selected from single bond, -CH(CH3)-, -CH(OCH3)-, -CH2-, -CH2CH2-, -NHC(O)-, -N(CH3)C(O)- and -C(O)-; in some embodiments, X is selected from single bond or -CH(CH3)-.

[0049] In some embodiments disclosed herein, Y is a single bond, -O(CR) 4e R 4f ) n -or-NR 5 (CR 4c R 4d ) r’ -; where R 4c R 4d R 4e R 4f R 5 , n and r' are as defined in general formula (I); in some embodiments, Y is selected from single bond, -O-, -OCH2-, -NH- and -N(CH3)-; in some embodiments, Y is -OCH2-.

[0050] In some embodiments of this disclosure, Z is -(CR 4a R 4b ) m-CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2-, and -C(O)-; in some embodiments, Z is -CH2-. 4a 4b and m are as defined in general formula (I); in some embodiments, Z is selected from a single bond, -CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2-, and -C(O)-; in some embodiments, Z is -CH2-.

[0051] In some embodiments of the disclosure, X-Y-Z is selected from -OCH2CH2-, -CH(CH3)OCH2CH2-, -CH(CH3)OCH2CH2CH2-, -CH(CH3)OCH2CH(CH3)-, -CH(OCH3)CH2CH2-, -CH(OCH3)CH2CH2CH2-, -CH(OCH3)CH2CH(CH3)-, -CH2OCH2CH2-, -OCH2CH2CH2-, -NHC(O)CH2CH2-, -N(CH3)C(O)CH2CH2-, -NHCH2CH2-, and -N(CH3)CH2CH2-, In some embodiments, X-Y-Z is selected from -OCH2CH2-, -CH(CH3)OCH2CH2-, -CH(CH3)OCH2CH2CH2-, -CH(CH3)OCH2CH(CH3)-, -CH(OCH3)CH2CH2-, -CH(OCH3)CH2CH2CH2-, -CH(OCH3)CH2CH(CH3)-, -CH2OCH2CH2-, -OCH2CH2CH2-, -NHC(O)CH2CH2-, -N(CH3)C(O)CH2CH2-, -NHCH2CH2-, and -N(CH3)CH2CH2-; in some embodiments, X-Y-Z is -CH(OCH3)CH2CH2- or -CH(CH3)OCH2CH2-; in some embodiments, X-Y-Z is -CH(CH3)OCH2CH2-.

[0052] In some embodiments of the disclosure, ring C is selected from phenyl, 5- or 6- membered heterocyclyl, and 5- or 6-membered heteroaryl; in some embodiments, ring C is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring C is 6-membered heterocyclyl; in some embodiments, ring C is morpholinyl; in some embodiments, ring C is thiazolyl or morpholinyl; in some embodiments, ring C is In some embodiments, ring C is ​In some embodiments, ring C is a 5-membered heteroaryl group; in some embodiments, ring C is phenyl or thiazolyl; in some embodiments, ring C is thiazolyl, thiophene, furanyl, oxazolyl, pyrazolyl, and imidazolyl; in some embodiments, ring C is thiazolyl; in some embodiments, ring C is... In some implementations, ring C is In some implementations, ring C is *The end is connected to a phenyl group. End and L 1 Connected.

[0053] In some embodiments disclosed herein, L 2 C 1-6 Alkylene; in some embodiments, L 2 For optional C 1-6 Alkyl-substituted propylene; in some embodiments, L 2 It is -CH2C(CH3)2CH2-.

[0054] In some embodiments disclosed herein, L 2 C 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R L2 Replace, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, L 2 For being two R L2 Substituted propylidene, two R L2 Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, L 2 For being two R L2 Substituted propylidene, two R L2 Together with the attached atom, it forms a cyclopropyl group; in some embodiments, L 2 for In some implementations, L 2 for In some implementations, L 2 for End and R 2 (In general formula I) or O (in general formula II) are connected, and the * end is connected to the pyrrole ring.

[0055] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0056] in:

[0057] t1 is 0, 1 or 2;

[0058] t is 0, 1, 2, 3, 4, 5 or 6;

[0059] R 4a , R 6 , R D , R A , n, R B , q, R C , L 1 and L are as defined in general formula (I).

[0060] In some embodiments of the present disclosure, the compound of general formula (I) or a pharmaceutically acceptable salt thereof is a compound of general formula (X-20) or a pharmaceutically acceptable salt thereof,

[0061] wherein Cy 1 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, which cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more R*;

[0062] R 4a , t1, R 6 , R A , n, R B , q, R C , R*, L 1 and L are as defined in general formula (III).

[0063] In some embodiments, is R 6 , t1, R 4a as defined in formula X-20.

[0064] In some embodiments, is In some embodiments is R 4a , R 6 , R B , t1, q as defined in formula X-20.

[0065] In some embodiments, is L 1 as defined in formula X-20.

[0066] In some embodiments, is R A , n as defined in formula X-20.

[0067] In some embodiments, Cy1 is heterocyclyl optionally substituted with R*; in some embodiments is Cy 1 is 3- to 12-membered heterocyclyl optionally substituted with R*; in some embodiments is 7- to 12-membered heterocyclyl optionally substituted with R*; in some embodiments is 7- to 8-membered heterocyclyl optionally substituted with R*; R* is as defined in Formula I; in some embodiments, Cy 1 is

[0068] In some embodiments of the disclosure, R D is selected from C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3- to 12-membered cycloalkyl, -O-C 1-6 alkyl-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 12-membered heterocyclyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, and 3- to 12-membered heterocyclyl C 2-6 alkynyl, wherein the C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3- to 12-membered cycloalkyl, -O-C 1-6 alkyl-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 12-membered heterocyclyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, and 3- to 12-membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from halogen, oxo, =N-R 64 , C 1-6 alkyl optionally substituted with one or more R*, C 2-6 alkynyl optionally substituted with one or more R*, 3- to 12-membered heterocyclyl optionally substituted with one or more R*, 3- to 12-membered cycloalkyl C 1-6 alkyl optionally substituted with one or more R*, 3- to 12-membered heterocyclyl C 1-6 alkyl and 5- to 10-membered heteroaryl C 1-6 alkyl, wherein R 7a , R 7b , R 64and R* are as defined in general formula (I);

[0069] In some embodiments of the present disclosure, wherein R D is selected from C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl, wherein said C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from halogen, oxo, =N-R 64 , C 1-6 alkyl optionally substituted with one or more R 2-6 , C 1-6 alkynyl, 3 to 12 membered heterocyclyl optionally substituted with one or more R 1-6 , 3 to 12 membered heterocyclyl C 7a alkyl and 5 to 10 membered heteroaryl C 7b alkyl optionally substituted with one or more R 64 and R* are as defined in general formula (I);

[0070] In some embodiments, R D is selected from -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C2-6 alkynyl, wherein the -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 hydroxyalkyl, 3 to 12 membered heterocyclyl optionally substituted with one or more R* and 5 to 10 membered heteroaryl optionally substituted with one or more R* C 1-6 one or more substituents of the alkyl group, wherein R* is as defined in general formula (I);

[0071] In some embodiments, R D is selected from -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl, wherein the -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, 3 to 12 membered heterocyclyl optionally substituted with one or more R* and 5 to 10 membered heteroaryl optionally substituted with one or more R* C 1-6 one or more substituents of the alkyl group, wherein R* is as defined in general formula (I);

[0072] In some embodiments, R D is selected from -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl-O-C1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein the -O-C 1-6 alkyl-3- to 8-membered cycloalkyl, -O-C 1-6 alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl- each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl, 3- to 9-membered heterocyclyl and 5- or 6-membered heteroaryl C 1-6 one or more substituents of the alkyl group;

[0073] In some embodiments, R D is selected from -O-C 1-6 alkyl-3- to 8-membered cycloalkyl, -O-C 1-6 alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein the -O-C 1-6 alkyl-3- to 8-membered cycloalkyl, -O-C 1-6 alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl- each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl;

[0074] In some embodiments, R D is selected from -O-C 1-6 alkyl-3- to 8-membered cycloalkyl, -O-C 1-6 alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein said -O-C 1-6 alkyl-3- to 8-membered cycloalkyl, -O-C 1-6 alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl- each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6alkyl and C 1-6 substituted with one or more substituents selected from the group consisting of halo, oxo, =NH, =NCH3, C

[0075] In some embodiments, R D is 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein said 3- to 9-membered heterocyclyl C 2-6 alkynyl- is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, =NH, =NCH3, C 1-6 alkyl, hydroxy, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl;

[0076] In some embodiments, R D is 3- to 9-membered heterocyclyl C3alkynyl-, wherein said 3- to 9-membered heterocyclyl C3alkynyl- is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, =NH, =NCH3, C 1-6 alkyl, hydroxy, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl;

[0077] In some embodiments, R D is 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein said 3- to 9-membered heterocyclyl C 2-6 alkynyl- is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl;

[0078] In some embodiments, R D is 3- to 8-membered cycloalkyl (C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl (C 1-6 alkylene) 0-6 3- to 8-membered cycloalkyl (C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl (C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl- is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl;

[0079] In some embodiments, R D is -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 8 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, and 3 to 8 membered heterocyclyl C 2-6 alkynyl, wherein the -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 8 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl, and 3 to 8 membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, 3 to 8 membered heterocyclyl, and 5 or 6 membered heteroaryl C 1-6 alkyl;

[0080] In some embodiments, R D is -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, the -O-C 1-6 alkyl-3 to 9 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl and C 2-6 alkynyl;

[0081] In some embodiments, R D is 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 8 membered heterocyclyl, the 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl and C 2-6 alkynyl;

[0082] In some embodiments, R D is 3 to 8 membered heterocyclyl(CH2) 0-1 3 to 8 membered heterocyclyl, the 3 to 8 membered heterocyclyl(CH2) 0-1 3 to 8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl and C 2-6one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C

[0083] In some embodiments, R D is a 3- to 10-membered heterocyclyl group, wherein said 3- to 10-membered heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkynyl, and 3- to 8-membered cycloalkyl C 1-6 alkyl; in some embodiments, R

[0084] In some embodiments, R D is selected from the group consisting of Cy 1 is a heterocyclyl group optionally substituted with one or more R*; R* is as defined in general formula I; in some embodiments, R D is selected from the group consisting of Cy 1 is

[0085] In some embodiments, R D is selected from the group consisting of In some embodiments, R D is selected from the group consisting of In some embodiments, R D is selected from the group consisting of In some embodiments, R D is

[0086] In some embodiments of the present disclosure, R 64 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, hydroxy, and C 1-6 alkoxy; in some embodiments, R 64 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 64 is a hydrogen atom or methyl.

[0087] In some embodiments of the present disclosure, R 61 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl; in some embodiments, R 61 is a hydrogen atom or methyl.

[0088] In some embodiments of the present disclosure, R 62 and R63 the same or different, and each independently is a hydrogen atom or a halogen; in some embodiments, R 62 and R 63 the same or different, and each independently is a hydrogen atom or F; in some embodiments, R 62 and R 63 the same are each a hydrogen atom; in some embodiments, R 62 and R 63 the same are each F; in some embodiments, R 62 is a hydrogen atom, R 63 is F.

[0089] In some embodiments of the disclosure, R 7a and R 7b the same or different, and each independently is selected from a hydrogen atom, C 1-6 alkyl, and C 1-6 alkoxy C 1-6 alkyl; in some embodiments, R 7a and R 7b the same or different, and each independently is selected from a hydrogen atom, methyl, ethyl, methoxyethyl, and methoxymethyl; in some embodiments, R 7a is a hydrogen atom or methyl; in some embodiments, R 7b is methoxyethyl or methoxymethyl.

[0090] In some embodiments of the disclosure, R 9a , R 9b the same or different, and each independently is selected from a hydrogen atom, C 1-6 alkyl, and C 1-6 alkoxy C 1-6 alkyl; in some embodiments, R 9a , R 9b the same or different, and each independently is selected from a hydrogen atom or C 1-6 alkyl.

[0091] In some embodiments of the disclosure, R*is selected from oxo, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 8-membered cycloalkyloxy; in some embodiments, R*is oxo; in some embodiments, R*is C 1-6 alkyl; in some embodiments, R*is methyl; in some embodiments, R*is cyclopropyloxy.

[0092] In some embodiments of the disclosure, L 1 is CH2; in some embodiments, L 1 is CH2or 3- to 6-membered cycloalkyl; in some embodiments, L 1is CH2or cyclopropyl; in some embodiments, L 1 is CH2or in some embodiments, L 1 is selected from CH2, -CH(3- to 8-membered heterocyclyl)-, and 3- to 6-membered cycloalkyl; in some embodiments, L 1 is selected from CH2, in some embodiments, L 1 is selected from in some embodiments, L 1 is selected from

[0093] in some embodiments of the disclosure, each R B are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, a cyano group, a 3- to 8-membered cycloalkyl group, or a 3- to 8-membered heterocyclyl group; in some embodiments, R B are the same or different and each is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R B is a hydrogen atom or a halogen; in some embodiments, R B is F.

[0094] in some embodiments of the disclosure, q is 0, 1, or 2; in some embodiments, q is 0; in some embodiments, q is 1; in some embodiments, (R B ) q is a hydrogen atom.

[0095] in some embodiments of the disclosure, each R 4a are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, or a C 1-6 haloalkyl group; or two R 4a on the same atom are connected together to form a 3- to 6-membered cycloalkyl group; in some embodiments, two R 4a on the same atom are connected together to form a cyclopropyl group; in some embodiments, R 4a are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, or a C 1-6 haloalkyl group; in some embodiments, R 4a are the same or different and each is independently a C 1-6 alkyl group; in some embodiments, R4a the same or different, and each independently is methyl.

[0096] In some embodiments of the disclosure, t is 0, 1, or 2; in some embodiments, t is 2; in some embodiments, t is 1.

[0097] In some embodiments of the disclosure, is selected from wherein R A and n are as defined in general formula (I); in some embodiments, is wherein R A and n are as defined in general formula (I); in some embodiments, is In some embodiments, is In some embodiments, is

[0098] In some embodiments of the disclosure, is selected from wherein R A and n are as defined in general formula (II); in some embodiments, is In some embodiments, is In some embodiments, is

[0099] In some embodiments of the disclosure, R 6 is selected from a hydrogen atom, halogen, C 1-6 alkyl, 2 to 6 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, cyano, amino, hydroxyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl, wherein said C 1-6 alkyl, 2 to 6 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl are each independently optionally substituted with a group selected from halogen, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, hydroxyl, and C1-6 one or more substituents selected from a halogen, C 6 atom, a halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 1-6 alkyl, C 1-6 alkoxy, each independently optionally substituted with one or more substituents selected from a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkyl; in some embodiments, R 6 atom, a halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 6 is a hydrogen atom.

[0100] In some embodiments of the disclosure, t1 is 0 or 1; in some embodiments, t1 is 0; in some embodiments, (R 6 ) t1 is a hydrogen atom.

[0101] In some embodiments of the disclosure, G is N or CH; in some embodiments, G is N.

[0102] In some embodiments of the disclosure, G 1 is CR 6 , R 6 is as defined in general formula (I); in some embodiments, G 1 is CH.

[0103] In some embodiments of the disclosure, G 2 is CR 6 , R 6 is as defined in general formula (I); in some embodiments, G 2 is CH.

[0104] In some embodiments of the disclosure, R C atom, a halogen, C 1-6 alkyl, and C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclyl; in some embodiments, R C atom, a halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R C is a hydrogen atom.

[0105] In some embodiments of this disclosure, p is 0, 1, or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 0; in some embodiments (R C ) p It is a hydrogen atom.

[0106] In some embodiments disclosed herein, R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups, or two R groups on the same atom A Or two R atoms on different atoms A Together with the attached atoms, it forms a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally reacted with one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution; in some embodiments, R A They may be the same or different, and each is independently selected from hydrogen atoms, halogens, or carbon atoms. 1-6 Alkyl; in some embodiments, R A They may be the same or different, and each is independently F or methyl.

[0107] In some embodiments of this disclosure, n is 0, 1, 2, or 3; in some embodiments, n is 0; in some embodiments, n is 2; in some embodiments, (R A ) n It is a hydrogen atom.

[0108] In some embodiments of this disclosure, L is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group are optionally converted by one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 62 R 63 C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano substitution, R 62 and R 63 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, L is a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally coated with one or more halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =CR62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and cyano, R 62 and R 63 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, L is a 3- to 8-membered heterocyclyl group optionally substituted with one or more halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, =CR 62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and cyano, R 62 and R 63 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, L is a 3- to 8-membered heterocyclyl group optionally substituted with one or more halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, =CR 62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and cyano, R R 62 and R 63 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, L is a 3- to 8-membered heterocyclyl group optionally substituted with one or more halogen, C in some embodiments, L is selected from the group consisting of in some embodiments, L is selected from the group consisting of in some embodiments, L is selected from the group consisting of in some embodiments, L is in some embodiments, L is in some embodiments, L is in some embodiments, L is

[0109] in some embodiments, L is selected from the group consisting of

[0110] in some embodiments, L is selected from the group consisting of in some embodiments, L is selected from the group consisting of In some embodiments, L is selected from

[0111] In some embodiments of the disclosure, L is a 3- to 8-membered cycloalkyl group, which is optionally substituted with one or more halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, =CR 62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and cyano, R 62 and R 63 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is In some embodiments, L is

[0112] In some embodiments of the disclosure, L is R 11 is a hydrogen atom, L 3 is -N(R L3 )C(O)-, L 4 is a bond (i.e., L is -CH(R 12 )-N(R 3 )C(O)-R 10 ), R 10 is a heterocyclyl group optionally substituted with one or more R F , R 12 , R L3 and R F are as defined in general formula (I); in some embodiments, L is -CH(R 12 )-N(R L3 )C(O)-R 10 , R 10 is a 3- to 6-membered heterocyclyl group optionally substituted with one or more R F , R 12 is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group, R L3 is a hydrogen atom or a C 1-6 alkyl group, and R F is selected from -C(O)R F1 , halogen, C1-6 alkyl, C 1-6 haloalkyl, NH2, (C 1-6 alkyl)NH-, and (C 1-6 alkyl)2N-, R F1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl is optionally substituted with one or more of halo, C 1-6 alkyl, C 1-6 haloalkyl, NH2, (C 1-6 alkyl)NH-, and (C 1-6 alkyl)2N-; in some embodiments, L is -CH(R 12 )-N(R L3 )C(O)-R 10 , R 10 is a 3- to 6-membered heterocyclyl optionally substituted with one or more R F , R 12 is C 1-6 alkyl, R L3 is a hydrogen atom or C 1-6 alkyl, R F is selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, NH2, (C 1-6 alkyl)NH-, and (C 1-6 alkyl)2N-; in some embodiments, L is selected from In some embodiments, L is

[0113] In some embodiments of the disclosure, R 12 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 12 is C 1-6 alkyl; in some embodiments, R 12 is isopropyl.

[0114] In some embodiments of the disclosure, R L3 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R L3 is C 1-6 alkyl; in some embodiments, R L3 is methyl.

[0115] In some embodiments of the disclosure, R F is selected from halo, C 1-6 alkyl, C1-6 Halogenated alkyl groups, NH2, (C 1-6 alkyl)NH- and (C 1-6 alkyl)2N-; in some embodiments, R F Selected from NH2, (C 1-6 alkyl)NH- and (C 1-6 alkyl)2N-; in some embodiments, R F For (C) 1-6 alkyl)2N-; in some embodiments, R F It is (CH3)2N-.

[0116] In some embodiments disclosed herein, R 11 C 1-6 Alkyl or 3- to 8-membered cycloalkyl; in some embodiments, R 11 It is isopropyl or cyclopentyl.

[0117] In some embodiments disclosed herein, R 12 It is a hydrogen atom.

[0118] In some embodiments disclosed herein, L 3 It is a bond or -N(CH3)C(O)-.

[0119] In some embodiments disclosed herein, R L3 It can be a hydrogen atom or a methyl group.

[0120] In some embodiments disclosed herein, L 4 For key.

[0121] In some embodiments disclosed herein, R L4 It can be a hydrogen atom or a methyl group.

[0122] In some embodiments of this disclosure, y is 0 or 1; in other embodiments, y is 0.

[0123] In some embodiments disclosed herein, R 10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F As defined in general formula (I); in some implementations, R 10 Selected from 3- to 12-membered cycloalkyl groups, 3- to 12-membered heterocyclic groups, and N(C) groups. 1-6 Alkyl)2, wherein the 3- to 12-membered cycloalkyl group or the 3- to 12-membered heterocyclic group is optionally surrounded by one or more R F Replace, R F Selected from halogens, C 1-6 Alkyl and -C(O)RF1 R F1 is selected from C 2-6 alkenyl, C 2-6 alkynyl and 3- to 8-membered heterocyclyl, said C 2-6 alkenyl, C 2-6 alkynyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more R # R # is selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, amino, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 and 3- to 8-membered cycloalkyl.

[0124] In some embodiments of the disclosure, the compounds of Formula (II) or pharmaceutically acceptable salts thereof, wherein X-Y-Z is -CH(OCH3)CH2CH2- or -CH(CH3)OCH2CH2-; G is N; G 1 is CH; G 2 is CH; R D is selected from C 2-6 alkenyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3- to 12-membered cycloalkyl, -O-C 1-6 alkyl-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 12-membered heterocyclyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 12-membered heterocyclyl C 2-6 alkynyl, wherein said C 2-6 alkenyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3- to 12-membered cycloalkyl, -O-C 1-6 alkyl-3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 12-membered heterocyclyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 12-membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more R* selected from halo, oxo, =N-R 64 , C 1-6 alkyl optionally substituted with one or more R*, C 2-6Alkyne group, 3- to 12-membered heterocyclic group optionally substituted with one or more R*, 3- to 12-membered heterocyclic group optionally substituted with one or more R* C 1-6 Alkyl groups and 5- to 10-membered heteroaryl C groups optionally substituted with one or more R* 1-6 One or more substituents in the alkyl group are substituted; R 64 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 7a and R 7b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl group; R* is selected from oxo group, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 8-membered cycloalkyloxy groups; R B They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; q is 0 or 1; L 1 It is CH2 or cyclopropyl; L 2 For optional C 1-6 Alkyl-substituted propylene group; ring C is thiazolyl; R C Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p is 0 or 1; for L is This indicates that the ring is an aromatic ring.

[0125] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein XYZ is -CH(OCH3)CH2CH2 or CH(CH3)OCH2CH2-; G is N; G 1 For CH; G 2 For CH; R D Selected from -OC 1-6 Alkyl-3 to 8-membered cycloalkyl, -OC 1-6 Alkyl-3 to 9-membered heterocyclic groups, 3 to 8-membered cycloalkyl-OC 1-6 alkylene-3 to 9-membered heterocyclic-, 3 to 9-membered heterocyclic-OC 1-6 alkylene-3 to 9-membered heterocyclic-, 3 to 8-membered cycloalkyl (C 1-6 Alkylene) 0-6 3- to 9-membered heterocyclic groups-, 3- to 9-membered heterocyclic groups (C 1-6 Alkylene) 0-6 3 to 9-membered heterocyclic -, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic and 3 to 9-membered heterocyclic C 2-6alkynyl-, wherein the -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 8 membered cycloalkyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 9 membered heterocyclyl C 2-6 alkynyl- are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; R B are the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1 ; L 1 is CH2or cyclopropyl; L 2 is propylene optionally substituted with C 1-6 alkyl; ring C is thiazolyl or morpholinyl; R C are selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; p is 0 or 1 ; L is represents that the ring is aromatic.

[0126] In some embodiments of the present disclosure, the compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D are selected from the group consisting of -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 8 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 8 membered heterocyclyl C 2-6 alkynyl, wherein the -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclyl(C 1-6 alkylene) 0-6 ​3- to 8-membered heterocyclyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 8-membered heterocyclyl C 2-6 alkynyl is each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, 1-6 alkyl, C 2-6 alkynyl, 3- to 8-membered heterocyclyl and 5- or 6-membered heteroaryl C 1-6 alkyl; R 4a are the same or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; R B are the same or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1; R C selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; (R A ) n is hydrogen atom; L is L 1 is CH2.

[0127] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is R 4a are the same or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; R B are the same or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1; R C selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; (R A ) n is hydrogen atom; L is L 1 is CH2.

[0128] In some embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is selected from -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 8 membered cycloalkyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 9 membered heterocyclyl C 2-6 alkynyl-, wherein the -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 8 membered cycloalkyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 9 membered heterocyclyl C 2-6 alkynyl- are each independently optionally substituted with one or more substituents selected from halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, hydroxy, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; L is selected from or L is R 4a are the same or different and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1 ; R B are the same or different and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 ​haloalkyl; q is 0 or 1 ; R C is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; L 1 is CH2or

[0129] In some embodiments of the present disclosure, the compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is selected from the group consisting of L is selected from the group consisting of or L is is R 4a are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group or a C 1-6 haloalkyl group; t is 0, 1 or 2; R 6 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; t1 is 0 or 1 ; R B are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; q is 0 or 1 ; R C is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; L 1 is CH2or

[0130] In some embodiments of the present disclosure, the compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is selected from the group consisting of -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6 alkyl-3 to 9 membered heterocyclyl, 3 to 8 membered cycloalkyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl-O-C 1-6 alkylene-3 to 9 membered heterocyclyl-, 3 to 8 membered cycloalkyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 9 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 9 membered heterocyclyl-, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 9 membered heterocyclyl C 2-6 alkynyl-, wherein the -O-C 1-6 alkyl-3 to 8 membered cycloalkyl, -O-C 1-6alkyl-3- to 9-membered heterocyclyl, 3- to 8-membered cycloalkyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl-O-C 1-6 alkylene-3- to 9-membered heterocyclyl-, 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl and 3- to 9-membered heterocyclyl C 2-6 alkynyl, each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; L is or L is is R 4a are identical or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 are identical or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1 ; R B are identical or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1 ; R C are identical or different and each independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is CH2.

[0131] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein the 3- to 9-membered heterocyclyl C 2-6 alkynyl- is optionally substituted by one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; L is is R 4athe same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; R B the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1; R C selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is CH2.

[0132] In some embodiments of the present disclosure, the compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, wherein the 3- to 8-membered cycloalkyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl-, 3- to 9-membered heterocyclyl(C 1-6 alkylene) 0-6 3- to 9-membered heterocyclyl- optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; L is is R 4a the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; R B the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1; R C selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is CH2.

[0133] In some embodiments of the disclosure, the compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is 3- to 9-membered heterocyclylC 2-6 alkynyl-, wherein the 3- to 9-membered heterocyclylC 2-6 alkynyl- is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl and C 1-6 hydroxyalkyl; L is is R 4a are the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 is selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; R B are the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1; R C is selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is CH2or

[0134] In some embodiments of the disclosure, the compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is 3- to 9-membered heterocyclylC 2-6 alkynyl-, wherein the 3- to 9-membered heterocyclylC 2-6 alkynyl- is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl and C 1-6 hydroxyalkyl; L is is R 4a are the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 is selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1; RB the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1 ; R C selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 selected from the group consisting of CH2,

[0135] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R D is a 3- to 9-membered heterocyclyl C 2-6 alkynyl-, wherein the 3- to 9-membered heterocyclyl C 2-6 alkynyl- is optionally substituted with one or more substituents selected from the group consisting of a halogen, oxo, =NH, =NCH3, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl and C 1-6 hydroxyalkyl; L is is R 4a the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl or C 1-6 haloalkyl; t is 0, 1 or 2; R 6 selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; t1 is 0 or 1 ; R B the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 0 or 1 ; R C selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; L 1 selected from

[0136] Typical compounds of the present disclosure include, but are not limited to, those listed in Table A.

