HETEROCYCLIC COMPOUND AND METHOD FOR ITS PRODUCTION, AS WELL AS ITS USE IN MEDICINE

Abstract

The present disclosure relates to a heterocyclic compound, and a preparation method therefor and a use thereof in medicine. In particular, the present disclosure relates to a heterocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a therapeutic agent, particularly as a GLP-1 receptor agonist. The definition of each group in the general formula (I) is as stated in the description.

Description

Heterocyclic compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to heterocyclic compounds, methods for preparing the same, and their use in medicine. In particular, the present disclosure relates to heterocyclic compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as GLP-1 receptor agonists. Background Art

[0002] Diabetes is a multi-factorial metabolic disease characterized by chronic hyperglycemia and disturbances in sugar, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative deficiency of insulin, leading to elevated blood glucose concentrations and subsequent excretion of sugar in the urine. Symptoms include polydipsia, polyuria, polyphagia, and weight loss.

[0003] Generally speaking, there are two types of diabetes. Patients with type 1 diabetes, also known as insulin-dependent diabetes, produce little or no insulin. Insulin is a hormone that regulates glucose utilization in the body. Patients with type 2 diabetes, also known as non-insulin-dependent diabetes, have plasma insulin levels that are comparable to or higher than those of non-diabetic patients. However, these patients develop resistance to insulin, which stimulates glucose and lipid metabolism in key insulin-sensitive tissues and cells, such as muscle, liver, and adipose tissue. Even increased plasma insulin levels cannot overcome this significant insulin resistance.

[0004] Insulin resistance arises not only from a decrease in the number of insulin receptors but also from insulin receptor defects, the mechanisms of which remain incompletely understood. Insulin resistance results in an inability of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, effectively inhibiting adipose tissue lipolysis and the production and secretion of glucose in the liver.

[0005] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its effects by binding to its ubiquitous specific receptors. GLP-1 receptors are known to be present in pancreatic islet cells, the gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and the cardiovascular system. GLP-1 receptors may also be found in the liver, adipose tissue, and skeletal muscle. GLP-1 not only acts on β-cells to promote insulin secretion but also acts on α-cells to inhibit glucagon secretion. Serum GLP-1 levels generally do not differ significantly between patients with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. However, the β-cell response to GLP-1 after a meal is impaired, and under certain conditions, this response is significantly enhanced by continuous GLP-1 infusion. Because the body's own GLP-1 has a very short duration of action (t½ <1.5 minutes after intravenous administration), it is not suitable for the clinical treatment of diabetes.

[0006] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the effect of lowering fasting and postprandial glucose and improving blood sugar levels in patients with type 2 diabetes. However, due to the poor oral bioavailability of peptide GLP-1 and the inconvenience of administration, small molecule GLP-1 receptor agonists with good oral bioavailability are highly desired.

[0007] Published patent applications for GLP-1 receptor small molecule agonists include WO2018056453A1, JP2019099571A, WO2021155841A1, WO2022017338A1, WO2022048665A1, WO2022052958A1, WO2022127868A1, WO2022246230A1, WO2022258805A1, WO2023016546A1, WO2023038039A1 and WO2023169456A1, etc. Summary of the Invention

[0008] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] is a single bond or a double bond;

[0011] Q 1 is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are each independently optionally substituted by one or more R Q1 replace;

[0012] Z 2is selected from hydrogen atom, deuterium atom, cycloalkyl, heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted by one or more R Z2 replace;

[0013] Z 1 Selected from bond, -heterocyclyl-, -heterocyclyl-L 2A -、-L 2A -heterocyclyl-, -L 2A -Heterocyclyl-L 2A -, -heteroaryl-L 2A -、-L 2A -heteroaryl-L 2A -、-N=、-NR aa -L 2A -and-NR aa -C(O)-NR bb -L 2A -, the heterocyclic group and heteroaryl are each independently optionally substituted by one or more R Z1 replaced by;

[0014] L 2A is selected from the group consisting of a bond, alkyl, deuterated alkyl, heteroalkyl, and -N=;

[0015] for

[0016] Y is selected from C(O), S(O), S(O)2, deuterated alkylene and alkylene;

[0017] R 1 、R 2 and R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxyalkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, an oxo group, -(CH2) x NR 11a R 11b 、-(CH2) x C(O)NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 、S(=NR 00 )R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0018] Ring A is selected from and R A and Q 2 substituted bicyclic heteroaryl; the bicyclic heteroaryl is optionally substituted by one or more R 01 replaced by;

[0019] R A for

[0020] Q 2 is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R Q2 replaced by;

[0021] X 1 CR x1 or N;

[0022] R 4 、R 5 、R 6 and R x1 When present, they are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxyalkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, -(CH2) x NR 11a R11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-(CH2) x C(O)NR 11a R 11b 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 、S(=NR 00 )R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0023] or Q 2 、R 6 Together with the carbon atom to which it is attached, it forms ring B, or Q 2 、R 5 Together with the carbon atom to which it is attached, it forms Ring B; or, R Q2 、R 6 Together with the ring atoms to which it is attached, it forms ring B 0 , or R Q2 、R 5 Together with the ring atoms to which it is attached, it forms ring B 0 ;

[0024] Each ring B is independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the ring B is optionally substituted by one or more R B Replaced; each ring B 0 are independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the ring B 0Optionally one or more R B replaced by;

[0025] R 9 Selected from -C(O)OR 12 、-C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O) t NR 11a R 11b , heterocyclic and heteroaryl, each of which is independently optionally substituted by one or more R 9a replaced by;

[0026] R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxyalkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, an oxo group, -(CH2) x NR 11a R 11b 、-(CH2) x C(O)NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 、S(=NR 00 )R 12, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced; or

[0027] R 7 、R 8 Together with the atoms to which it is attached, it forms a 3- to 5-membered cycloalkyl or heterocyclic group, wherein the 3- to 5-membered cycloalkyl and heterocyclic group are each independently optionally substituted by one or more R 78 replaced by;

[0028] n1 is 0, 1, 2, 3, 4 or 5; n2 is 0, 1, 2, 3, 4 or 5;

[0029] Each R Q1 、R Z2 、R Z1 、R 01 、R Q2 、R B 、R 9a and R 78 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a deuterated alkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, an oxo group, =S, -(CH2) x NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-(CH2) x C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 、S(=NR 00 )R 12 , cycloalkyl, heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl are each independently optionally substituted by one or more R * replaced by;

[0030] or, R Z2 、R Z1 Together with the ring atoms to which it is attached, they form Ring C;

[0031] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and said ring C is optionally substituted by one or more R C replaced by;

[0032] Each R * and R C are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, an oxo group, =S, -(CH2) x NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-(CH2) x C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-OC(O)R 12 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 、S(=NR 00 )R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more identical or different substituents selected from deuterium atoms, oxo groups, halogen, cyano groups, amino groups, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclyl, aryl and heteroaryl groups;

[0033] Each R 11a 、R 11b 、R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, -C(O)R 15 、-C(O)OR 15 、-OC(O)R 15 、-(CH2) y NR 14a R 14b 、-(CH2) y C(O)NR 14a R 14b 、-NR 0 C(O)R 15 、-S(O) t R 15 、-S(O) t NR 14a R 14b 、-NR 0 S(O) t R 15 、-S(O) t OR 15 、-OS(O) t R 15 、-OR 15 , 4 to 12 membered cycloalkyl and heterocyclic groups; or R 11a and R 11b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more identical or different substituents selected from the group consisting of a deuterium atom, an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group;

[0034] Each R aa 、R bb 、R 00 and R 0are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a C(O)alkyl group, an amide group, a cycloalkyl group, and a heterocyclic group;

[0035] Each R 12a and R 13a are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group; or R 12a 、R 13a The carbon atom to which it is attached forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more substituents selected from the group consisting of a deuterium atom, a halogen, a cyano group, an amino group, a hydroxyl group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group and a heterocyclic group;

[0036] Each R 15 、R 14a and R 14b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, a C(O)alkyl group, an amino group, an amide group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a deuterium atom, a halogen, a cyano group, a nitro group, an amino group, a hydroxyl group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, and a heterocyclic group;

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

[0038] t is 0, 1, or 2.

[0039] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0040] in:

[0041] is a single bond or a double bond;

[0042] Q 1 is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are each independently optionally substituted by one or more R Q1 replace;

[0043] Z 2is selected from hydrogen atom, cycloalkyl, heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted by one or more R Z2 replace;

[0044] Z 1 Selected from bond, -heterocyclyl-, -heterocyclyl-L 2A -、-L 2A -Heterocyclyl-, -heteroaryl-L 2A -、-N=、-NR aa -L 2A -and-NR aa -C(O)-NR bb -L 2A -, the heterocyclic group and heteroaryl are each independently optionally substituted by one or more R Z1 replaced by;

[0045] L 2A is selected from the group consisting of a bond, an alkyl group, and -N=;

[0046] for

[0047] Y is selected from C(O), S(O), S(O)2 and alkylene;

[0048] R 1 、R 2 and R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -(CH2) x NR 11a R 11b 、-(CH2) x C(O)NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0049] Ring A is selected from and R A and Q 2 substituted bicyclic heteroaryl; the bicyclic heterocyclic group is optionally substituted by one or more R 01 replaced by;

[0050] R A for

[0051] Q 2 is selected from cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R Q2 replaced by;

[0052] X 1 CR x1 or N;

[0053] R 4 、R 5 、R 6 and R x1 When present, they are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, -(CH2) x NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-(CH2) x C(O)NR 11a R11b 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0054] or Q 2 、R 6 Together with the carbon atom to which it is attached, it forms ring B, or Q 2 、R 5 Together with the carbon atom to which it is attached, it forms Ring B; or, R Q2 、R 6 Together with the ring atoms to which it is attached, it forms ring B 0 , or R Q2 、R 5 Together with the ring atoms to which it is attached, it forms ring B 0 ;

[0055] Each ring B is independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the ring B is optionally substituted by one or more R B Replaced; each ring B 0 are independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and the ring B 0 Optionally one or more R B replaced by;

[0056] R 9 Selected from -C(O)OR 12 、-C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O)t NR 11a R 11b , heterocyclic and heteroaryl, each of which is independently optionally substituted by one or more R 9a replaced by;

[0057] R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -(CH2) x NR 11a R 11b 、-(CH2) x C(O)NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced; or

[0058] R 7 、R 8Together with the atoms to which it is attached, it forms a 3- to 5-membered cycloalkyl or heterocyclic group, wherein the 3- to 5-membered cycloalkyl and heterocyclic group are each independently optionally substituted by one or more R 78 replaced by;

[0059] n1 is 0, 1, 2, 3, 4 or 5; n2 is 0, 1, 2, 3, 4 or 5;

[0060] Each R Q1 、R Z2 、R Z1 、R 01 、R Q2 、R B 、R 9a and R 78 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -(CH2) x NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-(CH2) x C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 , cycloalkyl, heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl are each independently optionally substituted by one or more R* replaced by;

[0061] or, R Z2 、R Z1 Together with the ring atoms to which it is attached, they form Ring C;

[0062] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and said ring C is optionally substituted by one or more R C replaced by;

[0063] Each R * and R C are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, -(CH2) x NR 11a R 11b 、-NR 00 C(O)R 12 、-C(O)R 12 、-C(O)OR 12 、-(CH2) x C(O)NR 11a R 11b 、-S(O) t R 12 、-S(O) t NR 11a R 11b 、-NR 00 S(O) t R 12 、-(CH2) x P(O)R 12 R 13 、-OC(O)R 12 、-S(O) t OR 12 、-OS(O) t R 12 、-OR 12 、=CR 12a R 13a 、=NR 00 、C(=NR 00 )R 12 、S(=NR 00 )(O)R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0064] Each R 11a 、R 11b 、R 12 and R 13 are the same or different and are each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyalkyl, haloalkyl, -C(O)R 15 、-C(O)OR 15 、-OC(O)R 15 、-(CH2) y NR 14a R 14b 、-(CH2) y C(O)NR 14a R 14b 、-NR0C(O)R 15 、-S(O) t R 15 、-S(O) t NR 14a R 14b 、-NR 0 S(O) t R 15 、-S(O) t OR 15 、-OS(O) t R 15 、-OR 15 , 4 to 12 membered cycloalkyl and heterocyclic groups; or R 11a and R 11b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0065] Each R aa 、R bb 、R 00 and R 0 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a haloalkyl group, a C(O)alkyl group, an amide group, a cycloalkyl group, and a heterocyclic group;

[0066] Each R 12a and R 13a are the same or different and are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic groups; or R 12a 、R 13aThe carbon atom to which it is attached forms a cycloalkyl group or a heterocyclyl group, wherein the cycloalkyl group and the heterocyclyl group are each independently optionally substituted by one or more substituents selected from halogen, cyano, amino, hydroxy, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl;

[0067] Each R 15 、R 14a and R 14b are the same or different and are each independently selected from hydrogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, C(O)alkyl, amino, amide, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, cyano, nitro, amino, hydroxy, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl;

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

[0069] t is 0, 1, or 2.

[0070] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof:

[0071] in,

[0072] X 2 、X 3 and X 4 The same or different, and each independently CR Z1a or N; R Z1a is a hydrogen atom or R Z1 ;

[0073] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、Z 2 and R Z1 As defined in general formula (I).

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM-1) or a pharmaceutically acceptable salt thereof:

[0075] Where a is 0, 1, 2 or 3;

[0076] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、R Z1 and Z 2 As defined in general formula (I).

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IM), (IM-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM-2) or a pharmaceutically acceptable salt thereof:

[0078] Among them, R cc is selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, and a cycloalkyl group;

[0079] a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4;

[0080] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、R Z1 and R Z2 As defined in general formula (I).

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof:

[0082] in, is a single bond or a double bond;

[0083] X is selected from a bond, CR Z2c R Z2d CR Z2c R Z2d , CR Z2c R Z2d 、O、NR cc , CR Z2c R Z2d O. OCR Z2c R Z2d and C(O);X 5 Select from key, CR Z2e R Z2f CR Z2e R Z2f , CR Z2e R Z2f 、O、NR cc , CR Z2e RZ2f O. OCR Z2e R Z2f and C(O);

[0084] R Z2a 、R Z2c 、R Z2d 、R Z2e and R Z2f are the same or different and are each independently a hydrogen atom or R Z2 ; or R Z2c 、R Z2d Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, or R Z2e 、R Z2f Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, or R Z2c 、R Z2e Together with the carbon atoms to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group formed are each independently optionally substituted by one or more selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl and heterocyclic groups;

[0085] R Za and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ;

[0086] Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; c is 0, 1, 2, 3, 4, 5 or 6;

[0087] R cc is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are each independently optionally substituted by one or more selected from a deuterium atom, a halogen, a hydroxyl group, an alkyl group, an alkoxy group and a cycloalkyl group;

[0088] Ring A, Y, R 1 、R 2 、R 3 , Q 1 and R Z2 As defined in general formula (I).

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof:

[0090] in,

[0091] is a single bond or a double bond;

[0092] X is selected from a bond, CR Z2c R Z2d CRZ2c R Z2d , CR Z2c R Z2d 、O、NR cc , CR Z2c R Z2d O. OCR Z2c R Z2d and C(O);X 5 Select from key, CR Z2e R Z2f CR Z2e R Z2f , CR Z2e R Z2f 、O、NR cc , CR Z2e R Z2f O. OCR Z2e R Z2f and C(O);

[0093] R Z2a 、R Z2c 、R Z2d 、R Z2e and R Z2f are the same or different and are each independently a hydrogen atom or R Z2 ;

[0094] R Za and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ;

[0095] Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0096] R cc is selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, and a cycloalkyl group; c is 0, 1, 2, 3, 4, 5, or 6;

[0097] Ring A, Y, R 1 、R 2 、R 3 , Q 1 and R Z2 As defined in general formula (I).

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IN) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN-1) or a pharmaceutically acceptable salt thereof:

[0099] in,

[0100] X 6 Selected from NR cc , O and S; X7 CR Zh or N; X 8 CR Ze or N;

[0101] R Ze and R Zh are the same or different and are each independently a hydrogen atom or R Z2 ;

[0102] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、R Z2a 、 X, X 5 、R Za 、R Zd 、R cc and R Z2 As defined in formula (IN).

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IP) or a pharmaceutically acceptable salt thereof:

[0104] Where a is 0, 1, 2 or 3;

[0105] R Z2b 、R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ;

[0106] or R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, or R Zc 、R Zd Together with the carbon atom to which it is attached, it forms ring D; ring D is optionally substituted by c R Z2 replaced by;

[0107] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、 R Z1 、R Z2 , Ring D and c are as defined in the general formula (IN).

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IP) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IP-1) or a pharmaceutically acceptable salt thereof:

[0109] in,

[0110] R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ;

[0111] or, R Za 、R Zb Together with the carbon atom to which it is attached, it forms a ring D, or R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, or R Zc 、R Zd Together with the carbon atom to which it is attached, it forms ring D; ring D is optionally substituted by c R Z2 substituted; a is 0, 1, 2 or 3;

[0112] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、 R Z2 ,X,X 5 , Ring D and c are as defined in the general formula (IN).

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP), or (IP-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IP-2) or (IP-3) or a pharmaceutically acceptable salt thereof:

[0114] in,

[0115] a is 0, 1, 2, or 3;

[0116] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、 R Z2 ,X,X 5 、R Za 、R Zd , Ring D and c are as defined in the general formula (IN); X 6 、X 7 and X8 As defined in general formula (IN-1).

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof:

[0118] in,

[0119] R Zf and R Zg are the same or different and are each independently a hydrogen atom or R Z2 , or R Zf 、R Zg Together with the carbon atom to which it is attached, it forms ring E; ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and ring E is optionally substituted by 1, 2, 3 or 4 R Z2 replaced by;

[0120] Ring A, Y, R 1 、R 2 、R 3 , Q 1 、R Z2a 、 X, X 5 and R Z2 As defined in formula (IN).

[0121] In some embodiments of the present 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:

[0122] in,

[0123] R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ;

[0124] R 9a ' is a hydrogen atom or an alkyl group; q is 0, 1, 2, 3, 4, 5 or 6;

[0125] Q 1 , Z 1 , Z 2 、R 1 to R 6 、X 1 、R 78 and R Q2 As defined in general formula (I).

[0126] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0127] in,

[0128] q is 0, 1, 2, 3, 4, 5 or 6; a is 0, 1, 2 or 3;

[0129] Q 1 、Z 2 、R Z1 、R 1 to R 6 、X 1 、R A and R Q2 As defined in general formula (I).

[0130] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or (IV') or a pharmaceutically acceptable salt thereof:

[0131] in,

[0132] m is 0, 1, 2, 3, 4, 5 or 6;

[0133] Ring B, X 1 , Q 1 、Z 1 、Z 2 、R 1 to R 4 、R 5 、R 6 、R A and R B As defined in general formula (I).

[0134] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, for

[0135] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein Y is C(O).

[0136] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (III), (IV), (IV'), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, for In some embodiments, for R 1 、R 2 and R 3 As defined in formula (I), and R 3 Not a hydrogen atom;

[0137] In some embodiments, Optionally 1, 2 or 3 selected from R 01 Substituents, R 01 As defined in general formula (I).

[0138] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein Ring A is X 1 , Q 2 、R A 、R 4 、R 5 and R 6 As defined in formula (I); in some embodiments, ring A is q is 0, 1, 2, 3, 4, 5, or 6; X 1 、R A 、R 4 、R 5 、R 6 and R Q2 As defined in formula (I);

[0139] In some embodiments, Ring A is q is 1, 2, 3, 4, 5, or 6; X 1 、R A 、R 4 、R 5 、R 6 and R Q2 As defined in formula (I);

[0140] In some embodiments, Ring A is Ring B, R B ,m,X1 、R A 、R 4 and R 5 As defined in formula (IV); in some embodiments, Ring A is Ring B, R B ,m,X 1 、R A 、R 4 and R 6 As defined in formula (IV');

[0141] In some embodiments, Ring A is

[0142] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IV), (IV') or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 12-membered heterocyclic group; in some embodiments, ring B is a 7- to 12-membered bicyclic heterocyclic group; in some embodiments, ring B is a 10-membered bicyclic heterocyclic group; in some embodiments, ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is For X 1 The fusion site of the ring.

[0143] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B 0 is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl; in some embodiments, ring B 0 is a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group; in some embodiments, ring B 0 is a 5- or 6-membered heterocyclic group; in some embodiments, ring B 0 is a hydrogenated furanyl or a hydrogenated pyranyl; in some embodiments, ring B 0 It is a hydrogenated furanyl.

[0144] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IV), (IV') or a pharmaceutically acceptable salt thereof, wherein each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R B The same or different, and each independently is C 1-6 alkyl; in some embodiments, each R B are the same or different and are each independently methyl.

[0145] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IV), (IV') or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; in some embodiments, m is 0.

[0146] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein Q 2 is a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the 3- to 12-membered heterocyclic group and the 5- to 10-membered heteroaryl group are each independently optionally substituted by one or more R Q2 Replaced by R Q2 As defined in formula (I); in some embodiments, Q 2 is optionally replaced by one or more R Q2 substituted 3 to 6 membered heterocyclic group, R Q2 As defined in formula (I); in some embodiments, Q 2 is optionally replaced by one or more R Q2 Substituted tetrahydropyranyl, R Q2 As defined in formula (I);

[0147] In some embodiments, Q 2 for q is 0, 1, 2, 3, 4, 5 or 6, R Q2 As defined in formula (I); in some embodiments, Q 2 for q is 1, 2, 3, 4, 5 or 6, R Q2 As defined in formula (I);

[0148] In some embodiments, Q 2 for R Qa is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl and heterocyclic groups, R Qb is a hydrogen atom or R Q2 , R Q2 As defined in formula (I); in some embodiments, Q 2 for

[0149] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein for In some embodiments, for In some embodiments, for q is 1, 2, 3, 4, 5 or 6, R Q2 As defined in formula (I);

[0150] In some embodiments, for R Qa is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl and heterocyclic groups, R Qb is a hydrogen atom or R Q2 , R Q2 As defined in formula (I); in some embodiments, for

[0151] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R Q2 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R Q2 is methyl; in some embodiments, each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl;

[0152] In some embodiments, each R Q2 The same or different, and each independently is C 1-6 Alkyl, or R Q2 、R 6 Together with the carbon atom to which it is attached, it forms ring B 0 , or R Q2 、R 5 Together with the carbon atom to which it is attached, it forms ring B 0 , Ring B 0 is a 5- or 6-membered heterocyclyl; in some embodiments, each R Q2 The same or different, and each independently is C 1-6 Alkyl; or R Q2 、R6 Together with the carbon atom to which it is attached, it forms ring B 0 , Ring B 0 is a 5- or 6-membered heterocyclic group.

[0153] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein q is 1, 2 or 3; in some embodiments, q is 2; in some embodiments, q is 0, 1 or 2.

[0154] In some embodiments of the present disclosure, R Qa Selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R Qb Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Qa C 1-6 Alkyl, and / or R Qb C 1-6 Alkyl; in some embodiments, R Qa is methyl, and / or R Qb It is a methyl group.

[0155] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (IV') or a pharmaceutically acceptable salt thereof, wherein Z 1 is optionally replaced by one or more R Z1 substituted 3 to 12 membered heterocyclic group, R Z1 As defined in formula (I); in some embodiments, Z 1 Selected from bond, -N=, and a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally substituted by one or more R Z1 substituted, a is 0, 1, 2 or 3, is a single bond or a double bond, R Z1 As defined in formula (I); in some embodiments, Z 1 is optionally replaced by one or more R Z1 substituted 5- or 6-membered heterocyclic group, R Z1 As defined in formula (I); in some embodiments, Z 1 is optionally replaced by one or more R Z1 Substituted dihydroimidazolyl, R Z1 As defined in formula (I); in some embodiments, Z 1 Selected from In some embodiments, Z 1 for In some embodiments, Z 1 for In some embodiments, Z 1 for In some embodiments, Z 1 is the key;

[0156] In some embodiments, Z 1 for X 2 、X 3 and X 4 The same or different, and each independently CR Z1a or N; R Z1a is a hydrogen atom or R Z1 ; R Z1 As defined in formula (I);

[0157] In some embodiments, Z 1 Selected from bond, -N=, R Z1a is a hydrogen atom or R Z1 ; a is 0, 1, 2 or 3; a1 is 0, 1, 2, 3 or 4; R Z1 As defined in formula (I);

[0158] In some embodiments, Z 1 Selected from bond, -N=, In some embodiments, Z 1 Select from key, R Z1 is a hydrogen atom, or R Z1 、R Z2 Together with the atoms to which it is attached, it forms a 6- or 7-membered heterocyclic group; in some embodiments, Z 1 Selected from R Z1a is a hydrogen atom or R Z1 , R Z1 As defined in formula (I); in some embodiments, Z 1 Selected from R Z1a Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, Z 1 Selected from

[0159] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM), (IM-1), (IM-2) or pharmaceutically acceptable salts thereof, wherein each R Z1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, oxo, and amino; in some embodiments, each R Z1 are the same or different and are each independently selected from oxo, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Z1 is oxo; in some embodiments, R Z1 is methyl; in some embodiments, each R Z1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0160] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IM-1), (IM-2), (IP) to (IP-3), (III) or pharmaceutically acceptable salts thereof, wherein a is 0.

[0161] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM) or a pharmaceutically acceptable salt thereof, wherein in some embodiments, X 2 is selected from C-methyl, CF, CH and N; X 2 is CH or N; in some embodiments, X 2 For CH.

[0162] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM) or a pharmaceutically acceptable salt thereof, wherein X 3 CR Z1a or N, R Z1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, X 3 is CH or N; in some embodiments, X 3 For CH.

[0163] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM) or a pharmaceutically acceptable salt thereof, wherein X 4 is CH or N; in some embodiments, X 4 For CH.

[0164] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM-2) or a pharmaceutically acceptable salt thereof, wherein b is 0, 1 or 2; in some embodiments, b is 0 or 1; in some embodiments, b is 0.

[0165] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IM) or a pharmaceutically acceptable salt thereof, wherein R Z1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, R Z1a A hydrogen atom or C 1-6 Alkyl; in some embodiments, R Z1a is a hydrogen atom or a methyl group; in some embodiments, R Z1a is a hydrogen atom; in some embodiments, R Z1a Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R Z1a is a hydrogen atom or a halogen; in some embodiments, R Z1a is selected from a hydrogen atom, F, a methyl group and a cyclopropyl group.

[0166] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM), (IM-1) or pharmaceutically acceptable salts thereof, wherein Z 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl and the 5- to 10-membered heteroaryl are each independently optionally substituted by one or more R Z2 In some embodiments, Z 2 is a hydrogen atom or optionally replaced by one or more R Z2 substituted 5- to 10-membered heteroaryl; in some embodiments, Z 2 is optionally replaced by one or more R Z2 substituted 5- to 10-membered heteroaryl; in some embodiments, Z 2 is optionally replaced by one or more R Z2 Substituted indazolyl; R Z2 As defined in formula (I);

[0167] In some embodiments, Z 2 for R Za 、R Zd 、X 6 、X 7 and X 8 As defined in formula (IN-1);

[0168] In some embodiments, Z 2 for R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ; c is 0, 1, 2, 3, 4, 5 or 6; Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R Z2 As defined in formula (I);

[0169] In some embodiments, Z 2 Selected from hydrogen atoms, In some embodiments, Z 2 for In some embodiments, Z 2 Selected from hydrogen atoms,

[0170] In some embodiments, Z 2 for R Z2b is a hydrogen atom or R Z2 , R Z2 、R Za 、R Zd 、X 6 、X 7 and X 8 As defined in Formula (IN-1); in some embodiments, Z 2 for R Z2b is a hydrogen atom or R Z2 , R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ; c is 0, 1, 2, 3, 4, 5 or 6; Ring D is heteroaryl; R Z2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and 3 to 6-membered cycloalkyl, or R Z2 、R Z1 Together with the ring atoms to which it is attached, it forms a heterocyclic group; said heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group;

[0171] In some embodiments, Z2 Selected from hydrogen atoms, R Z2b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and 3 to 6 membered cycloalkyl, or R Z2b 、R Z1 Together with the ring atoms to which it is attached, it forms a 6- or 7-membered heterocyclic group, R Zd Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and 3 to 6-membered cycloalkyl, R cc Selected from hydrogen atoms, C 1-6 Alkyl, 3 to 6 membered cycloalkyl and C 1-6 deuterated alkyl;

[0172] In some embodiments, Z 2 Selected from hydrogen atoms, R Z2b is a hydrogen atom, or R Z2b 、R Z1 Together with the ring atoms to which it is attached, it forms a 6- or 7-membered heterocyclic group; in some embodiments, Z 2 Selected from hydrogen atoms,

[0173] In some embodiments, Z 2 A hydrogen atom or R Z2b is a hydrogen atom, R Zd Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R cc Selected from hydrogen atoms, C 1-6 Alkyl, 3 to 6 membered cycloalkyl and C 1-6 deuterated alkyl; in some embodiments, Z 2 Selected from

[0174] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (IV') or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, Selected from In some embodiments, for

[0175] In some embodiments, Selected from Group A: In some embodiments, From Group B:

[0176] In some embodiments, From Group C:

[0177] In some embodiments, a group selected from Group A, Group B, and Group C (in some embodiments, a group from Group C);

[0178] In some embodiments, Selected from c is 0, 1 or 2, R cc Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6 The alkyl group and the 3 to 6 membered cycloalkyl group are each independently optionally selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 substituted by one or more of alkoxy, hydroxy and 3 to 6-membered cycloalkyl; each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3- to 6-membered cycloalkyl;

[0179] In some embodiments, for R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently a hydrogen atom or R Z2 ; or, R Za 、R Zb Together with the carbon atom to which it is attached, it forms a ring D, or R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, or R Zc 、R Zd Together with the carbon atom to which it is attached, it forms a ring D; said ring D is optionally substituted with c R Z2 replaced by; R Z2a ,X,X 5 、R Z2 , Ring D and c are as defined in the general formula (IN).

[0180] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IN-1), (IO) or a pharmaceutically acceptable salt thereof, wherein R Z2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, R Z2a A hydrogen atom.

[0181] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IN-1), (IP) to (IP-3), (IO) or a pharmaceutically acceptable salt thereof, wherein is a single bond; in some embodiments, For double bonds.

[0182] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IN), (IN-1), (IP-1) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein X is selected from CH2, CH2CH2, CHO, OCH2, O, NH and N(methyl); in some embodiments, X is selected from CHO, OCH2, CH2, O and N(methyl); in some embodiments, X is O; in some embodiments, X is selected from CH2, CH2CH2, CHO, OCH2, O, NH, N(methyl), CH(methyl), CHcyclopropyl, CF2 and

[0183] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IN-1), (IP-1) to (IP-3), (IO) or a pharmaceutically acceptable salt thereof, wherein X 5 is selected from CH2, CH2CH2, CHO, OCH2, O, NH and N(methyl); in some embodiments, X 5 is CH2; in some embodiments, X 5 is O or CH2.

[0184] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IN-1), (IP-1) to (IP-3), (IO) or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, Selected from

[0185] Among them, R cc A hydrogen atom or C 1-6 Alkyl (in some embodiments R cc is a hydrogen atom or a methyl group); in some embodiments, Selected from In some embodiments, Selected from

[0186] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP), (IP-1) or a pharmaceutically acceptable salt thereof, wherein R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NR 11a R 11b and P(O)R 12 R 13 , R 11a 、R 11b 、R 12 and R 13 As defined in formula (I); in some embodiments, R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently selected from hydrogen, halogen, NR 11a R 11b and P(O)R 12 R 13 ; R 11a 、R 11b 、R 12 and R 13 As defined in formula (I); in some embodiments, R Za 、R Zb 、R Zc and R Zd are the same or different and are each independently selected from hydrogen atom, F, methylamino and

[0187] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP), (IP-1) or a pharmaceutically acceptable salt thereof, wherein R Zb and R Zc are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NR 11a R 11b and P(O)R 12 R 13 , or R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, which is optionally substituted by c R Z2 Replaced by R 11a 、R 11b 、R 12 、R 13 、R Z2 , Ring D and c are as defined in Formula (IN); in some embodiments, R Zb and R Zc are the same or different and are each independently selected from hydrogen, halogen, NR 11a R 11b and P(O)R 12 R 13 , or R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, which is optionally substituted by c R Z2 Replaced by R 11a 、R 11b 、R 12 、R 13 、R Z2 , Ring D and c are as defined in Formula (IN); in some embodiments, R Zb 、R Zc Together with the carbon atom to which it is attached, it forms a ring D, which is optionally substituted by c R Z2 substituted; ring D, c and R Z2 As defined in formula (IN).

[0188] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP), (IP-1) or a pharmaceutically acceptable salt thereof, wherein R Zb Selected from hydrogen atoms, halogens and NR 11a R 11b , R 11a and R 11b As defined in formula (I); in some embodiments, R Zb NR 11a R 11b , R 11a and R 11b The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R Zb It is a methylamino group.

[0189] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP), (IP-1) or a pharmaceutically acceptable salt thereof, wherein R Zc Selected from hydrogen atoms, halogens and P(O)R 12 R 13 , R 12 and R 13 As defined in formula (I); in some embodiments, R Zc F or In some embodiments, R Zc is halogen; in some embodiments, R Zc P(O)R 12 R 13 , R 12 and R 13 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R Zc for

[0190] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (IN), (IN-1), (IP), (IP-1) to (IP-3) or pharmaceutically acceptable salts thereof, wherein R Za and R Zd are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Za and R Zd are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R Za is a hydrogen atom, and / or R Zd is halogen; in some embodiments, R Za is a hydrogen atom, and / or R Zd For F.

[0191] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), or (IP-2), or a pharmaceutically acceptable salt thereof, wherein ring D is a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group; in some embodiments, ring D is a 4- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; in some embodiments, ring D is a 5- to 10-membered heteroaryl group; in some embodiments, ring D is a 5-membered heteroaryl group; in some embodiments, ring D is a pyrazolyl group; in some embodiments, ring D is selected from In some embodiments, Ring D is Both are fused sites with phenyl groups.

[0192] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM), (IM-1), (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR 11a R 11b and P(O)R 12 R 13 , the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic groups are each independently optionally selected from deuterium atoms, oxo groups, halogens, cyano groups, C 1-6 Alkyl, C 1-6 is substituted by one or more of an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, and R 11a 、R 11b 、R 12 and R 13 As defined in Formula (I); in some embodiments, each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, NR 11a R 11b and P(O)R 12 R 13 , R 11a 、R 11b 、R 12 and R 13 As defined in Formula (I); in some embodiments, each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Z2 is methyl or F; in some embodiments, each R Z2 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R Z2 is methyl; in some embodiments, each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 deuterated alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R Z2 are the same or different and are each independently selected from F, methyl, deuterated methyl and cyclopropyl; in some embodiments, each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl, NR 11a R 11b and P(O)R 12 R 13 , R 11a 、R 11b 、R 12 and R 13 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3 to 6 membered cycloalkyl and C 1-6 Alkoxy C 1-6 alkyl; in some embodiments, each R Z2 are the same or different and are each independently selected from F, cyano, methyl, methoxy, trideuteromethyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoroethyl and methoxymethyl; in some embodiments, each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and 3 to 6 membered cycloalkyl are each independently optionally substituted with one or more selected from deuterium atoms, halogens and 3 to 6 membered cycloalkyl; in some embodiments, each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, 3 to 6 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; in some embodiments, R Z2 is tert-butyl or -CH2cyclopropyl.

[0193] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IP-2) or a pharmaceutically acceptable salt thereof, wherein c is 0, 1 or 2; in some embodiments, c is 0 or 1; in some embodiments, c is 1.

[0194] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN-1), (IP-3) or a pharmaceutically acceptable salt thereof, wherein X 6 NR cc , R cc As defined in Formula (IN); in some embodiments, X 6 NR cc , R cc is a hydrogen atom or a methyl group; in some embodiments, X 6 is N(methyl).

[0195] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN-1), (IP-3) or a pharmaceutically acceptable salt thereof, wherein X 7 is CH or N; in some embodiments, X 7 is N.

[0196] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN-1), (IP-3) or a pharmaceutically acceptable salt thereof, wherein X 8 is CH or N; in some embodiments, X 8 For CH.

[0197] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN), (IN-1), (IP-1) to (IP-3), (IO) or a pharmaceutically acceptable salt thereof, wherein R cc A hydrogen atom or C 1-6 Alkyl; in some embodiments, R cc C 1-6 Alkyl; in some embodiments, R cc is methyl; in some embodiments, R cc is a hydrogen atom; in some embodiments, R cc Selected from hydrogen atoms, C 1-6 Alkyl, 3 to 6 membered cycloalkyl and C 1-6 deuterated alkyl; in some embodiments, Rcc is selected from hydrogen, methyl, cyclopropyl, and deuterated methyl; in some embodiments, R cc Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl and C 1-6 Hydroxyalkyl; in some embodiments, R cc is selected from the group consisting of hydrogen, methyl, cyclopropyl, deuterated methyl, difluoromethyl, difluoroethyl, trifluoroethyl, and methoxymethyl; in some embodiments, R cc is methoxyethyl or isopropyl; in some embodiments, R cc is methoxyethyl; in some embodiments, R cc is isopropyl; in some embodiments, R cc is tert-butyl or -CH2cyclopropyl; in some embodiments, R cc is a hydrogen atom or R Z2 In some embodiments, R cc Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 8 membered cycloalkyl, the C 1-6 The alkyl group and the 3 to 8 membered cycloalkyl group are each independently optionally substituted with one or more R Z2 Replacement; R Z2 As defined in general formula (I).

[0198] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN-1), (IP-3) or a pharmaceutically acceptable salt thereof, wherein R Ze Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, R Ze A hydrogen atom.

[0199] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IN-1), (IP-3) or a pharmaceutically acceptable salt thereof, wherein R Zh Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, R Zh A hydrogen atom.

[0200] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IP) or a pharmaceutically acceptable salt thereof, wherein R Z2b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; in some embodiments, R Z2b A hydrogen atom.

[0201] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IO) or a pharmaceutically acceptable salt thereof, wherein R Zf and R Zg are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, phenyl and 5 or 6-membered heteroaryl, wherein the phenyl and 5 or 6-membered heteroaryl are each independently optionally selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R Zf is a hydrogen atom, R Zg is phenyl, or R Zg is a hydrogen atom, R Zf is phenyl, said phenyl being optionally selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R Zf is a hydrogen atom, R Zg is a halogenated phenyl group, or R Zg is a hydrogen atom, R Zf is a halogenated phenyl group; in some embodiments, R Zf is a hydrogen atom, R Zg for or R Zg is a hydrogen atom, R Zf for

[0202] In some embodiments, R Zf 、R Zg Together with the carbon atoms to which it is attached, it forms Ring E, and Ring E is optionally substituted by 1, 2, 3 or 4 R Z2 substituted, ring E and R Z2 As defined in Formula (IO); in some embodiments, R Zf 、R Zg The carbon atom to which it is attached forms an optionally substituted 1, 2, 3 or 4 R Z2 Substituted indazolyl, RZ2 As defined in general formula (I).