[0137] The present disclosure provides a compound represented by general formula (IA) or a salt thereof:

[0138] wherein,

[0139] G, G 1 , G 2 , X, Y, Z, R D , R 2 , L 2 , ring A, R A , n, L 1 , R R , ring C, R C , p, R B and q are as defined in general formula (I).

[0140] Further, the present disclosure provides a compound represented by general formula (IIA) or a salt thereof:

[0141] wherein:

[0142] dotted line, R B , q, G 1 , G 2 , G, X, Y, Z, R D , L 1 , L 2 , R A , n, ring C, R C and p are as defined in general formula (II).

[0143] The present disclosure provides a compound represented by general formula (IIIA) or a salt thereof:

[0144] wherein:

[0145] t1, t, R 4a , R 6 , R D , R A , n, R B , q, R C , and L 1 are as defined in general formula (III).

[0146] Table B Exemplary intermediate compounds of the present disclosure include, but are not limited to:

[0147] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0148] condensing a compound represented by general formula (IA) or a salt thereof with L-C(O)OH or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0149] wherein:

[0150] G, G 1 , G 2 , X, Y, Z, R D , R 2 , L 2 , ring A, R A , n, L 1 , R R , ring C, R C , p, R B and q are as defined in general formula (I).

[0151] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0152] condensation reaction of a compound represented by general formula (IIA) or a salt thereof with L-C(O)OH or a salt thereof to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0153] wherein:

[0154] dashed line, R B , q, G 1 , G 2 , G, X, Y, Z, R D , L 1 , L 2 , R A , n, ring C, R C , p and L are as defined in general formula (II).

[0155] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0156] condensation reaction of a compound represented by general formula (IIIA) or a salt thereof with L-C(O)OH or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0157] wherein:

[0158] t1, t, R 4a , R 6 , R D , R A , n, R B , q, R C , L 1 and L are as defined in general formula (III).

[0159] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X-20) or a pharmaceutically acceptable salt thereof, comprising a step of obtaining a compound represented by general formula (X-20) or a pharmaceutically acceptable salt thereof from one or more compounds represented by general formulae X-1 to X-19 or a salt thereof through one or more reactions.

[0160] In some specific embodiments, it comprises:

[0161] Scheme X

[0162] a compound represented by formula X-1 or a salt thereof is subjected to a substitution reaction, a Suzuki coupling reaction to obtain a compound represented by formula X-3 or a salt thereof, and then subjected to a deprotection reaction, a ring formation reaction, and a deprotection reaction to obtain a compound represented by formula X-6 or a salt thereof, and then subjected to a protecting group reaction, a borylation reaction, a halogenation reaction, and a coupling reaction to obtain a compound represented by formula X-10 or a salt thereof;

[0163] The compound of formula X-11 or a salt thereof is subjected to a substitution reaction, a Suzuki coupling reaction with a compound of formula X-10 or a salt thereof to obtain a compound of formula X-13 or a salt thereof, followed by a deprotection / hydrolysis reaction, a lactone ring formation reaction, and a deprotection reaction to obtain a compound of formula X-16 or a salt thereof, which is further subjected to a protecting group addition reaction, a substitution reaction, a deprotection reaction, and an acylation reaction to obtain a compound of formula X-20 or a pharmaceutically acceptable salt thereof;

[0164] wherein,

[0165] R P1 is a hydroxyl protecting group; in some embodiments, THP;

[0166] R P2 is a hydroxyl protecting group; in some embodiments, TBDPS;

[0167] R P3 is a hydroxyl protecting group; in some embodiments, Ac;

[0168] R P4 is a hydroxyl protecting group; in some embodiments, THP;

[0169] R P5 is an amino protecting group; in some embodiments, Boc;

[0170] R P6 is a hydroxyl protecting group; in some embodiments, Ms;

[0171] R P7 is an alkyl group; in some embodiments, Me;

[0172] R X1 is a halogen; in some embodiments, Br;

[0173] R X2 is a halogen; in some embodiments, Br;

[0174] R X3 is a halogen; in some embodiments, I;

[0175] R X4 is a halogen; in some embodiments, Br;

[0176] R B1 is -B(OH)2or

[0177] R B2 is -B(OH)2or

[0178] R B3 is -B(OH)2or

[0179] Cy 1 , t1, R 4a , R 6 , R A , n, R B , q, R C , L 1 and L are as defined in general formula (X-20).

[0180] The present disclosure provides a compound represented by formula X-19, formula X-18, formula X-17, formula X-16, formula X-15, formula X-14, formula X-13, formula X-12, formula X-11, formula X-10, formula X-9, formula X-8, formula X-7, formula X-6, formula X-5, formula X-4, formula X-3, or formula X-2, or a salt thereof, wherein the group definitions are as defined in Scheme X.

[0181] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (X-20), or a pharmaceutically acceptable salt thereof, comprising a step of obtaining the compound represented by general formula (X-20), or a pharmaceutically acceptable salt thereof, from one or more compounds represented by general formula X-1 to general formula X-18, or a pharmaceutically acceptable salt thereof, by one or more steps of reaction.

[0182] In some specific embodiments, it includes:

[0183] Scheme Y

[0184] The compound of general formula X-1 or a salt thereof is subjected to catalytic borylation reaction, halogenation reaction, coupling reaction, deprotection reaction to obtain the compound of general formula Y-4 or a salt thereof, then subjected to Suzuki coupling reaction with general formula Y-5 to obtain the compound of general formula Y-6 or a salt thereof, and then subjected to ring formation reaction to obtain general formula X-18, and further subjected to deprotection reaction and acylation reaction to obtain general formula X-20 or a pharmaceutically acceptable salt thereof;

[0185] wherein:

[0186] R X5 is halogen; in some embodiments, it is iodine;

[0187] R P1 , R X1 , R P5 , R B1 as defined in Scheme X,

[0188] Cy 1 , t1, R 4a , R 6 , R A , n, R B , q, R C , L1 and L is as defined in general formula (X-20).

[0189] The present disclosure provides a compound represented by formula Y-6, formula Y-5, formula Y-4, formula Y-3, or formula Y-2, or a salt thereof, wherein the group definitions are as defined in Scheme Y.

[0190] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X-20), or a pharmaceutically acceptable salt thereof, comprising a step of obtaining the compound represented by general formula (X-20), or a pharmaceutically acceptable salt thereof, from one or more compounds represented by general formula Z-1 to general formula Z-15, or a pharmaceutically acceptable salt thereof, by one or more steps of reaction.

[0191] In some specific embodiments, it includes:

[0192] Scheme Z

[0193] General formula Z-1 is subjected to a reduction reaction, a substitution reaction, a protecting group addition reaction, a substitution reaction to obtain a compound represented by general formula Z-4, or a salt thereof, and then subjected to a Fischer indole synthesis reaction, an esterification reaction, a ring formation reaction, a halogenation reaction, a coupling reaction, and a reduction reaction to obtain a compound represented by general formula Z-10, or a salt thereof; general formula X-11, or a salt thereof, is subjected to a deprotection reaction, an acylation reaction, and a substitution reaction to obtain a compound represented by general formula Z-13, or a salt thereof, and then subjected to a Suzuki coupling reaction with the compound represented by general formula Z-10, or a salt thereof, to obtain a compound represented by general formula Z-14, or a salt thereof, and then subjected to a hydrolysis reaction and a lactone ring formation reaction to obtain general formula X-20, or a pharmaceutically acceptable salt thereof;

[0194] wherein:

[0195] R P8 is alkyl; in some embodiments, Me;

[0196] R X1 , R B3 , R P1 , R X2 , R X3 , R X4 , R P5 , R P7 as defined in Scheme X,

[0197] Cy 1 , t1, R 4a , R 6 , R A , n, R B , q, R C , L 1 and L is as defined in general formula (X-20).

[0198] In some embodiments, the reaction in Scheme Z, step 2, further comprises vinyl sulfate or oxirane; in some embodiments, the solvent for the reaction comprises, but is not limited to, THF, ACN; in some embodiments, the temperature for the reaction can be from -10 to 100 °C, from 0 to 100 °C, from 0 to 70 °C, from 0 to 25 °C, 70 °C; in some embodiments, the reaction is performed under basic conditions; in some embodiments, the reaction time for the reaction is from 1 to 20 h, from 2 to 18 h, from 2 to 16 h, from 3 to 16 h, from 2 to 5 h, from 2 to 3 h, from 3 to 4 h.

[0199] In some embodiments, the solvent for the reaction in Scheme Z, step 3, comprises, but is not limited to, THF, DCM; in some embodiments, the temperature for the reaction can be from 0 to 100 °C, from 20 to 100 °C, from 25 to 100 °C, from 20 to 75 °C, from 25 to 70 °C, 25 °C, 70 °C; in some embodiments, the reaction is performed under basic conditions; in some embodiments, the reaction time for the reaction is from 0.5 to 50 h, from 0.5 to 40 h, from 0.5 to 30 h, from 0.5 to 20 h, from 0.5 to 10 h, from 0.5 to 5 h, from 0.5 to 2 h, from 0.5 to 1.5 h, 0.5 h, 1.5 h; in some embodiments, the reaction is performed under acidic conditions; in some embodiments, the equivalent of acid added to the reaction is from 0.1 to 2 eq, from 0.1 to 1 eq, from 0.1 to 0.5 eq, from 0.1 to 0.2 eq.

[0200] In some embodiments, the temperature for the reaction in Scheme Z, step 4, can be from -20 to 50 °C, from -20 to 30 °C, from -20 to 25 °C, from -20 to 10 °C, from -10 to 0 °C, from -20 to 0 °C, -10 °C, -20 °C; in some embodiments, the reaction is performed under basic conditions; in some embodiments, the equivalent of base added to the reaction is from 0.1 to 2 eq, from 1 to 2 eq, from 1 to 1.5 eq, from 1 to 1.4 eq, 1.1 eq, 1.4 eq; in some embodiments, the reaction time for the reaction is from 1 to 20 h, from 1 to 16 h, from 2 to 16 h, from 5 to 16 h, from 10 to 16 h, 16 h, 12 h.

[0201] In some embodiments, Scheme Z, step 5, is performed under acidic conditions; in some embodiments, the temperature for the reaction can be from 50 to 120 °C, from 50 to 100 °C, from 80 to 100 °C, 100 °C, 80 °C; in some embodiments, the reaction time for the reaction is from 1 to 20 h, from 2 to 20 h, from 4 to 20 h, from 2 to 16 h, from 4 to 16 h, 2 h, 4 h, 8 h, 10 h, 16 h.

[0202] In some embodiments, the temperature of the reaction of Scheme Z, sixth and seventh steps can be 10 to 50 °C, 10 to 30 °C, 20 to 30 °C, 10 °C, 20 °C, 25 °C, room temperature.

[0203] The present disclosure provides a compound represented by Formula Z-15 or Z-14, or a salt thereof,

[0204] wherein,

[0205] R P7 is alkyl; in some embodiments, methyl;

[0206] Cy 1 , t1, R 4a , R 6 , R A , n, R B , q, R C , L 1 and L are as defined in Formula X-20.

[0207] The present disclosure provides a compound represented by Formula Z-10, Z-9, Z-8, Z-7, Z-6, or Z-5, or a salt thereof,

[0208] wherein,

[0209] R P8 is alkyl; in some embodiments, methyl;

[0210] R X2 is halogen; in some embodiments, bromo;

[0211] R X3 is halogen; in some embodiments, iodo;

[0212] Cy 1 , t1, R 4a , R 6 , R B , q are as defined in Formula X-20.

[0213] The present disclosure provides a compound represented by Formula Z-4, Z-3, or X-1, or a salt thereof,

[0214] wherein,

[0215] R P1 is a hydroxyl protecting group; in some embodiments, THP;

[0216] R X1 is halogen; in some embodiments, Br;

[0217] t1, R 4aR 6 as defined in Formula X-20.

[0218] The present disclosure provides a compound represented by Formula Z-2, X-11, Z-11, Z-12, Z-13, or a salt thereof, wherein the groups are defined as in Formula Z-1 to Formula Z-15, Formula X-20.

[0219] Another aspect of the present disclosure relates to a method of preparing a compound represented by Formula (X-20), or a pharmaceutically acceptable salt thereof, comprising a step of obtaining the compound represented by Formula (X-20), or a pharmaceutically acceptable salt thereof, from one or more compounds selected from the group consisting of Formula X-15 to Formula W-3, or a pharmaceutically acceptable salt thereof, by one or more steps of reaction.

[0220] In some embodiments, it comprises:

[0221] Scheme W

[0222] Formula X-20, or a pharmaceutically acceptable salt thereof, from Formula X-15, or a salt thereof, via deprotection, acylation, upper protecting group, and substitution reactions;

[0223] wherein:

[0224] R P4 R P5 R P6 as defined in Scheme X,

[0225] Cy 1 t1, R 4a R 6 R A n, R B q, R C L 1 and L are defined in Formula (X-20).

[0226] The present disclosure provides a compound represented by Formula W-1, Formula W-2, or Formula W-3, or a salt thereof, wherein the groups are defined as in Scheme W.

[0227] In some embodiments, the coupling reaction (in some cases, Suzuki coupling) is carried out under the action of a catalyst, under basic conditions; the catalyst includes but is not limited to 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium, [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride.

[0228] In some embodiments, the hydrolysis reaction is carried out under basic conditions.

[0229] In some embodiments, the deprotection reaction is performed under acidic or basic conditions.

[0230] In some embodiments, the deprotection reaction is performed under acidic or basic conditions.

[0231] In some embodiments, the ring forming reaction is performed in the presence of a catalytic system; the catalytic system includes, but is not limited to, diisopropyl azodicarboxylate / triphenylphosphine, cyanomethylene tri-n-butylphosphine.

[0232] In some embodiments, the lactone ring forming reaction is performed in the presence of a catalytic system; the catalytic system includes, but is not limited to, 1-hydroxybenzotriazole / 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N-diisopropylethylamine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 4-dimethylaminopyridine / N,N-diisopropylethylamine.

[0233] In some embodiments, the acylation reaction is performed in the presence of a condensing agent, optionally under basic conditions.

[0234] In some embodiments, the condensation reaction in the preparation method is performed under basic conditions in the presence of a condensing agent.

[0235] In some embodiments, the reagent providing the basic conditions includes an organic base and an inorganic base; the organic base includes, but is not limited to, N-methylmorpholine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride solution in tetrahydrofuran, iPrMgCl, nBuLi, iPrMgCl LiCl, or 1,8-diazabicycloundec-7-ene (DBU); the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, it is N,N-diisopropylethylamine.

[0236] In the above synthesis scheme, the reagent providing the acidic conditions includes an organic acid and an inorganic acid; the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid-hydrate, BF3-Et20, Me3SiCl, and TMSOTf; the inorganic acid includes, but is not limited to, hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0237] In some embodiments, the condensing agent includes, but is not limited to, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, O- benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-oxabenzotriazol)- N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1-cyano-2-ethoxy-2- oximino)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), (2- oximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholino uronium hexafluorophosphate, or benzotriazole-1-yl-oxytris-pyrrolidino-phosphonium hexafluorophosphate; in some embodiments, the condensing agent is COMU.

[0238] The above synthesis schemes are preferably carried out in a solvent, which includes, but is not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0239] Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0240] The present disclosure further relates to the use of a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting a RAS mutant protein.

[0241] The present disclosure further relates to the use of a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing a disease or disorder mediated by or dependent on a RAS mutant protein.

[0242] The present disclosure further relates to the use of a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing a tumor.

[0243] The present disclosure also relates to a method of inhibiting a RAS mutant protein in a subject, comprising administering to a subject in need thereof a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0244] The present disclosure also relates to a method of treating and / or preventing a disease or disorder mediated by or dependent on RAS mutant proteins, comprising administering to a patient in need thereof a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0245] The present disclosure also relates to a method of treating and / or preventing a tumor, comprising administering to a patient in need thereof a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0246] The present disclosure further relates to a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0247] The present disclosure further relates to a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for treating and / or preventing a disease or disorder mediated by or dependent on RAS mutant proteins.

[0248] The present disclosure further relates to a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting RAS mutant proteins in a subject.

[0249] The present disclosure further relates to a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or disorder mediated by or dependent on RAS mutant proteins.

[0250] The present disclosure further relates to a compound of the above general formula or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a tumor.

[0251] In some embodiments, the disease or disorder mediated by or dependent on RAS mutant proteins described in the present disclosure is a tumor; in some embodiments, the disease or disorder mediated by or dependent on RAS mutant proteins described in the present disclosure is selected from the group consisting of thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, cholangiocarcinoma, colorectal cancer, urothelial cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the disease or disorder mediated by or dependent on RAS mutant proteins described in the present disclosure is selected from the group consisting of gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0252] In some embodiments, the tumor of the present disclosure is selected from the group consisting of thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, cholangiocarcinoma, colorectal cancer, urothelial cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma, and glioblastoma; in some embodiments, the tumor of the present disclosure is selected from the group consisting of gastric cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0253] In some embodiments, the tumor of the present disclosure is a solid tumor.

[0254] In some embodiments, the tumor of the present disclosure is a hematological tumor.

[0255] In some embodiments, the sarcoma of the present disclosure is angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, chondrosarcoma, Ewing's sarcoma, Kaposi's sarcoma.

[0256] In some embodiments, the colorectal cancer of the present disclosure is colon cancer or rectal cancer.

[0257] In some embodiments, the lymphoma of the present disclosure is diffuse large B-cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma.

[0258] In some embodiments, the lung cancer of the present disclosure is lung adenocarcinoma; in some embodiments, the lung cancer is squamous cell lung cancer, small cell lung cancer; in some embodiments, it is non-small cell lung cancer (NSCLC)

[0259] In some embodiments, the leukemia of the present disclosure is chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia.

[0260] In some embodiments, the myeloma of the present disclosure is multiple myeloma.

[0261] In some embodiments, the head and neck cancer of the present disclosure is head and neck squamous cell carcinoma (HNSCC).

[0262] In some embodiments, the esophageal cancer of the present disclosure is gastroesophageal cancer.

[0263] In some embodiments, the liver cancer of the present disclosure is hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma.

[0264] In some embodiments, the RAS protein described herein is selected from K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12A, K-Ras G12S, K-Ras G12R, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L; in some embodiments, the Ras protein is selected from N-Ras G12D, N-Ras G13D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P; in some embodiments, the Ras protein is selected from H-Ras G12V, H-Ras G13R, H-Ras Q61R, H-Ras Q61L.

[0265] The active compound can be prepared into a form suitable for administration by any appropriate route, and in some embodiments, the active compound is in unit dosage form, or in a form that the patient can self-administer in a single dose. The unit dosage form of the compound or composition of the present disclosure can be tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations.

[0266] As a general guide, a suitable unit dose can be 0.1 to 1000 mg.

[0267] The pharmaceutical composition of the present disclosure can contain one or more excipients in addition to the active compound, which are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition can contain 0.1 to 99% by weight of the active compound.

[0268] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0269] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically substituted thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically substituted thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically substituted thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically substituted thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically substituted thereof.

[0270] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

[0271] The pharmaceutically acceptable salts of the compounds described in the present disclosure can be selected from inorganic or organic salts.

[0272] The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. These compositions can be prepared so as to provide a dosage of the active ingredient in the form to be administered. Oral compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0273] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0274] Oral preparations can also be provided in the form of soft gelatin capsules prepared by known techniques with the active ingredient dissolved or suspended in an appropriate liquid carrier, such as an oil. Examples of oil that can be employed are vegetable or animal oils, including petro-diesel oil.

[0275] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. An aqueous suspension can also contain one or more preservatives, one or more coloring agents and one or more flavoring agents.

[0276] Oil suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspensions can contain a thickening agent. Sweetening and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0277] The pharmaceutical compositions of the present disclosure can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsors can be a naturally occurring phospholipid, and the emulsion can also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations can also contain a demulcent, preservative, coloring agent and antioxidant.

[0278] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. The injectable form can be injected intravenously over a long period of time by local massive injection into the bloodstream of the patient. Alternatively, it is preferable to administer the solution and microemulsion in such a way that a constant circulating concentration of the compound of the present disclosure is maintained. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 intravenous pump.

[0279] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular or subcutaneous administration. The suspension can be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids can also be used.

[0280] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are

[0281] The dosage of the drug to be administered depends on various factors as is well known to those skilled in the art, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the body weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment regime such as the mode of treatment, the daily amount of the compound or the kind of the pharmaceutically acceptable salt can be verified according to the conventional treatment regime.

[0282] Terminology

[0283] Unless otherwise stated, the terms used in the specification and claims are intended to have the following meanings.

[0284] The term "alkyl" refers to saturated straight-chain or branched-chain aliphatic hydrocarbon groups having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkyl groups). In some embodiments, the alkyl groups have from 1 to 12 carbon atoms (i.e., C 1-12 alkyl groups), and in some embodiments, from 1 to 6 carbon atoms (i.e., C 1-6 alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0285] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene groups). In some embodiments, the alkylene groups have from 1 to 10 carbon atoms (i.e., C 1-10 alkylene groups), and in some embodiments, from 1 to 8 carbon atoms (i.e., C 1-8Alkylenes), in some embodiments, alkylenes having 2 to 7 carbon atoms (i.e., C646-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0286] The term "heteroalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2, and the nitrogen atom may optionally be quaternized, wherein the alkyl group is as defined above; in some embodiments, the heteroalkyl group is C 1-6 One, two, or three carbon atoms in the alkyl group are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2; in some embodiments, the heteroalkyl group is a 2- to 6-membered heteroalkyl group (i.e., a total number of 2 to 6 atoms). The heteroalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker, with the substituent selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0287] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0288] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, wherein the definition of alkyl is as described above, having from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkynyl). In some embodiments, the alkynyl group has from 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group can be substituted or non-substituted, and when substituted, it can be substituted at any available attachment point with one or more of a D atom, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0289] The term "alkoxy" refers to -0-(alkyl), wherein the definition of alkyl is as described above. Non-limiting examples include: methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or non-substituted, and when substituted, it can be substituted at any available attachment point with one or more of a D atom, halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0290] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a multicyclic ring system (i.e., multicyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). In some embodiments, the cycloalkyl group has from 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl) or from 4 to 11 ring atoms (i.e., 4- to 11-membered cycloalkyl), in some embodiments, from 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), in some embodiments, from 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl).

[0291] Non-limiting examples of the monocyclic cycloalkyl group include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0292] The multicyclic cycloalkyl group includes: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0293] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds within the rings, or which can contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the rings (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), provided that at least one fully carbon ring is present and the point of attachment is on the fully carbon ring, having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl has from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), and in some embodiments, from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl includes mono- and polyspirocycloalkyl (e.g., dispirocycloalkyl, etc.), and in some embodiments, is a monospriocycloalkyl or dispirocycloalkyl, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monospriocycloalkyl. Non-limiting examples include:

[0294] which can be attached at any position;

[0295] etc.

[0296] The term "fused cycloalkyl" refers to a polycyclic ring system sharing two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused with one or more of heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group has 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), and in some embodiments, is bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, and in some embodiments, is 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused cycloalkyl. Non-limiting examples include:

[0297] which can be attached at any position; etc.

[0298] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system sharing two non-adjacent carbon atoms between the rings, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5- to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl group has 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), and in some embodiments, 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, is bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include: which can be attached at any position.

[0299] Cycloalkyl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more substituents selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0300] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic ring (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from the group consisting of nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), and having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered heterocyclyl). In some embodiments, the heterocyclyl group is a heterocyclyl group having from 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl) or a heterocyclyl group having from 4 to 11 ring atoms (i.e., 4- to 11-membered heterocyclyl); in some embodiments, a heterocyclyl group having from 3 to 9 ring atoms (i.e., 3- to 9-membered heterocyclyl); in some embodiments, a heterocyclyl group having from 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); in some embodiments, a heterocyclyl group having from 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl); in some embodiments, a heterocyclyl group having 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl).

[0301] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, and the like.

[0302] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0303] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system that shares one atom (referred to as a spiro atom) between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one monocyclic heterocyclyl is contained and the point of attachment is on the monocyclic heterocyclyl, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spiroheterocyclyl). In some embodiments, the spiroheterocyclyl has 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), and in some embodiments, 7 to 11 ring atoms (i.e., 7- to 11-membered spiroheterocyclyl). The spiroheterocyclyl includes mono- and polyspiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), and in some embodiments, is a monosprioheterocyclyl or dispiroheterocyclyl, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocyclyl. Non-limiting examples include: etc.

[0304] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system sharing adjacent ring atoms between rings, which rings can contain one or more double bonds, and which rings contain at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., forming an N-oxide; said sulfur optionally oxidized, i.e., forming a sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-), which is fused to a monocyclic heterocyclyl group or to one or more monocyclic heterocyclyl groups, or to one or more of a cycloalkyl, aryl, or heteroaryl group, with the point of attachment being on the monocyclic heterocyclyl group, and having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused heterocyclyl). In some embodiments, the fused heterocyclyl group has 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), and in some embodiments, 7 to 11 ring atoms (i.e., 7- to 11-membered fused heterocyclyl). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (e.g., tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, etc.), and in some embodiments, is a bicyclic fused heterocyclyl group or a tricyclic fused heterocyclyl group, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused heterocyclyl group. Non-limiting examples include: etc.

[0305] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system sharing two non-adjacent ring atoms between rings, which rings can contain one or more double bonds, and which rings contain at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., forming an N-oxide; said sulfur optionally oxidized, i.e., forming a sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered bridged heterocyclyl). In some embodiments, the bridged heterocyclyl group has 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). The bridged heterocyclyl group includes bicyclic and polycyclic bridged heterocyclyl groups (e.g., tricyclic bridged heterocyclyl groups, tetracyclic bridged heterocyclyl groups, etc.), and in some embodiments, is a bicyclic bridged heterocyclyl group or a tricyclic bridged heterocyclyl group. Non-limiting examples include:

[0306] etc.

[0307] Heterocyclyl can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0308] The term "aryl" refers to a monocyclic all-carbon aromatic ring having a conjugated pi-electron system (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6- to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). The monocyclic aryl group is exemplified by phenyl. The polycyclic aryl group is exemplified by, without limitation, naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused with one or more heterocyclyl or cycloalkyl groups, where the point of attachment is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, which is exemplified by, without limitation:

[0309] etc.

[0310] Aryl can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0311] The term "heteroaryl" refers to a monocyclic heteroaromatic ring having a conjugated pi-electron system (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (the nitrogen can optionally be oxidized, i.e., to an N-oxide; the sulfur can optionally be oxidized, i.e., to a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5- to 14-membered heteroaryl). In some embodiments, the heteroaryl group has 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), and in some embodiments, 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl).

[0312] Non-limiting examples of said monocyclic heteroaryl groups include furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridonyl (such as pyrazinyl, pyridazinyl, and the like.

[0313] Non-limiting examples of said polycyclic heteroaryl groups include indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. Said polycyclic heteroaryl groups also include a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Said polycyclic heteroaryl groups also include a monocyclic heteroaryl group fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include: and the like.