[0203] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (IO) or a pharmaceutically acceptable salt thereof, wherein ring E is a 6- to 10-membered aryl group or a 5- to 14-membered heteroaryl group; in some embodiments, ring E is a phenyl group or a 5- to 14-membered heteroaryl group; in some embodiments, ring E is a phenyl group or an indazolyl group; in some embodiments, ring E is a 5- to 14-membered heteroaryl group; in some embodiments, ring E is an indazolyl group; in some embodiments, ring E is a 9- or 10-membered bicyclic heteroaryl group; in some embodiments, ring E is a 6- to 10-membered aryl group; in some embodiments, ring E is a phenyl group.

[0204] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein Q 1 is a 6- to 14-membered aryl or a 5- to 14-membered heteroaryl, wherein the 6- to 14-membered aryl and the 5- to 14-membered heteroaryl are each independently optionally substituted by one or more R Q1 Replacement, R Q1 As defined in formula (I); in some embodiments, Q 1 is phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted by one or more R Q1 Replacement, R Q1 As defined in formula (I); in some embodiments, Q 1 is optionally replaced by one or more R Q1 Substituted phenyl, R Q1 As defined in formula (I); in some embodiments, Q 1 for In some embodiments, Q 1 for In some embodiments, Q 1 for

[0205] In some embodiments, Q 1 for In some embodiments, Q 1 for R Q1a 、R Q1b 、R Q1c 、R Q1d and R Q1f are the same or different and are each independently a hydrogen atom or R Q1 , Ring D is a heterocyclic group or a heteroaryl group, d is 0, 1, 2, 3 or 4; RQ1 As defined in formula (I); in some embodiments, Q 1 Selected from R Q1a 、R Q1b 、R Q1c 、R Q1d and R Q1f are the same or different and are each independently a hydrogen atom or R Q1 , R Q1 As defined in formula (I); in some embodiments, Q 1 Selected from In some embodiments, Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0206] In some embodiments, Q 1 is a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R Q1 Replacement, R Q1 As defined in general formula (I).

[0207] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein each R Q1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R Q1 are the same or different and are each independently methyl or F.

[0208] In some embodiments of the present disclosure, R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R Q1a C 1-6 Alkyl, and / or R Q1b is halogen, and / or R Q1c C 1-6 Alkyl; in some embodiments, RQ1a is methyl, and / or R Q1b F, and / or R Q1c is methyl; in some embodiments, R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen, F, methyl and cyclopropyl; in some embodiments, R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl and 3- to 6-membered cycloalkyl.

[0209] In some embodiments of the present disclosure, R Q1a 、R Q1d and R Q1f are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Q1a is a hydrogen atom, and / or R Q1d is a hydrogen atom, and / or R Q1f C 1-6 Alkyl; in some embodiments, R Q1a is a hydrogen atom, and / or R Q1d is a hydrogen atom, and / or R Q1f It is a methyl group.

[0210] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (III), (IV), (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 9 is a 3- to 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group, wherein the 3- to 6-membered heterocyclic group and the 5- or 6-membered heteroaryl group are each independently optionally substituted by one or more R 9a Replaced by R 9a As defined in formula (I); in some embodiments, R 9 is optionally replaced by one or more R 9a substituted 5-membered heterocyclic group, R 9a As defined in formula (I); in some embodiments, R 9 is optionally replaced by one or more R 9a The substituted 5-membered heterocyclic group, at least one R 9a is oxo; in some embodiments, R 9 for R 9a ' is a hydrogen atom or C 1-6 Alkyl; in some embodiments, R9 is optionally replaced by one or more R 9a substituted 5-membered heteroaryl, R 9a As defined in formula (I); in some embodiments, R 9 for In some embodiments, R 9 for In some embodiments, R 9 for

[0211] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (III), (IV), (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 7 、R 8 Together with the atoms to which it is attached, it forms a 3- to 5-membered cycloalkyl group, wherein the 3- to 5-membered cycloalkyl group is optionally substituted by one or more R 78 Replaced by R 78 As defined in formula (I); in some embodiments, R 7 、R 8 Together with the atoms to which it is attached, it forms a 78 Substituted cyclopropyl, R 78 As defined in formula (I); in some embodiments, R 7 、R 8 Together with the atoms to which it is attached, it forms a cyclopropyl group which is optionally substituted with a methyl group.

[0212] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (III), (IV), (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein n1 is 0 or 1, and / or n2 is 0 or 1; in some embodiments, n1 is 0, and / or n2 is 0.

[0213] (IN), (IN-1) In some embodiments of the present disclosure, the compounds represented by the general formula (I), (III), (IV), (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R A for R 7a and R 8a are the same or different and are each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C1-6 Alkyl, R 78 As defined in formula (I);

[0214] In some embodiments, R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, R 78 As defined in formula (I);

[0215] In some embodiments, R A for In some embodiments, R A for In some embodiments, R A for R 7a and R 8a are the same or different and are each independently a hydrogen atom or R 78 ; R 9a 'Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl and 3 to 6-membered cycloalkyl, R 78 As defined in formula (I); in some embodiments, R A for

[0216] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 7a and R 8a are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 7a and R 8a The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0217] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 7a and R 8a Different, and each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 7a and R 8a Different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0218] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 7a A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 7a C 1-6 Alkyl; in some embodiments, R 7a It is a methyl group.

[0219] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 8a A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 8a A hydrogen atom.

[0220] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 78 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 78 It is a methyl group.

[0221] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 9a’ Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 haloalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 9a’ A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 9a’ A hydrogen atom.

[0222] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each R 9a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 9a The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 9a It is a methyl group.

[0223] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 3 Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0224] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 1 is a hydrogen atom, and / or R 2 is a hydrogen atom, and / or R 3 C 1-6 alkyl.

[0225] In some embodiments of the present disclosure, R 1 is a hydrogen atom, and / or R 2 is a hydrogen atom, and / or R 3 C 1-6 Alkyl, and / or R 4 、R 5 and R 6 is a hydrogen atom, and / or X 1 For CH.

[0226] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 1 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 1 A hydrogen atom.

[0227] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 2 A hydrogen atom or C 1-6Alkyl; in some embodiments, R 2 A hydrogen atom.

[0228] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4 A hydrogen atom.

[0229] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 5 A hydrogen atom.

[0230] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 6 A hydrogen atom.

[0231] In some embodiments of the present disclosure, R 4 is a hydrogen atom, and / or R 5 is a hydrogen atom, and / or R 6 is a hydrogen atom. In some embodiments of the present disclosure, R 4 is a hydrogen atom, and / or R 5 is a hydrogen atom. In some embodiments of the present disclosure, R 4 is a hydrogen atom, and / or R 6 A hydrogen atom.

[0232] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or pharmaceutically acceptable salts thereof, wherein X 1 is CH or N; in some embodiments, X 1 is CH; in some embodiments, X1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl.

[0233] In some embodiments of the present disclosure, the compound represented by the general formula or a pharmaceutically acceptable salt thereof, wherein R x1 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R x1 A hydrogen atom.

[0234] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclyl; in some embodiments, ring C is a 5- or 6-membered heterocyclyl; in some embodiments, ring C is a 6- or 7-membered heterocyclyl.

[0235] In some embodiments of the present disclosure, each R * are the same or different and are each independently selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, oxo, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6 membered heterocyclic group C 1-6 alkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; in some embodiments, each R * are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0236] In some embodiments of the present disclosure, each R C are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0237] In some embodiments of the present disclosure, R 11a and R 11b The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 11a and R 11b are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 11a and R 11b are all hydrogen atoms; in some embodiments, R 11a is a hydrogen atom, and / or R 11b It is a methyl group.

[0238] In some embodiments of the present disclosure, R aa 、R bb 、R 00 and R 0 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R aa 、R bb 、R 00 and R 0 are the same or different and are each independently a hydrogen atom or a methyl group.

[0239] In some embodiments of the present disclosure, R 12 and R 13 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 12 and R 13 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 12 and R 13 All are methyl.

[0240] In some embodiments of the present disclosure, R 12 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 12 A hydrogen atom.

[0241] In some embodiments of the present disclosure, R 15 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 15 A hydrogen atom.

[0242] In some embodiments of the present disclosure, R 14a and R 14b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 14a and R 14b are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 14a and R 14b All are hydrogen atoms.

[0243] In some embodiments of the present disclosure, R 12a and R 13a are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl.

[0244] In some embodiments of the present disclosure, x is 0, 1, or 2; in some embodiments, x is 0.

[0245] In some embodiments of the present disclosure, y is 0, 1 or 2; in some embodiments, y is 0.

[0246] In some embodiments of the present disclosure, R Z2c 、R Z2d 、R Z2e and R Z2f are the same or different and are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3 to 6-membered cycloalkyl, or R Z2c 、R Z2d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, or R Z2c 、R Z2d The two adjacent carbon atoms to which it is connected together form a 3- to 6-membered cycloalkyl group, or R Z2e 、R Z2f Together with the same carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R Z2c 、R Z2d 、R Z2e and R Z2f are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and 3 to 6 membered cycloalkyl, or R Z2c 、R Z2d together with the same carbon atom to which they are attached to form a cyclopropyl group; in some embodiments, R Z2c 、R Z2d 、R Z2e and R Z2f are the same or different and are each independently selected from hydrogen, F, methyl and cyclopropyl, or R Z2c 、R Z2d Together with the same carbon atom to which it is attached, it forms a cyclopropyl group.

[0247] In some embodiments of the present disclosure, R Z2c and R Z2d The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R Z2c and R Z2d All are hydrogen atoms.

[0248] In some embodiments of the present disclosure, R Z2e and R Z2f The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R Z2e and RZ2f All are hydrogen atoms.

[0249] In this disclosure, The * end is connected to R 3 The fusion site of the connected rings.

[0250] In some embodiments of the present disclosure, the compound represented by the general formula (IM-2) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; a is 0; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; b is 0 or 1; R cc C 1-6 alkyl;

[0251] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; is a single bond; R Z2a is a hydrogen atom; X is selected from CH2O, OCH2, CH2, O and N (methyl); X 5 is CH2; Ring D is a 4- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; R Za and R Zd are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; c is 0 or 1;

[0253] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0254] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; is a single bond; R Z2a is a hydrogen atom; Selected from Ring D is R Za is a hydrogen atom, R Zd is a halogen; each R Z2 The same or different, and each independently is C 1-6 Alkyl; c is 0 or 1;

[0255] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0256] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 1 is a hydrogen atom, R 2is a hydrogen atom, R 3 C 1-6 Alkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom; X 1 for CH; for R 7a C 1-6 Alkyl; R 8a is a hydrogen atom; R 9a’ is a hydrogen atom; Z 1 for Z 2 Selected from hydrogen atoms,

[0257] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, wherein X 1 is CH; Ring B is a 10-membered bicyclic heterocyclic group; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 alkyl halide; for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; Z 1 for Z 2 is a hydrogen atom or optionally replaced by one or more R Z2substituted 5- to 10-membered heteroaryl; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0258] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, wherein X 1 is CH; Ring B is selected from Each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 alkyl halide; for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; Z 1 for Z 2 for X 6 NR cc , R cc is a hydrogen atom or a methyl group; X 7 CR Zh or N; X 8 CR Ze or N; R Za 、R Zd 、R Ze and R Zhare the same or different and are each independently a hydrogen atom or R Z2 ; Each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0259] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; is a single bond or a double bond; R Z2a is a hydrogen atom; X is selected from CH2O, OCH2, CH2, O and N (methyl); X 5 is O or CH2; Ring D is a 5- to 10-membered heteroaryl group; R Za and R Zd are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl and 3- to 6-membered cycloalkyl, c is 0, 1 or 2;

[0260] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0261] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X 2 is CH or N; X 3 CR Z1a or N, R Z1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; X 4 is CH or N; Z 2 A hydrogen atom or R Z2b is a hydrogen atom, R Zd Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R cc Selected from hydrogen atoms, C 1-6 Alkyl, 3 to 6 membered cycloalkyl and C 1-6 deuterated alkyl;

[0262] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0263] In some embodiments of the present disclosure, the compound represented by the general formula (IP-2) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 alkyl halide; is a single bond or a double bond; a is 0; X is selected from CH2O, OCH2, CH2, O and N(methyl); X 5 is O or CH2; Ring D is a 5- to 10-membered heteroaryl group; R Za and R Zd are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl and 3- to 6-membered cycloalkyl, c is 0, 1 or 2;

[0264] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0265] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3 to 6-membered cycloalkyl; X 2 、X 3 and X 4 The same or different, and each independently CR Z1a or N; R Z1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and 3 to 6 membered cycloalkyl; Z 2 is optionally replaced by one or more R Z2 substituted 5- to 10-membered heteroaryl, each R Z2 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3 to 6 membered cycloalkyl and C 1-6 Alkoxy C 1-6 alkyl;

[0266] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6haloalkyl; q is 0, 1 or 2; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0267] In some embodiments of the present disclosure, the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; is a single bond or a double bond, R Z2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; X is selected from CH2O, OCH2, CH2, O and N(methyl); X 5 is O or CH2; R Zf 、R Zg Together with the carbon atoms to which it is attached, it forms Ring E, and Ring E is optionally substituted by 1, 2, 3 or 4 R Z2 substituted, ring E is a 9- or 10-membered bicyclic heteroaryl group, each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3 to 6 membered cycloalkyl and C 1-6 Alkoxy C 1-6 Alkyl; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6Alkyl and 3 to 6 membered cycloalkyl, R 3 Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; Y is C(O); Ring A is X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0268] In some embodiments of the present disclosure, the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; is a single bond or a double bond, R Z2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6Haloalkoxy; X is selected from CH2, CH2CH2, CH2O, OCH2, O, NH, N(methyl), CH(methyl), CHcyclopropyl, CF2 and X 5 is O or CH2; R Zf 、R Zg The carbon atom to which it is attached forms an optionally substituted 1, 2, 3 or 4 R Z2 substituted indazolyl, each R Z2 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl, NR 11a R 11b and P(O)R 12 R 13 , R 11a 、R 11b 、R 12 and R 13 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and 3 to 6 membered cycloalkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and 3 to 6 membered cycloalkyl, R 3 Selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 6 membered cycloalkyl; Y is C(O); Ring A is X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6Alkyl and C 1-6 Haloalkyl; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0269] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3 to 6-membered cycloalkyl; R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 7a A hydrogen atom or C 1-6 Alkyl; R 8a is a hydrogen atom; R 9a’ is a hydrogen atom; Z 1 Selected from R Z1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group; Z 2 is optionally replaced by one or more R Z2 Substituted indazolyl; each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3 to 6 membered cycloalkyl and C 1-6 Alkoxy C 1-6 alkyl.

[0270] In some embodiments of the present disclosure, the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; is a single bond, R Z2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; X is selected from CH2O, OCH2, CH2, O and N(methyl); X 5 is CH2; R Zf 、R Zg Together with the carbon atoms to which it is attached, it forms Ring E, and Ring E is optionally substituted by 1, 2, 3 or 4 R Z2 substituted, ring E is a 6- to 10-membered aryl or a 5- to 14-membered heteroaryl, each R Z2 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR 11a R 11b and P(O)R 12 R 13 , the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic groups are each independently optionally selected from deuterium atoms, oxo groups, halogens, cyano groups, C 1-6 Alkyl, C 1-6 is substituted by one or more of an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group, and R 11a and R 11b The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; R 12 and R 13 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; for R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; for Each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0271] In some embodiments of the present disclosure, the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; is a single bond, R Z2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; X is selected from CH2O, OCH2, CH2, O and N(methyl); X 5 is CH2; R Zf 、R Zg Together with the carbon atoms to which it is attached, it forms Ring E, and Ring E is optionally substituted by 1, 2, 3 or 4 R Z2 substituted, ring E is phenyl, each R Z2 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl, NR 11a R 11b and P(O)R 12 R 13 , R 11a 、R 11b 、R 12 and R 13 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; for R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; Each R Q2are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R A for R 7a C 1-6 Alkyl; R 8a Hydrogen atom or C 1-6 Alkyl; R 9a ' is a hydrogen atom or C 1-6 alkyl.

[0272] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, wherein X 1 is CH; Ring B is a 3- to 12-membered heterocyclic group; each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1 or 2; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 alkyl halide; for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; A group selected from Group A, Group B, and Group C (in some embodiments, a group of Group C).

[0273] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; A group selected from Group C; R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; X 1 CR x1 , R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; for Each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7a C 1-6 Alkyl; R 8a A hydrogen atom or C 1-6 Alkyl; R 9a ' is a hydrogen atom or C 1-6 alkyl.

[0274] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Q 1 for R Q1a 、R Q1b and RQ1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; Selected from c is 0, 1 or 2, R cc Selected from hydrogen atoms, C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6 The alkyl group and the 3 to 6 membered cycloalkyl group are each independently optionally selected from deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 substituted by one or more of alkoxy, hydroxy and 3- to 6-membered cycloalkyl; each R Z2 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3- to 6-membered cycloalkyl; for R 1 is a hydrogen atom; R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 CH; R 4 、R 5 and R 6 is a hydrogen atom; for Each R Q2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; q is 0, 1 or 2; R A for R 7a and R 8a Different, and each independently a hydrogen atom or R 78 ; R 9a ' is a hydrogen atom or C 1-6 Alkyl, each R 78 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0275] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein for Q 1 for R Q1a 、R Q1b and R Q1c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; is a single bond; R Z2a is a hydrogen atom; X is O; X 5 is CH2; Ring D is R Za and R Zd are the same or different and are each independently a hydrogen atom or a halogen; each R Z2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 1-6 The alkoxy group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted by one or more selected from a deuterium atom, a halogen, and a 3- to 6-membered cycloalkyl group; c is 0 or 1;

[0276] for R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 C 1-6 Alkyl; Y is C(O); Ring A is X 1 is CH; each R Q2 The same or different, and each independently is C 1-6 Alkyl; q is 2; R A for R 7a C 1-6 Alkyl; R 8a is a hydrogen atom; R 9a’ is a hydrogen atom; R 4 is a hydrogen atom, R 5 is a hydrogen atom, R 6 A hydrogen atom.

[0277] Table A Typical compounds of the present disclosure include, but are not limited to:

[0278] Another aspect of the present disclosure relates to a compound represented by formula (IA) or a salt thereof:

[0279] in, Q 1 , Z 1 , Z 2 、R 1 、R 2 and R 3 As defined in general formula (I).

[0280] Another aspect of the present disclosure relates to a compound represented by the general formula (IMA), (IM-1A) or (IM-2A) or a salt thereof:

[0281] in,

[0282] Q 1 , Z 2 、X 2 、X 3 、X 4 、R Z1 ,a,R 1 、R 2 、R 3 、R Z2 , b and R cc As defined in formula (IM), (IM-1) or (IM-2).

[0283] Another aspect of the present disclosure relates to a compound represented by the general formula (INA) or a salt thereof:

[0284] in, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd , Ring D, RZ2 and c are as defined in formula (IN).

[0285] Another aspect of the present disclosure relates to a compound represented by the general formula (IN-1A) or a salt thereof:

[0286] in, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd 、X 6 、X 7 , and X 8 As defined in general formula (IN-1).

[0287] Another aspect of the present disclosure relates to a compound represented by formula (IIA) or (IVA) or a salt thereof:

[0288] in,

[0289] Q 1 、Z 1 、Z 2 、R 1 、R 2 and R 3 As defined in general formula (II).

[0290] Another aspect of the present disclosure relates to a compound represented by formula (IIIA) or a salt thereof:

[0291] in,

[0292] Q 1 、Z 2 、R Z1 ,a,R 1 、R 2 and R 3 As defined in general formula (III).

[0293] Another aspect of the present disclosure relates to a compound represented by formula (IVB) or (IV'B) or a salt thereof:

[0294] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy; in some embodiments, hydroxy;

[0295] Ring B, X 1 、R A 、R 4 、R5 、R 6 、R B and m are as defined in formula (IV) or (IV').

[0296] Another aspect of the present disclosure relates to a compound represented by the general formula (IPA) or a salt thereof:

[0297] in, Q 1 、R 1 、R 2 、R 3 、R Z1 、a、 R Z2b 、R Za 、R Zb 、R Zc and R Zd As defined in formula (IP).

[0298] Another aspect of the present disclosure relates to a compound represented by the general formula (IP-1A) or a salt thereof:

[0299] in, Q 1 、R 1 、R 2 、R 3 、R Z2 、a、 X, X 5 、R Za 、R Zb 、R Zc and R Zd As defined in general formula (IP-1).

[0300] Another aspect of the present disclosure relates to a compound represented by the general formula (IOA) or a salt thereof:

[0301] in, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Zf and R Zg As defined in formula (IO).

[0302] Another aspect of the present disclosure relates to a compound represented by general formula (IIA-1) or a salt thereof:

[0303] Among them, X1 , Q 1 、Z 1 、Z 2 、R 1 to R 6 、R 7a 、R 8a 、R Q2 and q are as defined in general formula (II).

[0304] Table B Typical compounds of the present disclosure include, but are not limited to:

[0305] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0306] The compound represented by general formula (IA) or its salt undergoes a condensation reaction with the compound represented by general formula (IB) or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

[0307] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0308] Ring A, Q 1 、Z 1 、Z 2 、R 1 、R 2 and R 3 As defined in general formula (I).

[0309] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0310] The compound represented by the general formula (IMA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;

[0311] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0312] Ring A, Q 1 、X 2 、X 3 、X 4 、Z 2 、R 1 、R 2 and R 3 As defined in formula (IM).

[0313] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0314] The compound represented by the general formula (IM-1A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IM-1) or a pharmaceutically acceptable salt thereof;

[0315] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0316] Ring A, Q 1 、Z 2 、R Z1 ,a,R 1 、R 2 and R 3 As defined in general formula (IM-1).

[0317] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0318] The compound represented by the general formula (IM-2A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IM-2) or a pharmaceutically acceptable salt thereof;

[0319] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0320] Ring A, Q1 、R Z1 ,a,R Z2 ,b,R cc 、R 1 、R 2 and R 3 As defined in general formula (IM-2).

[0321] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0322] The compound represented by the general formula (INA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof;

[0323] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0324] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd , Ring D, R Z2 and c are as defined in formula (IN).

[0325] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0326] The compound represented by the general formula (IN-1A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IN-1) or a pharmaceutically acceptable salt thereof;

[0327] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0328] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd、X 6 、X 7 and X 8 As defined in general formula (IN-1).

[0329] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0330] The compound represented by general formula (IIA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0331] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0332] X 1 , Q 1 、Z 1 、Z 2 、R 1 to R 6 、R 7a 、R 8a 、R 9a’ 、R Q2 and q are as defined in general formula (II).

[0333] 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, the method comprising:

[0334] The compound represented by general formula (IIIA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIIB) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0335] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0336] X 1 , Q 1 、Z 2 、R Z1 ,a,R 1 to R 6 、R A 、R Q2 and q are as defined in general formula (III).

[0337] Another aspect of the present disclosure relates to a method for preparing a compound represented by formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0338] The compound represented by general formula (IVA) or its salt undergoes a condensation reaction with the compound represented by general formula (IVB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0339] The compound represented by the general formula (IVA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IV'B) or its salt to obtain the compound represented by the general formula (IV') or its pharmaceutically acceptable salt;

[0340] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0341] Ring B, X 1 , Q 1 , Z 1 , Z 2 、R 1 to R 4 、R 5 、R 6 、R A 、R B and m are as defined in formula (IV) or (IV').

[0342] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IO) or a pharmaceutically acceptable salt thereof, the method comprising:

[0343] The compound represented by the general formula (IOA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof to obtain the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof;

[0344] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0345] Q 1 , Ring A, R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Zf and R Zg As defined in formula (IO).

[0346] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0347] The compound represented by general formula (IIA-1) or a salt thereof undergoes an addition reaction with hydroxylamine or a salt thereof (in some embodiments, hydrochloride), followed by a ring-closing reaction with N,N'-carbonyldiimidazole to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0348] Among them, R 9a’ is a hydrogen atom;

[0349] X 1 , Q 1 , Z 1 , Z 2 、R 1 to R 6 、R 7a 、R 8a 、R Q2 and q are as defined in general formula (II).

[0350] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IP) or a pharmaceutically acceptable salt thereof, the method comprising:

[0351] The compound represented by the general formula (IB) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IPA) or a salt thereof to obtain the compound represented by the general formula (IP) or a pharmaceutically acceptable salt thereof;

[0352] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0353] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z1 、a、 R Z2b 、R Za 、R Zb 、R Zc and R Zd As defined in formula (IP).

[0354] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IP-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0355] The compound represented by the general formula (IB) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IP-1A) or a salt thereof to obtain the compound represented by the general formula (IP-1) or a pharmaceutically acceptable salt thereof;

[0356] Among them, R Lis selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0357] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z2 、a、 X, X 5 、R Za 、R Zb 、R Zc and R Zd As defined in general formula (IP-1).

[0358] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0359] The present disclosure further relates to the use of compounds shown in Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for agonizing the GLP-1 receptor.

[0360] The present disclosure further relates to the use of compounds shown in Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of GLP-1 receptor agonists.

[0361] The present disclosure further relates to the use of compounds of formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance; in some embodiments, in the preparation of medicaments for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0362] The present disclosure further relates to the use of compounds of formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing idiopathic type 1 diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0363] The present disclosure further relates to a method for agonizing the GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0364] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by the GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0365] The present disclosure further relates to a method for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the method is for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0366] The present disclosure further relates to a method for treating and / or preventing idiopathic type I diabetes, latent immune diabetes of adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0367] The present disclosure further relates to a compound of formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0368] The present disclosure further relates to a compound of Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a GLP-1 receptor agonist.

[0369] The present disclosure further relates to a compound shown in Formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in agonizing the GLP-1 receptor.

[0370] The present disclosure further relates to a compound of formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance; in some embodiments, for treating and / or preventing type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0371] The present disclosure further relates to a compound of formula (I) to (IV'), (IM) to (IM-2), (IN), (IN-1), (IP) to (IP-3), (IO) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing idiopathic type 1 diabetes, latent immune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0372] In some embodiments, the GLP-1 receptor-mediated disease or condition described in the present disclosure is selected from type I diabetes, type II diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, glucose intolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and hepatic insulin resistance; in some embodiments, type I diabetes, type II diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis and cardiovascular disease.

[0373] In some embodiments, the GLP-1 receptor mediated disease or condition described in the present disclosure is selected from idiopathic type 1 diabetes, latent immune diabetes of adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and coronary heart disease.

[0374] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and can be acute or chronic. The term "acute complications" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary system infections, respiratory infections, urinary tract infections), and "chronic complications" include, for example, microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders), and gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0375] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0376] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia, and diabetic dementia.

[0377] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0378] As a general guide, the active compounds of the present disclosure are presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0379] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0380] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0381] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0382] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

[0383] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0384] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0385] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0386] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0387] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0388] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0389] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0390] The disclosed compounds 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 that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0391] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0392] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the 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, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0393] Terminology

[0394] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0395] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, and in some embodiments, an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0396] 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 In some embodiments, the alkylene group has an alkylene group of 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0397] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by one or more heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding -OO-, -OS- or -SS- moieties, and the remaining atoms are carbon, wherein alkyl is as defined above.

[0398] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, and in some embodiments, has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkenyl), in some embodiments alkenyl having 2 to 6 carbon atoms (ie, C 2-6 Alkenyl). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, in some embodiments the substituent is selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0399] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. In some embodiments, an alkynyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 Alkynyl), in some embodiments an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, in some embodiments, the substituent is selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0400] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, in some embodiments comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12-membered cycloalkyl) or 4 to 12-membered cycloalkyl, in some embodiments 3 to 10-membered, in some embodiments comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), in some embodiments comprising 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl) or comprising 3 to 5 carbon atoms (i.e., 3 to 5-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0401] Term " spiroalkyl " refers to 5 to 20 yuan, the polycyclic group of sharing a carbon atom (claiming spiral atom) between monocycle, and it can contain one or more double bonds.In some embodiments, it is 6 to 14 yuan, in some embodiments, it is 7 to 12 yuan, in some embodiments, it is 7 to 10 yuan (for example 7,8,9 or 10 yuan).According to the number of shared spiral atom between ring and ring, spiroalkyl is divided into single spiroalkyl or polyspiroalkyl (for example double spiroalkyl), in some embodiments, it is single spiroalkyl and double spiroalkyl.In some embodiments, it is 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0402] Its connection point can be at any position; wait.

[0403] The term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares a full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, wherein one or more rings can contain one or more double bonds. In some embodiments, it is 6 to 14 yuan, in some embodiments, it is 7 to 12 yuan, in some embodiments, it is 7 to 10 yuan (such as 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic or polycyclic fused cycloalkyl (such as tricyclic, tetracyclic), in some embodiments, it is bicyclic or tricyclic, in some embodiments, it is 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic alkyl. The limiting examples of fused cycloalkyl include: The connection point can be anywhere Place; wait.

[0404] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. In some embodiments, it is 6 to 14 members, and in some embodiments, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl group, in some embodiments, it is bicyclic, tricyclic, or tetracyclic, and in some embodiments, it is bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0405] Its connection point can be at any position.

[0406] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; in some embodiments

[0407] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0408] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, in some embodiments the substituent is selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0409] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 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., a 3- to 20-membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. In some embodiments, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., 3- to 12-membered heterocyclyl) or 7- to 12-membered heterocyclyl, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; in some embodiments, it is 3 to 10-membered, in some embodiments, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3- to 8-membered heterocyclyl) or 3- to 6-membered heterocyclyl or 4- to 7-membered heterocyclyl or 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14) (i.e., 6- to 14-membered heterocyclyl), of which 1-3 are heteroatoms (e.g., 1, 2, and 3); in some embodiments, it contains 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl), of which 1-3 are heteroatoms; in some embodiments, it is 5-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0410] Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0411] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 yuan, a single atom (called spiral atom) shared between the monocycles, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. In some embodiments, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan spiral heterocyclic radicals), in some embodiments, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan spiral heterocyclic radicals). According to the number of spiral atoms shared between the rings, the spiral heterocyclic radical is divided into a single spiral heterocyclic radical or a multi-spiro heterocyclic radical (e.g., a double spiral heterocyclic radical), in some embodiments, a single spiral heterocyclic radical and a double spiral heterocyclic radical. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

[0412] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. In some embodiments, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14 membered fused heterocyclyl), and in some embodiments, it is 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10 membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups, in some embodiments bicyclic or tricyclic, in some embodiments 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0413] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. In some embodiments, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan bridged heterocyclic groups), in some embodiments, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, in some embodiments, it is bicyclic, tricyclic or tetracyclic, in some embodiments, it is bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0414] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0415] wait.

[0416] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0417] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, in some embodiments 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0418] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0419] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl group is 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) yuan (i.e., a 5- to 10-membered heteroaryl group), in some embodiments, 8 to 10 (e.g., 8, 9, or 10) yuan, in some embodiments, 5 or 6 yuan (i.e., a 5- or 6-membered heteroaryl group), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.; in some embodiments, a 5-membered heteroaryl group. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

[0420] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0421] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same parent ring atom or two different ring atoms by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0422] The term "amino-protecting group" is used to protect the amino group with a readily removable group, thereby preserving the amino group while reacting other parts of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, p-methylphenylsulfonyl (Ts), and p-methoxybenzyl (PMB). These groups may optionally be substituted with one to three substituents selected from halogen, alkoxy, and nitro. In some embodiments, the amino-protecting group is Boc or PMB.

[0423] The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group and react on other functional groups of a compound. As examples, the hydroxy protecting group includes triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl. In some embodiments, the hydroxy protecting group is MOM or TBDPS.

[0424] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0425] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0426] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0427] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0428] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0429] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0430] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0431] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0432] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0433] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0434] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above.

[0435] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above.

[0436] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above, and non-limiting examples include deuterated methyl, deuterated ethyl, etc., wherein the deuterated methyl group is selected from CH2D, CHD2 and CD3.

[0437] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0438] The term "hydroxy" refers to -OH.

[0439] The term "mercapto" refers to -SH.

[0440] The term "amino" refers to -NH2.

[0441] The term "cyano" refers to -CN.

[0442] The term "nitro" refers to -NO2.

[0443] The term "oxo" or "oxo" refers to "=0".

[0444] The term "carbonyl" refers to C=O.

[0445] The term "carboxy" refers to -C(O)OH.

[0446] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0447] MOM stands for methoxymethyl.

[0448] Boc refers to tert-butyloxycarbonyl.

[0449] TIPS refers to triisopropylsilyl.

[0450] TBS refers to tert-butyldimethylsilyl.

[0451] The compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation about a single bond, where the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation barrier to allow separation of individual conformers. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer.

[0452] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations. An example of a keto-enol equilibrium is shown below:

[0453] Another example:

[0454] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0455] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of the present disclosure may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included. 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. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0456] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations; key indicates an unspecified configuration, which may be a Z configuration or an E configuration, or contain both configurations.

[0457] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 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, etc., in some embodiments, deuterium.

[0458] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0459] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0460] "Substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, and in some embodiments 1 to 3, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experimentation or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group having free hydrogens may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

[0461] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0462] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. Salts may be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0463] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0464] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0465] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0466] 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 sometimes within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting.

[0467] Synthesis method of the disclosed compound

[0468] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0469] Option 1

[0470] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0471] The compound represented by general formula (IA) or its salt undergoes a condensation reaction with the compound represented by general formula (IB) or its salt under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

[0472] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0473] Ring A, Q 1 , Z 1 , Z 2 、R 1 、R 2 and R 3 As defined in general formula (I).

[0474] Option 2

[0475] The present invention discloses a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0476] The compound represented by the general formula (IMA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;

[0477] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0478] Ring A, Q 1 、X 2 、X 3 、X 4 , Z 2 、R 1 、R 2 and R 3 As defined in formula (IM).

[0479] Option 2

[0480] The present invention discloses a method for preparing a compound represented by general formula (IM-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0481] The compound represented by the general formula (IM-1A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IM-1) or a pharmaceutically acceptable salt thereof;

[0482] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0483] Ring A, Q 1 、Z 2 、R Z1 ,a,R 1 、R 2 and R 3 As defined in general formula (IM-1).

[0484] Option 3

[0485] The present invention discloses a method for preparing a compound represented by general formula (IM-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0486] The compound represented by the general formula (IM-2A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IM-2) or a pharmaceutically acceptable salt thereof;

[0487] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0488] Ring A, Q 1 、R Z1 ,a,R Z2 ,b,R cc 、R 1 、R 2 and R 3 As defined in general formula (IM-2).

[0489] Option 4

[0490] The present invention discloses a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0491] The compound represented by the general formula (INA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof;

[0492] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0493] Ring A, Q 1 、R1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd , Ring D, R Z2 and c are as defined in formula (IN).

[0494] Plan 5

[0495] The present invention discloses a method for preparing a compound represented by general formula (IN-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0496] The compound represented by the general formula (IN-1A) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IN-1) or a pharmaceutically acceptable salt thereof;

[0497] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0498] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Za 、R Zd 、X 6 、X 7 and X 8 As defined in general formula (IN-1).

[0499] Plan 6

[0500] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0501] The compound represented by general formula (IIA) or its salt undergoes a condensation reaction with the compound represented by general formula (IIB) or its salt under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0502] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0503] X 1 , Q 1, Z 1 , Z 2 、R 1 to R 6 、R 7a 、R 8a 、R 9a’ 、R Q2 and q are as defined in general formula (II).

[0504] Plan 6-1

[0505] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0506] The compound represented by general formula (IIA-1) or a salt thereof undergoes an addition reaction with hydroxylamine or a salt thereof (in some embodiments, hydrochloride), followed by a ring-closing reaction with N,N'-carbonyldiimidazole to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0507] Among them, R 9a’ is a hydrogen atom;

[0508] X 1 , Q 1 , Z 1 , Z 2 、R 1 to R 6 、R 7a 、R 8a 、R Q2 and q are as defined in general formula (II).

[0509] Plan 7

[0510] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0511] The compound represented by general formula (IIIA) or a salt thereof undergoes a condensation reaction with the compound represented by general formula (IIIB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0512] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0513] X 1 , Q 1 , Z 2 、R Z1 ,a,R 1 to R 6 、R A 、R Q2and q are as defined in general formula (III).

[0514] Plan 8

[0515] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0516] The compound represented by general formula (IVA) or a salt thereof undergoes a condensation reaction with the compound represented by general formula (IVB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0517] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0518] Ring B, X 1 , Q 1 、Z 1 、Z 2 、R 1 to R 4 、R 5 、R A 、R B and m are as defined in formula (IV).

[0519] Plan 9

[0520] The present invention discloses a method for preparing a compound represented by general formula (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0521] The compound represented by general formula (IVA) or a salt thereof undergoes a condensation reaction with the compound represented by general formula (IV'B) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by general formula (IV') or a pharmaceutically acceptable salt thereof;

[0522] Among them, R L is selected from the group consisting of halogen, hydroxy, and alkoxy, and in some embodiments is hydroxy;

[0523] Ring B, X 1 , Q 1 、Z 1 、Z 2 、R 1 to R 4 、R 6 、R A 、R B and m are as defined in formula (IV').

[0524] Plan 10

[0525] The present invention discloses a method for preparing a compound represented by general formula (IO) or a pharmaceutically acceptable salt thereof, the method comprising:

[0526] The compound represented by the general formula (IOA) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IB) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain the compound represented by the general formula (IO) or a pharmaceutically acceptable salt thereof;

[0527] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0528] Q 1 , Ring A, R 1 、R 2 、R 3 、R Z2a 、 X, X 5 、R Zf and R Zg As defined in formula (IO).

[0529] Plan 11

[0530] The present invention discloses a method for preparing a compound represented by general formula (IP) or a pharmaceutically acceptable salt thereof, the method comprising:

[0531] A compound represented by general formula (IB) or a salt thereof undergoes a condensation reaction with a compound represented by general formula (IPA) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by general formula (IP) or a pharmaceutically acceptable salt thereof;

[0532] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0533] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z1 、a、 R Z2b 、R Za 、R Zb 、R Zc and R Zd As defined in formula (IP).