[0314] Heteroaryl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachment with one or more substituents selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0315] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include the residue derived from removal of one hydrogen atom from a parent ring atom, or the residue derived from removal of two hydrogen atoms from a parent ring atom or two different ring atoms, i.e. "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene". Non-limiting examples include: and the like.

[0316] When a polycyclic system formed by fusion of a monocyclic heterocyclyl group with a cycloalkyl, aryl, or heteroaryl group is bivalent, and as long as one of the points of attachment is on the monocyclic heterocyclyl group, then the polycyclic system belongs to the "fused heterocyclyl" group; non-limiting examples include:

[0317] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0318] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0319] The term "arylalkyl" means alkyl substituted by one or more aryl groups, wherein aryl, alkyl are as defined above.

[0320] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0321] The term "cycloalkylalkenyl" means alkenyl substituted by one or more cycloalkyl groups, wherein cycloalkyl, alkenyl are as defined above.

[0322] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0323] The term "arylalkyl" means alkyl substituted by one or more aryl groups, wherein aryl, alkyl are as defined above.

[0324] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0325] The term "cycloalkylalkynyl" means alkynyl substituted by one or more cycloalkyl groups, wherein cycloalkyl, alkynyl are as defined above.

[0326] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0327] The term "arylalkyl" means alkyl substituted by one or more aryl groups, wherein aryl, alkyl are as defined above.

[0328] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0329] The term "cycloalkyloxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0330] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0331] The term "aryloxy" means -O-aryl, wherein aryl is as defined above.

[0332] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0333] The term "aminoalkyl" means alkyl substituted by one or more amino groups, wherein alkyl is as defined above.

[0334] The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein alkoxy, alkyl are as defined above.

[0335] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0336] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0337] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0338] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0339] The term "hydroxy" means -OH.

[0340] The term "mercapto" means -SH.

[0341] The term "amino" means -NH2.

[0342] The term "cyano" means -CN.

[0343] The term "nitro" means -NO2.

[0344] The term "oxo" or "oxo group" means "=O".

[0345] The term "carbonyl" means C=O.

[0346] The term "alkylthio" means -S-alkyl, wherein alkyl is as defined above.

[0347] The term "haloalkylthio" means an alkylthio group substituted with one or more halogens, wherein alkylthio is as defined above.

[0348] The term "cycloalkylthio" means -S-cycloalkyl, wherein cycloalkyl is as defined above.

[0349] The term "heterocyclylthio" means -S-heterocyclyl, wherein heterocyclyl is as defined above.

[0350] "THP" means 2-tetrahydropyranyl.

[0351] "TBDPS" means tert-butyldiphenylsilyl.

[0352] "Ms" means methanesulfonyl.

[0353] "Cbz" means benzyloxycarbonyl.

[0354] "Boc" means tert-butoxycarbonyl.

[0355] "Ac" means acetyl.

[0356] "Bn" means benzyl.

[0357] The term "amino protecting group" refers to an easily removed group introduced on the amino group to keep the amino group unchanged while reactions are carried out on other parts of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), formylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like; the amino protecting group is preferably Boc.

[0358] The term "hydroxyl protecting group" refers to an easily removed group introduced on the hydroxyl group to block or protect the hydroxyl group while reactions are carried out on other functional groups of the compound. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl (Ac), benzoyl, p-nitrobenzoyl, Ms, and the like.

[0359] A "leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that can readily accept electrons and bear a negative charge well are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the more easily the leaving group departs from other molecules. The reason is that the smaller the pKa of the conjugate acid, the greater the tendency of the corresponding leaving group to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogen, -OTs, or -OH.

[0360] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0361] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0362] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0363] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0364] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0365] The compounds of the present disclosure can comprise atropisomers. The term “atropisomers” are conformational stereoisomers that arise due to hindered or greatly slowed rotation about single bonds in a molecule as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are not symmetric, whose interconversion is slow enough to permit separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure can exist in the form of a mixture of atropisomers (e.g., equimolar mixture, mixture enriched in one atropisomer, etc.) or as a purified atropisomer. The configuration of atropisomers can be designated using the nomenclature (M)- and (P)- to designate the absolute configuration (refer to WO2021124222A1, WO2022109242A1, etc.).

[0366] Non-limiting examples of atropisomers include:

[0367] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds. The term “isotopic derivatives” refers to compounds wherein at least one atom has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, in some embodiments deuterium.

[0368] Deuterated drugs have advantages over non-deuterated drugs, such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biohalf-life. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, wherein the replacement of hydrogen with deuterium can be partial or complete. Partial replacement of hydrogen with deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0369] When a position is specifically designated as deuterium D, the position is understood to have deuterium in an abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 15% deuterium incorporation). The deuterium in an example compound can have an abundance greater than the natural abundance of deuterium by at least 1000-fold (i.e., at least 15% deuterium incorporation), by at least 2000-fold (i.e., at least 30% deuterium incorporation), by at least 3000-fold (i.e., at least 45% deuterium incorporation), by at least 3340-fold (i.e., at least 50.1% deuterium incorporation), by at least 3500-fold (i.e., at least 52.5% deuterium incorporation), by at least 4000-fold (i.e., at least 60% deuterium incorporation), by at least 4500-fold (i.e., at least 67.5% deuterium incorporation), by at least 5000-fold (i.e., at least 75% deuterium incorporation), by at least 5500-fold (i.e., at least 82.5% deuterium incorporation), by at least 6000-fold (i.e., at least 90% deuterium incorporation), by at least 6333.3-fold (i.e., at least 95% deuterium incorporation), by at least 6466.7-fold (i.e., at least 97% deuterium incorporation), by at least 6600-fold (i.e., at least 99% deuterium incorporation), by at least 6633.3-fold (i.e., at least 99.5% deuterium incorporation), or greater.

[0370] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and encompasses the two instances of the event or circumstance occurring and not occurring. For example, “optionally substituted with halo or cyano” means that the C 1-6 “Alkyl” includes instances where alkyl is substituted with halo or cyano and instances where alkyl is not substituted with halo or cyano.

[0371] “Substituted” or “substitution” means that one or more hydrogen atoms, in some embodiments, 1 to 6, in some embodiments, 1 to 3, of a group are independently replaced with a corresponding number of substituents. One of skill in the art can determine, without undue experimentation (through experiment or theory), what substitutions are possible or impossible. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated bond (e.g., alkene).

[0372] A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0373] A "pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is safe and effective for use in a mammal, and possesses the desired biological activity. The salts can be prepared from an intermediate during final isolation and purification, or by reacting the appropriate salt of the compound with the appropriate base or acid. Bases commonly employed to form pharmaceutically acceptable salts from acidic compounds include inorganic bases, such as sodium bicarbonate and potassium bicarbonate, and organic bases, such as ammonia. Acids commonly employed to form pharmaceutically acceptable salts from basic compounds include inorganic acids, such as hydrochloric acid and hydroiodic acid, and organic acids, such as acetic acid.

[0374] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent refers to the amount of the agent that is sufficient to achieve, at least partially, the intended effect. Determination of a therapeutically effective amount is within the capability of those skilled in the art, depending on the age and general condition of the subject, as well as the particular active substance, and appropriate therapeutically effective amounts for a given case can be determined by one skilled in the art according to routine testing.

[0375] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0376] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0377] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments, within ±5%. As will be understood by those skilled in the art, numbers are often presented only for illustrative purposes, and are not limiting, when the parameter is not critical. DETAILED DESCRIPTION

[0378] The present disclosure is further described in the following examples, which do not limit the scope of the disclosure.

[0379] EXAMPLES

[0380] The structure of the compounds was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in parts per million (ppm) and are relative to tetramethylsilane as 0.0 ppm. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; and dd, doublet of doublets. -6The NMR measurement was performed using a Bruker AVANCE-400 NMR spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as an internal standard.

[0381] The MS measurement was performed using a FINNIGAN LCQ Ad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0382] The HPLC analysis was performed using an Agilent HPLC 1200 DAD, an Agilent HPLC 1200 VWD, and a Waters HPLC e2695-2489 high-pressure liquid chromatograph.

[0383] The chiral HPLC analysis measurement was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0384] The high-performance liquid preparation was performed using a Waters 2767, a Waters 2767-SQ Detecor2, a Shimadzu LC-20AP, and a Gilson-281 preparative chromatograph.

[0385] The chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0386] The CombiFlash rapid preparation instrument was a Combiflash Rf200 (TELEDYNE ISCO).

[0387] The thin-layer chromatography silica gel plate was a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the silica gel plate used in the thin-layer chromatography were 0.15 mm to 0.2 mm, and the specifications of the thin-layer chromatography separation and purification product were 0.4 mm to 0.5 mm.

[0388] The silica gel column chromatography generally used Yantai Huanghai silica gel 200 to 300 mesh silica gel as a carrier.

[0389] The measurement of the average inhibition rate and IC 50 The measurement of the average inhibition rate and IC

[0390] The known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals, etc.

[0391] Unless otherwise specified in the examples, the reactions were carried out under argon or nitrogen atmosphere.

[0392] Argon or nitrogen atmosphere means that a reaction flask is connected to an argon or nitrogen balloon of about 1 L volume.

[0393] Hydrogen atmosphere means that a reaction flask is connected to a hydrogen balloon of about 1 L volume.

[0394] The pressurized hydrogenation reaction used a Parr 3916EKX hydrogenation apparatus and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus.

[0395] The hydrogenation reaction was usually performed by repeating the operation of vacuuming and filling with hydrogen three times.

[0396] The microwave reaction used a CEM Discover-S 908860 microwave reactor.

[0397] Unless otherwise specified in the examples, the solution means an aqueous solution.

[0398] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃ to 30℃.

[0399] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compound, and the developing agent system of thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, D: ethyl acetate / methanol, E: dichloromethane / ethyl acetate, I: dichloromethane / ethyl acetate / methanol, J: dichloromethane / ethanol, the volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of triethylamine and an alkaline or acidic reagent such as acetic acid can also be added for adjustment.

[0400] Example 1

[0401] M-(1S,2S)-2-methyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-methylpiperazin-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Octahydro-1 5 H-8-oxa-1-(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)- thiazol[1,3]-pyridazinocycloundecaphan-4-yl)cyclopropane-1-carboxamide 1-1

[0402] First step

[0403] (S)-1-(3-bromopyridin-2-yl)ethan-1-ol 1b

[0404] Formic acid (8.46 g, 180.13 mmol) was added to triethylamine (91.85 g, 907.74 mmol) at 0 °C, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-cymene) ruthenium (II) chloride (477 mg, 749.75 μmol, Shanghai Titan) was added, and the mixture was heated to 40 °C for 15 min under a nitrogen atmosphere, cooled to room temperature, and 1-(3-bromopyridin-2-yl)ethanone 1a (15 g, 75 mmol, Jiangsu Aikang) was added. The mixture was heated to 40 °C for 2 h under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1b (15.1 g, yield: 99%).

[0405] Second step

[0406] 3-bromo-2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridine 1c

[0407] Compound 1b (18.02 g, 19.18 mmol) was dissolved in N,N-dimethylformamide (120 mL), sodium hydride (4.28 g, 107 mmol, 60% purity) was added at 0 °C, the temperature was kept stirring for 1 h, 2-(2-bromoethoxy)tetrahydro-2H-pyran (28 g, 133.92 mmol, Shanghai Titan) was added, the temperature was naturally restored to room temperature and stirred for 2 h, saturated aqueous ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with water, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (9.6 g, yield: 32.5%).

[0408] Third step

[0409] 3-bromo-2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 1d

[0410] Compound 1c (9.6 g, 29.07 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.17 g, 4.36 mmol), bis(pinacolato)diboron (11.1 g, 43.7 mmol), bis(1,5-cyclooctadiene)iridium(I) chloride dimer (586 mg, 872.4 μmol, Shanghai Titan) were dissolved in tetrahydrofuran (150 mL), under nitrogen atmosphere, the temperature was raised to 75 °C and reacted for 16 h, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1d (18.1 g), which was used directly in the next step without purification.

[0411] Fourth step

[0412] 3-bromo-5-iodo-2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridine 1e

[0413] Compound 1d (18.1 g, 39.67 mmol), chloramine T (p-toluenesulfonyl chloride sodium salt) (72.2 g, 317.16 mmol, Shanghai Shaoyuan), sodium iodide (47.58 g, 317.42 mol) were dissolved in tetrahydrofuran (270 mL) and water (135 mL), after stirring for 20 minutes, the reaction was heated to 50°C for 64 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The residue was added with saturated sodium sulfite solution, extracted with ethyl acetate (150 mL x 3), the combined organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure. The residue was slurried with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1e (3.75 g, yield: 20.7%).

[0414] MS m / z (ESI): 455.9 [M+1] + .

[0415] Fifth step

[0416] 4-(5-bromo-6-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate 1f

[0417] Compound 1e (3.75 g, 8.23 mmol), 1-benzyloxycarbonylpiperazine (1.81 g, 8.23 mmol), cesium carbonate (6.71 g, 20.59 mmol), palladium acetate (185 mg, 824.02 μmol), S-(-)-1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (256 mg, 411.1 μmol) were dissolved in toluene (80 mL). After being heated to 100°C under nitrogen atmosphere for 6 hours, the reaction solution was filtered after being cooled to room temperature. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1f (4 g, yield: 59.2%).

[0418] MS m / z (ESI): 548.1 [M+1] + .

[0419] Sixth step

[0420] 4-(6-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzyl piperazine-1-carboxylate 1g

[0421] Compound 1f (4 g, 7.34 mmol), potassium acetate (3.6 g, 36.68 mmol), bis(pinacolato)diboron (5.6 g, 22 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (538 mg, 735 µmol) were dissolved in toluene (100 mL), under nitrogen atmosphere, heated to 105 °C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g (3.4 g, yield: 77.7%).

[0422] MS m / z (ESI): 596.5 [M+1] + .

[0423] Seventh step

[0424] Benzyl 4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)piperazine-1-carboxylate 1h

[0425] Compound 1g (3.08 g, 5.18 mmol), 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (3.35 g, 5.18 mmol, prepared by the method disclosed in the description of page 284 of the patent application “WO2022060836” Intermediate 1), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (380 mg, 519.33 µmol), potassium phosphate (2.75 g, 12.96 mmol) were dissolved in toluene (15 mL), 1,4-dioxane (45 mL) and water (15 mL), under nitrogen atmosphere, 70 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (3.12 g, yield: 60.9%).

[0426] Eighth step

[0427] Benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)piperazine-1-carboxylate 1i

[0428] Compound 1h (3.12 g, 3.15 mmol) was dissolved in methanol (25 mL) and dichloromethane (25 mL), p-toluenesulfonic acid-hydrate (3 g, 15.77 mmol) was added, the reaction was stirred for 1 hour, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, after removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound 1i (2.85 g), which was used directly in the next step without purification.

[0429] Ninth step

[0430] (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-(2-((methylsulfonyl)oxy)ethoxy)ethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester 1j

[0431] Compound 1i (600 mg, 663.7 μmol) was dissolved in dichloromethane (30 mL), triethylamine (401 mg, 3.96 mmol), methane sulfonic anhydride (289 mg, 1.661 mmol) was added, the reaction was stirred for 15 minutes, the reaction solution was extracted with saturated sodium bicarbonate solution, dichloromethane (15 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, after removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound 1j (626 mg), which was used directly in the next step without purification.

[0432] Tenth step

[0433] (S)-4-(12-bromo-14-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H-pyrrolo[3,2':6,7][1,4]oxazocino[4,5-a]indol-2-yl)piperazine-1-carboxylic acid benzyl ester 1k

[0434] Compound 1j (426 mg, 433.76 μmol) was dissolved in N,N-dimethylformamide (18 mL), sodium hydride (35 mg, 875.1 μmol, 60% purity) was added at 0°C, the reaction was stirred for 4 hours, saturated ammonium chloride aqueous solution was added to quench the reaction, extracted with ethyl acetate (15 mL x 3), the organic phase was combined, washed with water, saturated sodium chloride solution in turn, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1k (258 mg, yield: 67.1%)

[0435] Eleventh step

[0436] (S)-4-(12-bromo-14-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H- pyrido[3',2':6,7][1,4]oxazocin[4,5-a]indol-2-yl)piperazine-1 -carboxylic acid benzyl ester 1l

[0437] Compound 1k (629 mg, 708 μmol) was dissolved in tetrahydrofuran (20 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (3.5 mL) was added, the reaction was stirred at 50 °C for 16 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, saturated sodium chloride solution in turn, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1l (851 mg). The product was used directly in the next step without purification.

[0438] MS m / z (ESI): 647.5 [M+1] + .

[0439] Twelfth step

[0440] (S)-4-(14-(3-acetoxy-2,2-dimethylpropyl)-12-bromo-5-methyl-7,8-dihydro-5H- pyrido[3',2':6,7][1,4]oxazocin[4,5-a]indol-2-yl)piperazine-1 -carboxylic acid benzyl ester 1m

[0441] Compound 1l (851 mg, 1.31 mmol) was dissolved in dichloromethane (40 mL), triethylamine (400 mg, 3.95 mmol), acetic anhydride (134 mg, 1.31 mmol) and 4-dimethylaminopyridine (16 mg, 130.97 μmol) were added, the reaction was stirred for 16 hours, saturated aqueous sodium bicarbonate solution was added to the reaction, extracted with dichloromethane (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1m (383 mg, yield: 42.2%).

[0442] MS m / z (ESI): 689.2 [M+1] + .

[0443] Thirteenth step

[0444] (S)-4-(14-(3-acetoxy-2,2-dimethylpropyl)-5-methyl-12-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocin[4,5-a]indol-2- yl)piperazine-1 -carboxylic acid benzyl ester 1n

[0445] Compound 1m (383 mg, 555.36 µmol), potassium acetate (276 mg, 2.81 mmol), bis(pinacolato)diboron (423 mg, 1.66 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (41 mg, 56 µmol) were dissolved in toluene (30 mL), under nitrogen atmosphere, heated to 105 °C for 16 hours, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1n (326 mg, yield: 79.6%).

[0446] MS m / z (ESI): 737.7 [M+1] + .

[0447] Fourteenth step

[0448] (S)-1-((S)-3-(4-((S)-14-(3-acetyloxy-2,2-dimethylpropyl)-2-(4- (benzyloxy)carbonyl)piperazin-1-yl)-5-methyl-7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocino[4,5-a]indol-12-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 1o

[0449] Compound 1n (276 mg, 374.6 µmol), (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester (197 mg, 412.6 µmol, prepared by the method disclosed in the description of patent application “WO2022060836” on page 289, Intermediate 2), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (41 mg, 56 µmol), potassium phosphate (200 mg, 942.2 µmol) were dissolved in toluene (3 mL), 1,4-dioxane (9 mL) and water (3 mL), under nitrogen atmosphere, 70 °C for 16 hours, the reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate (15 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system D to obtain the title compound 1o (218 mg, yield: 57.7%).

[0450] MS m / z (ESI): 1007.9 [M+1] + .

[0451] Fifteenth step

[0452] (S)-1-((S)-3-(4-((S)-2-(4-(benzyloxy)carbonyl)piperazin-1-yl)-14-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indol-12-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazin-3-carboxylic acid 1p

[0453] Compound 1o (218 mg, 216.44 μmol) was dissolved in tetrahydrofuran (8 mL) and water (2 mL). Lithium hydroxide monohydrate (28 mg, 667.2 μmol) was added at 0 °C, and the mixture was allowed to return to room temperature with stirring for 16 hours. The pH of the reaction solution was adjusted to <7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1p (215 mg). The product was used directly in the next reaction without purification.

[0454] MS m / z (ESI): 951.8 [M+1] + .

[0455] Step Sixteen

[0456] M-4-((1 5 S,6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctane[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine-hexacyclic undecaban-12-yl)piperazine-1-carboxylic acid benzyl ester 1q-1

[0457] The crude title compound 1p (215 mg, 226 μmol) was dissolved in dichloromethane (20 mL), and 1-hydroxybenzotriazole (172 mg, 1.13 mmol) and N,N-diisopropylethylamine (874.8 mg, 6.76 mmol) were added. The mixture was cooled to 0 °C, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (867 mg, 4.52 mmol) was added in portions. The mixture was stirred at room temperature for 64 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system E to give the title compound 1q-1 (101 mg, yield: 47.8%).

[0458] MS m / z(ESI): 933.8 [M+1] + .

[0459] Step Seventeen

[0460] M-((1 5 S,6 3 S,4S,Z)-1 5 10,10-Trimethyl-12-(4-methylpiperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1-(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazo-6(1,3-pyridazine-hexacyclic undecapan-4-yl)carbamate tert-butyl ester 1r-1

[0461] Compound 1q-1 (75 mg, 80.3 μmol) was dissolved in methanol (20 mL), and paraformaldehyde (24 mg, 799.3 μmol) and palladium hydroxide on carbon (wet) (75 mg) were added. The mixture was stirred for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1r-1 (72 mg). The product was used directly in the next reaction without purification.

[0462] MS m / z(ESI): 813.8 [M+1] + .

[0463] Step 18

[0464] M-(15 S,6 3 (S,4S,Z)-4-amino-1 5 10,10-Trimethyl-12-(4-methylpiperazin-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine-hexacyclic undecabanone-5,7-dione 2,2,2-trifluoroacetate 1s-1

[0465] Compound 1r-1 (73 mg, 89.7 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added at 0 °C. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 1s-1 (135 mg). The product was used directly in the next reaction without purification.

[0466] MS m / z(ESI): 713.7 [M+1] + .

[0467] Step 19

[0468] (1S,2S)-2-methyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-methylpiperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide

[0469] The crude compound 1s-1 (135 mg, 163.2 μmol) was dissolved in N,N- dimethylformamide (6 mL), N,N-diisopropylethylamine (525 mg, 4.06 mmol) was added, (1S,2S)-2-methylcyclopropane-1-carboxylic acid (49 mg, 489.4 μmol) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino- morpholinio-carbenium hexafluorophosphate (70 mg, 163.4 μmol) were added at 0 °C, and the reaction was stirred for 2 h. Water was added to the reaction solution, and extraction was performed with ethyl acetate (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% - 60%, flow rate: 30 mL / min) to obtain the title compound 1-1 (42 mg, yield: 32.3%).

[0470] MS m / z (ESI): 795.8 [M+1] + .

[0471] 1 H NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.42 (d, 1H), 7.73 (dd, 1H), 7.57 (s, 1H), 7.46-7.44 (m, 2H), 5.67 (d, 1H), 4.80 (d, 1H), 4.53-4.46 (m, 2H), 4.31 (td, 1H), 4.21 (q, 1H), 4.16 (dd, 1H), 3.86-3.81 (m, 1H), 3.74-3.66 (m, 2H), 3.62-3.60 (d, 1H), 3.47 (d, 1H), 3.39-3.41 (m, 3H), 3.30-3.27 (m, 2H), 2.81-2.77 (m, 2H), 2.69 (t, 4H), 2.40 (s, 3H), 2.30-2.27 (m, 1H), 2.00-1.98 (m, 1H), 1.87 (qt, 1H), 1.63 (dt, 1H) 1.54-1.51 (m, 1H), 1.47 (d, 3H), 1.29-1.23 (m, 1H), 1.15 (d, 3H), 1.13-1.09 (m, 1H), 1.05 (s, 3H), 0.69-0.66 (m, 1H), 0.30 (s, 3H).

[0472] Example 2

[0473] M-(1r,2R,3S)-2,3-dimethyl-N-((15 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-(oxecyclobutane-3-ylmethyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 2-1

[0474] first step

[0475] M-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-5,7-dioxo-1 2 -(piperazine-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapan-4-yl)carbamate tert-butyl ester 2a-1

[0476] Compound 1q-1 (220 mg, 235.8 μmol) was dissolved in ethanol (10 mL), and palladium hydroxide on carbon (wet) (220 mg) was added. The mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 2a-1 (175 mg). The product was used directly in the next step of the reaction without purification.

[0477] MS m / z(ESI): 799.7 [M+1] + .

[0478] Step 2

[0479] M-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-(oxecyclobutane-3-ylmethyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapan-4-yl)carbamate tert-butyl ester 2b-1

[0480] The crude compound 2a-1 (160 mg, 200.2 μmol) was dissolved in tetrahydrofuran (10 mL), and oxetane-3-carboxaldehyde (35 mg, 406.5 μmol, Shanghai Leyan), sodium cyanoborohydride (36 mg, 601.8 μmol), and acetic acid (36 mg, 599.5 μmol) were added. The mixture was stirred for 2 hours, and the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography with solvent system A to give the title compound 2b-1 (110 mg, yield: 63.2%).

[0481] MS m / z(ESI): 869.8 [M+1] + .

[0482] Step 3

[0483] M-(1 5 S,6 3 (S,4S,Z)-4-amino-1 5 ,10,10-trimethyl-1 2 -(4-(oxetane-3-ylmethyl)piperazin-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine heterocyclic undecabanone-5,7-dione 2c-1

[0484] Compound 2b-1 (110 mg, 126.6 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The pH of the residue was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2c-1 (97 mg). The product was used directly in the next reaction without purification.

[0485] MS m / z(ESI): 769.7 [M+1] + .

[0486] Step 4

[0487] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-(oxecyclobutane-3-ylmethyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 2-1

[0488] The crude compound 2c-1 (97 mg, 126.1 μmol) was dissolved in N,N- dimethylformamide (2 mL), N,N-diisopropylethylamine (50 mg, 386.9 μmol) was added, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (23 mg, 201.5 μmol, Shanghai Bide) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino- morpholinio-carbenium hexafluorophosphate (54 mg, 126.1 μmol) were added at 0 °C, the reaction was stirred for 2 hours, the reaction solution was filtered, the filtrate was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% - 60%, flow rate: 30 mL / min), to obtain the title compound (10 mg, yield: 9.1%).

[0489] MS m / z (ESI): 865.8 [M+1] + .

[0490] 1 H NMR (500 MHz, CD3OD): δ 8.60-8.59 (m, 1H), 8.42-8.41 (m, 1H), 7.74-7.72 (m, 1H), 7.58 (s, 1H), 7.47-7.44 (m 2H), 5.68-5.65 (m, 1H), 4.97-4.93 (m, 2H), 4.53-4.45 (m, 4H), 4.31-4.28 (m, 1H), 4.23-4.15 (m, 2H), 3.88-3.81 (m, 1H), 3.77-3.67 (m, 2H), 3.62-3.60 (m, 1H), 3.47-3.44 (m, 1H), 3.34-3.32 (m, 4H), 2.81-2.77 (m, 2H), 2.68-2.67 (m, 1H), 2.29-2.26 (m, 1H), 2.05-1.97 (m, 2H), 1.87-1.85 (m, 2H), 1.69-1.59 (m, 2H), 1.48-1.46 (m, 3H), 1.43-1.31 (m, 7H), 1.20-1.15 (m, 6H), 1.05 (s, 3H), 0.94-0.91 (m, 1H), 0.30 (s, 3H).

[0491] Example 3

[0492] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2- (4-(cyclopentylmethyl)piperazin-1-yl)-1 5 , 10, 10-trimethyl-5, 7-dioxo-1 7 , 1 8 , 6 1 , 6 2 , 6 3 , 6 4 , 6 5 , 6 6 - octahydro-1 5 H-8-oxa-1(12, 14)-pyrido[3', 2':6, 7][1, 4]oxazocino[4, 5-a]indolizine-2(4, 2)-thiazol[1, 3]- pyridazinocycloundecaphan-4-yl)-2, 3-dimethylcyclopropane-1-carboxamide 3-1

[0493] The title compound was prepared by following the synthetic route in Example 2, steps 2 to 4, replacing oxetan-3-carboxaldehyde in step 2 with cyclobutanecarboxaldehyde (Shanghai Leyen) (10 mg, yield: 20.2%).