[0534] Plan 12

[0535] The present invention discloses a method for preparing a compound represented by general formula (IP-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0536] A compound represented by the general formula (IB) or a salt thereof undergoes a condensation reaction with a compound represented by the general formula (IP-1A) or a salt thereof under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by the general formula (IP-1) or a pharmaceutically acceptable salt thereof;

[0537] Among them, R L is selected from halogen, hydroxy and alkoxy, in some embodiments hydroxy; Y is C(O);

[0538] Ring A, Q 1 、R 1 、R 2 、R 3 、R Z2 、a、 X, X 5 、R Za 、R Zb 、R Zc and R Zd As defined in general formula (IP-1).

[0539] The addition reaction in the above-mentioned synthesis scheme six-1 occurs under alkaline conditions; in some embodiments, the reagent providing alkaline conditions is sodium bicarbonate; the ring-closure reaction in scheme six-1 occurs in the presence of a catalyst, and in some embodiments, the catalyst is 1,8-diazacyclo[5,4,0]undecene-7.

[0540] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; in some embodiments, it is N,N-diisopropylethylamine.

[0541] The condensing agents described in the above synthesis scheme include but are 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-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; in some embodiments, HATU.

[0542] The reaction in the above steps is optionally carried out in a solvent, and the solvent used includes but is not limited to: pyridine, 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, 1,2-dibromoethane and a mixture thereof. DETAILED DESCRIPTION

[0543] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0544] Example

[0545] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0546] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0547] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0548] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0549] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0550] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0551] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0552] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0553] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0554] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0555] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0556] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0557] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0558] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0559] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0560] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0561] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0562] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0563] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0564] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0565] Example 1

[0566] 2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-methyl-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 1

[0567] first step

[0568] 6-Bromo-4-fluoro-1H-indazole 1b

[0569] 4-Bromo-2,6-difluorobenzaldehyde 1a (14.6 g, 66.1 mmol, Shanghai Shaoyuan) and hydrazine hydrate (28 g, 475 mmol, 85% wt aqueous solution) were dissolved in dioxane (80 mL) and stirred at 100°C for 7 hours. The reaction solution was cooled to room temperature and 200 mL of water was added. Solids precipitated and were filtered, washed with water (100 mL x 2), and dried to obtain the crude title compound 1b (13.9 g).

[0570] MS m / z(ESI):213.1[M-1].

[0571] Step 2

[0572] 6-Bromo-4-fluoro-1-methyl-1H-indazole 1c

[0573] Compound 1b (13.9 g, 64.6 mmol) was dissolved in N,N-dimethylformamide (150 mL). Sodium hydride (3.4 g, 85.0 mmol, 60% wt) was added portionwise at 0°C and stirred for 30 minutes. Methyl iodide (11 g, 77.5 mmol) was then added dropwise and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL), extracted with ethyl acetate (100 mL x 2), and washed with saturated sodium chloride solution. 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 eluent C to afford the title compound 1c (8.57 g, 57.8% yield). MS m / z (ESI): 228.9 [M+1].

[0574] Step 3

[0575] 4-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 1d

[0576] Compound 1c (8.57 g, 37.4 mmol), potassium acetate (11.1 g, 113.1 mmol), pinacol diboron (14 g, 55.1 mmol, Shanghai Shaoyuan) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.7 g, 3.69 mmol, Shanghai Bid) were dissolved in dioxane (120 mL), replaced with nitrogen three times, reacted at 85°C for 16 hours, added with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with 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 elution system C to give the title compound 1d (10 g, yield: 96.7%).

[0577] MS m / z(ESI):277.0[M+1].

[0578] Step 4

[0579] 4-Fluoro-1-methyl-1H-indazol-6-ol 1e

[0580] Compound 1d (10 g, 36.2 mmol) was dissolved in tetrahydrofuran (100 mL). A solution of sodium perborate tetrahydrate (12 g, 78.0 mmol) in water (50 mL) was added dropwise at 0°C and allowed to react at room temperature for 2 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (100 mL x 3). The mixture 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 C to afford the title compound 1e (6.0 g, 99.7% yield).

[0581] MS m / z(ESI):166.9[M+1].

[0582] Step 5

[0583] 4-Fluoro-6-(methoxymethoxy)-1-methyl-1H-indazole 1f

[0584] Compound 1e (6.0 g, 36.1 mmol) and N,N-diisopropylethylamine (9.4 g, 72.7 mmol) were dissolved in dichloromethane (100 mL), and bromomethyl methyl ether (6.8 g, 54.4 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours, quenched with water (100 mL), and extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with 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 elution system C to give the title compound 1f (7.2 g, yield: 94.8%).

[0585] MS m / z(ESI):211.1[M+1].

[0586] Step 6

[0587] 4-Fluoro-5-iodo-6-(methoxymethoxy)-1-methyl-1H-indazole 1g

[0588] Compound 1f (4.0 g, 19.0 mmol) and tetramethylethylenediamine (3.3 g, 28.4 mmol, Adamas) were dissolved in tetrahydrofuran (60 mL). Under a nitrogen atmosphere, sec-butyllithium (21.6 mL, 28.1 mmol, 1.3 M, Anaiji) was added dropwise at -78°C. Stirring was continued at -78°C for 2 hours. A solution of iodine (5.0 g, 19.7 mmol) in tetrahydrofuran (10 mL) was then added dropwise. Stirring was continued at -78°C for 1 hour. The reaction was quenched with saturated sodium thiosulfate solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 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 C to afford the title compound 1g (1.0 g, 15.6% yield).

[0589] MS m / z(ESI):336.9[M+1].

[0590] Step 7

[0591] 4-Fluoro-5-iodo-1-methyl-1H-indazol-6-ol 1h

[0592] Compound 1g (700 mg, 2.08 mmol) was dissolved in dichloromethane (5.0 mL). A hydrogen chloride / dioxane solution (5.0 mL, 4.0 M) was added dropwise at 0°C and stirred at room temperature for 1 hour. The mixture was concentrated, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to provide the title compound 1h (430 mg, 70.1% yield).

[0593] MS m / z(ESI):292.9[M+1].

[0594] Step 8

[0595] N-(tert-Butoxycarbonyl)-O-(tert-Butyldiphenylsilyl)-L-serine methyl ester 1j

[0596] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoate 1i (6.2 g, 28.3 mmol, Shanghai Shaoyuan) and imidazole (2.9 g, 42.6 mmol, Shanghai Shaoyuan) were dissolved in dichloromethane (80 mL). tert-Butyldiphenylsilyl chloride (8.6 g, 31.3 mmol, Shanghai Shaoyuan) was added at 0°C. The reaction was stirred at room temperature for 16 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with 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 C to obtain the title compound 1j (12.9 g, 99.6% yield).

[0597] MS m / z(ESI):458.1[M+1].

[0598] Step 9

[0599] tert-Butyl (R)-(1-((tert-Butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate 1k

[0600] Compound 1j (5.7 g, 12.5 mmol) was dissolved in tetrahydrofuran (60 mL), and a lithium borohydride / n-hexane solution (12.4 mL, 24.8 mmol, 2.0 M) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 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 C to provide the title compound 1k (5.08 g, 94.9% yield).

[0601] MS m / z(ESI):430.1[M+1].

[0602] Step 10

[0603] (R)-2-((tert-Butoxycarbonyl)amino)-3-((tert-Butyldiphenylsilyl)oxy)propyl 4-fluorobenzoate

[0604] Compound 1k (5.08 g, 11.8 mmol) and 4-fluorobenzoic acid (1.66 g, 11.8 mmol, Adamas) were dissolved in N,N-diformamide (60 mL). 4-Dimethylaminopyridine (2.9 g, 23.5 mmol, Shanghai Shaoyuan) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g, 23.5 mmol, Shanghai Shaoyuan) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 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 C to obtain the title compound 1l (4.54 g, 69.5% yield).

[0605] MS m / z(ESI):552.1[M+1].

[0606] Step 11

[0607] (R)-2-Amino-3-((tert-butyldiphenylsilyl)oxy)propyl 4-fluorobenzoate 1m

[0608] Compound 11 (4.54 g, 8.23 ​​mmol) was dissolved in dichloromethane (50 mL), and zinc bromide (5.6 g, 24.9 mmol, Adamas) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 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 C to obtain the title compound 1m (3.48 g, 93.6% yield).

[0609] MS m / z(ESI):452.2[M+1].

[0610] Step 12

[0611] (S)-tert-Butyl 3-(3-((R)-1-((tert-butyldiphenylsilyl)oxy)-3-((4-fluorobenzoyl)oxy)propan-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0612] (S)-3-Amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 1n (1.0 g, 2.67 mmol, Shanghai Bidex) and N,N-diisopropylethylamine (1.8 g, 13.9 mmol) were dissolved in tetrahydrofuran (10 mL). Phenyl chloroformate (640 mg, 4.09 mmol, Adamas) was added dropwise under ice bath. The reaction was stirred at room temperature for 2 hours. Compound 1m (3.4 g, 7.52 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 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 C to give the title compound 1o (2.2 g, yield: 95.6%).

[0613] MS m / z(ESI):850.7[M-1].

[0614] Step 13

[0615] (4S)-2-(4-Fluoro-3,5-dimethylphenyl)-3-(3-(1-((4-fluorobenzoyl)oxy)-3-hydroxypropan-2-yl)urea

[0616] tert-Butyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 1p

[0617] Compound 1o (2.2 g, 2.58 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrabutylammonium fluoride / tetrahydrofuran solution (8.0 mL, 8.0 mmol, 1.0 M) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 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 C to afford the title compound 1p (1.2 g, 72.7% yield).

[0618] MS m / z(ESI):614.2[M+1].

[0619] Step 14

[0620] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(4-(((4-fluorobenzoyl)oxy)methyl)-2-oxoimidazolidine-1-

[0621] tert-Butyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 1q

[0622] Compound 1p (1.2 g, 1.96 mmol) and triphenylphosphine (1.0 g, 3.82 mmol, Adamas) were dissolved in tetrahydrofuran (100 mL), and di-tert-butyl azodicarboxylate (900 mg, 3.91 mmol, Adamas) was added at 0°C and reacted at room temperature for 16 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 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 C and then purified by preparative high performance liquid chromatography (instrument model: Waters-2545 column: Sharpsil-T, Prep 30 × 150 mm; 5 μm; C18 mobile phase: water (0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 50%-95%, flow rate: 30 mL / min) to give the title compound 1q (480 mg, yield: 41.2%).

[0623] MS m / z(ESI):596.2[M+1].

[0624] Step 15 (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(4-(hydroxymethyl)-2-oxoimidazolidin-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 1r

[0625] Compound 1q (460 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5.0 mL) and water (1.0 mL), and lithium hydroxide monohydrate (160 mg, 3.81 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1r (365 mg).

[0626] MS m / z(ESI):474.3[M+1].

[0627] Step 16 (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4-(((methylsulfonyl)oxy)methyl)-2-oxoimidazolidine

[0628] -1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 1s

[0629] Compound 1r (365 mg, 0.77 mmol) and triethylamine (235 mg, 2.32 mmol) were dissolved in dichloromethane (5.0 mL) and water (1.0 mL). Methanesulfonyl chloride (130 mg, 0.88 mmol) was added at 0°C and allowed to react at room temperature for 1 hour. The reaction solution was poured into 20 mL of water and extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1s (420 mg).

[0630] MS m / z(ESI):552.5[M+1].

[0631] Step 17

[0632] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(4-(((4-fluoro-5-iodo-1-methyl-1H-indazol-6-yl)oxy)methyl)-2-oxoimidazolidin-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0633] Compound 1s (420 mg, 0.76 mmol) and compound 1h (200 mg, 0.68 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), potassium carbonate (250 mg, 1.81 mmol) was added, and the mixture was allowed to react at 80°C for 5 hours. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 A to obtain the title compound 1t (280 mg, 54.7% yield).

[0634] MS m / z(ESI):748.2[M+1].

[0635] Step 18

[0636] (4S)-2-(4-Fluoro-3,5-dimethylphenyl)-3-(10-fluoro-7-methyl-1-oxo-3a,4-dihydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-2(3H)-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0637] Compound 1t (280 mg, 0.37 mmol) and L-proline (40 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (15.0 mL). Potassium carbonate (130 mg, 0.94 mmol) and cuprous iodide (36 mg, 0.19 mmol, Leyan) were added. The nitrogen atmosphere was replaced three times and microwave-treated at 120°C for 3 hours. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 C to afford the title compound 1u (140 mg, 60.3% yield).

[0638] MS m / z(ESI):620.2[M+1].

[0639] Step 19

[0640] 10-Fluoro-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-7-methyl-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 1v

[0641] Compound 1u (140 mg, 0.23 mmol) was dissolved in methanol (2 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1v (110 mg), which was used directly in the next reaction without purification.

[0642] MS m / z(ESI):520.2[M+1].

[0643] Step 20

[0644] 2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-methyl-2,3,3a,4-tetrahydro-1H,7H-imidazole[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 1

[0645] The crude compound 1v (110 mg, 0.21 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid 1w (90 mg, 0.22 mmol, according to the specification of patent application WO2022017338A1) were mixed. The product (prepared by the method disclosed in Intermediate 47 on page 185) was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (140 mg, 1.08 mmol) was added. Once the starting material was completely dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (240 mg, 0.63 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound 1 (a mixture of diastereomers, 140 mg).

[0646] MS m / z(ESI):913.4[M+1].

[0647] Example 1-1 and Example 1-2

[0648] (S)-2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-methyl-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 1-1 and (R)-2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-methyl-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 1-2

[0649] Compound 1 (140 mg, 0.15 mmol) was purified by preparative high performance liquid chromatography (instrument model: Waters-2545 column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-95%, flow rate: 30 mL / min) to give the title compounds (57 mg, yield: 29.5%) and (51 mg, yield: 26.4%).

[0650] Single-configuration compound (shorter retention time, retention time 1.33 minutes, 57 mg, yield: 29.5%): MS m / z (ESI): 913.8 [M+1].

[0651] 1 H NMR (500MHz, CDCl3): δ8.03-7.99(m,1H),7.61(d,1H),7.54-7.50(m,1H),7.29-7.27 (m,1H),7.20-7.17(m,2H),6.72-6.66(m,2H),5.82-5.78(m,1H),4.49-4.45(m,1H), 4.27-4.24(m,1H),4.11-4.08(m,1H),4.02-3.96(m,3H),3.91-3.83(m,3H),3.67-3. 60(m,2H),3.61-3.00(m,4H),2.37-2.30(m,6H),1.94(t,1H),1.73-1.50(m,7H),1.36 -1.25(m,10H),1.07(d,1H).

[0652] Single-configuration compound (longer retention time, retention time 1.42 minutes, 51 mg, yield: 26.4%): MS m / z (ESI): 913.8 [M+1].

[0653] 1H NMR (500MHz, CDCl3): δ8.06(s,1H),7.79-7.60(m,2H),7.53(d,1H),7.33-7.27(m,1H), 7.17(d,1H),6.76-6.71(m,2H),5.72-5.68(m,1H),4.48-4.44(m,2H),4.15-4.08(m,1H) ,4.01-3.96(m,3H),3.92-3.84(m,3H),3.73-3.60(m,2H),3.30(d,1H),3.15-3.00(m,3 H),2.37-2.30(m,6H),1.92(t,1H),1.80-1.54(m,7H),1.40-1.22(m,10H),1.07(d,1H).

[0654] Example 2

[0655] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0656] first step

[0657] (S)-tert-Butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 2a

[0658] Compound 1n (1.0 g, 2.67 mmol, Bid) was dissolved in acetonitrile (20 mL), and copper bromide (596 mg, 2.67 mmol) was added. The reaction solution was cooled to 0°C, and isoamyl nitrite (469 mg, 4.00 mmol) was added dropwise. After stirring at 0°C for 0.5 hour, the temperature was raised to 60°C and stirring was continued for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to obtain the title compound 2a (350 mg, yield: 29.9%). MS m / z (ESI): 438.3 [M+1].

[0659] Step 2

[0660] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 2b

[0661] 1,2-Dihydro-2-oxo-pyridin-3-ylboronic acid (317 mg, 2.28 mmol, WuXi AppTec), compound 2a (500 mg, 1.14 mmol), sodium carbonate (363 mg, 3.42 mmol), and tetrakistriphenylphosphine palladium (132 mg, 0.11 mmol) were dissolved in toluene (3 mL) and methanol (3 mL). Nitrogen was bubbled through the reaction solution for 3 minutes, followed by microwave reaction at 110°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent A to provide the title compound 2b (100 mg, 19.4% yield).

[0662] MS m / z(ESI):453.1[M+1].

[0663] Step 3

[0664] (S)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)pyridin-2(1H)-one 2c

[0665] Compound 2b (25 mg, 0.055 mmol) was dissolved in dichloromethane (1 mL), and a 4M solution of hydrogen chloride in dioxane (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (20 mg), which was used directly in the next reaction without purification.

[0666] MS m / z(ESI):353.0[M+1].

[0667] Step 4

[0668] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0669] Crude compound 2c (20 mg, 0.057 mmol) and compound 1w (20 mg, 0.049 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (32 mg, 0.25 mmol) was added. Once all the starting materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (56 mg, 0.15 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was collected and purified by preparative HPLC (Waters-2545 column: Sharpsil-T, Prep 30×150 mm, 5 μm; C18 mobile phase: water (10 mM ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 27% to 47%, flow rate: 30 mL / min) to obtain the title compound 2 (5 mg, yield: 13.8%).

[0670] MS m / z(ESI):746.7[M+1].

[0671] 1 H NMR (500MHz, CD3OD): δ7.62-7.42(m,3H),7.39-7.17(m,2H),7.11-6.95(m,2H ),6.91-6.74(m,1H),6.45-6.16(m,1H),5.90-5.30(m,2H),4.67-4.38(m,2H) ,3.93-3.76(m,2H),3.71-3.43(m,2H),3.25-2.88(m,3H),2.33-2.14(m,6H), 1.85-1.44(m,7H),1.42-1.32(m,5H),1.27(s,2H),1.19(d,1H),1.06(d,1H).

[0672] Example 3

[0673] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0674] Step 1 (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 3a

[0675] Compound 2b (50 mg, 0.11 mmol), 1-methylindazole-5-boronic acid (60 mg, 0.34 mmol, Leyan), pyridine (100 mg, 1.26 mmol), and copper acetate (50 mg, 0.25 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 3a (35 mg, 54.4% yield).

[0676] MS m / z(ESI):583.1[M+1].

[0677] Step 2

[0678] (S)-3-(2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one 3b

[0679] Compound 3a (35 mg, 60.0687 μmol) was dissolved in dichloromethane (2 mL), and a 4M solution of hydrogen chloride in dioxane (2 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 3b (29 mg), which was used directly in the next reaction without purification.

[0680] MS m / z(ESI):483.1[M+1].

[0681] Step 3

[0682] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0683] Crude compound 3b (29 mg, 0.073 mmol) and compound 1w (30 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (50 mg, 0.39 mmol) was added. Once all the starting materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was collected and purified by preparative HPLC (Waters-2545 column: Welch Xtimate, Prep 30×250 mm, 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40% to 70%, flow rate: 30 mL / min) to obtain the title compound 3 (15 mg, yield: 23.5%).

[0684] MS m / z(ESI):876.7[M+1].

[0685] 1 H NMR (500MHz, CDCl3): δ8.07-7.89(m,1H),7.77-7.26(m,7H),7.16-6.92(m,2H),6.89-6 .52(m,2H),6.37-6.14(m,1H),5.79(q,1H),5.29-5.15(m,2H),4.86-4.36(m,1H),4.22 -4.01(m,3H),3.92-3.78(m,2H),3.62-3.41(m,1H),3.22-2.93(m,3H),2.39-2.13(m,6 H),2.05-1.71(m,5H),1.49-1.44(m,2H),1.37-1.26(m,8H),1.18(d,2H),0.98(d,1H).

[0686] Example 4

[0687] 3-((1S,2S)-1-(9-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1,4a,5,11b-tetrahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indol-8(2H)-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0688] first step

[0689] 1-Bromo-2-(methoxymethoxy)-4-nitrobenzene 4b

[0690] 2-Bromo-5-nitrophenol 4a (13 g, 59.63 mmol, Shanghai Bidex) and N,N-diisopropylethylamine (23.12 g, 178.89 mmol) were dissolved in dichloromethane (100 mL). Bromomethyl methyl ether (8.19 g, 69.59 mmol, Shanghai Shaoyuan) was added dropwise and allowed to react at room temperature for 16 hours. The mixture was quenched with water and extracted with dichloromethane (100 mL x 3). 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 eluent B to afford the title compound 4b (15 g, 95% yield).

[0691] MS m / z(ESI):262.1[M+1].

[0692] Step 2

[0693] 2-(2-(Methoxymethoxy)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4c

[0694] Compound 4b (8.1 g, 30.909 mmol) and pinacol diboronate (11.78 g, 46.37 mmol) were dissolved in 1,4-dioxane (100 mL). 1,1-Bis(diphenylphosphino)ferrocenepalladium dichloride (2.26 g, 3.09 mmol) and potassium acetate (9.1 g, 92.72 mmol) were added, respectively. The mixture was heated to 95°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 4c (8 g, 83% yield).

[0695] MS m / z(ESI):310.1[M+1].

[0696] Step 3

[0697] Ethyl 4-(2-(methoxymethoxy)-4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylate 4d

[0698] Compound 4c (8.0 g, 25.88 mmol), ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate (7.878 g, 25.884 mmol, prepared by the disclosed method of compound 0025 in step 2 of the example on page 93 of the specification of patent application WO2017 / 103824A1), was dissolved in toluene (100 mL) and water (30 mL), and tetrakistriphenylphosphine palladium (2.99 g, 2.59 mmol) and sodium carbonate (8.23 g, 77.64 mmol) were added under nitrogen protection. The reaction was heated at 100°C with stirring for 16 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent B to give the title compound 4d (7.0 g, yield: 80%).

[0699] MS m / z(ESI):338.3[M+1].

[0700] Step 4

[0701] Ethyl 4-(2-hydroxy-4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylate 4e

[0702] Compound 4d (6.0 g, 17.79 mmol) was dissolved in ethanol (50 mL) and tetrahydrofuran (10 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added dropwise at room temperature. The mixture was stirred for 6 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 4e (3.7 g). The product was used directly in the next reaction without purification.

[0703] MS m / z(ESI):294.2[M+1].

[0704] Step 5

[0705] 2-(5-(Hydroxymethyl)-3,6-dihydro-2H-pyran-4-yl)-5-nitrophenol 4f

[0706] Compound 4e (3.7 g, 12.616 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -70°C. A 1 mol / L n-hexane solution of diisobutylaluminum hydride (6.27 g, 44.16 mmol, 44.16 mL) was added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then cooled in an ice bath and quenched with potassium sodium tartrate tetrahydrate. The reaction mixture was stirred for 1 hour. Filtered, the residue was concentrated under reduced pressure, and purified by silica gel column chromatography using Elution System B to afford the title compound 4f (2.1 g, 66% yield).

[0707] MS m / z(ESI):252.3[M+1].

[0708] Step 6

[0709] 8-Nitro-1,5-dihydro-2H,4H-pyrano[3,4-c]chromene 4g

[0710] Compound 4f (2.1 g, 8.36 mmol) was dissolved in toluene (50 mL), and cyanomethylenetri-n-butylphosphine (4.04 g, 16.72 mmol, Jiangsu Aikon) was added dropwise. After the addition was complete, the mixture was heated to 100°C and stirred for 3 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (50 mL×3). 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 with elution system B to give 4g of the title compound (1.6 g, yield: 82%).

[0711] MS m / z(ESI):234.2[M+1].

[0712] Step 7

[0713] 1,4a,5,10b-Tetrahydro-2H,4H-pyrano[3,4-c]chromen-8-amine 4h

[0714] Compound 4g (1.6 g, 6.86 mmol) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), and palladium carbon (0.731 g, 0.69 mmol) was added. The mixture was replaced with hydrogen three times, and the reaction was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4h (1.3 g). The product was used directly in the next reaction without purification.

[0715] MS m / z(ESI):206.2[M+1].

[0716] Step 8

[0717] Ethyl 2-(2-(1,4a,5,10b-tetrahydro-2H,4H-pyrano[3,4-c]chromen-8-yl)hydrazinylidene)propanoate 4i

[0718] Compound 4h (1.3 g, 6.33 mmol) was dissolved in acetonitrile (16 mL), cooled to 0°C in an ice bath, and a 6 M aqueous solution of hydrogen chloride (5.3 mL) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. Sodium nitrite (0.87 g, 12.65 mmol) was dissolved in water (10 mL) and added dropwise to the reaction mixture. The mixture was stirred at 0°C for 1 hour. Ethyl 2-methylacetoacetate (1.0 g, 6.97 mmol) was dissolved in ethanol (16 mL), cooled to 0°C in an ice bath, and sodium acetate (5.20 g, 63.34 mmol) was added and stirred for 1 hour. The two reaction solutions were combined, mixed and stirred at room temperature for 2 hours, neutralized to neutrality with sodium carbonate, and extracted with dichloromethane (50 mL × 3). 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 with eluent B to give the intermediate, which was dissolved in ethanol (20 mL) and added dropwise with 4 M hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 4i (2 g), which was used directly in the next step without purification.

[0719] MS m / z(ESI):319.3[M+1].

[0720] Step 9

[0721] 1,2,4a,5,8,11b-Hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxylic acid ethyl ester 4j

[0722] Compound 4i (2 g, 6.28 mmol) was dissolved in dichloromethane (50 mL), and Eaton's reagent (2.99 g, 12.56 mmol) was added. The reaction was stirred at 50°C for 3 hours, quenched with water, and neutralized with sodium bicarbonate solution until neutral. The mixture was extracted with dichloromethane (50 mL × 3). 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 eluent B to give the title compound 4j (900 mg, 47% yield). MS m / z (ESI): 302.3 [M+1].

[0723] Step 10

[0724] 1,2,4a,5,8,11b-Hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxylic acid 4k

[0725] Compound 4j (900 mg, 2.99 mmol) was dissolved in methanol (10 mL) and water (1 mL), and sodium hydroxide (598 mg, 14.95 mmol) was added. The mixture was heated at 65°C with stirring for 3 hours, quenched with water, and the pH was adjusted to 3 with dilute hydrochloric acid solution. Solid precipitated, filtered, and dried to give the crude title compound 4k (700 mg). The product was used directly in the next reaction without purification.

[0726] MS m / z(ESI):274.2[M+1].

[0727] Step 11

[0728] N-Methyl-N-phenyl-1,2,4a,5,8,11b-hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxamide

[0729] Compound 4k (300 mg, 1.10 mmol) was dissolved in N,N-dimethylacetamide (10 mL). Thionyl chloride (458 mg, 3.85 mmol) was added under ice-cooling and stirred at room temperature for 5 hours. Triethylamine (666 mg, 6.58 mmol) and N-methylaniline (236 mg, 2.20 mmol) were then added and stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). 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 eluent B to give the title compound 4l (200 mg, 50% yield). MS m / z (ESI): 363.4 [M+1].

[0730] Step 12

[0731] 8-(Cyanomethyl)-N-methyl-N-phenyl-1,2,4a,5,8,11b-hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxamide

[0732] Compound 4l (300 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (332 mg, 8.28 mol, 60% wt) was added under ice bath. The mixture was stirred at room temperature for 5 hours. Chloroacetonitrile (625 mg, 8.28 mmol) was added and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 4m (200 mg, yield: 60%).

[0733] MS m / z(ESI):402.1[M+1].

[0734] Step 13

[0735] 8-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-1,2,4a,5,8,11b-hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxamide 4n

[0736] Compound 4m (300 mg, 0.75 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (362 mg, 0.83 mmol) were dissolved in N,N-dimethylpropyleneurea (3.832 g, 29.90 mmol). Potassium bis(trimethylsilyl)amide (1.19 g, 5.98 mmol, 1 M tetrahydrofuran solution) was added under ice-cooling. The reaction was stirred at room temperature for 3 hours, quenched with water, and extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 4n (170 mg, yield: 51%).

[0737] MS m / z(ESI):442.5[M+1].

[0738] Step 14

[0739] N-Methyl-8-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1,2,4a,5,8,11b-hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxamide

[0740] Compound 4n (170 mg, 0.39 mmol) and hydroxylamine hydrochloride (267 mg, 3.84 mmol) were dissolved in dimethyl sulfoxide (5 mL), and sodium bicarbonate (323 mg, 3.84 mmol) was added. The mixture was stirred at 60°C for 3.5 hours, cooled to room temperature, quenched with water, and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL), and N,N'-carbonyldiimidazole (166 mg, 1.15 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (387 mg, 1.54 mmol) were added. The mixture was stirred at room temperature for 3 hours, quenched with water, and extracted with ethyl acetate (30 mL×3). 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 with eluent B to give the title compound 4o (100 mg, yield: 51%).

[0741] MS m / z(ESI):501.5[M+1].

[0742] Step 15

[0743] 8-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1,2,4a,5,8,11b-hexahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indole-9-carboxylic acid 4p

[0744] Compound 4o (50 mg, 0.099 mmol) and potassium hydroxide (561 mg, 10.00 mmol) were dissolved in ethylene glycol monomethyl ether (5 mL) and water (1 mL), heated at 120°C with stirring for 60 hours, cooled to room temperature, quenched with water, adjusted to pH 3 with 1 M dilute hydrochloric acid, extracted with ethyl acetate (30 mL×3), 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 with eluent A to give the title compound 4p (10 mg, yield: 24%).

[0745] MS m / z(ESI):412.4[M+1].

[0746] Step 16

[0747] 3-((1S,2S)-1-(9-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1,4a,5,11b-tetrahydro-4H-pyrano[4',3':4,5]pyrano[3,2-f]indol-8(2H)-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0748] Compound 4p (10 mg, 0.024 mmol) and (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (12 mg, 0.024 mmol, prepared by the method of patent application W The compound 00412 (prepared according to the method disclosed in the Examples on page 139 of the specification of O2022017338A1) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11 mg, 0.026 mmol) and N,N-diisopropylethylamine (10 mg, 0.073 mmol) were added. The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (instrument model: Waters 2489 & SQD2, column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (0.1% TFA) and acetonitrile, gradient ratio: acetonitrile 45%-95%, flow rate: 30 mL / min) to obtain the title compound 4 (stereoisomer mixture, 8 mg, yield: 37%).

[0749] MS m / z(ESI):883.4[M+1].

[0750] 1 H NMR (500MHz, CDCl3): δ8.19-8.02(m,1H),7.52-7.49(m,1H),7.38(d,1H),7.32-7.29(m,1H) ,7.22-7.12(m,2H),7.10-7.02(m,1H),6.68-6.61(m,1H),6.37-6.30(m,1H),5.77(q,1H),4 .59-4.38(m,3H),4.19-4.07(m,3H),3.98-3.79(m,3H),3.69-3.54(m,2H),3.23-2.95(m,3H ),2.38-2.21(m,7H),1.92(t,1H),1.73-1.50(m,5H),1.36(s,3H),1.13(d,2H),0.91(d,1H).

[0751] Example 5

[0752] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-5H-imidazo[1,5-a]imidazol-6(7H)-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0753] first step

[0754] (S)-tert-Butyl 3-(((1H-imidazol-2-yl)methyl)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 5a

[0755] Compound 1n (500 mg, 1.34 mmol) and 2-imidazolecarboxaldehyde (260 mg, 2.71 mmol, Adamas) were dissolved in 1,2-dichloroethane (20 mL). Tetraisopropyl titanate (1.14 g, 4.01 mmol, Adamas) was added and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, methanol (20 mL) was added, and sodium borohydride (102 mg, 2.70 mmol) was slowly added at room temperature. Stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 5a (500 mg, 82.4% yield). MS m / z (ESI): 455.0 [M+1].

[0756] Step 2

[0757] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-5H-imidazo[1,5-a]imidazol-6(7H)-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 5b

[0758] Compound 5a (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL). Triphosgene (33 mg, 0.11 mmol) and triethylamine (89 mg, 0.88 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 5b (60 mg, 56.8% yield).

[0759] MS m / z(ESI):481.2[M+1].

[0760] Step 3

[0761] (S)-6-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one 5c

[0762] Compound 5b (25 mg, 0.052 mmol) was dissolved in dichloromethane (1 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5c (20 mg), which was used directly in the next reaction without purification.

[0763] MS m / z(ESI):381.1[M+1].

[0764] Step 4

[0765] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-5H-imidazo[1,5-a]imidazol-6(7H)-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0766] The crude compound 5c (20 mg, 0.053 mmol) and compound 1w (25 mg, 0.061 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (40 mg, 0.30 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (instrument model: Gilson-GX-281 column: SP-120-5-ODS-BIO, Prep 30×150 mm; 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-80%, flow rate: 30 mL / min) to give the title compound 5 (18 mg, yield: 38.3%).

[0767] MS m / z(ESI):772.6[M-1].

[0768] 1H NMR (500MHz, CDCl3): δ7.62-7.41(m,3H),7.28-7.26(m,1H),7.21-6.94(m,3H),6.72-6. 63(m,1H),5.75(q,1H),5.36-4.80(m,2H),4.57-4.42(m,2H),4.40-4.31(m,1H),4.23(q, 1H),3.90-3.78(m,2H),3.61-3.52(m,1H),3.42-2.96(m,4H),2.27-2.18(m,6H),1.80-1 .74(m,2H),1.52(d,3H),1.35-1.32(m,3H),1.29-1.24(m,5H),1.18(d,2H),1.05(d,1H).

[0769] Example 6

[0770] 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-8,8-dimethyl-5a,8,9,9a-tetrahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indol-1(6H)-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0771] first step

[0772] 4-Hydroxy-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylic acid ethyl ester 6b

[0773] 2,2-Dimethyltetrahydro-4H-pyran-4-one 6a (5.0 g, 39.0 mmol, Adamas) was dissolved in tetrahydrofuran (60 mL). Sodium hydride (3.9 g, 97.5 mmol, 60% wt) was added portionwise at 0°C and stirred for 0.5 hours. Diethyl carbonate (11.5 g, 97.3 mmol) was added dropwise and the mixture was allowed to react at 65°C for 3 hours. The reaction mixture was cooled to room temperature and poured into 100 mL of ice water. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (100 mL x 2), and washed with saturated sodium chloride solution. 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 eluent C to afford the title compound 6b (4.68 g, 59.9% yield).

[0774] MS m / z(ESI):201.1[M+1].

[0775] Step 2

[0776] 6,6-Dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylic acid ethyl ester 6c

[0777] Compound 6b (3.6 g, 18.0 mmol) and N,N-diisopropylethylamine (7.0 g, 54.2 mmol) were dissolved in dichloromethane (50 mL). Trifluoromethanesulfonic anhydride (7.6 g, 26.9 mmol) was added dropwise at -70°C. The temperature was then slowly raised to room temperature. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (50 mL x 2), and washed with saturated sodium chloride solution. 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 eluent C to afford the title compound 6c (4.37 g, 73.1% yield).

[0778] MS m / z(ESI):333.1[M+1].

[0779] Step 3

[0780] 2-Benzyloxy-3-bromobenzaldehyde 6e

[0781] 2-Hydroxy-3-bromobenzaldehyde 6d (7.0 g, 34.8 mmol, Shanghai Bidex) and benzyl bromide (6.3 g, 36.8 mmol) were dissolved in N,N-diformamide (70 mL), potassium carbonate (10 g, 71.9 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined and washed with saturated sodium chloride solution. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with elution system C to obtain the title compound 6e (10 g, yield: 98.6%).

[0782] MS m / z(ESI):291.2[M+1].

[0783] Step 4

[0784] 2-(2-(Benzyloxy)-3-bromophenyl)-1,3-dioxolane 6f

[0785] Compound 6e (3.0 g, 10.3 mmol) and p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) were dissolved in toluene (40 mL) and a water separator was added. The mixture was reacted at 120°C for 16 hours. The mixture was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 3), 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 C to give the title compound 6f (3.0 g, yield: 86.8%).

[0786] MS m / z(ESI):335.0[M+1].

[0787] Step 5

[0788] 2-(2-benzyloxy-3-(1,3-dioxolane-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6g

[0789] Compound 6f (2.9 g, 8.65 mmol), potassium acetate (2.5 g, 25.5 mmol), pinacol diboron (2.8 g, 11.0 mmol, Shanghai Shaoyuan) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (630 mg, 0.86 mmol, Shanghai Bid) were dissolved in dioxane (40 mL), replaced with nitrogen three times, reacted at 85 ° C for 16 hours, added with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with 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 elution system C to obtain the title compound 6g (2.5 g, yield: 75.6%).

[0790] MS m / z(ESI):383.1[M+1].

[0791] Step 6

[0792] 4-(2-(Benzyloxy)-3-(1,3-dioxolan-2-yl)phenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylic acid ethyl ester 6h

[0793] Compounds 6g (1.0 g, 2.62 mmol) and 6c (1.0 g, 3.01 mmol) were dissolved in dioxane (10 mL) and water (2.0 mL), and sodium carbonate (880 mg, 8.00 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (190 mg, 0.26 mmol, Shanghai Bidex) were added. The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90°C for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated sodium chloride solution. 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 with elution system C to give the title compound 6h (760 mg, yield: 66.3%).

[0794] MS m / z(ESI):439.3[M+1].

[0795] Step 7

[0796] (4-(2-(Benzyloxy)-3-(1,3-dioxolan-2-yl)phenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol 6i

[0797] Compound 6h (760 mg, 1.73 mmol) was dissolved in tetrahydrofuran (10 mL), and diisobutylaluminum hydride / n-hexane solution (4.3 mL, 4.3 mmol, 1.0 M) was added dropwise at 0°C, followed by stirring at 0°C for 1 hour. Solid potassium sodium tartrate tetrahydrate was added to quench the reaction, which was stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to afford the title compound 6i (640 mg, 93.1% yield).

[0798] MS m / z(ESI):397.2[M+1].

[0799] Step 8

[0800] 2-(1,3-dioxolan-2-yl)-6-(5-(hydroxymethyl)-2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)phenol 6j

[0801] Compound 6i (4.5 g, 11.4 mmol) was dissolved in tetrahydrofuran (50 mL), and palladium hydroxide (1.0 g, 7.12 mmol, Adamas) was added. The reaction was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the title compound 6j (2.6 g, yield: 74.7%). MS m / z (ESI): 307.3 [M+1].

[0802] Step 9

[0803] 7-(1,3-Dioxolan-2-yl)-2,2-dimethyl-1,5-dihydro-2H,4H-pyrano[3,4-c]chromene 6k

[0804] Compound 6j (2.6 g, 8.49 mmol) and azodicarbonyl dipiperidine (4.3 g, 17.0 mmol, Adamas) were dissolved in toluene (150 mL). Tributylphosphine (3.4 g, 16.8 mmol, Adamas) was added, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to provide the title compound 6k (2.25 g, 91.9% yield).

[0805] MS m / z(ESI):289.3[M+1].