[0494] MS m / z (ESI): 864.0 [M+1] + .

[0495] 1 H NMR (500 MHz, CD3OD): δ 8.59 (s, 1H), 8.43-8.42 (m, 1H), 7.74-7.72 (m, 1H), 7.58 (s, 1H), 7.49-7.44 (m, 2H), 5.68-5.66 (m, 1H), 4.53-4.45 (m, 2H), 4.31-4.28 (m, 1H), 4.22-4.20 (m, 1H), 4.18-4.15 (m, 1H), 3.86-3.82 (m, 1H), 3.73-3.67 (m, 2H), 3.62-3.60 (m, 1H), 3.47-3.45 (m, 3H), 3.01-2.98 (m, 3H), 2.81-2.77 (m, 3H), 2.29-2.26 (m, 1H), 2.20-2.19 (m, 2H), 2.05-1.97 (m, 3H), 1.91-1.85 (m, 4H), 1.66-1.62 (m, 1H), 1.48-1.47 (m, 3H), 1.43-1.31 (m, 8H), 1.20-1.15 (m, 6H), 1.05 (s, 3H), 0.94-0.91 (m, 1H), 0.30 (s, 3H).

[0496] Example 4

[0497] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-((1-methylcyclobutyl)methyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 4-1

[0498] Using steps two through four of the synthetic route in Example 2, the oxetane-3-carboxaldehyde in step two was replaced with 1-methylcyclobutane-1-carboxaldehyde (prepared using the method disclosed in the patent literature "European Journal of Organic Chemistry, 2021, vol. 2021, #47, p. 6561-6569") to obtain the title compound (6 mg, yield: 24.2%).

[0499] MS m / z(ESI): 878.0 [M+1] + .

[0500] 1H NMR (500MHz, CD3OD): δ8.60(s,1H),8.39(d,1H),7.73(dd,1H),7.58(s,1H),7.50–7.34(m,2H),5.67(d,1H),4.80(d,2H) ,4.60(s,1H),4.54–4.42(m,3H),4.38–4.27(m,2H),4.24–4.10(m,3H),3.83(dd,2H),3.81–3.64(m,3H),3.61(d,1H),3. 50–3.42(m,2H),3.29(d,3H),2.85–2.74(m,3H),2.65(s,4H),2.42(s,2H),2.28(d,1H),2.12–1.93(m,4H),1.86(dd,2H) ,1.77–1.71(m,2H),1.69–1.57(m,2H),1.47(d,3H),1.40(tt,1H),1.29(s,2H),1.17(dd,4H),1.05(s,2H),0.30(s,2H).

[0501] Example 5

[0502] M-(1r,2R,3)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-((1-methylazacyclobutane-3-yl)methyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 5-1

[0503] first step

[0504] M-4-((1 5 S,6 3 (S,4S,Z)-4-amino-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,18 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctane[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine heterocyclic undecapon-12-yl)piperazine-1-carboxylic acid benzyl ester trifluoroacetate 5a-1

[0505] Compound 1q-1 (50 mg, 53.6 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 5a-1 (51 mg). The product was used directly in the next reaction without purification.

[0506] MS m / z (ESI): 833.7 [M+1] + .

[0507] Step 2

[0508] M-4-((1 5 S,6 3 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-formamido)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctane[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine heterocyclic undecaban-12-yl)piperazine-1-carboxylic acid benzyl ester 5b-1

[0509] The crude compound 5a-1 (51 mg, 53.9 μmol) was dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (35 mg, 270.8 μmol) was added. Then, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (13 mg, 113.9 μmol) and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (23 mg, 53.7 μmol) were added at 0 °C. The mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography using solvent system A to give the title compound 5b-1 (50 mg, yield: 99%).

[0510] MS m / z(ESI): 929.8 [M+1] + .

[0511] Step 3

[0512] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-5,7-dioxo-1 2 -(piperazine-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 5c-1

[0513] Compound 5b-1 (50 mg, 53.8 μmol) was dissolved in ethanol (5 mL), and palladium hydroxide on carbon (wet) (50 mg) was added. The mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 5c-1 (42 mg). The product was used directly in the next step of the reaction without purification.

[0514] MS m / z(ESI): 795.9 [M+1] + .

[0515] Step 4

[0516] M-3-((4-((1 5 S,6 3 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-formamido)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazinazine-12-yl)piperazinazin-1-yl)methyl)azacyclobutane-1-tert-butyl carboxylate 5d-1

[0517] The crude compound 5c-1 (31 mg, 39 μmol) was dissolved in tetrahydrofuran (2 mL), and tert-butyl 3-formylazetane-1-carboxylic acid (35 mg, 406.5 μmol, Shanghai Titan), sodium cyanoborohydride (7 mg, 117 μmol), and acetic acid (7 mg, 116.5 μmol) were added. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography using solvent system A to give the title compound 5d-1 (22 mg, yield: 58.5%).

[0518] MS m / z (ESI): 962.8 [M⁻¹] - .

[0519] Step 5

[0520] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(azacyclobutane-3-ylmethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-15 H-8-oxa-l(12,14)-pyrido[3',2':6,7][l,4]oxazocinophan[4,5-a]indolizine-2(4,2)- thiazol[6(l,3)-pyridazinocycloundecaphan-4-yl)-2,3-dimethylcyclopropane-l- carboxamide 5e-1

[0521] Compound 5d-1 (22 mg, 22.8 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 2 h. The reaction solution was concentrated under reduced pressure, the residue was adjusted to Ph > 7 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5e-1 (20 mg). The product was used directly in the next reaction without purification.

[0522] MS m / z (ESI): 865.2 [M+1] + .

[0523] Sixth step

[0524] M-(lR,2R,3)-2,3-dimethyl-N-((l 5 S,6 3 S,4S,Z)-l 5 ,10,10-trimethyl-l 2 -(4-((l-methylazetidin-3-yl)methyl)piperazin-l-yl)-5,7-dioxo-l 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-l 5 H-8-oxa-l(12,14)-pyrido[3',2':6,7][l,4]oxazocinophan[4,5-a]indolizine-2(4,2)- thiazol[6(l,3)-pyridazinocycloundecaphan-4-yl) cyclopropane-l-carboxamide 5-1

[0525] ​The crude compound 5e-1 (20 mg, 23.1 μmol) was dissolved in methanol (2 mL), and 35% formaldehyde aqueous solution (20 mg, 233.1 μmol), sodium cyanoborohydride (7 mg, 117 μmol), and acetic acid (2 mg, 33.3 μmol) were added. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography using solvent system A to give the title compound (5 mg, yield: 24.6%).

[0526] MS m / z (ESI): 878.8 [M+1] + .

[0527] 1 H NMR (500MHz, CD3OD): δ8.60(s,1H),8.41-8.40(m,1H),7.74-7.72(m,1H) ,7.58(s,1H),7.46-7.44(m,2H),5.68-5.67(m,1H),4.81-4.79(m,1H),4. 61-4.60(m,1H),4.53-4345(m,2H),4.33-4.28(m,2H),4.21-4.15(m,2H), 3.86-3.81(m,3H),3.74-3.67(m,2H),3.62-3.60(m,1H),3.47-3.45(m,1H ),3.21-3.19(m,1H),2.96-2.92(m,2H),2.80-2.77(m,2H),2.71-2.67(m, 4H),2.59-2.58(m,2H),3.29-3.27(m,1H),2.23-2.18(m,2H),2.05-1.98( m,2H),1.88-1.85(m,2H),1.64-1.60(m,4H),1.48-1.46(m,2H),1.20-1.1 5(m,4H),1.05(s,3H),0.94-0.91(m,4H),0.61-0.57(m,1H),0.30(s,3H).

[0528] Example 6

[0529] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(2-Cyclopropoxyethyl)piperazine-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,18 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Octahydro-1 5 H-8-oxa-1(12,14)- pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazolo[6(1,3)-pyridazino]cycloundecan-4-yl)-2,3- dimethylcyclopropane-1-carboxamide 6-1

[0530] M- (1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(2- cyclopropoxyethyl)piperazin-1-yl)-1 5 ,10,10- trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Octahydro-1 5 H-8-oxa-1(12,14)- pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazolo[6(1,3)-pyridazino]cycloundecan-4-yl)-2,3- dimethylcyclopropane-1-carboxamide 6-3

[0531] First step

[0532] M-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(2- cyclopropoxyethyl)piperazin-1-yl)-1 5 ,10,10- trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Octahydro-1 5tert-Butyl H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine- 2(4,2)-thiazolo[6(1,3)-pyridazino]cycloundecaphan-4-ylcarbamate 6a-1

[0533] The title compound 6a-1 (90 mg, yield: 17.8%) was prepared using the synthetic route of Example 2, second to fourth steps, replacing the second step starting material oxetan-3-carbaldehyde with 2-cyclopropoxyacetaldehyde (prepared using the method disclosed in the patent application “WO2022132696” on page 52, Intermediate A1).

[0534] MS m / z (ESI): 884.1 [M-1].

[0535] Second step

[0536] M-(1 5 S,6 3 S,4S,Z)-4-aminol 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)- thiazolo[6(1,3)-pyridazino]cycloundecaphan-5,7-dione 6b-1

[0537] M-(1 5 S,6 3 S,4S,Z)-4-aminol 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine-hexacyclic undecabanone-5,7-dione 6b-3

[0538] Compound 6a-1 (20 mg, 126.6 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The residue was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture (20 mg) of crude title compounds 6b-1 and 6b-3. The product was used directly in the next reaction without purification.

[0539] 6b-1MS m / z(ESI): 783.8 [M+1] + .

[0540] 6b-3MS m / z(ESI): 743.8 [M+1] + .

[0541] Step 3

[0542] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(2-Cyclopropoxyethyl)piperazine-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 6-1

[0543] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,18 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 6-3

[0544] The above crude product mixture (20 mg, 25 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and N,N-diisopropylethylamine (16 mg, 123.8 μmol) was added. Then, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (4 mg, 35 μmol) and 1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (14 mg, 29 μmol) were added at 0 °C, and the mixture was stirred for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30mL / min) to give title compounds 6-1 (4mg, yield: 17.8%) and 6-3 (2mg, yield: 9.3%).

[0545] 6-1:

[0546] MS m / z (ESI): 877.8 [M-1] - .

[0547] 1H NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.40 (d, 1H), 7.73 (dd, 1H), 7.58 (s, 1H), 7.49 - 7.42 (m, 2H), 5.67 (d, 1H), 4.60 (s, 1H), 4.55 - 4.43 (m, 2H), 4.31 (ddd, 1H), 4.24 - 4.13 (m, 2H), 3.83 (dd, 1H), 3.75 - 3.70 (m, 2H), 3.68 (d, 1H), 3.61 (d, 1H), 3.46 (d, 2H), 3.41 - 3.37 (m, 3H), 3.37 - 3.35 (m, 1H), 3.30 - 3.27 (m, 2H), 2.82 - 2.77 (m, 2H), 2.76 (t, 3H), 2.68 (t, 2H), 2.28 (d, 1H), 2.05 (d, 1H), 1.87-1.85 (m, 1H), 1.98 (d, 1H), 1.62 (dt, 2H), 1.47 (d, 3H), 1.44 - 1.34 (m, 3H), 1.19 (d, 3H), 1.15 (d, 3H), 1.13 - 1.10 (m, 1H), 1.05 (s, 3H), 0.62 - 0.45 (m, 4H), 0.30 (s, 3H).

[0548] 6-3:

[0549] MS m / z (ESI): 837.5 [M-1] - .

[0550] 1H NMR (500MHz, CD3OD): δ8.60(d,1H),8.41(d,1H),7.73(dd,1H),7.58(s,1H),7.45(dd,2H),5.70–5.65(m,1H),4.80(d,1H),4.60(s ,2H),4.51(dd,1H),4.46(d,1H),4.30(td,1H),4.21(t,1H),4.19–4.14(m,1H),3.84(dd,1H),3.76(t,2H),3.68(d,1H),3.61(d,1H ),3.50–3.44(m,2H),3.40(q,3H),3.29(t,1H),2.83–2.74(m,4H),2.64(t,1H),2.32–2.25(m,1H),2.21(t,1H),2.08–2.03(m,1H) ,1.99(d,1H),1.88-1.85m,1H),1.63(td,2H),1.47(d,2H),1.45–1.35(m,3H),1.19(d,3H),1.15(d,3H),1.05(s,3H),0.30(s,3H).

[0551] Example 7

[0552] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-(oxecyclobutane-3-yl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctane[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 7-1

[0553] Using steps two through four of the synthetic route in Example 2, the starting material oxetane-3-carboxaldehyde in step two was replaced with 3-oxetane-3-butanone (Shanghai Bide) to obtain the title compound (5 mg, yield: 46.4%).

[0554] MS m / z (ESI): 849.8 [M⁻¹] - .

[0555] 1 H NMR (500MHz, CD3OD): δ8.60(d,1H),8.41(d,1H),7.73(dd,1H),7.57(s,1H),7.48–7.41(m,2H),5.67(d,1H),4.75(t,2H),4.6 7(td,2H),4.60(s,1H),4.54–4.43(m,2H),4.29(dd,1H),4.24–4.13(m,2H),3.83(dd,1H),3.75–3.64(m,2H),3.60(dd,2H),3. 46(d,1H),3.40(q,4H),3.28(t,1H),2.83–2.72(m,2H),2.58(t,4H),2.30–2.20(m,1H),1.98(d,1H),1.90–1.78(m,1H),1.62 (dd,1H),1.47(d,3H),1.44–1.41(m,1H),1.40–1.38(m,1H),1.36(d,1H),1.19(d,3H),1.15(d,3H),1.05(s,3H),0.30(s,3H).

[0556] Example 8

[0557] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(4-((3-methyloxetane-3-yl)methyl)piperazin-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctane[4,5-a]indolaza-2(4,2-thiazo-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 8-1

[0558] Using steps two through four of the synthetic route in Example 2, the starting material oxetane-3-carboxaldehyde in step two was replaced with 3-methyl-3-aldehyde-1-oxetane (Shanghai Shaoyuan) to obtain the title compound (2 mg, yield: 11.9%).

[0559] MS m / z(ESI): 880.0 [M+1] + .

[0560] 1 H NMR (500MHz, CD3OD): δ8.60(d,1H),8.39(d,1H),7.73(dd,1H),7.58(s,1H),7.50–7.35(m,2H),5.67(dd,1H),5.36(d d,1H),4.59(d,5H),4.53–4.44(m,2H),4.37(d,2H),4.30(dd,1H),4.24–4.11(m,2H),3.83(dd,1H),3.74–3.65(m,3H) ,3.61(d,1H),3.50–3.43(m,1H),2.90–2.74(m,2H),2.67(s,2H),2.60(t,3H),2.33–2.17(m,3H),2.08–1.95(m,3H),1 .92–1.79(m,1H),1.63(qd,2H),1.47(d,5H),1.44–1.40(m,2H),1.17(dd,5H),1.05(s,3H),0.92(t,2H),0.30(s,3H).

[0561] Example 9

[0562] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazapyrocyclohep-4-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocin-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 9-1

[0563] Scheme One

[0564] First Step

[0565] 2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine 9a

[0566] Compound 1c (39.5 g, 119.61 mmol), potassium acetate (58.8 g, 599.13 mmol), bis(pinacolato)diboron (91.1 g, 358.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.8 g, 11.8 mmol) were dissolved in toluene (400 mL), heated to 105 °C under nitrogen atmosphere for 16 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 9a (41 g, yield: 90.8%).

[0567] MS m / z (ESI): 378.6 [M+1] + .

[0568] Second Step

[0569] 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-(2-((1S)-1-(2-(tetrahydro- 2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)-1H-indole 9b

[0570] Compound 9a (24.6 g, 65.2 mmol), 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-2-iodo-1H-indole (30 g, 46.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.5 g, 4.72 mmol), potassium phosphate (24.7 g, 116.36 mmol) were dissolved in toluene (100 mL), 1,4-dioxane (300 mL) and water (100 mL), and the reaction was carried out at 70°C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 9b (32 g, yield: 59.5%).

[0571] MS m / z (ESI): 769.6 [M+1] + .

[0572] Third step

[0573] (S)-2-(1-(3-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)pyridin-2-yl)ethoxy)ethan-1-ol 9c

[0574] Compound 9b (32 g, 41.56 mmol) was dissolved in methanol (110 mL) and dichloromethane (110 mL), and p-toluenesulfonic acid-hydrate (39.5 g, 207.66 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was adjusted to pH > 7 with a saturated sodium bicarbonate solution, and extraction was performed with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 9c (24 g, yield: 84.2%).

[0575] MS m / z (ESI): 685.5 [M+1] + .

[0576] Fourth step

[0577] (S)-12-bromo-14-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocino[4,5-a]indole 9d

[0578] Compound 9c (24 mg, 35 mmol), triphenylphosphine (13.8 g, 52.61 mmol) were dissolved in tetrahydrofuran (500 mL), diisopropyl azodicarboxylate (10.7 g, 52.91 mmol) was added dropwise under ice bath, and the reaction was allowed to recover to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9d (36.1 g, yield: 154%).

[0579] Fifth step

[0580] (S)-3-(12-bromo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indol- 14-yl)-2,2-dimethylpropan-1-ol 9e

[0581] Compound 9d (23.3 g, 34.89 mmol) was dissolved in tetrahydrofuran (300 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (174.5 mL) was added, and the reaction was stirred at 50°C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution in sequence, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9e (17 g, yield: 113%).

[0582] MS m / z (ESI): 429.3 [M+1] + .

[0583] Sixth step

[0584] (S)-3-(12-bromo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indol- 14-yl)-2,2-dimethylpropan-1-ol 9e

[0585] Compound 9e (15 g, 34.93 mmol) was dissolved in dichloromethane (300 mL), triethylamine (10.6 g, 104.75 mmol), acetic anhydride (5.4 g, 52.89 mmol), and 4-dimethylaminopyridine (431 mg, 3.50 mmol) were added, and the reaction was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane (150 mL x 3), and the combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9f (12 g, yield: 72.8%)

[0586] MS m / z (ESI): 471.4 [M+1]+ .

[0587] Seventh step

[0588] 3-((5S)-12-bromo-5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8- dihydro-5H-pyrido[3',2':6,7][l,4]oxazocino[4,5-a]indol-l 4-yl)-2,2-dimethylpropyl acetate 9g

[0589] Compound 9f (12 g, 25.45 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl (1 g, 3.72 mmol), bis(pinacolato)diboron (9.7 g, 38.20 mmol), bis(l,5-cyclooctadiene)iridium(I) dimer (858 mg, 1.27 mmol) were dissolved in tetrahydrofuran (350 mL), and the reaction was carried out under a nitrogen atmosphere at 75 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain the crude title compound 9g (20.2 g). The product was used directly in the next step without purification.

[0590] MS m / z (ESI): 597.2 [M+1] + .

[0591] Eighth step

[0592] (S)-3-(12-bromo-2-iodo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][l,4]oxazocino[4,5- a]indol- 14-yl)-2,2-dimethylpropyl acetate 9h

[0593] The crude compound 9g (20.2 g, 39.34 mmol) and chloramine-T (p-toluenesulfonyl chloride sodium salt) (53.8 g, 236.33 mmol) were dissolved in tetrahydrofuran (320 mL), and the reaction was carried out under a nitrogen atmosphere by dropwise addition of a sodium iodide aqueous solution (35.4 g, 236.16 mmol) (160 mL) under ice bath at 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and saturated sodium sulfite solution was added to the residue. The mixture was extracted with ethyl acetate (150 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 9h (12 g, yield: 51%).

[0594] MS m / z (ESI): 597.2 [M+1] + .

[0595] Ninth step

[0596] 3-((5S)-12-bromo-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-7,8- dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropyl acetate 9i

[0597] Compound 9h (1 g, 1.67 mmol), 2-(2-propargyloxy)tetrahydro-pyran (279 mg, 1.99 mmol), triethylamine (342 mg, 3.38 mmol), bis(triphenylphosphine)palladium(II) dichloride (176 mg, 250.7 μmol), copper(I) iodide (48 mg, 252 μmol) were dissolved in tetrahydrofuran (30 mL), under nitrogen atmosphere, the reaction was heated to 35 °C for 16 hours. After the reaction was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 9i (848 mg, yield: 83%).

[0598] MS m / z (ESI): 609.0 [M+1] + .

[0599] Step 10

[0600] (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 9k

[0601] Compound (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 9j (100 mg, 209.5 μmol, prepared by the method disclosed in the description of patent application “WO2022060836” on page 289, Intermediate 2), potassium acetate (62 mg, 631.7 μmol), pinacol diboronic acid (133 mg, 523.7 μmol), tris(dibenzylideneacetone)dipalladium (10 mg, 10.9 μmol), 2-dicylohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mg, 41.9 μmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen atmosphere, the reaction was heated to 110 °C for 8 hours, after the reaction was cooled to room temperature, it was filtered to obtain the filtrate containing the title compound 9k for use.

[0602] MS m / z (ESI): 443.1 [M+1] + .

[0603] Step 11

[0604] (3S)-1-((2S)-3-(4-((5S)-14-(3-acetoxy-2,2-dimethylpropyl)-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indol-12-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester 9l

[0605] Compound 9i (64 mg, 105 μmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (14 mg, 20.5 μmol), potassium carbonate (44 mg, 218.3 μmol), and water (2 mL) were added to the filtrate from the previous step. The reaction mixture was reacted at 70 °C for 3 hours under a nitrogen atmosphere. After the reaction mixture cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography using solvent system A to give the title compound 9l (60 mg, yield: 61.7%).

[0606] MS m / z (ESI): 927.5 [M+1] + .

[0607] Step Twelve

[0608] (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-((5S)-14-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indol-12-yl)thiazo-2-yl)propionyl)hexahydropyridazine-3-carboxylic acid 9m

[0609] Compound 9l (60 mg, 64.7 μmol) was dissolved in tetrahydrofuran (3 mL) and water (0.75 mL), and lithium hydroxide monohydrate (8 mg, 190.4 μmol) was added. The mixture was stirred for 5 hours. The pH of the reaction solution was adjusted to <7 with 0.5 M hydrochloric acid. The solution was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9m (61 mg). The product was used directly in the next reaction without purification.

[0610] MS m / z (ESI): 871.4 [M+1] + .

[0611] Step Thirteen

[0612] M-((1 5 S,6 3 S,4S,Z)-1 5 10,10-Trimethyl-5,7-dioxo-12-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine heterocyclic undecapan-4-yl) tert-butyl carbamate 9n-1

[0613] The crude compound 9m (61 mg, 70 μmol) was dissolved in dichloromethane (15 mL). 1-hydroxybenzotriazole (53 mg, 348.3 μmol) and N,N-diisopropylethylamine (270 mg, 2.09 mmol) were added at 0 °C, followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system E to give the title compound 9n-1 (52 mg, yield: 87%).

[0614] MS m / z (ESI): 853.5 [M+1] + .

[0615] Step Fourteen

[0616] M-((1 5 S,6 3 S,4S,Z)-12-(3-hydroxyprop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6-octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine heterocyclic undecapan-4-yl) tert-butyl carbamate 9o-1

[0617] Compound 9n-1 (52 mg, 61 μmol) was dissolved in methanol (5 mL) and dichloromethane (5 mL), and p-toluenesulfonic acid hydrate (58 mg, 304.9 μmol) was added. The mixture was stirred for 3 hours. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9o-1 (30 mg). The product was used directly in the next reaction without purification.

[0618] MS m / z(ESI): 769.5 [M+1] + .

[0619] Step 15

[0620] M-3-((1 5 S,6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine-hexacyclic undecapon-12-yl)prop-2-yn-1-ylmethanesulfonate 9p-1

[0621] Compound 9o-1 (30 mg, 39 μmol) was dissolved in dichloromethane (10 mL), and triethylamine (34 mg, 237.2 μmol) and methanesulfonic anhydride (20 mg, 114.8 μmol) were added at 0 °C. The mixture was stirred for 30 minutes. The reaction solution was extracted with saturated sodium bicarbonate solution and dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9p-1 (33 mg). The product was used directly in the next reaction without purification.

[0622] MS m / z (ESI): 847.2 [M+1] + .

[0623] Sixteenth step

[0624] M-((1 5 S,6 3 S,4S,Z)-12-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indolizido-2(4,2)-thiazolo-6(1,3)-pyridazino-cycloundecaphan-4-yl)carbamic acid tert-butyl ester 9q-1

[0625] The crude compound 9p-1 (426 mg, 433.7 μmol) was dissolved in dichloromethane (5 mL), 1,4-oxazepane (34 mg, 237.2 μmol) was added, the reaction was stirred for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography with the developing agent system A to obtain the title compound 9q-1 (7 mg, yield: 21%).

[0626] MS m / z (ESI): 852.3 [M+1] + .

[0627] Seventeenth step

[0628] M-(1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-4-amino-1 5 ,10,10-trimethyl-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5H-8-oxa-l(12,14)-pyrido[3',2':6,7][l,4]oxazocinophan[4,5-a]indolizine- 2(4,2)-thiazolo[6(l,3)-pyridazino]cycloundecapenta-5,7-dione hydrochloride 9r-1

[0629] Compound 9q-1 (6 mg, 8.2 μmol) was dissolved in dichloromethane (0.5 mL) and methanol (0.25 mL), 4 M hydrogen chloride in 1,4-dioxane (1 mL) was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure to give the crude title compound 9r-1 (6 mg), which was used directly in the next step without purification.

[0630] MS m / z (ESI): 752.7 [M+1] + .

[0631] Eighth step

[0632] M-(lr,2R,3S)-N-((l 5 S,6 3 S,4S,Z)-12-(3-(l,4-oxazocan-4-yl)prop-l-yn-l-yl)-l 5 ,10,10-trimethyl-5,7-dioxo-l 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-l 5 H-8-oxa-l(12,14)-pyrido[3',2':6,7][l,4]oxazocinophan[4,5-a]indolizine- 2(4,2)-thiazolo[6(l,3)-pyridazino]cycloundecapenta-5,7-dione hydrochloride 9r-1

[0633] The crude compound 9r-1 (6 mg, 7.6 μmol) was dissolved in N,N- dimethylformamide (2 mL), N,N-diisopropylethylamine (4 mg, 20.9 μmol) was added, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (49 mg, 489.4 μmol) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino- morpholinio-carbenium hexafluorophosphate (1.5 mg, 13.1 μmol) were added at 0 °C, the reaction was stirred for 2 hours. Purification was performed by high performance liquid chromatography-preparative (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% - 60%, flow rate: 30 mL / min) to give the title compound (3 mg, yield: 44.3%).

[0634] MS m / z (ESI): 848.8 [M+1] + .

[0635] 1 H NMR (500 MHz, CD3OD): δ 8.77 (d, 1H), 8.60 (d, 1H), 7.98 (d, 1H), 7.75 (dd, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 5.67 (dd, 1H), 4.54 (dd, 1H), 4.47-4.44 (m, 1H), 4.33-4.26 (m, 2H), 4.18 (dd, 1H), 3.90-3.83 (m, 3H), 3.83-3.79 (m, 2H), 3.76 (s, 2H), 3.73-3.64 (m, 2H), 3.60 (d, 1H), 3.45 (d, 1H), 3.31-2.27 (m, 2H), 2.99-2.91 (m, 4H), 2.79 (td, 1H), 2.71 (d, 1H), 2.29-2.26 (m, 1H), 2.05-1.95 (m, 3H), 1.85 (dt, 1H), 1.62 (qd, 1H), 1.49 (d, 3H), 1.46-1.40 (m, 1H), 1.39-1.34 (m, 1H), 1.21-1.18 (m, 4H), 1.15 (d, 3H), 1.05 (s, 3H), 0.28 (s, 3H).

[0636] Scheme Two

[0637] First Step

[0638] 4-(prop-2-yn-1-yl)-1,4-oxazepane 9A-2

[0639] Dissolve 1,4-oxazepane 9A-1 (490 g, 4.84 mol, Shanghai Xinyuan) in dichloromethane (5000 mL), add triethylamine (735.3 g, 7.27 mol), the internal temperature is 10 °C, drop 2-propyn-1-ol methanesulfonic acid (779.9 g, 5.81 mol, Shanghai Bide), after adding, room temperature reaction for 16 hours. Add water (4000 mL) to the reaction solution, separate the layers, extract the aqueous phase with dichloromethane (3000 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 9A-2 (688 g). The product is used directly in the next step without purification.

[0640] MS m / z (ESI): 140.1 [M+1] + .

[0641] 1 H NMR (500 MHz, CDCl3) δ 3.79 (t, 2H), 3.74-3.7 (m, 2H), 3.38 (d, 2H), 2.78-2.71 (m, 4H), 2.21 (t, 1H), 1.94-1.86 (m, 2H).

[0642] Second step

[0643] 3-bromo-5-iodo-2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridine 9A-3

[0644] Dissolve the crude compound 1c (218 g, 660.2 mmol) in tetrahydrofuran (1100 mL), add 4,4'-di-tert-butyl-2,2'-bipyridine (26.6 g, 99.1 mmol), 1,5-cyclooctadiene iridium dichloride dimer (4.4 g, 6.6 mmol), bis(pinacolato)diboron (251.5 g, 990.4 mmol), after adding, replace with nitrogen for 3 times, rise to reflux reaction for 2 hours, cool the reaction solution to 0 °C, add water (1100 mL), tetrahydrofuran (1100 mL), then add chloramine T (601 g, 2.64 mol), sodium iodide (396 g, 2.64 mol), after adding, stir at room temperature for 30 minutes, rise to reflux reaction for 16 hours, cool the reaction solution to room temperature, filter with diatomite, add water to the filtrate, extract with ethyl acetate (3000 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system B to obtain the title compound 9A-3.

[0645] MS m / z (ESI): 455.5 [M+1] + .

[0646] Third step

[0647] 4-(3-(5-bromo-6-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)prop-2-yn-1-yl)-1,4-oxazepane 9A-4

[0648] Compound 9A-3 (163.8 g, 359.1 mmol), compound 9A-2 (60 g, 431.1 mmol) were dissolved in triethylamine (1000 mL), and dichlorobispalladiumtriphenylphosphine (12.6 g, 18 mmol), cuprous iodide (6.9 g, 36.2 mmol) were added. After addition, nitrogen was replaced for 3 times, and the reaction was carried out at room temperature for 4 hours. Water (2000 mL) and ethyl acetate (1000 mL) were added to the reaction solution, and the water phase was extracted with ethyl acetate (1000 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9A-4 (182.9 g). The product was directly used in the next reaction without purification.

[0649] MS m / z (ESI): 466.7 [M+1] + .

[0650] Fourth step

[0651] (S)-2-(1-(5-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-3-bromopyridin-2-yl)ethoxy)ethan-1-ol 9A-5

[0652] The crude compound 9A-4 (167.9 g, 359.1 mmol) was dissolved in dichloromethane (1250 mL), methanol (1250 mL), and p-toluenesulfonic acid monohydrate (205 g, 1.08 mol) was added at room temperature. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was added to water (1000 mL), dichloromethane (2000 mL), and the pH was adjusted to basic with saturated aqueous sodium bicarbonate solution. The water phase was extracted with dichloromethane (1000 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system I to obtain the title compound 9A-5.

[0653] MS m / z (ESI): 382.7 [M+1] + .

[0654] 1H NMR (500 MHz, CDC13) δ 8.56 (d, 1H), 7.83 (d, 1H), 4.97 (q, 1H), 3.77 (t, 2H), 3.74-3.67 (m, 3H), 3.63-3.56 (m, 4H), 3.37-3.31 (m, 1H), 2.82-2.75 (m, 4H), 1.94-1.87 (m, 2H), 1.44 (d, 3H).

[0655] Fifth step

[0656] ((6 3 S,4S,Z)-1 2 -(5-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-2-((S)-1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - hexahydro-1 1 H-8-oxa-2(4,2)-thiazol-1(5,3)-indol-6(1,3)-pyridazinacycloundecaphan-4-yl)carbamic acid tert-butyl ester 9A-7

[0657] Compound 9A-5 (95 g, 137 mmol), compound 9A-6 (51.5 g, 134 mmol, prepared by the method disclosed in Intermediate 3 on page 293 of the specification of patent application “WO2022060836”) were dissolved in dioxane (1000 mL), water (100 mL), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride (9.9 g, 13.5 mmol), potassium phosphate (71.5 g, 336.8 mmol) were added, replaced with nitrogen for 3 times, and the internal temperature was raised to 70 degrees for 1 hour. The reaction liquid was cooled to room temperature, poured into ice water, extracted with ethyl acetate (500 mL x 3), the combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9A-7 (123 g). The product was used directly in the next step without purification.

[0658] MS m / z (ESI): 870.6 [M+1] + .

[0659] Sixth step

[0660] M-((1 5 S,6 3(S, S)-12-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indolizine-2(4,2)-thiazol-6(1,3)- pyridazinocycloundecaphan-4-yl)carbamic acid tert-butyl ester 9q-1

[0661] The crude compound 9A-7 (123 g, 141.4 mmol) was dissolved in toluene (1950 mL), replaced with nitrogen for 3 times, and cyanomethylidene tri-n-butyl phosphonium (85.3 g, 353.4 mmol) was added. The reaction was raised to reflux for 90 minutes. The reaction was cooled to room temperature, poured into ice water, extracted with ethyl acetate (1000 mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system J to obtain the title compound 9q-1.

[0662] MS m / z (ESI): 852.5 [M+1] + .

[0663] The seventh and eighth steps were performed according to the seventeenth and eighteenth steps in Scheme One of Reference Example 9 to obtain the title product 9-1.

[0664] MS m / z (ESI): 848.8 [M+1] + .

[0665] 1H NMR (500 MHz, CD3OD): δ 8.74 (d, 1H), 8.59 (d, 1H), 7.94 (d, 1H), 7.72 (dd, 1H), 7.56 (s, 1H), 7.44 (d, 1H), 5.65 (dd, 1H), 4.50 (dd, 1H), 4.47-4.44 (m, 1H), 4.30-4.23 (m, 2H), 4.15 (dd, 1H), 3.87-3.80 (m, 3H), 3.8-3.76 (m, 2H), 3.73 (s, 2H), 3.70-3.61 (m, 2H), 3.57 (d, 1H), 3.42 (d, 1H), 3.28-2.24 (m, 2H), 2.96-2.88 (m, 4H), 2.77 (td, 1H), 2.69 (d, 1H), 2.27-2.24 (m, 1H), 2.04-1.93 (m, 3H), 1.83 (dt, 1H), 1.60 (qd, 1H), 1.47 (d, 3H), 1.46-1.40 (m, 1H), 1.38-1.33 (m, 1H), 1.20-1.17 (m, 4H), 1.12 (d, 3H), 1.02 (s, 3H), 0.25 (s, 3H).

[0666] Scheme Three

[0667] First Step

[0668] (S)-1-(3-bromopyridin-2-yl)ethan-1-ol 9B-2

[0669] Formic acid (276 g, 6.0 mol) was added to triethylamine (2.02 kg, 19.96 mol, 2.77 L) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene) ruthenium chloride (7.95 g, 12.50 mmol) was added under ice water bath at 0-5 °C, nitrogen was replaced for three times, heated to 40 °C for 15 minutes. Cooled to room temperature, compound 9B-1 (500 g, 2.50 mol, Shanghai Bide) was added, nitrogen was replaced for three times again, heated to 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water, saturated sodium chloride solution in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the title compound 9B-2 (yield: 95%~110%)

[0670] MS m / z (ESI): 201.8 [M+1] + .

[0671] Second Step

[0672] (S)-2-(1-(3-bromopyridin-2-yl)ethoxy)ethan-1-ol 9B-3

[0673] Compound 9B-2 (5 g, 24.746 mmol) was dissolved in solvent, potassium tert-butoxide (1 M, 37.00 mmol, 37 mL) was added at 0-5 °C, then ethylene sulfate (4.61 g, 37.14 mmol) in tetrahydrofuran (15 mL) was added, and the reaction was carried out at 0 °C for 30 min, potassium tert-butoxide (1 M, 3.70 mmol, 3.70 mL) and ethylene sulfate (0.46 g, 3.71 mmol) were added, and the reaction was carried out at room temperature for 2-3 h. The pH was adjusted to 2 with 12 N hydrochloric acid (concentrated hydrochloric acid), and the reaction was carried out at 65 °C for 0.5-1 h. Saturated sodium carbonate was added at ice bath to adjust the pH to 8, and the reaction was extracted with ethyl acetate three times and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7.59 g of a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title compound 9B-3 (yield: 70%-100%).

[0674] MS m / z (ESI): 245.8 [M+1] + .

[0675] Third step

[0676] 3-bromo-2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridine 9B-4

[0677] Compound 9B-3 (3.6 g, 14.63 mmol) and 3,4-dihydropyran (1.9 g, 22.59 mmol) were dissolved in solvent, and p-toluenesulfonic acid monohydrate (278 mg, 1.46 mmol) was added, and the reaction was carried out at room temperature to 70 °C for 30 min, and 2% or so was converted, 3,4-dihydropyran (1.23 g, 14.62 mmol) and p-toluenesulfonic acid monohydrate were added, and the reaction was carried out at room temperature for an appropriate period of time. The reaction solution was poured into saturated sodium bicarbonate solution, extracted with DCM twice, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 9B-4.

[0678] MS m / z (ESI): 329.8 [M+1] + .

[0679] Fourth step

[0680] 2,2-dimethyl-5-oxo-5-(2-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)pentanoic acid 9B-5

[0681] Compound 9B-4 (7 g, 21.20 mmol) was dissolved in tetrahydrofuran (70 mL) and stirred at -10 °C for 15 min. 1-2 eq of isopropylmagnesium chloride lithium chloride was added dropwise, and the mixture was stirred at -20 to -10 °C for 1 h. 2,2-Dimethylglutaric anhydride (3.16 g, 22.23 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise slowly. After the addition was completed, the mixture was stirred at -10 °C for 4 h. 2,2-Dimethylglutaric anhydride (0.6 g, 4.22 mmol) was added, and the mixture was stirred for another 1 h. The reaction solution was added to water (21 mL), and tetrahydrofuran was removed under reduced pressure. Acetic acid (3.5 mL) and water (80 mL) were added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system A to give the title compound 9B-5.

[0682] MS m / z (ESI): 393.9 [M+1] + .

[0683] Fifth step

[0684] (S)-3-(5-bromo-2-(2-(1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2- dimethylpropanoic acid 9B-6

[0685] Compound 9B-5 (274 mg, 696.36 μmol) and 1-2 eq of 4-bromophenylhydrazine hydrochloride, boron trifluoride etherate (300 mg, 2.11 mmol) were added to a solvent, and the mixture was stirred at 100 °C overnight. The reaction solution was cooled, and toluene was concentrated. Ethyl acetate and water were added, the aqueous phase was adjusted to pH 4-5, and the aqueous phase was back-extracted with ethyl acetate (3 x 30 mL). The organic phase was combined, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using eluent system B to give the title compound 9B-6.

[0686] MS m / z (ESI): 460.6 [M+1] + .

[0687] Sixth step

[0688] (S)-3-(5-bromo-2-(2-(1-(2-hydroxyethoxy)ethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2- dimethylpropanoic acid methyl ester 9B-7

[0689] Compound 9B-6 (64.9 g, 140.67 mmol), 0.5-1.5 equivalent of methanol and concentrated sulfuric acid (69 g, 703.52 mmol, 37.50 mL), external temperature 60 °C, stirring for 2 hours. The reaction solution was adjusted to pH 5-6 with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to obtain the title compound 9B-7 (yield: 80-100%). The product was used directly in the next step without purification.

[0690] MS m / z (ESI): 474.6 [M+1] + .

[0691] Seventh step

[0692] M-(S)-3-(12-bromo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5- a]indol-14-yl)-2,2-dimethylpropanoic acid methyl ester 9B-8

[0693] The crude compound 9B-7 (66.8 g, 140.67 mmol) was dissolved in tetrahydrofuran (1000 mL), and the solution was clarified at room temperature. Triphenylphosphine (55.3 g, 210.84 mmol) was added, and diisopropyl azodicarboxylate (42.7 g, 211.17 mmol) was added dropwise at an internal temperature of 0-10 °C. After the dropwise addition was completed, the mixture was allowed to naturally warm to room temperature, and stirring was performed at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using eluent system A to obtain the product. The product was slurried in 42 mL of methyl tert-butyl ether at room temperature overnight, filtered, and dried under vacuum to obtain the title compound 9B-8 (47 g, yield: 73.0%).

[0694] MS m / z (ESI): 456.7 [M+1] + .

[0695] 1 H NMR (500 MHz, CDCl3) δ 8.80 (dd, 1H), 7.78 (dd, 2H), 7.39 (dd, 1H), 7.34 (dd, 1H), 7.17 (d, 1H), 4.32-4.16 (m, 3H), 3.84 (dd, 1H), 3.71 (dd, 1H), 3.38 (s, 3H), 3.20-3.08 (m, 2H), 1.61 (d, 3H), 0.97 (d, 6H).

[0696] Eighth step

[0697] M-(S)-3-(12-bromo-2-iodo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5- a]indol-14-yl)-2,2-dimethylpropionic acid methyl ester 9B-9

[0698] Compound 9B-8 (10 g, 21.86 mmol), bis(pinacolato)diboron (8.32 g, 32.76 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (880 mg, 3.28 mmol) were added into tetrahydrofuran (50 mL), then bis(1,5-cyclooctadiene)iron(I) dimer (44 mg, 65.51 μmol) was added, and the mixture was stirred at 82 °C for 1 h under nitrogen atmosphere. The reaction solution was cooled to 0-10 °C, and water (50 mL) and tetrahydrofuran (50 mL) were added dropwise. Chloramine T (30 g, 131.79 mmol) and sodium iodide (20 g, 133.43 mmol) were added at room temperature, and the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. Chloramine T (5 g, 21.97 mmol) and sodium iodide (3.4 g, 22.68 mmol) were added, and the stirring was continued for 1 h. The reaction solution was cooled to room temperature, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 9B-9 (8.37 g, yield: 65.6%).

[0699] MS m / z (ESI): 582.4 [M+1] + .

[0700] Ninth step

[0701] M-(S)-3-(2-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-12-bromo-5-methyl-7,8-dihydro-5H- pyrido[3',2',6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropionic acid methyl ester 9B-10

[0702] Compound 9B-9 (12 g, 20.57 mmol), compound 9A-2 (3.5 g, 25.14 mmol), dichlorobis(triphenylphosphine)palladium (722 mg, 1.03 mmol), and cuprous iodide (392 mg, 2.06 mmol) were sequentially added to a solvent of triethylamine (72 mL), and stirred at 25 °C under an atmosphere of nitrogen for 5 hours. Dichlorobis(triphenylphosphine)palladium (361 mg, 0.56 mmol) and cuprous iodide (200 mg, 1.05 mmol) were added, and the mixture was further stirred at 40 °C for 2 hours. Water (75 mL) was added, and the mixture was extracted twice with ethyl acetate (75 mL). The organic phase was combined, washed with water (75 mL), saturated brine (75 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel using eluent system A to obtain the title compound 9B-10 (11 g, yield: 89.9%).

[0703] MS m / z (ESI): 593.6 [M+1] + .

[0704] Tenth step

[0705] (S)-3-(2-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-12-bromo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropan-1-ol 9B-11

[0706] Compound 9B-10 (11 g, 18.50 mmol) was dissolved in tetrahydrofuran (220 mL), and diisopropylaluminum hydride (1 M, 55.52 mmol, 55.52 mL) was added dropwise at an internal temperature of -70 °C. After the dropwise addition, the mixture was stirred at -70 °C for 30 minutes, and then allowed to warm to room temperature. The reaction solution was cooled to 0-5 °C, quenched with a saturated potassium sodium tartrate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system B to obtain the title compound 9B-11 (10.4 g, yield: 99.2%).

[0707] MS m / z (ESI): 565.6 [M+1] + .

[0708] Eleventh step

[0709] (S)-1-((S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester dihydrochloride 9B-12

[0710] Compound 9j (15 g, 31.42 mmol) was dissolved in methanol (60 mL), 4M hydrochloric acid solution in dioxane (50 mL) was added dropwise under ice bath, and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 9B-12 (yield: 100%~120%), which was used in the next step without purification.

[0711] MS m / z (ESI): 376.7 [M+1] + .

[0712] Twelfth step

[0713] (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1- carboxamido)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester 9B-13

[0714] The crude compound 9B-12 (14.15 g, 31.43 mmol) was dissolved in dichloromethane (210 mL), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (4.67 g, 40.91 mmol), 1-hydroxybenzotriazole (114 mg, 0.75 mmol), N-methylmorpholine (12.8 g, 126.55 mmol) were added, and stirred at 0~5°C for 5 minutes. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.9 g, 57.04 mmol) was added, and stirred at 0~5°C for 17 hours. The reaction solution was diluted with water, extracted with dichloromethane (2 x 200 mL) twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the title compound 9B-13 (12.2 g, yield: 82%) using eluent system A.

[0715] MS m / z (ESI): 472.6 [M+1] + .

[0716] Thirteenth step

[0717] (S)-1-((S)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester 9B-14

[0718] Compound 9B-13 (6 g, 12.68 mmol), bis(pinacolato)diboron (6.4 g, 25.20 mmol), 1,4-dioxane (120 mL), potassium acetate (5 g, 50.9464 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.42 g, 5.0764 mmol), and tris(dibenzylideneacetone)dipalladium (1.16 g, 1.27 mmol) were stirred at 110°C for 3 hours under nitrogen atmosphere. The reaction solution was directly filtered, the filter cake was washed with a small amount of 1,4-dioxane, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9B-14 (yield: 99.3-100%). The product was used directly in the next reaction without purification.

[0719] MS m / z (ESI): 438.8 [M+1] + .

[0720] Fourteenth step

[0721] M-(S)-1-((R)-3-(4-((S)-2-(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-14-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indol-12-yl)thiazol-2-yl)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 9B-15

[0722] The crude compound 9B-11 (2 g, 3.53 mmol), compound 9B-14 (1.93 g, 3.71 mmol), water (8 mL), 1,4-dioxane (40 mL), potassium carbonate (1.46 g, 10.56 mmol), and [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium(II) (120 mg, 176.16 µmol) were stirred at 77°C (65-70°C inside) for 2 hours under nitrogen replacement for 3 times. The reaction solution was cooled to room temperature, 1,4-dioxane was concentrated, EA and water were added, the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography eluted with eluent system B to obtain the title compound 9B-15 (3.1 g, yield: 99.8%).

[0723] MS m / z (ESI): 880.5 [M+1] + .

[0724] Fifteenth step

[0725] M-(S)-1-((R)-3-(4-((S)-2-(3-(1,4-oxazacyclohep-4-yl)prop-1-yn-1-yl)-14-(3-hydroxy-2,2-dimethylpropyl)-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indol-12-yl)thiazo-2-yl)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)propionyl)hexahydropyridazine-3-carboxylic acid 9B-16

[0726] Compound 9B-15 (3.1 g, 3.52 mmol) was dissolved in methanol (23 mL) and allowed to dissolve completely at room temperature. The internal temperature was then lowered to 0–5 °C. Lithium hydroxide monohydrate (222 mg, 5.29 mmol) was dissolved in water (15 mL) and slowly added dropwise. After the addition was complete, the mixture was kept at 0–5 °C with stirring overnight. The reaction solution was transferred to room temperature, and 10 mL of methanol was added. The mixture was stirred at room temperature for 2 hours. The methanol in the reaction solution was concentrated under reduced pressure at 10–15 °C. The pH was adjusted to 3–4 with 1N dilute hydrochloric acid. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and dried under vacuum at room temperature for 24 hours to obtain the title compound 9B-16 (3.05 g, yield: 99.9%).

[0727] MS m / z (ESI): 866.5 [M+1] + .

[0728] Step Sixteen

[0729] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazapyrocyclohep-4-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido

[0730] [3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazinazacycloundecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 9-1

[0731] 1-Hydroxybenzotriazole (1.9 g, 14.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.05 g, 21.13 mmol), 4-dimethylaminopyridine (431 mg, 3.53 mmol), and N,N-diisopropylethylamine (1.82 g, 14.08 mmol) were added to dichloromethane (90 mL) and dissolved at room temperature. Compound 9B-16 (3.05 g, 3.52 mmol) was dissolved in dichloromethane (30 mL) and slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 9-1 (1.38 g, yield: 46.0%).

[0732] MS m / z (ESI): 848.4 [M+1] + .

[0733] 1 H NMR(500MHz, CDCl3)δ8.82(d,1H),8.65(d,1H),7.84(d,1H),7.65(dd,1H),7.32(s,1H),7.26(s,1H),6.39(d,1H),5.90(t ,1H),4.62(d,1H),4.42–4.33(m,2H),4.30(q,1H),4.22(dd,1H),4.00(d,1H),3.95–3.81(m,7H),3.81–3.70(m,2H),3.66( d,1H),3.47(d,1H),3.33(d,1H),3.14(dd,1H),2.95(s,4H),2.69(td,2H),2.33–2.24(m,1H),2.00(d,2H),1.93–1.78(m, 1H),1.62(qd,3H),1.54(d,4H),1.50–1.43(m,1H),1.31–1.26(m,1H),1.18(d,3H),1.12(d,3H),1.03(s,3H),0.92(t,1H).

[0734] Example 10

[0735] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,1-Thiomorpholine)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-17 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido

[0736] [3',2':6,7][1,4]Oxaazaoctylcyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazinazacycloundecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 10-1

[0737] Using steps sixteen to eighteen of the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with the compound thiomorpholine-1,1-dioxide (Shanghai Bide) to obtain the title compound (16 mg, yield: 40.7%).

[0738] MS m / z (ESI): 882.7 [M+1] + .

[0739] 1 H NMR (500MHz, DMSO-d6): δ8.80(d,1H),8.54(d,1H),8.43(d,1H),8.00(d,1H),7.85(s,1H),7.78(dd,1H),7.60(d,1H),5.51( t,1H),5.03(d,1H),4.57(dd,1H),4.31(q,1H),4.26-4.21(m,2H),4.08(dd,1H),3.80-3.75(m,3H),3.61(dd,1H),3.53-3.4 7(m,2H),3.22-3.10(m,5H),3.07-3.04(m,3H),2.77-2.72(m,1H),2.62(d,1H),2.14(d,1H),1.85-1.78(m,2H),1.56-1.48( m,1H),1.38(d,3H),1.29(t,2H),1.21-1.14(m,3H),1.11(d,3H),1.08(d,3H),1.05-1.01(m,1H),0.98(s,3H),0.18(s,3H).

[0740] Example 11

[0741] M-(1r,2R,3S)-N-((1 5S,6 3 S,4S,Z)-12-(3-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctane[4]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine-hexacyclic undecano-4-yl)-2-dimethylcyclopropane-1-carboxamide 11-1

[0742] Using the synthetic route in Scheme 1 of Example 9, the starting material 1,4-oxazacycloheptane in step sixteen was replaced with compound 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (Shanghai Bide) to obtain the title compound (19.5 mg, yield: 78.7%).

[0743] MS m / z(ESI): 861.1 [M+1] + .

[0744] 1H NMR (500MHz, CD3OD): δ8.78-8.77(m,1H),8.62-8.61(m,1H),8.01-8.00(m,1H),7.76-7.74(m,1H),7.59(s,1H),7.48-7.46(m,1H),5.6 9-5.66(m,1H),4.60-4.52(m,2H),4.47-4.45(m,1H),4.31-4.28(m,2H),4.19-4.16(m,1H),3.88-3.84(m,1H),3.78-3.76(m,2H),3.71 -3.66(m,2H),3.63-3.56(m,5H),3.47-3.45(m,3H),3.31-3.27(m,2H),2.81-2.76(m,1H),2.73-2.70(m,1H),2.29-2.26(m,1H),2.10- 2.03(m,3H),2.00-1.97(m,3H),1.90-1.82(m,1H),1.67-1.58(m,2H),1.49-1.48(m,3H),1.20-1.14(m,6H),1.05(s,3H),0.28(s,3H).

[0745] Example 12

[0746] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-12-(3-(4-oxa-7-azaspiro[2.5]oct-7-yl)prop-1-ynyl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctane[4-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 12-1

[0747] Using the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with compound 4-oxa-7-azaspiro[2.5]octane hydrochloride (Shanghai Bide) to obtain the title compound (8 mg, yield: 24.5%).

[0748] MS m / z (ESI): 860.9 [M+1] + .

[0749] 1 H NMR (500MHz, CD3OD): δ8.77(d,1H),8.61(d,1H),8.00(d,1H),7.75(dd,1H),7.59(s,1H),7.47(d,1H),5.67(d,1H),4.54(dd,1H),4. 46(dd,1H),4.33-4.27(m,2H),4.18(dd,1H),3.90-3.86(m,1H),3.86-3.80(m,2H),3.74-3.64(m,4H),3.61(d,1H),3.46(d,1H),3.31 -3.26(m,2H),2.84-2.75(m,3H),2.74-2.70(m,3H),2.29-2.27(m,1H),2.02-1.96(m,1H),1.86(qt,1H),1.63(qd,1H),1.49(d,3H),1 .45-1.40(m,1H),1.40-1.34(m,1H),1.21-1.18(m,4H),1.15(d,3H),1.05(s,3H),0.81-0.78(m,2H),0.67–0.60(m,2H),0.28(s,3H).

[0750] Example 13

[0751] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-Trimethyl-12-(3-((R)-3-methylmorpholino)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctano[4-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 13-1

[0752] Using the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with compound (R)-3-methylmorpholine (Shanghai Shaoyuan) to obtain the title compound (1.5 mg, yield: 14.8%).

[0753] MS m / z(ESI): 849.0 [M+1] + .

[0754] 1 H NMR (500MHz, CD3OD): δ8.82(d,1H),8.62(s,1H),8.55(d,1H),8.05(d,1H),7.76(d,1H),7.60(s,1H),7.48(d, 1H),5.68(t,1H),5.36(t,1H),4.61–4.41(m,2H),4.32–4.26(m,2H),4.19(dd,2H),3.99(s,1H),3.87(dd,2H), 3.82–3.67(m,3H),3.61(d,1H),3.51–3.43(m,2H),2.84–2.60(m,2H),2.35–2.17(m,2H),2.11–1.97(m,2H),1. 86(d,1H),1.64(dt,2H),1.50(d,3H),1.45–1.35(m,6H),1.17(dd,7H),1.05(s,3H),0.92(t,2H),0.29(s,2H).