[0806] Step 10

[0807] 2,2-Dimethyl-1,5-dihydro-2H,4H-pyrano[3,4-c]chromene-7-carbaldehyde 6l

[0808] Compound 6k (2.1 g, 7.28 mmol) was dissolved in tetrahydrofuran (30 mL), concentrated hydrochloric acid (3.0 mL) was added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with 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 C to give the title compound 6l (1.6 g, yield: 89.9%).

[0809] MS m / z(ESI):245.3[M+1].

[0810] Step 11

[0811] Ethyl 2-azido-3-(2,2-dimethyl-1,5-dihydro-2H,4H-pyrano[3,4-c]chromen-7-yl)acrylate 6m

[0812] Compound 61 (1.6 g, 6.55 mmol) and ethyl azidoacetate (2.6 g, 20.1 mmol) were dissolved in anhydrous ethanol (20 mL). Sodium ethoxide / ethanol solution (7.0 g, 20.5 mmol, 20% wt, Adamas) was added dropwise at -10°C, with the temperature maintained at <-5°C. After addition, the reaction was stirred at -5°C for 1 hour. The reaction solution was poured into 50 mL of ice water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 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 C to afford the title compound 6m (a mixture of two isomers, 1.48 g, yield: 63.6%).

[0813] MS m / z(ESI):356.2[M+1].

[0814] Step 12

[0815] 8,8-Dimethyl-1,6,8,9-tetrahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxylic acid ethyl ester 6n

[0816] Compound 6m (1.48 g, 4.16 mmol) was dissolved in xylene (30 mL), refluxed for 1 hour, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 6n (760 mg, yield: 55.7%).

[0817] MS m / z(ESI):328.2[M+1].

[0818] Step 13

[0819] 8,8-Dimethyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxylic acid ethyl ester

[0820] Compound 6n (760 mg, 2.32 mmol) was dissolved in ethanol (10 mL), and palladium / carbon (100 mg, 10% wt) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the title compound 6o (stereoisomer mixture, 620 mg, yield: 81.1%). MS m / z (ESI): 330.2 [M+1].

[0821] Step 14

[0822] 8,8-Dimethyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxylic acid 6p

[0823] Compound 6o (610 mg, 1.85 mmol) was dissolved in methanol (10 mL) / water (5.0 mL). Sodium hydroxide (250 mg, 6.25 mmol) was added and the mixture was allowed to react at 65°C for 1.5 hours. The reaction mixture was poured into 30 mL of ice water and the pH was adjusted to 3-4 with 2M dilute hydrochloric acid. A solid precipitated. The solid was filtered and dried to obtain the crude title compound 6p (mixture of stereoisomers, 530 mg).

[0824] MS m / z(ESI):302.0[M+1].

[0825] Step 15

[0826] N,8,8-Trimethyl-N-phenyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxamide 6q

[0827] Compound 6p (500 mg, 1.66 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and thionyl chloride (500 mg, 4.20 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 5 hours. Triethylamine (840 mg, 8.30 mmol) and N-methylaniline (270 mg, 2.52 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent C to give the title compound 6q (stereoisomer mixture, 180 mg, yield: 27.7%).

[0828] MS m / z(ESI):391.4[M+1].

[0829] Step 16

[0830] 1-(Cyanomethyl)-N,8,8-trimethyl-N-phenyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxamide 6r

[0831] Compound 6q (180 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (190 mg, 4.75 mol, 60% wt) was added under ice-cooling. The mixture was stirred at room temperature for 5 hours. Chloroacetonitrile (360 mg, 4.77 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 6r (stereoisomer mixture, 140 mg, yield: 70.7%).

[0832] MS m / z(ESI):430.1[M+1].

[0833] Step 17

[0834] 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N,8,8-trimethyl-N-phenyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxamide 6s

[0835] Compound 6r (140 mg, 0.33 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (135 mg, 0.98 mmol) were dissolved in N,N-dimethylpropyleneurea (1.7 g, 13.3 mmol). Potassium bis(trimethylsilyl)amide (3.2 mL, 3.2 mmol, 1 M tetrahydrofuran solution) was added under ice-cooling. The reaction was stirred at room temperature for 3 hours, quenched with water, and extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 6s (stereoisomer mixture, 40 mg, yield: 26.1%).

[0836] MS m / z(ESI):470.2[M+1].

[0837] Step 18

[0838] N,8,8-Trimethyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxamide 6t

[0839] Compound 6s (40 mg, 0.085 mmol) and hydroxylamine hydrochloride (60 mg, 0.86 mmol) were dissolved in dimethyl sulfoxide (2.0 mL), and sodium bicarbonate (71 mg, 0.85 mmol) was added. The mixture was stirred at 60 °C for 3.5 hours, cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2.0 mL) and N , N'-carbonyldiimidazole (37 mg, 0.26 mmol), 1,8-diazacyclo[5,4,0]undecene-7 (85 mg, 0.34 mmol), stirred at room temperature for 3 hours, quenched with water, extracted with ethyl acetate (30 mL×3), 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 with elution system C to give the title compound 6t (stereoisomer mixture, 14 mg, yield: 31.1%).

[0840] MS m / z(ESI):529.5[M+1].

[0841] Step 19

[0842] 8,8-Dimethyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1,5a,6,8,9,9a-hexahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indole-2-carboxylic acid 6u

[0843] Compound 6t (14 mg, 0.026 mmol) was dissolved in tetrahydrofuran (1.0 mL), and potassium tert-butoxide (120 mg, 1.07 mmol) and water (4.0 mg) were added. The reaction was stirred at room temperature for 16 hours, quenched with water, and the pH was adjusted to 4-5 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 6u (stereoisomer mixture, 10 mg).

[0844] MS m / z(ESI):440.4[M+1].

[0845] Step 20

[0846] 3-((1S,2S)-1-(2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-8,8-dimethyl-5a,8,9,9a-tetrahydro-5H-pyrano[4',3':4,5]pyrano[2,3-e]indol-1(6H)-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0847] Compound 6u (10 mg, 0.023 mmol) and (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (12 mg, 0.024 mmol, prepared by the method of patent application W The product (prepared by the method for compound 00412 in the examples on page 139 of the specification for O2022017338A1) was dissolved in N,N-dimethylformamide (1.0 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mg, 0.026 mmol) and N,N-diisopropylethylamine (10 mg, 0.077 mmol) were added. The reaction was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Waters 2545, column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-95%, flow rate: 30 mL / min) to obtain the title compound 6 (5.0 mg, yield: 24.1%, mixture of diastereomers).

[0848] MS m / z(ESI):911.3[M+1].

[0849] 1 H NMR (500MHz, CDCl3): δ8.15-8.06(m,1H),7.64-7.61(m,1H),7.52-7.39(m,2H),7.33-7.29(m,1H), 7.20-7.10(m,2H),7.09-7.01(m,1H),6.80(s,1H),6.63-6.50(m,1H),5.80(q,1H),4.55-4.41(m,2H ),4.30-4.28(m,1H),4.15-4.06(m,3H),3.92-3.75(m,2H),3.64-3.58(m,1H),3.23-2.90(m,3H),2. 36-2.19(m,7H),1.90(t,1H),1.73-1.52(m,5H),1.42-1.21(m,8H),1.09-1.05(m,2H),0.90(t,1H).

[0850] Example 7

[0851] 3-((1S,2S)-1-(6-((S)-3-(3-(4-fluoro-1-methyl-1H-imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indol-3,4'-pyran]-7-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0852] first step

[0853] (3,6-Dihydro-2H-pyran-4-yl)methanol 7b

[0854] Methyl 3,6-dihydro-2H-pyran-4-carboxylate 7a (5.00 g, 35.17 mmol, Bidler) was dissolved in tetrahydrofuran and N,N-dimethylformamide (50 mL). A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (77.38 mL, 77.38 mmol, Adamas) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour, then warmed to room temperature and allowed to react for 16 hours. Saturated aqueous ammonium chloride (50 mL) was added under ice-water bath conditions, followed by stirring for three hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to afford the title compound 7b (3.8 g, 94.7% yield).

[0855] Step 2

[0856] 4-((2-Bromo-5-nitrophenoxy)methyl)-3,6-dihydro-2H-pyran 7c

[0857] Compound 7b (628 mg, 5.50 mmol), 2-bromo-5-nitrophenol (1.0 g, 4.59 mmol, Bid) and triphenylphosphine (2.41 g, 9.17 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.86 g, 9.17 mmol) was added and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to provide the title compound 7c (1.2 g, 83.3% yield).

[0858] Step 3

[0859] 6-Nitro-2',3'-dihydro-2H-spiro[benzofuran-3,4'-pyran]7d

[0860] Compound 7c (1.0 g, 3.18 mmol), palladium acetate (143 mg, 0.64 mmol), n-tetrabutylammonium bromide (911 mg, 3.18 mmol), and triethylamine (644 mg, 6.36 mmol) were dissolved in N,N-dimethylacetamide (50 mL), heated to 90°C, and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to provide the title compound 7d (600 mg, 80.8% yield).

[0861] Step 4

[0862] 2',3',5',6'-Tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-6-amine 7e

[0863] Compound 7d (300 mg, 1.29 mmol) was dissolved in tetrahydrofuran (5 mL) and ethanol (10 mL). Palladium on carbon (31 mg, 0.26 mmol) containing 10% water was added, and the mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to provide the title compound 7e (200 mg, 75.8% yield).

[0864] MS m / z(ESI):206.3[M+1].

[0865] Step 5

[0866] ((2',3',5',6'-tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-6-yl)amino)alanine ethyl ester 7f

[0867] Compound 7e (300 mg, 1.46 mmol) was dissolved in acetonitrile (5 mL) and cooled to 0°C in an ice bath. A 6M aqueous solution of hydrogen chloride (1.46 mL) was added dropwise and stirred for 10 minutes. Sodium nitrite (242 g, 3.51 mmol) was dissolved in water (3 mL) and added dropwise to the reaction mixture. The reaction was stirred at 0°C for 1 hour. Ethyl 2-methylacetoacetate (278 g, 1.93 mmol) was dissolved in ethanol (5 mL) and cooled to 0°C in an ice bath. Sodium acetate (1.44 g, 17.54 mmol) was added and stirred for 1 hour. The two reaction solutions were combined and stirred at room temperature for 2 hours. The mixture was neutralized with sodium carbonate until neutral and extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the intermediate, which was dissolved in ethanol (6 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 7f (300 mg). The product was used directly in the next reaction without purification.

[0868] MS m / z(ESI):319.4[M+1].

[0869] Step 6

[0870] 2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxylic acid ethyl ester 7g

[0871] Compound 7f (300 mg, 0.94 mmol) was dissolved in dichloromethane (10 mL), and Eaton's reagent (449 g, 1.89 mmol) was added. The reaction was stirred at 50°C for 3 hours, quenched with water, and neutralized with sodium bicarbonate solution until neutral. The mixture was extracted with dichloromethane (50 mL x 3). 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 eluent C to give the title compound 7g (280 mg, yield: 98.6%). MS m / z (ESI): 302.3 [M+1].

[0872] Step 7

[0873] 2',3',5',6'-Tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxylic acid 7h

[0874] Compound 7g (100 mg, 0.33 mmol) was dissolved in methanol (2 mL) and water (2 mL), and sodium hydroxide (66 mg, 1.66 mmol) was added. The reaction was stirred at 65°C for 3 hours, quenched with water, and the pH was adjusted to 3 with dilute hydrochloric acid solution. Solid precipitated, filtered, and dried to obtain the crude title compound 7h (80 mg). The product was used directly in the next reaction without purification.

[0875] MS m / z(ESI):274.2[M+1].

[0876] Step 8

[0877] N-Methyl-N-phenyl-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxamide 7i

[0878] Compound 7h (80 mg, 0.29 mmol) was dissolved in N,N-dimethylacetamide (2 mL). Thionyl chloride (139 mg, 3.85 mmol) was added under ice-cooling and stirred at room temperature for 5 hours. Triethylamine (237 mg, 2.34 mmol) and N-methylaniline (63 mg, 0.59 mmol) were then added and stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). 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 eluent C to afford the title compound 7i (105 mg, 99.0% yield).

[0879] MS m / z(ESI):363.4[M+1].

[0880] Step 9

[0881] 7-(Cyanomethyl)-N-methyl-N-phenyl-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxamide 7j

[0882] Compound 7i (100 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (110 mg, 2.75 mol, 60% wt) was added under ice bath. The mixture was stirred at room temperature for 5 hours. Chloroacetonitrile (208 mg, 2.75 mmol) was added and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 7j (105 mg, yield: 94.8%).

[0883] MS m / z(ESI):402.0[M+1].

[0884] Step 10

[0885] 7-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxamide 7k

[0886] Compound 7j (105 mg, 0.26 mmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (126 mg, 0.91 mmol) were dissolved in N,N-dimethylpropyleneurea (1.341 g, 10.46 mmol). Potassium bis(trimethylsilyl)amide (417 mg, 2.09 mmol, 1 M tetrahydrofuran solution) was added under ice-cooling. The reaction was stirred at room temperature for 3 hours, quenched with water, and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 7k (60 mg, yield: 52.0%).

[0887] MS m / z(ESI):442.4[M+1].

[0888] Step 11

[0889] N-Methyl-7-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxamide 7l

[0890] Compound 7k (60 mg, 0.14 mmol) and hydroxylamine hydrochloride (94 mg, 1.35 mmol) were dissolved in dimethyl sulfoxide (2 mL), and sodium bicarbonate (114 mg, 1.35 mmol) was added. The mixture was stirred at 60°C for 3.5 hours, cooled to room temperature, quenched with water, extracted with ethyl acetate (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2 mL), and N,N'-carbonyldiimidazole (66 mg, 0.41 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (137 mg, 0.54 mmol) were added. The mixture was stirred at room temperature for 3 hours, quenched with water, extracted with ethyl acetate (10 mL×3), 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 with elution system C to give the title compound 7l (40 mg, yield: 58.8%).

[0891] MS m / z(ESI):501.4[M+1].

[0892] Step 12

[0893] 7-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indole-3,4'-pyran]-6-carboxylic acid 7m

[0894] Compound 7l (40 mg, 0.08 mmol) was dissolved in tetrahydrofuran (3.5 mL), and potassium tert-butoxide (314 mg, 2.80 mmol) and water (10 mg, 0.56 mmol) were added. The reaction was stirred for 1 hour, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 7m (30 mg, yield: 91.2%).

[0895] MS m / z(ESI):412.3[M+1].

[0896] Step 13

[0897] 3-((1S,2S)-1-(6-((S)-3-(3-(4-fluoro-1-methyl-1H-imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2',3',5',6'-tetrahydro-2H,7H-spiro[furo[3,2-f]indol-3,4'-pyran]-7-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0898] Compound 7m (30 mg, 0.073 mmol) and (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (34 mg, 0.069 mmol, using the patent application The product (prepared according to the method for compound 00412 in the examples on page 139 of WO2022017338A1) was dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (83 mg, 0.22 mmol) and N,N-diisopropylethylamine (47 mg, 0.36 mmol) were added. The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Waters 2489 & SQD2, column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (0.1% TFA) and acetonitrile, gradient ratio: acetonitrile 45%-95%, flow rate: 30 mL / min) to obtain the title compound 7 (25 mg, yield: 38.8%).

[0899] MS m / z(ESI):883.3[M+1].

[0900] 1 H NMR (500MHz, CDCl3): δ11.52-11.30(m,1H),8.21-8.00(m,1H),7.52-7.49(m,1H),7.38(d,1H),7.32-7.29(m,1H),7.2 2-7.12(m,2H),7.10-7.02(m,1H),6.70(s,1H),6.65-6.48(m,1H),6.36-6.11(m,1H),5.77(q,1H),4.57-4.49(m,2H), 4.14(s,3H),4.10-4.00(m,2H),3.63-3.49(m,2H),3.19-3.11(m,1H),3.06-2.98(m,1H),2.29(s,6H),2.28-2.20(m,4 H),2.10-1.98(m,2H),1.89(t,1H),1.76-1.67(m,2H),1.60-1.54(m,2H),1.50-1.45(m,1H),1.22(d,2H),1.07(d,1H).

[0901] Example 8-1 or 8-2

[0902] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,Z)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 8-1

[0903] or

[0904] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,E)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 8-2

[0905] first step

[0906] (S)-tert-Butyl 3-(3-((S)-1-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)propan-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8b

[0907] Compound 1n (1.0 g, 2.67 mmol, Shanghai Bidex) and N,N-diisopropylethylamine (1.73 g, 13.4 mmol) were dissolved in tetrahydrofuran (30 mL), and phenyl chloroformate (627 mg, 4.0 mmol, Adamas) was added dropwise under ice bath, and the reaction was stirred at room temperature for 2 hours. (S)-1-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)propan-2-amine 8a (2.36 g, 7.98 mmol, prepared by the method disclosed in Intermediate D Part D on page 149 of the specification of patent application WO2006074003) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 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 C to give the title compound 8b (1.1 g, yield: 59.8%).

[0908] MS m / z(ESI):696.6[M+1].

[0909] Step 2

[0910] (S)-tert-Butyl 3-(3-((S)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8c

[0911] Compound 8b (1.1 g, 7.18 mmol) was dissolved in tetrahydrofuran (30 mL), and palladium on carbon (335 mg, 3.15 mmol, 10 wt% (containing approximately 55% water)) was added. The mixture was heated to 60°C under a hydrogen atmosphere for 8 hours. The mixture was cooled to room temperature, filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to provide the title compound 8c (850 mg, 88% yield).

[0912] MS m / z(ESI):606.7[M+1].

[0913] Step 3

[0914] (S)-tert-Butyl 3-(((S,Z)-4-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-ylidene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8d-1 or

[0915] (S)-tert-Butyl 3-(((S,E)-4-(((tert-Butyldimethylsilyl)oxy)methyl)oxazolidin-2-ylidene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8d-2

[0916] Compound 8c (850 mg, 1.40 mmol) was dissolved in dichloromethane (30 mL). Diethylaminosulfur trifluoride (DAST) (271 mg, 1.68 mmol, Adamas) was added dropwise at -78°C. The reaction was stirred at -78°C for 1 hour, then warmed to room temperature and stirred for 1 hour. The mixture was quenched by the addition of saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with 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 Elution System A to obtain the title compound 8d-1 or 8d-2 (600 mg, 72.7% yield).

[0917] MS m / z(ESI):588.6[M+1].

[0918] Step 4

[0919] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,Z)-4-(hydroxymethyl)oxazolidin-2-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8e-1 or

[0920] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,E)-4-(hydroxymethyl)oxazolidin-2-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8e-2

[0921] Compound 8d-1 or 8d-2 (600 mg, 1.02 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrabutylammonium fluoride / tetrahydrofuran solution (1.12 mL, 1 M) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 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 B to afford the crude title compound 8e-1 or 8e-2 (500 mg).

[0922] MS m / z(ESI):474.3[M+1].

[0923] Step 5

[0924] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(((S,Z)-4-(((methylsulfonyl)oxy)methyl)oxazolidin-2-ylidene)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8f-1 or

[0925] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(((S,E)-4-(((methylsulfonyl)oxy)methyl)oxazolidin-2-ylidene)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 8f-2

[0926] Compound 8e-1 or 8e-2 (500 mg, 1.06 mmol) and triethylamine (534 mg, 5.27 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonic anhydride (275 mg, 1.58 mmol) was added at 0°C and allowed to react at room temperature for 1 hour. The reaction solution was poured into 10 mL of water and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 8f-1 or 8f-2 (582 mg).