[0755] Example 14

[0756] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-15 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 14-1

[0757] Using the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with the compound azacyclobutane (Shanghai Shaoyuan) to obtain the title compound (5.2 mg, yield: 38.1%).

[0758] MS m / z(ESI): 805.0 [M+1] + .

[0759] 1 H NMR (500MHz, CD3OD): δ8.80-8.79(m,1H),8.62-8.61(m,1H),8.02-8.01(m,1H),7.76-7.74(m,1H),7.59(s,1H),7.48-7.46(m,1H), 5.68-5.67(m,1H),4.60(s,1H),4.56-4.52(m,1H),4.47-4.45(m,1H),4.32-4.28(m,2H),4.20-4.16(m,1H),3.89-3.84(m,2H),3.77 (s,2H),3.72-3.66(m,5H),3.61-3.59(m,1H),3.47-3.44(m,2H),2.81-2.76(m,1H),2.73-2.67(m,1H),2.29-2.24(m,3H),2.07-2. 03(m,1H),1.99-1.95(m,1H),1.90-1.82(m,2H),1.67-1.59(m,2H),1.49-1.48(m,3H),1.20-1.14(m,6H),1.05(s,3H),0.28(s,3H).

[0760] Example 15

[0761] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-12-(1-amino-1-oxo-1λ) 6 -Thiomorpholine-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 61 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 15-1

[0762] first step

[0763] (S)-3-(2-(1-(((benzyloxy)carbonyl)aminoyl)-1-oxid-1λ 6 -Thiomorpholine)-12-bromo-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazaoctylcyclo[4,5-a]indol-14-yl)-2,2-dimethylpropylacetate 15a

[0764] Compound 9h (200 mg, 334.8 μmol), (1-thiomorpholine-1-yl)carbamate (99 mg, 368.3 μmol, Shanghai Leyan), cesium carbonate (273 mg, 837.1 μmol), palladium acetate (8 mg, 33.4 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (10 mg, 16.7 μmol) were dissolved in toluene (15 mL). The reaction mixture was heated to 100 °C for 16 hours under a nitrogen atmosphere. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 15a (196 mg, yield: 79.3%).

[0765] MS m / z(ESI): 737.7 [M+1] + .

[0766] Step 2

[0767] M-(4-((1 5 S,6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 63 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine heterocyclic undecaban-12-yl))-1-oxo-1λ 6 15b-1-thiomorpholine-1-yl)benzyl carbamate

[0768] Using steps thirteen to sixteen of the synthetic route in Example 1, the starting compound 1m in step thirteen was replaced with compound 15a to obtain title compound 15b-1 (21 mg, yield: 25.4%).

[0769] MS m / z(ESI): 982.1 [M+1] + .

[0770] Step 3

[0771] M-(4-((1 5 S,6 3 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-formamido)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine-hexacyclic undecaban-12-yl)-1-oxo-1λ 6 15c-1-thiomorpholine-1-yl)benzyl carbamate

[0772] Using steps 18 to 19 of the synthetic route in Example 1, the starting compound 1r-1 in step 18 was replaced with compound 15b-1 to obtain the title compound 15c-1 (15 mg, yield: 71.7%).

[0773] MS m / z(ESI): 978.0 [M+1] + .

[0774] Step 4

[0775] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-12-(1-amino-1-oxo-1λ) 6 -Thiomorpholine-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 15-1

[0776] Compound 15b-1 (15 mg, 15.3 μmol) was dissolved in tetrahydrofuran (2 mL), and palladium hydroxide on carbon (wet) (15 mg) was added. The mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound (3 mg, yield: 23.1%).

[0777] MS m / z(ESI): 844.0 [M+1] + .

[0778] 1H NMR (500 MHz, CD3OD): δ: 8.60 (d, 1H), 8.52-8.49 (m, 1H), 7.76-7.72 (m, 1H), 7.61-7.57 (m, 2H), 7.49-7.45 (m, 2H), 5.70-5.66 (m, 1H), 4.53-4.44 (m, 3H), 4.33-4.08 (m, 6H), 3.91-3.60 (m, 9H), 2.84-2.75 (m, 2H), 2.31-2.18 (m, 4H), 2.09-1.97 (m, 4H), 1.67-1.60 (m, 4H), 1.50-1.46 (m, 2H), 1.20-1.14 (m, 4H), 1.07-1.03 (m, 2H), 0.95-0.89 (m, 3H), 0.33-0.28 (m, 3H).

[0779] Example 16

[0780] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-((1-ethylazetidin-3-yl)methyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazolo[6(1,3)-pyridazino]cycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 16-1

[0781] First step

[0782] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(azetidin-3-ylmethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,63 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-16a-1)-undecano-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 2,2,2-trifluoroacetate 16a-1

[0783] Compound 5e-1 (36 mg, 37.3 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 16a-1 (36 mg). The product was used directly in the next reaction without purification.

[0784] MS m / z (ESI): 865.2 [M+1] + .

[0785] Step 2

[0786] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-((1-ethylazacyclobutane-3-yl)methyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 16-1

[0787] The crude compound 16a-1 (36.8 mg, 36.8 μmol) was dissolved in tetrahydrofuran (2 mL), acetaldehyde (16.2 mg, 368 μmol), sodium triacetoxyborohydride (23.4 mg, 110.4 μmol) were added, and the reaction was stirred for 2 hours. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography preparation chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% to 60%, flow rate: 30 mL / min) to obtain the title compound (3 mg, yield: 9.1%).

[0788] MS m / z (ESI): 893.3 [M+1] + .

[0789] 1 H NMR (500 MHz, CD3OD): δ 8.59 (d, 1H), 8.40 (d, 1H), 7.73 (dd, 1H), 7.58 (s, 1H), 7.49-7.42 (m, 2H), 5.72-5.64 (m, 1H), 5.36 (t, 1H), 4.54-4.46 (m, 2H), 4.35-4.26 (m, 1H), 4.23-4.12 (m, 2H), 3.83 (dd, 1H), 3.74-3.66 (m, 2H), 3.61 (d, 2H), 3.48-3.43 (m, 1H), 3.41-3.37 (m, 2H), 3.27 (s, 2H), 3.19 (p, 1H), 3.02 (s, 2H), 2.86-2.73 (m, 3H), 2.72-2.64 (m, 6H), 2.60 (d, 2H), 2.28 (d, 1H), 2.22 (d, 1H), 2.05 (d, 2H), 1.99 (d, 1H), 1.93-1.81 (m, 1H), 1.62 (t, 2H), 1.47 (d, 3H), 1.19 (d, 3H), 1.15 (d, 2H), 1.05 (s, 3H), 1.01 (d, 2H), 0.92 (t, 2H), 0.30 (s, 3H).

[0790] Example 17

[0791] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-((1-(methoxymethyl)cyclobutyl)methyl)piperazin-1-yl)-15 10,10-dimethyl-5,7-dioxo-1 7 1 8 6 1 6 2 6 3 6 4 6 5 6 6 - octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)-thiazolo-6(1,3)- pyridazino-cyclotridecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-1

[0792] First step

[0793] tert-butyl(1-(methoxymethyl)cyclobutyl)methoxy)diphenylsilane 17b

[0794] tert-Butyl(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol 17a (5 g, 14.10 mmol, prepared using the method disclosed in the literature “Chinese Chemical Letters, 2021, vol. 32, #1, p. 1-4”) was dissolved in tetrahydrofuran (25 mL), sodium hydride (1.7 g, 42.50 mmol, 60% purity) was added portionwise under ice bath, after 30 minutes of stirring at temperature, iodomethane (4 g, 28.18 mmol) was added dropwise, the reaction was stirred at room temperature for 16 hours. The reaction solution was quenched with ice water, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 17b (4.1 g, yield: 78.8%)

[0795] Second step

[0796] (1-(Methoxymethyl)cyclobutyl)methanol 17c

[0797] Compound 17b (500 mg, 1.35 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride solution in tetrahydrofuran (5 mL) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 17c (170 mg). The product was used directly in the next step without purification.

[0798] MS m / z (ESI): 131.1 [M+1]+ .

[0799] Third step

[0800] 1-(Methoxymethyl)cyclobutane-1-carbaldehyde 17d

[0801] The crude compound 17c (170 mg, 1.30 mmol) was dissolved in dichloromethane (10 mL), 1 Dess-Martin Oxidizer (1.1 g, 2.59 mmol) was added, the reaction was stirred for 2 hours, the reaction solution was filtered, water was added to the filtrate, extracted with dichloromethane (10 mL x 3), the combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 17d (160 mg). The product was used directly in the next step without purification.

[0802] Fourth step

[0803] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-((1-(Methoxymethyl)cyclobutyl)methyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)-thiazol-6(1,3)- pyridazinocycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 17-1

[0804] The title compound (4 mg, yield: 17.5%) was prepared by using the synthetic route in Example 2, second to fourth steps, replacing the second step raw material oxetan-3-carbaldehyde with 17d.

[0805] MS m / z (ESI): 907.8 [M+1] + .

[0806] 1H NMR (500 MHz, CD3OD): δ 8.58 (d, 1H), 8.35 (d, 1H), 7.73-7.67 (m, 1H), 7.55 (s, 1H), 7.45-7.34 (m, 2H), 5.65 (d, 2H), 4.77-4.73 (m, 1H), 4.58 (s, 1H), 4.52-4.38 (m, 2H), 4.33-4.21 (m, 1H), 4.21-4.06 (m, 2H), 3.85-3.74 (m, 1H), 3.71-3.62 (m, 2H), 3.61-3.55 (m, 1H), 3.50 (s, 2H), 3.45-3.49 (m, 1H), 3.38 (s, 3H), 3.29-3.20 (m, 4H), 2.81-2.68 (m, 2H), 2.61 (t, 3H), 2.47 (s, 2H), 2.29-2.18 (m, 1H), 2.04-1.91 (m, 2H), 1.92-1.74 (m, 4H), 1.66-1.54 (m, 1H), 1.48-1.26 (m, 8H), 1.20-1.09 (m, 6H), 1.02 (s, 3H), 0.27 (s, 3H).

[0807] Example 18

[0808] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(oxetan-3-ylmethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-oxa-6 2 ,6 3 -azepin-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 18-1

[0809] The title compound was prepared by following the synthetic route in Example 2, Steps one to four, replacing the first step starting compound 1q-1 with compound 19d-1.

[0810] MS m / z (ESI): 877.4 [M+1] + .

[0811] Example 19

[0812] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-(oxecyclobutane-3-yl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 19-1

[0813] first step

[0814] (S)-2-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester 19c

[0815] Methyl bis(2,2,2-trifluoroacetic acid) salt of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 19b (9.6 g, 24.99 mmol, prepared by the method disclosed in Reference Example 8 on page 64 of patent application "WO2024067857") was dissolved in dichloromethane (300 mL), and (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid 19a (9.42 g) was added. 26.81 mmol (prepared by the method disclosed in Reference Example 1 on page 57 of patent application "WO2024067857"), N-methylmorpholine (25.27 g, 249.85 mmol) was added at 0 °C, followed by the addition of 1-hydroxybenzotriazole (761 mg, 5 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.58 g, 49.97 mmol), and the reaction was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 19c (7.4 g, yield: 61.1%).

[0816] MS m / z(ESI): 489.2 [M+1] + .

[0817] Step 2

[0818] M-4-((1 5 S,6 4 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecabanone-1 2 19d-1-yl)piperazine-1-carboxylic acid benzyl ester

[0819] Using steps fourteen to sixteen of the synthetic route in Example 1, the starting compound (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester in step fourteen was replaced with compound 19c to obtain title compound 19d-1 (80 mg, yield: 8.2%).

[0820] MS m / z (ESI): 945.5 [M+1] + .

[0821] Step 3

[0822] M-(1r,2R,3S)-N-((1 5 S,6 4 S,4S,Z)-1 2 -(4-(oxecyclobutane-3-yl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 19-1

[0823] Using steps one through four of the synthetic route in Example 2, the starting material 1q-1 in the first step was replaced with compound 19d-1, and oxetane-3-carboxaldehyde in the second step was replaced with 3-oxetane-3-ketone (Shanghai Shaoyuan) to obtain the title compound (15 mg, yield: 30.6%).

[0824] MS m / z (ESI): 863.4 [M+1] + .

[0825] 1 H NMR (500MHz, CD3OD): δ8.47(d,1H),8.41(d,1H),7.72(dd,1H),7.59(s,1H),7.48–7.32(m,2H),5.90(d,1H),5.45(dd, 1H),4.84–4.72(m,4H),4.71–4.62(m,3H),4.60(s,2H),4.51(dd,1H),4.31–4.10(m,2H),3.84(dd,1H),3.71(dd,1H), 3.65–3.49(m,3H),3.50–3.36(m,4H),3.32–3.22(m,2H),2.85–2.71(m,2H),2.65(ddd,1H),2.59(t,3H),2.48(dt,1H) ,2.19(dd,1H),1.71(t,1H),1.48(s,3H),1.39–1.30(m,4H),1.23–1.19(m,3H),1.16(d,3H),1.03(s,2H),0.30(s,2H).

[0826] Example 20

[0827] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-12-(3-(2-oxa-6-azaspiro[3.3]hept-6-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-l(12,14)-pyrido[3',2':6,7][l,4]oxazocin[4,5-a]indolizine-2(4,2)- thiazol[6(l,3)-pyridazinyl] -4-yl)-2,3-dimethylcyclopropane-l-carboxamide 20-1

[0828] The title compound was prepared according to the procedure described in Example 9, Scheme 1, using 2-oxa-6-azaspiro[3.3]heptane hemi oxalate salt (Nanjing Yaguoshi) as the starting material in place of 1,4-oxazepane. (2.5 mg, yield: 17%).

[0829] MS m / z (ESI): 847.0 [M+1] + .

[0830] 1 H NMR (500 MHz, CD3OD): δ 8.76 (d, 1H), 8.61 (s, 1H), 7.98 (d, 1H), 7.82-7.69 (m, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 5.68 (d, 1H), 5.36 (t, 1H), 4.78 (s, 4H), 4.60 (s, 2H), 4.54 (dd, 1H), 4.46 (d, 1H), 4.32-4.28 (m, 2H), 4.18 (dd, 1H), 3.86 (dd, 1H), 3.72-3.53 (m, 10H), 3.46 (d, 1H), 2.82-2.75 (m, 1H), 2.71 (d, 1H), 2.31-2.24 (m, 1H), 2.21 (t, 1H), 2.05 (q, 1H), 1.98 (d, 1H), 1.93-1.80 (m, 1H), 1.49 (d, 3H), 1.20-1.15 (m, 6H), 1.05 (s, 3H), 0.92 (t, 2H), 0.27 (s, 3H).

[0831] Example 21

[0832] M-(lr,2R,3S)-N-((l 5 S,6 3 S,4S,Z)-12-(2-(l,4-oxazepan-4-yl)ethoxy)-l 5 ,10,10-trimethyl-5,7-dioxo-l 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,66 - Octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)- thiazol[6(1,3)-pyridazinocycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 21-1

[0833] First step

[0834] (S)-3-(12-bromo-2-hydroxy-5-methyl-7,8-dihydro-5H-pyrido[3',2':6,7][1,4]oxazocino[4,5- a]indol-14-yl)-2,2-dimethylpropyl acetate 21a

[0835] Compound 9g (8.62 g, 14.43 mmol) was dissolved in acetonitrile (85 mL), and hydrogen peroxide (4.1 g, 36.16 mmol, 30% purity) was added dropwise at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was quenched by adding saturated sodium sulfite solution, and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 21a (8.2 g). The product was used directly in the next step without purification.

[0836] MS m / z (ESI): 487.5 [M+1] + .

[0837] Second step

[0838] 3-((5S)-12-bromo-5-methyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-7,8-dihydro-5H- pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropyl acetate 21b

[0839] The crude compound 21a (900 mg, 1.85 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (511 mg, 3.70 mmol) was added. After stirring for 10 min, 2-(2-bromoethoxy)tetrahydro-2H-pyran (773 mg, 3.70 mmol, Shanghai Leyuan) was added, and the mixture was stirred at 60 °C for 16 h. The reaction was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system B to give the title compound 21b (230 mg, yield: 20.2%).

[0840] MS m / z (ESI): 615.6 [M+1] + .

[0841] Step 3

[0842] M-((1 5 S,6 3 S,4S,Z)-1 5 10,10-Trimethyl-5,7-dioxo-12-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)pyridazine-hexacyclic undecapan-4-yl) tert-butyl carbamate 21c-1

[0843] Using steps thirteen to sixteen of the synthetic route in Example 1, the starting compound 1m in step thirteen was replaced with compound 21b to obtain title compound 21c-1 (130 mg, yield: 46.5%).

[0844] MS m / z (ESI): 859.8 [M+1] + .

[0845] Step 4

[0846] M-2-(((1 5 S,6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 5 10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecano-12-yl)oxy)ethyl methanesulfonate 21d-1

[0847] Using the synthetic route in the scheme one of Example 9, Steps fourteen to fifteen, replacing the starting material compound 9n-1 in Step fourteen with compound 21c-1 to produce the crude title compound 21d-1 (130 mg) was prepared.

[0848] MS m / z (ESI): 853.7 [M+1] + .

[0849] Fifth step

[0850] M-((1 5 S,6 3 S,4S,Z)-12-(2-(1,4-oxazepan-4-yl)ethoxy)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indolizine-2(4,2)-thiazol[3,2- e]pyridazinocycloundecaphan-4-yl)carbamic acid tert-butyl ester 21e-1

[0851] Compound 21d-1 (30 mg, 35.2 μmol) was dissolved in acetonitrile (1 mL), 1,4-oxazepane (11 mg, 108.7 μmol), potassium carbonate (14 mg, 101.3 μmol), sodium iodide (10 mg, 66.7 μmol) were added, stirred at 60 °C for 16 hours, the reaction solution was reduced to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 21e-1 (30 mg, yield: 99.4%).

[0852] MS m / z (ESI): 858.9 [M+1] + .

[0853] Sixth step

[0854] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-12-(2-(1,4-oxazepan-4-yl)ethoxy)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,61 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 21-1

[0855] Using steps 18 to 19 of the synthetic route in Example 1, the title compound (10 mg, yield: 32.8%) was obtained by replacing the starting compound 1r-1 in step 18 with compound 21e-1.

[0856] MS m / z (ESI): 855.1 [M+1] + .

[0857] 1 H NMR (500MHz, CD3OD): δ8.61(d,1H),8.43(d,1H),7.74(dd,1H),7.58(s,1H),7.52(d,1H),7.46(d,1H),5.71-5.62(m,1 H),4.79(d,1H),4.56-4.41(m,2H),4.33-4.27(m,3H),4.24(q,1H),4.16(dd,1H),3.92-3.75(m,5H),3.75-3.63(m,2H ),3.61(d,1H),3.46(d,1H),3.07(t,2H),2.97-2.85(m,4H),2.85-2.72(m,1H),2.28(dd,1H),2.00-1.92(m,2H),1.89 -1.78(m,1H),1.67-1.57(m,1H),1.48(d,3H),1.44-1.28(m,6H),1.19(d,3H),1.15(d,3H),1.05(s,3H),0.30(s,3H).

[0858] Example 22

[0859] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(4-((3-ethyloxetane-3-yl)methyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-17 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazolo[1,3]-pyridazino[6,1-cd]cyclopenta[2,1-b]pyrrol-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 22-1

[0860] The crude compound 5c-1 (20 mg, 25.1 μmol) was dissolved in tetrahydrofuran (0.5 mL), 3-ethyloxetane-3-carboxaldehyde (28 mg, 249.6 μmol, Shanghai Leyue) and sodium triacetoxyborohydride (16 mg, 75.5 μmol) were added, and the reaction was stirred for 2 hours. A small amount of water was added to quench the reaction, and the mixture was filtered. The filtrate was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% - 60%, flow rate: 30 mL / min) to give the title compound (2.8 mg, yield: 12.4%).

[0861] MS m / z (ESI): 893.9 [M+1] + .

[0862] 1H NMR (500 MHz, CD3OD): δ 8.60 (s, 1H), 8.39 (d, 1H), 7.73 (d, 1H), 7.58 (s, 1H), 7.48-7.41 (m, 2H), 5.67 (dd, 1H), 5.36 (dd, 1H), 4.59 (d, 5H), 4.53-4.44 (m, 2H), 4.37 (d, 2H), 4.30 (dd, 1H), 4.24-4.11 (m, 2H), 3.83 (dd, 1H), 3.74-3.65 (m, 3H), 3.61 (d, 1H), 3.50-3.43 (m, 1H), 2.90-2.74 (m, 2H), 2.67 (s, 2H), 2.60 (t, 3H), 2.33-2.17 (m, 3H), 2.08-1.95 (m, 3H), 1.92-1.79 (m, 1H), 1.69-1.57 (m, 2H), 1.47 (d, 5H), 1.44-1.40 (m, 2H), 1.17 (dd, 5H), 1.05 (t, 3H), 0.92 (t, 2H), 0.30 (s, 3H).

[0863] Example 23

[0864] M-N-((2S)-1-(((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazepan-4-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indolizido-2(4,2)-thiazido-6(1,3)- pyridazino-cycloundecaphan-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-3-(dimethylamino)-N- methylazetidine-1-carboxamide 23-1

[0865] Using the synthetic route in Scheme 1 of Example 9, the starting compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid in step 18 was replaced with N-(3-(dimethylamino)azacyclobutane-1-carbonyl)-N-methyl-L-valine (prepared by the method disclosed in Example 1 on page 61 of patent application "WO2024017859") to obtain the title compound (5.6 mg, yield: 18.4%).

[0866] MS m / z(ESI): 992.1 [M+1] + .

[0867] 1 H NMR (500MHz, CD3OD): δ8.74(d,1H),8.60(d,1H),7.96(d,1H),7.73(dd,1H),7.57(s,1H),7.45(d,1H),5.67(dd,1H), 4.52(dd,1H),4.43(d,1H),4.35-4.26(m,3H),4.22-4.09(m,3H),4.00-3.98(m,1H),3.91-3.78(m,6H),3.72-3.59(m, 5H),3.47-3.44(m,1H),3.17-3.12(m,1H),2.93-2.89(m,6H),2.82-2.76(m,1H),2.70(d,1H),2.29-2.18(m,7H),2.0 6-1.96(m,4H),1.89-1.83(m,1H),1.66-1.58(m,2H),1.47(d,3H),1.33-1.28(m,5H),1.04(s,3H),0.97-0.89(m,6H).

[0868] Example 24

[0869] MN-((2S)-1-(((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazapyrocyclohep-4-yl)prop-1-yn-1-yl)-1 5 10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1 (12, 14)-pyrido[3', 2':6, 7][1, 4]oxazocino[4, 5-a]indolizine-2 (4, 2)-thiazol[1, 3]- pyridazinacycloundecaphan-4-yl) amino)-3-methyl-1-oxobutan-2-yl)-N-methylmorpholine 4- carboxamide 24-1

[0870] First step

[0871] N-methyl-N-(morpholine-4-carbonyl)-L-valine benzyl ester 24b

[0872] Methyl-L-valine benzyl ester 24a (2 g, 9.03 mmol, prepared by the method disclosed in Example 1 on page 61 of the specification of patent application “WO2024017859”) was dissolved in dichloromethane (15 mL), N, N-diisopropylethylamine (3.50 g, 27.11 mmol) was added, and at 0 °C, triphosgene (2.7 g, 9.10 mmol) was added. After stirring for 30 minutes at the temperature, a solution of morpholine (1.02 g, 11.75 mmol) in dichloromethane (5 mL) was added, and stirring was resumed at room temperature for 1 hour. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35% - 60%, flow rate: 30 mL / min) to give the title compound 24b (1.3 g, yield: 43.3%).

[0873] MS m / z (ESI): 335.5 [M+1] + .

[0874] Second step

[0875] N-methyl-N-(morpholine-4-carbonyl)-L-valine 24c

[0876] Compound 24b (1.3 g, 3.89 μmol) was dissolved in methanol (20 mL), and palladium hydroxide on carbon (wet) (1.1 g) was added. After stirring under a hydrogen atmosphere for 16 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 24c (900 mg), which was used directly in the next step without purification.

[0877] MS m / z (ESI): 245.4 [M+1] + .

[0878] Step 3

[0879] MN-((2S)-1-(((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-oxazapyrocyclohep-4-yl)prop-1-yn-1-yl)-1 5 10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)amino)-3-methyl-1-oxobut-2-yl)-N-methylmorpholino-4-carboxamide 24-1

[0880] Using the synthetic route in Scheme 1 of Example 9, the title compound (3.8 mg, yield: 20.8%) was obtained by replacing the starting compound (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid in step 18 with compound 24c.

[0881] MS m / z(ESI): 979.2 [M+1] + .

[0882] 1H NMR (500MHz, CD3OD): δ8.74(d,1H),8.60(d,1H),7.96(d,1H),7.73(dd,1H),7.58(s,1H),7.45(d,1H),5.69(dd,1H) ,4.51(dd,1H),4.43(d,1H),4.35-4.26(m,3H),4.16(dd,1H),4.04(d,1H),3.86-3.75(m,6H),3.73-3.65(m,6H),3.6 0(d,1H),3.50-3.39(m,4H),3.24-3.16(m,2H),2.95(s,3H),2.93-2.90(m,4H),2.83-2.77(m,2H),2.70(d,1H),2.30 -2.25(m,2H),2.19(t,1H),2.05-1.96(m,5H),1.89-1.82(m,2H),1.66-1.58(m,2H),1.47(d,3H),0.97-0.89(m,7H).

[0883] Example 25

[0884] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 25-1

[0885] Option 1

[0886] first step

[0887] M-(1 5 S,6 3 (S,4S,Z)-4-amino-12 -(3-hydroxyprop-1-yn-1-yl)-1 5 ,10,10-trimethyl-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)-thiazolo[6(1,3)-pyridazino]cycloundecapenta-5,7-dione 2,2,2-trifluoroacetate 25a-1

[0888] Compound 9n-1 (1.05 g, 1.23 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (7 mL) was added, the reaction was stirred for 1 hour, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 25a-1 (960 mg), which was used directly in the next step without purification.

[0889] MS m / z (ESI): 669.2 [M+1] + .

[0890] Second step

[0891] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-hydroxyprop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)-thiazolo[6(1,3)-pyridazino]cycloundecapenta-5,7-dione 2,2,2-trifluoroacetate 25a-1

[0892] The crude compound 25a-1 (1 g, 1.28 mmol) was dissolved in N,N- dimethylformamide (20 mL), N,N-diisopropylethylamine (386 mg, 2.99 mmol) was added, (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (221 mg, 1.94 mμmol) and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino- morpholinio-carbenium hexafluorophosphate (832 mg, 1.94 mmol) were added at 0 °C, the reaction was stirred for 2 hours. Water was added to the reaction solution, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound (690 mg, yield: 60.5%).

[0893] MS m / z (ESI): 765.8 [M+1] + .

[0894] Third step

[0895] M-3-((1 5 S,6 3 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizino-2(4,2)- thiazolo[1,3]pyridazino[3,4-b]cyclopenta[1,2-d]pyrrol-1 2 -yl)prop-2-yn-1-yl methanesulfonate 25c-1

[0896] The compound 25b-1 (690 mg, 902 μmol) was dissolved in dichloromethane (20 mL), triethylamine (456 mg, 4.51 μmol), methane sulfonic anhydride (314 mg, 1.80 mmol) were added at 0 °C, the reaction was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (730 mg). The product was used directly in the next step without purification.

[0897] MS m / z (ESI): 843.5 [M+1] + .

[0898] Step 4

[0899] M-7-(3-((1 5 S,6 3 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-formamido)-1 5 10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine heterocyclic undecafen-1 2 -yl)prop-2-yn-1-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester 25d-1

[0900] The crude compound 25c-1 (200 mg, 237 μmol) was dissolved in dichloromethane (10 mL), and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (101 mg, 474 μmol, Shanghai Leyan) was added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound (220 mg, yield: 96%).

[0901] MS m / z (ESI): 959.6 [M+1] + .

[0902] Step 5

[0903] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-1 5 10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 65 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 25e-1

[0904] Compound 25d-1 (220 mg, 229 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (180 mg). The product was used directly in the next reaction without purification.

[0905] MS m / z (ESI): 859.7 [M+1] + .

[0906] 1 H NMR (500MHz, CD3OD): δ8.77(d,1H),8.61(d,1H),8.00(d,1H),7.75(dd,1H),7.59(s,1H),7.47(d,1H),5.68(d,1H),4.80(d,1H),4 .54(dd,1H),4.46(d,1H),4.35–4.26(m,2H),4.18(dd,1H),3.86(dd,1H),3.73–3.67(m,2H),3.63(d,3H),3.46(d,1H),3.28(d,1H) ,2.99(t,2H),2.83–2.74(m,2H),2.72(d,2H),2.58(s,1H),2.28(d,1H),2.21(t,1H),2.05(d,1H),1.99(d,1H),1.85(s,1H),1.68 –1.57(m,2H),1.49(d,2H),1.47–1.36(m,4H),1.19(d,3H),1.15(d,2H),1.06(s,2H),0.65(d,2H),0.64–0.58(m,2H),0.28(s,3H).

[0907] Step 6

[0908] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-15 10,10-dimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizine-2(4,2)-thiazole-6(1,3)- pyridazinocycloundecaphan-4-yl)cyclopropane-1-carboxamide 25-1

[0909] The crude compound 25e-1 (180 mg, 209 μmol) was dissolved in methanol (4 mL), 35% aqueous formaldehyde solution (85 mg, 1.04 mmol), sodium cyanoborohydride (25 mg, 419 μmol), acetic acid (50 mg, 838 μmol) were added, and the reaction was stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (5 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to obtain the title compound 25-1 (50 mg, yield: 27%).

[0910] MS m / z (ESI): 874.3 [M+1] + .

[0911] 1H NMR (500 MHz, CD3OD): δ 8.77 (t, 1H), 8.61 (s, 1H), 7.99 (t, 1H), 7.75 (dt, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 5.67 (d, 1H), 4.80 (d, 1H), 4.54 (dd, 1H), 4.50 - 4.43 (m, 1H), 4.31 (ddd, 2H), 4.18 (dd, 1H), 3.86 (dd, 1H), 3.69 (dd, 2H), 3.65 - 3.58 (m, 3H), 3.46 (d, 1H), 3.28 (d, 1H), 3.00 (d, 2H), 2.82 - 2.74 (m, 3H), 2.72 (d, 1H), 2.38 (d, 3H), 2.28 (d, 1H), 2.05 (d, 1H), 1.98 (d, 1H), 1.87 (dd, 1H), 1.63 (tt, 2H), 1.51 - 1.46 (m, 3H), 1.46 - 1.35 (m, 3H), 1.22 - 1.17 (m, 4H), 1.15 (dd, 3H), 1.05 (s, 2H), 0.77 (d, 2H), 0.57 (s, 2H), 0.28 (s, 3H).

[0912] Scheme Two

[0913] First Step

[0914] 7-(prop-2-yn-1-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester 25A-2

[0915] tert-Butyl 4,7-diazaspiro[2.5]octane-carboxylate 25A-1 (100 g, 471 mmol), dichloromethane (1000 mL), N,N-diisopropylethylamine (91.4 g, 707.2 mmol) were added into a reaction flask, cooled with ice water bath, prop-2-yn-1-yl methanesulfonate (75.9 g, 565.8 mmol) was added, stirred at room temperature for 12 hours. Water (1 L) was added and dichloromethane (1 L x 2) was extracted, combined organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude title compound 25A-2 (120 g), which was used directly in the next step without purification.

[0916] MS m / z (ESI): 251.0 [M+1] + .

[0917] Second Step

[0918] 4-methyl-7-(prop-2-yn-1-yl)-4,7-diazaspiro[2.5]octane 25A-3

[0919] To a reaction flask was added crude compound 25A-2 (118 g, 471 mmol), formic acid (590 mL), formaldehyde solution (115 g, 1.417 mol, 37% wt), heated to 100 °C and stirred for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give crude title compound 25A-3 (187 g). The product was used in the next step without further purification.

[0920] MS m / z (ESI): 165.0 [M+1] + .

[0921] Third Step

[0922] 7-(3-(5-bromo-6-((1S)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)pyridin-3-yl)prop-2-yn-1-yl)-4-methyl-4,7-diazaspiro[2.5]octane 25A-4

[0923] To a reaction flask was added crude compound 25A-3 (163 g, 357.4 mmol), compound 9A-3 (90.2 g, 429 mmol), dichlorobispalladium(triphenylphosphine) (12.6 g, 17.9 mmol), cuprous iodide (6.8 g, 35.8 mmol), triethylamine (800 mL), purged with nitrogen three times, and stirred for 12 h. Water (1 L) and ethyl acetate (500 mL) were added, and the insoluble material was filtered off using celite. The aqueous phase was extracted with ethyl acetate (1 L), and the combined organic phase was concentrated under reduced pressure. Saturated sodium chloride solution (500 mL) was added, and the mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give crude title compound 25A-4 (202 g). The product was used in the next step without further purification.

[0924] MS m / z (ESI): 492.7 [M+1] + .

[0925] Fourth Step

[0926] (S)-2-(1-(3-bromo-5-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)prop-1-yn-1-yl)pyridin-2-yl)ethoxy)ethan-1-ol 25A-5

[0927] Crude compound 25A-4 (332 g, 674.2 mmol), dichloromethane (1500 mL), methanol (1500 mL), and p-toluenesulfonic acid monohydrate (320.6 g, 1.686 mol) were added to a reaction flask and stirred for 2 hours. Most of the solvent was removed by concentration. Dichloromethane (2 L) and water (1 L) were added to the residual mixture. The aqueous phase was adjusted to alkalinity with sodium bicarbonate solids. The aqueous phase was extracted with dichloromethane (1 L × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 25A-5.

[0928] Step 5

[0929] ((6 3 S,4S,Z)-1 2 -(2-((S)-1-(2-hydroxyethoxy)ethyl)-5-(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecafen-4-yl) tert-butyl carbamate 25A-6

[0930] Compound 9A-6 (261.6 g, 377.1 mmol), compound 25A-5 (154 g, 377.2 mmol), 1,4-dioxane (2500 mL), water (250 mL), potassium phosphate (200.2 g, 943.2 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13.8 g, 18.9 mmol) were added to a reaction flask. The mixture was purged with nitrogen three times, heated to 70 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, and extracted with water (2 L) and ethyl acetate (4 L × 2). The organic phases were combined, most of the solvent was concentrated, and the mixture was washed with saturated sodium chloride solution (1 L). The solution was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 25A-6 (405 g). The product was used directly in the next reaction without purification.

[0931] MS m / z (ESI): 895.5 [M+1] + .

[0932] Step 6

[0933] M-((1 5S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapan-4-yl)carbamate tert-butyl ester 25A-7

[0934] Crude compound 25A-6 (99 g, 110.6 mmol), toluene (1000 mL), and cyanomethylenetri-n-butylphosphine (53.4 g, 221.2 mmol) were added to a reaction flask. The mixture was purged with nitrogen three times, heated to 150 °C under reflux, and stirred for 1.5 hours. The reaction solution was cooled to room temperature, and water (500 mL) was added. The aqueous phase was extracted with ethyl acetate (1 L × 2). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system J to obtain the title compound.

[0935] MS m / z (ESI): 877.5 [M+1] + .

[0936] Step 7

[0937] M-(1 5 S,6 3 (S,4S,Z)-4-amino-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2)-thiazoza-6(1,3)-pyridazine heterocyclic undecabanone-5,7-dione 25A-8

[0938] Compound 25A-7 (64 g, 73 mmol), ethyl acetate (700 mL), and ethanol (70 mL) were added to a reaction flask and cooled to 0 °C. A 4 M hydrogen chloride solution of 1,4-dioxane (274 mL) was slowly added dropwise, and the mixture was slowly restored to room temperature. The reaction was stirred for 12 hours, filtered, and the solid was dissolved in 500 mL of water. The mixture was cooled to 0–5 °C, and saturated sodium carbonate solution was added to adjust the pH to 8–9. Then, 2-methyltetrahydrofuran was added for extraction (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL). The organic phases were combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 25A-8. The product was used directly in the next reaction without purification.

[0939] MS m / z (ESI): 777.5 [M+1] + .

[0940] Step 8

[0941] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 25-1

[0942] Into a reaction flask was placed crude compound 25A-8 (52.9 g, 68.1 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (7.8 g, 68.1 mmol), dichloromethane (500 mL), (N,N-diisopropylethylamine (17.6 g, 136.2 mmol), cooled to 0 °C, added (2-hydroxyimino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinium urea hexafluorophosphate (35 g, 82 mmol) in portions, stirred at 0-5 °C for 2 hours. Added 500 mL water to quench the reaction, the aqueous phase was extracted with dichloromethane (100 mL x 2), the combined organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system J to give the title compound 25-1 (64 g, yield: 66%).

[0943] MS m / z (ESI): 874.3 [M+1] + .

[0944] 1 H NMR (500 MHz, CD3OD): δ 8.77 (t, 1H), 8.61 (s, 1H), 7.99 (t, 1H), 7.75 (dt, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 5.67 (d, 1H), 4.80 (d, 1H), 4.54 (dd, 1H), 4.50-4.43 (m, 1H), 4.31 (ddd, 2H), 4.18 (dd, 1H), 3.86 (dd, 1H), 3.69 (dd, 2H), 3.65-3.58 (m, 3H), 3.46 (d, 1H), 3.28 (d, 1H), 3.00 (d, 2H), 2.82-2.74 (m, 3H), 2.72 (d, 1H), 2.38 (d, 3H), 2.28 (d, 1H), 2.05 (d, 1H), 1.98 (d, 1H), 1.87 (dd, 1H), 1.63 (tt, 2H), 1.51-1.46 (m, 3H), 1.46-1.35 (m, 3H), 1.22-1.17 (m, 4H), 1.15 (dd, 3H), 1.05 (s, 2H), 0.77 (d, 2H), 0.57 (s, 2H), 0.28 (s, 3H).

[0945] Scheme Three

[0946] First Step

[0947] M-(S)-3-(12-bromo-5-methyl-2-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)prop-1-yn-1-yl)- 7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropan-1-ol 25B-2

[0948] Compound 9B-9 (3.8 g, 6.52 mmol) and compound 25A-3 (1.45 g, 6.90 mmol) were dissolved in a mixed solvent of triethylamine (20 mL) and N,N-dimethylformamide (20 mL), and dichlorobis(triphenylphosphine)palladium (504 mg, 718 µmol) and cuprous iodide (28 mg, 147 µmol) were added. After stirring for 16 hours under a nitrogen atmosphere, water was added to quench the reaction, and dichloromethane (50 mL x 3) was used to extract the product. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound (3.2 g, yield: 79%).

[0949] MS m / z (ESI): 618.6 [M+1] + .

[0950] Second step

[0951] M-(S)-3-(12-bromo-5-methyl-2-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)prop-1-yn-1-yl)- 7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocino[4,5-a]indol-14-yl)-2,2-dimethylpropan-1-ol 25B-2

[0952] Compound 25B-1 (6 g, 9.68 mmol) was dissolved in tetrahydrofuran (120 mL), and diisobutylaluminum hydride (1 M, 29 mmol, 29 mL) was added dropwise at -70°C. After stirring for 30 minutes at -70°C, the temperature was allowed to rise to room temperature, and stirring was performed for 2 hours. The reaction solution was cooled to 0-5°C and quenched with a saturated potassium sodium tartrate solution. Ethyl acetate (100 mL) was used to extract the product, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound (4.3 g, yield: 75%).

[0953] MS m / z (ESI): 590.6 [M+1] + .

[0954] Third step

[0955] M-(S)-1-((S)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-3-(4-((S)-14-(3- hydroxy-2,2-dimethylpropyl)-5-methyl-2-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)prop-1- yn-1-yl)-7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocin[4,5-a]indol-12-yl)thiazol-2-yl)propanoyl) hexahydropyridazine-3-carboxylic acid 25B-4

[0956] Compound 25B-2 (4.2 g, 7.10 mmol) was dissolved in a mixed solvent of 1,4-dioxane (84 mL) and water (17 mL), and compound 9B-14 (4.42 g, 8.49 mmol), potassium carbonate (2.95 g, 21.34 mmol), and 1,1'-dibutylphosphino ferrocene palladium dichloride (969 mg, 1.42 mmol) were added. After stirring at 75°C for 1 hour under a nitrogen atmosphere, the reaction solution was diluted with water and extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography using elution system A to obtain the title compound (5.06 g, yield: 79%).

[0957] MS m / z (ESI): 905.5 [M+1] + .

[0958] Fourth step

[0959] M-(S)-1-((S)-2-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-3-(4-((S)-14-(3- hydroxy-2,2-dimethylpropyl)-5-methyl-2-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)prop-1- yn-1-yl)-7,8-dihydro-5H-pyrrolo[3',2':6,7][1,4]oxazocin[4,5-a]indol-12-yl)thiazol-2-yl)propanoyl) hexahydropyridazine-3-carboxylic acid 25B-4

[0960] Compound 25B-3 (5.05 g, 7.10 mmol) was dissolved in methanol (38 mL), and a solution of lithium hydroxide monohydrate (352 mg, 8.39 mmol) in water (25 mL) was added at 0-5°C. The reaction solution was stirred at 0-5°C for 16 hours. The reaction solution was adjusted to neutral pH with 1M hydrochloric acid at 0-5°C, most of the methanol was concentrated, and the pH was adjusted to 3-4 with 1M hydrochloric acid, and then diluted with water. The product was extracted with dichloromethane (50 mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (yield: 80-100%). The product was used in the next reaction without purification.

[0961] MS m / z (ESI): 891.5 [M+1] + .

[0962] Fifth step

[0963] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizino-2(4,2)-thiazino-6(1,3)- pyridazinocycloundecaphan-4-yl)cyclopropane-1-carboxamide 25-1

[0964] 1-hydroxybenzotriazole (1.22 g, 9.03 mmol) was dissolved in dichloromethane (60 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.58 g, 13.46 mmol), 4-dimethylaminopyridine (275 mg, 2.25 mmol), and N,N-diisopropylethylamine (1.16 g, 8.98 mmol) were added. A solution of crude compound 25B-4 (2 g, 2.24 mmol) in dichloromethane (20 mL) was added dropwise, and the mixture was stirred for 90 minutes. The reaction solution was diluted with water, extracted with dichloromethane (50 mL x 3), and the organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using system A to obtain the title compound 25-1 (1.3 g, yield: 66%).

[0965] MS m / z (ESI): 874.3 [M+1] + .

[0966] 1 H NMR (500MHz, CD3OD): δ8.77(t,1H),8.61(s,1H),7.99(t,1H),7.75(dt,1H),7.59(s,1H),7.47(d,1H),5.67(d,1H),4.80(d,1H), 4.54(dd,1H),4.50–4.43(m,1H),4.31(ddd,2H),4.18(dd,1H),3.86(dd,1H),3.69(dd,2H),3.65–3.58(m,3H),3.46(d,1H),3.28 (d,1H),3.00(d,2H),2.82–2.74(m,3H),2.72(d,1H),2.38(d,3H),2.28(d,1H),2.05(d,1H),1.98(d,1H),1.87(dd,1H),1.63(tt ,2H),1.51–1.46(m,3H),1.46–1.35(m,3H),1.22–1.17(m,4H),1.15(dd,3H),1.05(s,2H),0.77(d,2H),0.57(s,2H),0.28(s,3H).

[0967] Example 26

[0968] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1-amino-1-oxide-1λ) 6 -Thiomorpholino)prop-1-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 26-1

[0969] First step

[0970] 2,2,2-trifluoro-N-(1-oxido-1λ 6 -thiomorphin-1-ylidene)acetamide hydrochloride 26b

[0971] To a solution of 1-((2,2,2-trifluoroacetyl)amino)-1λ 6 -tert-butyl 1-oxidothiomorpholine-4-carboxylate 26a (145 mg, 439 pmol, prepared using the method disclosed in Example A59 of the specification of patent application “WO2022136174”) in 4 M hydrogen chloride in 1,4-dioxane (2 mL) was stirred for 1 h. The reaction was concentrated under reduced pressure to give the crude title compound 26b (117 mg), which was used directly in the next step without purification.

[0972] MS m / z (ESI): 231.1 [M+1] + .

[0973] Second step

[0974] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(1-oxido-1-((2,2,2-trifluoroacetyl)amino)-1λ 6 -thiomorphinyl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazido-6(1,3)-pyridazino-cyclotridecan-4-yl)cyclopropane-1-carboxamide 26c-1

[0975] Compound 25c-1 (15 mg, 18 μmol) and crude compound 26b (15 mg, 56 μmol) were dissolved in acetonitrile (1 mL), and potassium carbonate (14 mg, 101 μmol) was added. The mixture was stirred at 60 °C for 16 hours. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 26c-1 (17 mg). The product was used directly in the next reaction without purification.

[0976] MS m / z(ESI): 977.8 [M+1] + .

[0977] Step 3

[0978] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1-amino-1-oxide-1λ) 6 -Thiomorpholino)prop-1-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 26-1

[0979] The crude compound 26c-1 (17 mg, 17 μmol) was dissolved in methanol (0.5 mL), and potassium carbonate (5 mg, 35 μmol) was added. The mixture was stirred for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: BostoN phlex prep C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / minN) to give the title compound 26-1 (2.6 mg, yield: 16.9%).

[0980] MS m / z (ESI): 881.9 [M+1] +.

[0981] 1 H NMR (500MHz, CD3OD): δ8.78(d,1H),8.61(s,1H),8.01(d,1H),7.75(d,1H),7.59(s,1H), 7.48(d,1H),5.68(d,1H),4.53(s,1H),4.47(d,1H),4.30(d,2H),4.19(d,1H),3.90–3.84 (m,2H),3.81(s,3H),3.73–3.66(m,4H),3.61(d,3H),2.83–2.69(m,3H),2.28(s,2H),1. 98(s,2H),1.90(d,2H),1.49(d,4H),1.19(d,6H),1.16(d,4H),1.06(s,3H),0.29(s,3H).

[0982] Example 27

[0983] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-((R)-3,4-dimethylpiperazin-1-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 27-1

[0984] Using steps one to four of the synthetic route in Scheme 1 of Example 25, the starting material 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester was replaced with compound (R)-1,2-dimethylpiperazine (Shanghai Bide) to obtain title compound 27-1 (2.5 mg, yield: 24.4%).

[0985] MS m / z (ESI): 861.4 [M+1] + .

[0986] 1 H NMR(500MHz,CD3OD):8.77(d,1H),8.61(d,1H),8.01(d,1H),7.75(dd,1H),7.59(s,1H),7.48(d,1H),5.68(d,1H),5.36 (t,1H),4.60(s,2H),4.54(dd,1H),4.46(d,1H),4.35–4.27(m,2H),4.18(dd,1H),3.86(dd,1H),3.73-3.64(m,4H),3.61 (d,1H),3.47(d,1H),2.95(d,1H),2.93-2.86(m,2H),2.82-2.75(m,1H),2.73(d,1H),2.62(td,1H),2.42(td,1H),2.33 (s,3H),2.21(t,3H),2.09-2.02(m,3H),1.49(d,3H),1.19(d,3H),1.14(dd,6H),1.06(s,3H),0.92(t,2H),0.29(s,3H).

[0987] Example 28

[0988] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-5,7-dioxo-1 2 -(3-(3,3,4-trimethylpiperazin-1-yl)prop-1-yn-1-yl)-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 28-1

[0989] Using steps one to four of the synthetic route in Scheme 1 of Example 25, the starting material 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester was replaced with compound 1,2,2-trimethylpiperazine (Shanghai Bide) to obtain title compound 28-1 (3 mg, yield: 28.9%).

[0990] MS m / z (ESI): 875.4 [M+1] + .

[0991] 1 H NMR (500MHz, CD3OD): δ8.77(d,1H),8.61(d,1H),7.99(d,1H),7.76(dd,1H),7.60(s,1H),7.48(d,1H),5.68( d,1H),5.36(t,1H),4.60(s,1H),4.57–4.41(m,2H),4.31(q,2H),4.18(dd,1H),3.87(dd,1H),3.79–3.54(m,5 H),3.49–3.42(m,2H),3.02(d,1H),2.78(dd,2H),2.62(d,4H),2.46–2.19(m,2H),2.14–1.94(m,3H),1.86(d, 1H),1.72–1.61(m,2H),1.49(d,3H),1.43–1.23(m,6H),1.17(dd,6H),1.06(s,3H),0.92(t,2H),0.29(s,3H).

[0992] Example 29

[0993] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methyl-1,4-diazacycloheptane-1-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazine-hexacyclic undecapon-4-yl)cyclopropane-1-carboxamide 29-1

[0994] Using steps one to four of the synthetic route in Scheme 1 of Example 25, the starting material compound 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester in step four was replaced with compound N-methylperiprazine (Shanghai Bide) to obtain title compound 29-1 (2.8 mg, yield: 27.4%).

[0995] MS m / z (ESI): 861.4 [M+1] + .

[0996] 1 H NMR (500MHz, CD3OD): δ8.77(d,1H),8.61(s,1H),7.99(d,1H),7.75(d,1H),7.59(s,1H),7.48(d,1H),5.68( d,1H),5.36(t,1H),4.60(s,2H),4.54(dd,1H),4.47(d,1H),4.35–4.27(m,2H),4.18(dd,1H),3.91–3.83(m ,2H),3.73(s,2H),3.68(d,1H),3.61(d,1H),3.50–3.43(m,2H),2.98(q,2H),2.88(s,3H),2.83–2.69(m,1H ),2.48(s,3H),2.28(d,2H),2.21(t,5H),1.49(d,3H),1.17(dd,8H),1.06(s,3H),0.92(t,2H),0.29(s,3H).

[0997] Example 30

[0998] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(1,4-diazacycloheptane-1-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 66 - Octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)-thiazolo-6(1,3)- pyridazino-cyclotridecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 30-1

[0999] The title compound was prepared by replacing the starting material tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate in the first four steps of the synthetic route one in example 25 with compound homopiperazine (Shanghai Biotech).

[1000] MS m / z (ESI) : 847.4 [M+1] + .

[1001] Example 31

[1002] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)-thiazolo-6(1,3)- pyridazino-cyclotridecaphan-4-yl) cyclopropane-1-carboxamide 31-1

[1003] The title compound 31-1 (2.8 mg, yield: 27.8%) was prepared by replacing the starting material tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate in the first four steps of the synthetic route one in example 25 with compound N-methylpiperazine (Shanghai Biotech).

[1004] MS m / z (ESI) : 847.4 [M+1] + .

[1005] 1H NMR (500MHz, CD3OD): δ8.77(d,1H),8.61(d,1H),8.00(d,1H),7.75(dd,1H),7.59(s,1H),7.47(d,1H),5.68(d,1H) ,5.36(dd,1H),4.80(d,1H),4.60(s,1H),4.54(dd,1H),4.46(d,1H),4.35-4.26(m,2H),4.18(dd,1H),3.86(dd,1H) ,3.74-3.65(m,4H),3.61(d,1H),3.46(d,2H),2.83-2.75(m,2H),2.72(d,1H),2.34(s,3H),2.28(d,1H),2.21(t,2H ),2.12–1.96(m,3H),1.86(d,1H),1.62(dd,3H),1.49(d,4H),1.17(dd,8H),1.06(s,3H),0.92(t,2H),0.29(s,3H).

[1006] Example 32

[1007] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 32-1

[1008] Using steps sixteen to eighteen of the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (Shanghai Bide) to obtain the title compound (15 mg, yield: 31.7%).

[1009] MS m / z (ESI): 846.0 [M+1] + .

[1010] 1 H NMR (500 MHz, CD3OD): δ 8.77 (d, 1H), 8.61 (d, 1H), 7.99 (d, 1H), 7.75 (dd, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 5.78 (d, 1H), 4.54 (dd, 1H), 4.50-4.45 (m, 2H), 4.32-4.26 (m, 2H), 4.18 (dd, 1H), 4.06 (d, 1H), 3.88-3.83 (m, 2H), 3.76 (q, 2H), 3.72-3.68 (m, 2H), 3.67 (d, 1H), 3.60 (d, 1H), 3.46 (d, 1H), 3.31-3.26 (m, 2H), 2.97 (dd, 1H), 2.83 (dd, 1H), 2.78 (td, 1H), 2.72 (d, 1H), 2.28 (dd, 1H), 2.04-1.95 (m, 2H), 1.85 (qt, 1H), 1.82 (dt, 1H), 1.62 (qd, 1H), 1.49 (d, 3H), 1.45-1.40 (m, 1H), 1.40-1.35 (m, 1H), 1.20-1.18 (m, 4H), 1.15 (d, 3H), 1.05 (s, 3H), 0.28 (s, 3H).

[1011] Example 33

[1012] M-(1r,2R,3S)-2,3-dimethyl-N-((1 5 S,6 3 S,4S,Z)-1 5 ,10,10-trimethyl-1 2 -(3-((S)-3-methylmorpholin)prop-1-yn-1-yl)-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)- thiazolo[1,3]pyridazino[6,1-cd]cyclohexa[1,2-b]pyrrolo[3,4-d]pyrimidin-4-yl)cyclopropane-1- carboxamide 33-1

[1013] Using steps sixteen to eighteen of the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with 3-(S)-3-methylmorpholine (Shanghai Leyan) to obtain the title compound (21 mg, yield: 44.3%).

[1014] MS m / z (ESI): 848.2 [M+1] + .

[1015] 1 H NMR (500MHz, CD3OD): δ8.77(d,1H),8.62(s,1H),7.98(d,1H),7.75(dd,1H),7.59(s,1H),7.47(d,1H),5.68(d,1H),4.80( d,1H),4.54(dd,1H),4.46(d,1H),4.33-4.28(m,2H),4.18(dd,1H),3.93-3.84(m,3H),3.79-3.72(m,2H),3.68-3.65(m,2H ),3.61(d,1H),3.46(d,2H),3.31-3.22(m,3H),2.87-2.69(m,4H),2.29(d,1H),1.99(d,1H),1.86(qt,1H),1.63(qd,1H), 1.49(d,3H),1.46-1.41(m,1H),1.40-1.34(m,1H),1.21-1.19(m,4H),1.15(d,3H),1.07(d,3H),1.06(s,3H),0.29(s,3H).

[1016] Example 34

[1017] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(4-hydroxypiperidin-1-yl)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxaazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 34-1

[1018] Using steps sixteen to eighteen of the synthetic route in Scheme 1 of Example 9, the starting compound 1,4-oxazacycloheptane in step sixteen was replaced with 4-hydroxypiperidine (Shanghai Titan) to obtain the title compound (16 mg, yield: 40.6%).

[1019] MS m / z(ESI): 848.0 [M+1] + .

[1020] 1 H NMR (500MHz, CD3OD): δ8.81(d,1H),8.61(d,1H),8.04(d,1H),7.76(dd,1H),7.60(s,1H),7.48(d,1H),5.67(d,1H),4.55(dd,1 H),4.46(d,1H),4.34-4.27(m,2H),4.18(dd,1H),3.96(s,2H),3.89-3.84(m,3H),3.73-3.65(m,2H),3.61(d,1H),3.46(d,1H), 3.31-3.23(m,3H),2.91(s,2H),2.79(td,1H),2.72(d,1H),2.29-2.26(m,1H),2.05-1.95(m,3H),1.85(qt,1H),1.80-1.72(m,2 H),1.63(qd,1H),1.49(d,3H),1.44-1.39(m,1H),1.39-1.34(m,1H),1.20-1.18(m,4H),1.15(d,3H),1.05(s,3H),0.28(s,3H).

[1021] Example 35

[1022] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(3-(cis-3,5-dimethylmorpholino)prop-1-yn-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 62 ,6 3 ,6 4 ,6 5 ,6 6 - Eight-hydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazocino[4,5-a]indolizido-2(4,2)-thiazolo-6(1,3)- pyridazino-cyclotridecaphan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 35-1

[1023] The title compound was prepared according to the procedures in Scheme 16-18 of Example 9, replacing the starting compound 1,4-oxazepane in Step 16 with cis-3,5-dimethylmorpholine hydrochloride (Shanghai Biotech).

[1024] Alternatively, the title compound was prepared according to the procedures in Scheme 1-4 of Example 25, replacing the starting compound tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate in Step 4 with cis-3,5-dimethylmorpholine hydrochloride (Shanghai Biotech) (8 mg, yield: 32.6%).

[1025] MS m / z (ESI): 862.4 [M+1] + .

[1026] 1 H NMR (500 MHz, CD3OD): δ 8.77 (d, 1H), 8.62 (s, 1H), 7.98 (d, 1H), 7.75 (dd, 1H), 7.59 (s, 1H), 7.48 (d, 1H), 5.68 (d, 1H), 4.80 (d, 1H), 4.54 (dd, 1H), 4.46 (d, 1H), 4.36-4.26 (m, 2H), 4.18 (dd, 1H), 3.99 (s, 2H), 3.87 (dd, 1H), 3.77 (dd, 2H), 3.73-3.67 (m, 2H), 3.61 (d, 1H), 3.46 (d, 1H), 3.32-3.25 (m, 3H), 2.97-2.90 (m, 2H), 2.79 (dt, 1H), 2.73 (d, 1H), 2.29 (d, 1H), 1.99 (d, 1H), 1.86 (qt, 1H), 1.63 (qd, 1H), 1.49 (d, 3H), 1.46-1.40 (m, 1H), 1.40-1.34 (m, 1H), 1.20-1.19 (m, 4H), 1.15 (d, 3H), 1.08 (d, 3H), 1.07 (d, 3H), 1.06 (s, 3H), 0.30 (s, 3H).

[1027] Example 36

[1028] M-(1r,2R,3S)-N-((1 5 S,6 4 S,4S,Z)-1 2 -(4-((R)-2-hydroxypropyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 36-1

[1029] first step

[1030] M-((1 5 S,6 4 S,4S,Z)-1 5 ,10,10-trimethyl-5,7-dioxo-1 2 -(piperazine-1-yl)-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapan-4-yl)tert-butyl carbamate 36a-1

[1031] Compound 19d-1 (150 mg, 159 μmol) was dissolved in ethanol (10 mL), and palladium hydroxide on carbon (wet) (178 mg) was added. The mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 36a-1 (128 mg). The product was used directly in the next step of the reaction without purification.

[1032] MS m / z(ESI): 811.8 [M+1] + .

[1033] Step 2

[1034] M-((1 5 S,64 S,4S,Z)-1 2 -(4-((R)-2-hydroxypropyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapan-4-yl)carbamate tertiary ester 36b-1

[1035] The crude compound 36a-1 (20 mg, 25 μmol) was dissolved in ethanol (10 mL), and R-propylene oxide (14 mg, 246 μmol, Shanghai Bide) was added. The mixture was stirred at 70 °C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel column chromatography using solvent system A to give the title compound 36b-1 (4 mg, yield: 19%).

[1036] MS m / z (ESI): 869.5 [M+1] + .

[1037] Step 3

[1038] M-(1r,2R,3S)-N-((1 5 S,6 4 S,4S,Z)-1 2 -(4-((R)-2-hydroxypropyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 36-1

[1039] Using steps three and four of the synthetic route in Example 2, the title compound (1 mg, yield: 25%) was obtained by replacing 2b-1 in step three with 36b-1.

[1040] MS m / z (ESI): 863.6 [M⁻¹]- .

[1041] 1 H NMR (500 MHz, CD3OD): δ 8.47 (d, 1H), 8.41 (d, 1H), 7.72 (dd, 1H), 7.59 (s, 1H), 7.52 - 7.28 (m, 2H), 5.90 (d, 1H), 5.45 - 5.41 (m, 1H), 5.36 (dd, 1H), 4.78 - 4.70 (m, 1H), 4.68 (q, 1H), 4.60 (s, 2H), 4.51 (dd, 1H), 4.29 - 4.09 (m, 3H), 4.01 (s, 1H), 3.84 (dd, 1H), 3.77 - 3.67 (m, 2H), 3.65 - 3.59 (m, 1H), 3.54 (d, 1H), 3.50 - 3.43 (m, 1H), 3.31 - 3.23 (m, 2H), 2.87 - 2.71 (m, 4H), 2.65 (ddd, 1H), 2.56 - 2.39 (m, 3H), 2.29 - 2.15 (m, 2H), 2.04 (d, 2H), 1.95 - 1.84 (m, 1H), 1.72 (d, 1H), 1.62 (d, 2H), 1.53 - 1.42 (m, 3H), 1.26 (t, 1H), 1.21 - 1.13 (m, 2H), 1.04 (s, 3H), 0.95 - 0.82 (m, 4H), 0.30 (s, 2H).

[1042] Example 37

[1043] M-((1 5 S,6 4 S,4S,Z)-1 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-oxa-6 2 ,6 3 -diazepin-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 37-1

[1044] First step

[1045] M-((1 5 S,6 4S,4S,Z)-1 2 -(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-oxa-6 2 ,6 3 -diazepin-4-yl)carbamic acid tert-butyl ester 37a-1

[1046] The crude compound 36a-1 (20.3 mg, 25 pmol) was dissolved in tetrahydrofuran (1 mL), 2-((tetrahydro-2H-pyran-2-yl)oxy)acetaldehyde (36 mg, 250 pmol, prepared by the method disclosed in the literature “Journal of Fluorine Chemistry, 2018, vol. 216, p. 11-23”) and sodium triacetoxyborohydride (16 mg, 75 pmol) were added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 37a-1 (16 mg, yield: 69.5%).

[1047] MS m / z (ESI): 939.5 [M+1] + .

[1048] Second step

[1049] M-((1 5 S,6 4 S,4S,Z)-1 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-oxa-6 2 ,6 3 -diazepin-4-yl)carbamic acid tert-butyl ester 37b-1

[1050] Compound 37a-1 (16 mg, 17 μmol) was dissolved in methanol (0.5 mL) and dichloromethane (0.5 mL), and p-toluenesulfonic acid hydrate (16 mg, 85 μmol) was added. The mixture was stirred for 2 hours. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain crude title compound 37b-1 (14 mg). The product was used directly in the next reaction without purification.

[1051] MS m / z (ESI): 855.8 [M+1] + .

[1052] Step 3

[1053] M-(1r,2R,3S)-N-((1 5 S,6 4 S,4S,Z)-1 2 -(4-(2-hydroxyethyl)piperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-Oza-6 2 6 3 -diaza-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctanocyclo[4,5-a]indolaza-2(4,2)-thiazoza-6(2,4)-bicyclo[3.1.1]heptaneheterocyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 37-1

[1054] Using the synthetic route in Example 2, the title compound (3 mg, yield: 12.5%) was obtained by replacing the starting compound 2b-1 in the third step with compound 37b-1.

[1055] MS m / z (ESI): 851.8 [M+1] + .

[1056] 1H NMR (500 MHz, CD3OD): δ 8.47 (d, 1H), 8.41 (d, 1H), 7.72 (dd, 1H), 7.59 (s, 1H), 7.49 - 7.35 (m, 2H), 5.90 (d, 1H), 5.45 (dd, 1H), 5.36 (t, 1H), 4.76 - 4.72 (m, 1H), 4.68 (q, 1H), 4.60 (s, 1H), 4.52 (dd, 1H), 4.30 - 4.12 (m, 2H), 3.84 (dd, 1H), 3.76 (t, 2H), 3.70 (d, 1H), 3.61 (d, 1H), 3.54 (d, 1H), 3.41 (q, 2H), 3.31 - 3.24 (m, 2H), 2.86 - 2.75 (m, 3H), 2.66 (td, 3H), 2.49 (dt, 1H), 2.31 - 2.16 (m, 2H), 2.05 (d, 1H), 1.71 (t, 1H), 1.65 - 1.59 (m, 1H), 1.48 (d, 3H), 1.41 - 1.29 (m, 2H), 1.20 (d, 3H), 1.16 (d, 3H), 1.04 (s, 3H), 0.92 (t, 2H), 0.30 (s, 3H).

[1057] Example 38

[1058] M-((1 5 S,6 4 S,4S,Z)-1 2 -(4-ethylpiperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 -dihydro-1 5 H-8-oxa-6 2 ,6 3 -diazepin-1(12,14)-pyrido[3',2':6,7][1,4]oxazepino[4,5-a]indolizan-2(4,2)- thiazinan-6(2,4)-bis-cyclo[3.1.1]heptazin-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 38-1

[1059] First step

[1060] M-((1 5 S,6 4 S,4S,Z)-1 2 -(4-ethylpiperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,18 - dihydro-1 5 H- 8-oxa-6 2 ,6 3 - diaza-1 (12, 14)-pyrido [3 ',2': 6,7] [1,4] oxazocino [4,5-a] indolizine-2 (4,2)-thiazine-6 (2,4)-bicyclo [3.1.1] heptazine-4-yl) carbamic acid tert-butyl ester 38a-1

[1061] Compound 19d-1 (10 mg, 10 μmol) was dissolved in ethanol (2 mL), and palladium hydroxide (wet) (10 mg) was added. The reaction was stirred under hydrogen atmosphere for 16 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 38a-1 (10 mg), which was used directly in the next step without purification.

[1062] MS m / z (ESI): 839.5 [M+1] + .

[1063] Second step

[1064] M- (1r, 2R, 3S)-N- ((1 5 S,6 4 S,4S,Z)-1 2 -(4-ethylpiperazin-1-yl)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 - dihydro-1 5 H- 8-oxa-6 2 ,6 3 - diaza-1 (12, 14)-pyrido [3 ',2': 6,7] [1,4] oxazocino [4,5-a] indolizine-2 (4,2)-thiazine-6 (2,4)-bicyclo [3.1.1] heptazine-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 38-1

[1065] The title compound (1.3 mg, yield: 11.5%) was prepared by using the synthetic route in Example 2, replacing the third step starting material compound 2b-1 with compound 38a-1.

[1066] MS m / z (ESI): 836.0 [M+1] + .

[1067] 1H NMR (500MHz, CD3OD): δ8.47(d,1H),8.42(d,1H),7.73(dd,1H),7.59(s,1H),7.47(dd,2H),5.90(d,1H),5.47–5.42(m,1H),5 .36(t,3H),4.74(d,1H),4.68(d,1H),4.60(s,1H),4.55–4.49(m,1H),4.25–4.14(m,2H),3.88–3.80(m,1H),3.72(dd,1H),3 .61(d,1H),3.54(d,1H),2.85–2.75(m,1H),2.72(t,2H),2.68–2.62(m,2H),2.55(q,2H),2.49(dd,1H),2.25–2.16(m,4H),2 .08–2.01(m,2H),1.72(t,2H),1.62(d,3H),1.48(d,3H),1.34(s,2H),1.18(dd,3H),1.04(s,3H),0.92(t,2H),0.30(s,3H).

[1068] Example 39

[1069] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(2-(5-oxa-8-azaspiro[2.6]non-8-yl)ethoxy)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 5 H-8-oxa-1(12,14)-pyrido[3',2':6,7][1,4]oxazaoctano[4,5-a]indolaza-2(4,2-thiazoza-6(1,3-pyridazinazine-hexacyclic undecapon-4-yl)-2,3-dimethylcyclopropane-1-carboxamide 39-1

[1070] The synthetic route in Example 21 was adopted, and the starting material of the fifth step, 1,4-oxazepane, was replaced with 5-oxa-8-azaspiro[2.6]nonane (prepared using the method disclosed in the specification of patent application “US2020339568” on page 55, Embodiment 38), to produce the title compound (3.2 mg, yield: 23.7%).

[1071] MS m / z (ESI): 881.1 [M+1] + .

[1072] 1 H NMR (500 MHz, CD3OD): δ 8.61 (s, 1H), 8.46-8.40 (m, 1H), 7.73 (d, 1H), 7.58 (s, 1H), 7.56-7.48 (m, 1H), 7.45 (d, 1H), 5.67 (d, 1H), 4.79 (d, 1H), 4.55-4.41 (m, 2H), 4.34-4.20 (m, 4H), 4.16 (dd, 1H), 3.94-3.78 (m, 3H), 3.75-3.64 (m, 2H), 3.66-3.53 (m, 4H), 3.45 (d, 2H), 3.13-2.97 (m, 4H), 2.84-2.68 (m, 4H), 2.31-2.17 (m, 2H), 2.11-2.01 (m, 1H), 2.02-1.92 (m, 1H), 1.90-1.78 (m, 1H), 1.68-1.55 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H), 1.24-1.08 (m, 8H), 1.05 (d, 3H), 0.91 (t, 1H), 0.29 (s, 3H).

[1073] Example 40

[1074] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(2-((3aR,6aS)-3a,6a-dimethyltetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5H-8-oxa-1 (12, 14)-pyrido[3',2':6,7][1,4]oxazocin[4,5-a]indolizine-2(4,2)- thiazol[6(1,3)-pyridazin]cycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 40-1

[1075] First step

[1076] (3aR,6aS)-3a,6a-dimethylhexahydro-1H-furo[3,4-c]pyrrole 40b

[1077] (3aR,6aS)-5-benzyl-3a,6a-dimethylhexahydro-1H-furo[3,4-c]pyrrole 40a (2 g, 8.64 μmol, prepared by the method disclosed in the literature “Synthesis, 2017, vol. 49, #14, p. 3112-3117”) was dissolved in methanol (20 mL), palladium hydroxide (wet) (1 g) was added, the reaction was stirred under hydrogen atmosphere for 16 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 40b (950 mg). The product was used directly in the next step without purification.

[1078] MS m / z (ESI): 142.2 [M+1] + .

[1079] Second step

[1080] M-(1r,2R,3S)-N-((1 5 S,6 3 S,4S,Z)-1 2 -(2-((3aR,6aS)-3a,6a-dimethyltetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)-1 5 ,10,10-trimethyl-5,7-dioxo-1 7 ,1 8 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -octahydro-1 5 H-8-oxa-1 (12, 14)-pyrido[3',2':6,7][1,4]oxazocin[4,5-a]indolizine-2(4,2)- thiazol[6(1,3)-pyridazin]cycloundecaphan-4-yl)-2,3-dimethylcyclopropane-1- carboxamide 40-1

[1081] Using the synthetic route in Example 21, the title compound (1.8 mg, yield: 9%) was obtained by replacing the starting material 1,4-oxazacycloheptane in step 5 with compound 40b.

[1082] MS m / z(ESI): 894.8 [M+1] + .

[1083] 1 H NMR (500MHz, CD3OD): δ8.61(d,1H),8.42(s,1H),7.78-7.70(m,1H),7...

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: represents that the ring is an aromatic ring or a non-aromatic ring; X, Y and Z are the same or different and each independently selected from the group consisting of -(CR 4a R 4b ) m -; -NR 5 (CR 4c R 4d ) r’ -; -C(O)NR 5 -; -NR 5 C(O)-; -C(O)-; and -O(CR 4e R 4f ) n -; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r' is 0, 1, 2, 3, or 4; R 4a , R 4b , R 4c , R 4d , R 4e and R 4f are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted by one or more R*; R 5 and R R are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted with one or more R*; or R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 5 together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, which is optionally substituted with one or more R*; G 1 , G 2 and G are the same or different and each independently CR 6 , CR 66 R 67 , C(O), NR 68 , N=O or N; ring A is a heterocyclyl group; rings C are the same or different, and each is independently selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R A , R B , R C , R 66 , R 67 , R 68 , and R 6 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b , -NR 7a OR 7b , -ONR 7a R 7b , -NR 7c NR 7a R 7b , hydroxyl, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) w R 8 , oxo, =S, =N-O-R 61 , =CR 62 R 63 , =N-R 64 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two R A with the attached atom form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, which cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted with one or more R AA substituents; R D selected from halo, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b , -NR 7a OR 7b , -ONR 7a R 7b , -NR 7c NR 7a R 7b , hydroxy, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 7a R 7b , -S(O) w R 8 , -S(=O)(=N-R 64 )R 8 , -alkyl-NR 7a R 7b , -alkenyl-NR 7a R 7b , -alkynyl-NR 7a R 7b , -O-alkyl-cycloalkyl, -O-alkyl-heterocyclyl, heterocyclyl(alkylene) 0-6 heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkenyl, heterocyclylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, heterocyclylalkynyl, arylalkynyl, and heteroarylalkynyl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, -alkyl-NR 7a R 7b , -alkenyl-NR 7a R 7b , -alkynyl-NR 7a R 7b , -O-alkyl-cycloalkyl, -O-alkyl-heterocyclyl, heterocyclyl(alkylene) 0-6 heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkenyl, heterocyclylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, heterocyclylalkynyl, arylalkynyl, and heteroarylalkynyl, are each independently optionally substituted with one or more R*, and wherein each R* is independently selected from halo, oxo, =S, =N-R 64 , alkyl optionally substituted with one or more R*, alkenyl optionally substituted with one or more R*, alkynyl optionally substituted with one or more R*, alkoxy optionally substituted with one or more R*, haloalkyl, haloalkoxy, cyano, -NR 9a R 9b one or more of R*; each R* is independently H, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-6cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-6cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, halo, oxo, hydroxy, hydroxyalkyl, cycloalkyl optionally substituted with one or more R*, heterocyclyl optionally substituted with one or more R*, aryl optionally substituted with one or more R*, heteroaryl optionally substituted with one or more R*, cycloalkylalkyl optionally substituted with one or more R*, heterocyclylalkyl optionally substituted with one or more R*, arylalkyl optionally substituted with one or more R*, and heteroarylalkyl optionally substituted with one or more R*; R 2 is selected from O, NH and N-alkyl; L 2 alkylene, said alkylene being optionally substituted by one or more R L2 substituents; R L2 the same or different and each independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, oxo, =S, =N-O-R 61 , =CR 62 R 63 , =N-R 64 , cycloalkyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more R*; or two R L2 with the attached atom form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, which cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted with one or more R LL2 substituents; L 1 alkylene or cycloalkyl, said alkylene or cycloalkyl being optionally substituted by one or more R L1 substituents; L is R 10 or R 11 and R 12 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl being optionally substituted with one or more R E groups; L 3 is a bond or -N(R L3 )C(O)-; L 4 is a bond or -(alkylene) y -N(R L4 )C(=O)-; R 10 selected from alkyl, cycloalkyl, heterocyclyl, and NR 101 R 102 , each of said alkyl, cycloalkyl, and heterocyclyl being independently optionally substituted with one or more R F ; each R F are the same or different, and each is independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 7a R 7b , hydroxyl, oxo, =S, =N-O-R 61 , =CR 62 R 63 , =N-R 64 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R F1 , -C(O)OR F1 , -C(O)NR F2 R F3 , -S(O) w R F1 , and -S(O) w OR F1 , each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R FF ; R 7a , R 7b , R 7c , R 9a , R 9b , R L3 , R L4 , R 101 , R 102 , R F2 and R F3 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a heteroalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein each of said alkyl group, heteroalkyl group, hydroxyalkyl group, aminoalkyl group, cycloalkyl group, and heterocyclyl group is independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group; or R 7a and R 7b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 9a and R 9b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 101 and R 102 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R F2 and R F3 together with the nitrogen atom to which they are attached form a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of halo, oxo, =S, =N-R 64 , alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 8 , R F1 , R 61 , R 62 , R 63 , and R 64 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein each of said alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, and heterocyclyl group is independently optionally substituted with one or more R # ; or R 62 R 63 with the attached atoms form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R FF substituents; each R, R AA , R DD , R LL2 , R L1 , R E , R FF and R # are the same or different and each is independently selected from oxo, =S, =N-alkyl, =NH, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amido, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy, each of said =N-alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy is independently optionally substituted with one or more substituents selected from oxo, =S, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkylthio, amino, -NHalkyl, -N(alkyl)2, -alkylene-amino, -alkylene-NHalkyl, -alkylene-N(alkyl)2, amido, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy; w is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; and y is 0, 1, 2, 3, 4, 5, or 6. The compound of Formula (I) according to claim 1, wherein ring A is a 6-membered heterocyclyl group, or a pharmaceutically acceptable salt thereof. The compound of general formula (I) or pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of general formula (II) or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents a single bond or a double bond; R B , q, G 1 , G 2 , G, X, Y, Z, R D , L 1 , L 2 , R A , n, ring C, R C , p and L are as defined in claim 1. The compound of Formula (I) according to any one of claims 1 to 3, wherein X-Y-Z is selected from -OCH2CH2-, -CH(CH3)OCH2CH2-, -CH(CH3)OCH2CH2CH2-, -CH(CH3)OCH2CH(CH3)-, -CH(OCH3)CH2CH2-, -CH(OCH3)CH2CH2CH2-, -CH(OCH3)CH2CH(CH3)-, -CH2OCH2CH2-, -OCH2CH2CH2-, -NHC(O)CH2CH2-, -N(CH3)C(O)CH2CH2-, -NHCH2CH2-, and -N(CH3)CH2CH2-, or a pharmaceutically acceptable salt thereof. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein: t1 is 0, 1, or 2; t is 0, 1, 2, 3, 4, 5, or 6; R 4a , R 6 , R D , R A , n, R B , q, R C , L 1 and L are as defined in claim 1. The compound of general formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein selected from the group consisting of wherein R A and n are as defined in claim 1. The compound of general formula (I) according to any one of claims 1 to 6, wherein R D is selected from C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl, wherein the C 2-6 alkynyl, C 1-6 alkoxy, -C 2-6 alkynyl-NR 7a R 7b , -O-C 1-6 alkyl-3 to 12 membered cycloalkyl, -O-C 1-6 alkyl-3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl(C 1-6 alkylene) 0-6 3 to 12 membered heterocyclyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocyclyl and 3 to 12 membered heterocyclyl C 2-6 alkynyl are each independently optionally substituted with one or more substituents selected from halogen, oxo, =N-R 64 , C 1-6 alkyl optionally substituted with one or more R*, C 2-6 alkynyl, 3 to 12 membered heterocyclyl optionally substituted with one or more R*, 3 to 12 membered heterocyclyl C 1-6 alkyl optionally substituted with one or more R* and 5 to 10 membered heteroaryl C 1-6 alkyl are substituted; or a pharmaceutically acceptable salt thereof. wherein, R 7a , R 7b , R 64 and R* are as defined in claim 1. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4a are identical or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and / or t is 0 or 1. The compound of Formula (I) according to any one of claims 1 to 8, wherein, R 6 the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and / or t1 is 0 or 1 ; and / or R B the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; and / or q is 0 or 1 ; and / or R C selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, a cyano group, a 3- to 8-membered cycloalkyl group, or a 3- to 8-membered heterocyclyl group; and / or L 1 is methylene or cyclopropyl. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R A are the same or different and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano, or two R A on the same atom, or two R A on different atoms, together with the atoms to which they are attached form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, said 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl being optionally substituted with one or more halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein L is a 3- to 8-membered cycloalkyl group, which is optionally substituted by one or more halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, =CR 62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano, R 62 and R 63 are the same or different and each independently selected from the group consisting of a hydrogen atom, halogen and C 1-6 alkyl; or L is a 3- to 8-membered heterocyclyl group, said 3- to 8-membered heterocyclyl group being optionally substituted by one or more halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, =CR 62 R 63 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano, R 62 and R 63 are the same or different and each independently selected from the group consisting of a hydrogen atom, halogen and C 1-6 alkyl; or L is -CH(R 12 )-N(R L3 )C(O)-R 10 , R 10 is 3- to 6-membered heterocyclyl optionally substituted with one or more R F , R 12 is C 1-6 1-4 alkyl or 3- to 6-membered cycloalkyl, R L3 is a hydrogen atom or C 1-6 1-4 alkyl, R F is selected from -C(O)R F1 , halogen, C 1-6 1-4 alkyl, C 1-6 1-4 haloalkyl, NH2, (C 1-6 1-4 alkyl)NH-, and (C 1-6 1-4 alkyl)2N-, R F1 is selected from C 1-6 1-4 alkyl, C 2-6 2-4 alkenyl, C 2-6 2-4 alkynyl, said C 1-6 1-4 alkyl, C 2-6 2-4 alkenyl, C 2-6 2-4 alkynyl optionally substituted with one or more of halogen, C 1-6 1-4 alkyl, C 1-6 1-4 haloalkyl, NH2, (C 1-6 1-4 alkyl)NH-, and (C 1-6 1-4 alkyl)2N-; or L is or L is The compound of general formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, is selected from the following compounds: A compound represented by General Formula (IA) or a salt thereof, wherein: G, G 1 G, G 2 X, Y, Z, R D R 2 L 2 ring A, R A n, L 1 R R ring C, R C p, R B and q are as defined in claim 1. a compound or salt thereof selected from the following compounds: A process for the preparation of a compound of general formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of: The compound of Formula (IA) or a salt thereof is subjected to a condensation reaction with L-C(O)OH or a salt thereof to obtain the compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein: G, G 1 G, G 2 X, Y, Z, R D R 2 L 2 ring A, R A n, L 1 R R ring C, R C p, R B and q are as defined in claim 1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting a RAS mutant protein. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for treating and / or preventing a disease or disorder mediated by or dependent on a RAS mutant protein. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the manufacture of a medicament for the treatment and / or prevention of a tumor; wherein the tumor is preferably selected from the group consisting of thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, brain cancer, skin cancer, testicular cancer, cholangiocarcinoma, colorectal cancer, urothelial cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, leukemia, lymphoma, myeloma, appendiceal cancer, melanoma, sarcoma and glioblastoma; more preferably selected from the group consisting of gastric cancer, pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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