[0927] MS m / z(ESI):552.6[M+1].

[0928] Step 6

[0929] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,Z)-4-(((4-fluoro-5-iodo-1-methyl-1H-indazol-6-yl)oxy)methyl)oxazolidin-2-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 8g-1 or

[0930] (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,E)-4-(((4-fluoro-5-iodo-1-methyl-1H-indazol-6-yl)oxy)methyl)oxazolidin-2-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 8g-2

[0931] Compound 8f-1 or 8f-2 (582 mg, 1.05 mmol) and compound 1h (308 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), potassium carbonate (437 mg, 3.16 mmol) was added, and the mixture was reacted at 60°C for 2 hours. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 A to obtain the title compound 8g-1 or 8g-2 (450 mg, yield: 57.1%).

[0932] MS m / z(ESI):748.4[M+1].

[0933] Step 7

[0934] (S)-2-(4-Fluoro-3,5-dimethylphenyl)-3-(((R,Z)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 8h-1 or

[0935] (S)-2-(4-Fluoro-3,5-dimethylphenyl)-3-(((R,E)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 8h-2

[0936] Compound 8g-1 or 8g-2 (350 mg, 0.47 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (66 mg, 0.46 mmol, Adamas) were dissolved in dimethyl sulfoxide (6.0 mL). Potassium carbonate (192 mg, 1.39 mmol) and cuprous iodide (42 mg, 0.22 mmol, Leyan) were added. The nitrogen atmosphere was replaced three times, and the mixture was heated at 100°C with stirring for 2 hours. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 A to obtain the title compound 8h-1 or 8h-2 (160 mg, 55.1% yield).

[0937] MS m / z(ESI):620.6[M+1].

[0938] Step 8

[0939] (R,Z)-10-fluoro-N-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazole-1-imine 8i-1 or

[0940] (R,E)-10-Fluoro-N-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazole-1-imine 8i-2

[0941] Dissolve compound 8h-1 or 8h-2 (80 mg, 0.13 mmol) in dichloromethane (5 mL), add zinc bromide (88 mg, 0.39 mmol), and stir at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography using eluent A to obtain the crude title compound 8i-1 or 8i-2 (50 mg).

[0942] MS m / z(ESI):520.2[M+1].

[0943] Step 9

[0944] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,Z)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 8-1 or

[0945] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((R,E)-10-fluoro-7-methyl-3a,4-dihydro-1H,3H,7H-oxazolo[3',4':4,5][1,4]oxazino[3,2-f]indazol-1-ylidene)amino)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 8-2

[0946] Compound 8i-1 or 8i-2 (50 mg, 0.096 mmol) and compound 1w (43 mg, 0.104 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (37 mg, 0.29 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was filtered to remove insoluble matter, and the residue was purified by preparative high performance liquid chromatography (instrument model: Waters-2545, column: Sharpsil-T Prep C18 5μm 30×150mm SN 03212989, mobile phase: water (10mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-95%, flow rate: 30mL / min) to obtain the title compound 8-1 or 8-2 (25mg, yield: 28.4%).

[0947] MS m / z(ESI):913.5[M+1].

[0948] 1 H NMR (500MHz, CDCl3): δ8.06-7.89(m,1H),7.66-7.49(m,2H),7.48-7.36(m,2H),7.27 -7.20(m,1H),6.78(s,1H),6.71-6.66(m,1H),5.63-5.33(m,1H),4.85-4.71(m,1H),4 .68-4.51(m,1H),4.38-3.29(m,1H),4.20-3.64(m,8H),3.48-3.27(m,1H),3.12-2.82 (m,3H),2.50-2.27(m,6H),1.87-1.49(m,6H),1.42-1.16(m,13H),1.11-1.04(m,1H).

[0949] Example 9

[0950] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 9

[0951] first step

[0952] (S)-(5-(tert-Butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)boronic acid 9a

[0953] Compound 2a (500 mg, 1.14 mmol) was dissolved in tetrahydrofuran (10 mL), the atmosphere was replaced with nitrogen, and n-butyllithium (0.92 mL, 2.5 M, Adamas) was added dropwise at -78°C and stirred for 1 hour. Subsequently, trimethyl borate (475 mg, 4.57 mmol, Adamas) was added, and the reaction was stirred at -78°C for another 0.5 hour. The reaction solution was quenched with 20 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (30 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 Elution System A to obtain the title compound 9a (220 mg, 47.8% yield).

[0954] MS m / z(ESI):404.4[M+1].

[0955] Step 2

[0956] 5-Iodo-3-(1-methyl-1H-indazol-5-yl)pyrimidin-4(3H)-one 9c

[0957] 5-Iodopyrimidin-4(3H)-one 9b (1.0 g, 4.50 mmol, Adamas), 1-methylindazole-5-boronic acid (1.2 g, 6.82 mmol, Leyan), pyridine (3.57 g, 45.13 mmol), and copper acetate (1.8 g, 9.02 mmol) were dissolved in 1,2-dichloroethane (30 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent A to afford the crude product, which was then slurried with dichloromethane to afford the title compound 9c (500 mg, 31.5% yield).

[0958] MS m / z(ESI):353.1[M+1].

[0959] Step 3

[0960] (S)-tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 9d

[0961] Compound 9c (150 mg, 0.43 mmol), compound 9a (210 mg, 0.52 mmol), anhydrous potassium carbonate (177 mg, 1.28 mmol), and tetrakistriphenylphosphine palladium (132 mg, 0.043 mmol, Bid) were dissolved in dioxane (8 mL) and water (2 mL). The atmosphere was replaced with nitrogen, and the reaction was stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent A to obtain the crude title compound 9d (20 mg).

[0962] MS m / z(ESI):584.4[M+1].

[0963] Step 4

[0964] (S)-5-(2-(4-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)pyrimidin-4(3H)-one 9e

[0965] Compound 9d (20 mg, 0.034 mmol) was dissolved in dichloromethane (1 mL), and a 4M solution of hydrogen chloride in dioxane (2 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 9e (17 mg), which was used directly in the next reaction without purification.

[0966] MS m / z(ESI):484.4[M+1].

[0967] Step 5

[0968] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(1-methyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 9

[0969] Compound 9e (17 mg, 0.035 mmol) and compound 1w (15 mg, 0.036 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (24 mg, 0.19 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17 mg, 0.045 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument model: Gilson-GX-281, chromatographic column: Boston Phlex, Prep 30 × 150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-55%, flow rate: 30 mL / min) to give the title compound 9 (15 mg, yield: 46.9%).

[0970] MS m / z(ESI):877.8[M+1].

[0971] 1H NMR (500MHz, CDCl3): δ11.44-11.26(m,1H),8.31(s,1H),8.21-8.04(m,1H),7.99-7.88(m,1H),7.74-7.64(m, 1H),7.61-7.40(m,3H),7.36-7.27(m,1H),7.16-6.94(m,2H),6.78-6.63(m,1H),5.82(q,1H),5.43-5.18(m,1H ),4.89-4.38(m,1H),4.18-4.03(m,3H),3.91-3.76(m,2H),3.64-3.38(m,1H),3.22-2.92(m,3H),2.29-2.21( m,6H),1.90(t,1H),1.73-1.56(m,7H),1.47(d,2H),1.37-1.30(m,5H),1.19(d,2H),1.00(d,1H),0.88(t,1H).

[0972] Example 10

[0973] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(5-fluoro-1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 10

[0974] first step

[0975] 3-Bromo-5-fluoro-1-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one 10c

[0976] 3-Bromo-5-fluoropyridin-2(1H)-one 10b (1.0 g, 5.68 mmol, Leyan), (1-methyl-1H-indazol-5-yl)boronic acid 10a (1.3 g, 6.82 mmol, Leyan), 2,2'-bipyridine (1.77 g, 11.33 mmol, Adamas), copper acetate (2.0 g, 11.33 mmol), and sodium carbonate (1.8 g, 7.07 mmol) were dissolved in 1,2-dichloroethane (30 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent B to obtain the title compound 10c (70 mg, 3.82% yield).

[0977] MS m / z(ESI):322.1[M+1].

[0978] Step 2

[0979] (S)-3-(5-fluoro-1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 10d

[0980] Compound 10c (120 mg, 0.37 mmol), compound 9a (165 mg, 0.41 mmol), anhydrous potassium carbonate (102 mg, 0.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (54 mg, 0.07 mmol) were dissolved in dioxane (30 mL) and water (6 mL). The atmosphere was purged with nitrogen and the reaction was stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to give the crude title compound 10d (120 mg, 53.6% yield).

[0981] MS m / z(ESI):601.5[M+1].

[0982] Step 3

[0983] (S)-5-Fluoro-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(1-methyl-1H-indazol-5-yl)pyridin-2(1H)-one 10e

[0984] Compound 10d (120 mg, 0.05 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 10e (25 mg), which was used directly in the next reaction without purification.

[0985] MS m / z(ESI):501.4[M+1].

[0986] Step 4

[0987] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(5-fluoro-1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 10

[0988] Compound 10e (25 mg, 0.05 mmol) and compound 1w (25 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.1 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (instrument model: Waters-2545 column: Welch Xtimate, Prep 30 × 150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-65%, flow rate: 30 mL / min) to give the title compound 10 (5 mg, yield: 11.1%).

[0989] MS m / z(ESI):894.7[M+1].

[0990] 1 H NMR (500MHz, CDCl3): δ11.42(s,1H),11.33(s,1H),8.05(s,1H),7.89(s,1H),7.67(s,1H),7. 58-7.47(m,2H),7.40-7.29(m,2H),7.10(d,2H),6.97(d,1H),6.88(s,1H),5.90-5.30(m,2H) ,4.67-4.38(m,2H),4.12(s,3H),3.93-3.76(m,2H),3.71-3.43(m,2H),3.25-2.88(m,3H),2. 33-2.14(m,6H),1.85-1.44(m,7H),1.42-1.32(m,5H),1.27(s,2H),1.19(d,1H),1.06(d,1H).

[0991] Example 11

[0992] 2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-(trideuteriomethyl)-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 11

[0993] first step

[0994] 6-Bromo-4-fluoro-1-(methyl-d3)indazole 11a

[0995] Compound 1b (5.0 g, 23.3 mmol) was dissolved in N,N-dimethylformamide (60 mL). Sodium hydride (1.86 g, 46.5 mmol, 60% dispersion in mineral oil) was added portionwise at 0°C and stirred for 30 minutes. Deuterated iodomethane (6.74 g, 46.5 mmol) was then added dropwise. After addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 mL x 2), washed with saturated sodium chloride solution, 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 eluent C to afford the title compound 11a (3.6 g, 66.7% yield).

[0996] MS m / z(ESI):232.2[M+1].

[0997] Step 2

[0998] 4-Fluoro-1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)indazole 11b

[0999] Compound 11a (3.6 g, 15.5 mmol), potassium acetate (3.8 g, 38.7 mmol), pinacol diboron (5.90 g, 23.2 mmol, Shanghai Shaoyuan) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (2.27 g, 3.10 mmol, Shanghai Bid) were dissolved in dioxane (100 mL), replaced with nitrogen three times, reacted at 85 ° C for 16 hours, added with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with 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 elution system C to obtain the title compound 11b (4.3 g, yield: 99.3%).

[1000] MS m / z(ESI):280.1[M+1].

[1001] Step 3

[1002] 4-Fluoro-1-(methyl-d3)-1H-indazol-6-ol 11c

[1003] Compound 11b (500 mg, 1.79 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of sodium perborate tetrahydrate (880 mg, 5.37 mmol) in water (5 mL) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 1 h. The reaction mixture was poured into 50 mL of water and extracted with dichloromethane (30 mL x 3). The mixture 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 C to afford the title compound 11c (300 mg, 99.0% yield). MS m / z (ESI): 170.1 [M+1].

[1004] Step 4

[1005] 4-Fluoro-6-(methoxymethoxy)-1-(methyl-d3)-1H-indazole 11d

[1006] Compound 11c (2.2 g, 12.8 mmol) and N,N-diisopropylethylamine (3.3 g, 25.5 mmol) were dissolved in dichloromethane (50 mL), and bromomethyl methyl ether (2.39 g, 19.1 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours, and water (50 mL) was added to quench the mixture. The mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with 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 elution system C to give the title compound 11d (2.0 g, yield: 73.4%).

[1007] MS m / z(ESI):214.2[M+1].

[1008] Step 5

[1009] 4-Fluoro-5-iodo-6-(methoxymethoxy)-1-(methyl-d3)-1H-indazole 11e

[1010] Compound 11d (500 mg, 2.34 mmol) was dissolved in tetrahydrofuran (50 mL). Lithium diisopropylamide (1.8 mL, 3.6 mmol, 2.0 M, Adamas) was added dropwise at -78°C under a nitrogen atmosphere. Stirring was continued at -78°C for 2 hours. A solution of iodine (900 mg, 3.6 mmol) in tetrahydrofuran (5 mL) was then added dropwise. Stirring was continued at -78°C for 1 hour, and the temperature was slowly warmed to room temperature. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with 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 C to afford the title compound 11e (600 mg, 75.4% yield).

[1011] MS m / z(ESI):340.1[M+1].

[1012] Step 6

[1013] 4-Fluoro-5-iodo-1-(methyl-d3)-1H-indazol-6-ol 11f

[1014] Compound 11e (600 mg, 1.77 mmol) was dissolved in dichloromethane (10 mL). A hydrogen chloride / dioxane solution (10 mL, 4.0 M) was added dropwise at 0°C and stirred at room temperature for 1 hour. The mixture was concentrated, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to provide the title compound 11f (400 mg, 76.6% yield).

[1015] MS m / z(ESI):296.1[M+1].

[1016] Step 7

[1017] tert-Butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(4-(((4-fluoro-5-iodo-1-(methyl-d3)-1H-indazol-6-yl))oxy)methyl)-2-oxoimidazolidin-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 11g

[1018] Compounds 1s (209 mg, 0.38 mmol) and 11f (100 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), potassium carbonate (130 mg, 0.94 mmol) was added, and the mixture was allowed to react at 80°C for 5 hours. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 A to obtain the title compound 11 g (250 mg, 98.2% yield).

[1019] MS m / z(ESI):751.2[M+1].

[1020] Step 8 (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(10-fluoro-7-(methyl-d3)-1-oxo-3a,4-dihydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-2(3H)-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 11h

[1021] Compound 11g (250 mg, 0.33 mmol) and L-proline (10 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (15.0 mL). Potassium carbonate (140 mg, 1.01 mmol) and cuprous iodide (7.0 mg, 0.037 mmol, Leyan) were added. The nitrogen atmosphere was replaced three times and the mixture was microwaved at 125°C for 1 hour. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 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 C to obtain the title compound 11h (130 mg, yield: 62.6%).

[1022] MS m / z(ESI):623.3[M+1].

[1023] Step 9

[1024] 10-Fluoro-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-7-(methyl-d3)-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 11i

[1025] Compound 11h (130 mg, 0.21 mmol) was dissolved in methanol (2 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 11i (110 mg), which was used directly in the next reaction without purification.

[1026] MS m / z(ESI):523.2[M+1].

[1027] Step 10

[1028] 2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-(methyl-d3)-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 11

[1029] Crude compound 11i (110 mg, 0.20 mmol) and compound 1w (85 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (130 mg, 1.0 mmol) was added. After complete dissolution of the starting materials, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (150 mg, 0.39 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 11 (diastereoisomer mixture, 150 mg).

[1030] MS m / z(ESI):916.8[M+1].

[1031] Examples 11-1, 11-2

[1032] (R)-2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-(methyl-d3)-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 11-1 and

[1033] (S)-2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-(methyl-d3)-2,3,3a,4-tetrahydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 11-2

[1034] Compound 11 (150 mg, 0.15 mmol) was purified by preparative HPLC (instrument model: Waters-2545, chromatographic column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-95%, flow rate: 30 mL / min) to give the title compounds (48 mg, yield: 26.6%) and (85 mg, yield: 47.1%).

[1035] Single-configuration compound (shorter retention time, retention time 1.35 minutes, 48 ​​mg, yield: 26.6%): MS m / z (ESI): 916.8 [M+1].

[1036] 1H NMR (500MHz, CDCl3): δ8.03-7.99(m,1H),7.61(d,1H),7.54-7.50(m,1H),7.29- 7.27(m,1H),7.20-7.17(m,2H),6.72-6.66(m,2H),5.82-5.78(m,1H),4.49-4.4 5(m,1H),4.27-4.24(m,1H),4.09-3.99(m,1H),3.92-3.80(m,2H),3.67-3.60(m ,2H),3.61-3.00(m,4H),2.37-2.30(m,6H),1.94(t,1H),1.73-1.50(m,7H),1.36 -1.25(m,11H),1.07(d,1H).

[1037] Single-configuration compound (longer retention time, retention time 1.43 minutes, 85 mg, yield: 47.1%): MS m / z (ESI): 916.8 [M+1].

[1038] 1 H NMR (500MHz, CDCl3): δ8.06(s,1H),7.79-7.60(m,2H),7.53(d,1H),7.33-7 .27(m,1H),7.17(d,1H),6.76-6.71(m,2H),5.72-5.68(m,1H),4.48-4.43(m ,1H),4.15-4.06(m,1H),3.96-3.82(m,3H),3.73-3.57(m,2H),3.30(d,1H) ,3.15-3.00(m,3H),2.37-2.30(m,6H),1.92(t,1H),1.80-1.54(m,7H),1.40 -1.22(m,11H),1.07(d,1H).

[1039] Example 12

[1040] 2-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-10-fluoro-7-methyl-2,4-dihydro-1H,7H-imidazo[1',5':4,5][1,4]oxazino[3,2-f]indazol-1-one 12

[1041] first step

[1042] tert-Butyl (R)-(1-((tert-butyldiphenylsilyl)oxy)-3-((4-fluoro-5-iodo-1-methyl-1H-indazol-6-yl)oxy)propan-2-yl)carbamate 12a

[1043] Compound 1k (1.0 g, 2.38 mmol) and triethylamine (700 mg, 6.9 mmol) were dissolved in dichloromethane (30 mL). Methanesulfonyl chloride (350 mg, 3.05 mmol) was added at 0°C and allowed to react at room temperature for 1 hour. The reaction solution was poured into 20 mL of water and extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product for later use.

[1044] Compound 1h (500 mg, 1.71 mmol) and the above crude product were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (600 mg, 4.34 mmol) was added, and the mixture was reacted at 60°C for 5 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2), washed with saturated sodium chloride solution, 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 with eluent C to give the title compound 12a (1.04 g, yield: 86.3%).

[1045] MS m / z(ESI):704.2[M+1].

[1046] Step 2

[1047] (R)-1-((tert-Butyldiphenylsilyl)oxy)-3-((4-fluoro-5-iodo-1-methyl-1H-indazol-6-yl)oxy)propan-2-amine 12b

[1048] C...

Claims

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, Where represents a single bond or a double bond; Q 1 is aryl or heteroaryl, and each of aryl and heteroaryl is independently and optionally substituted with one or more R Q1 ; Z 2 selected from the group consisting of a hydrogen atom, a deuterium atom, cycloalkyl, heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl, wherein each of the cycloalkyl, heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl is independently and optionally substituted with one or more R Z2 ; Z 1 selected from the group consisting of a bond, -heterocyclyl-, -heterocyclyl-L 2A -, -L 2A -heterocyclyl-, -L 2A -heterocyclyl-L 2A -, -heteroaryl-L 2A -, -L 2A -heteroaryl-L 2A-, -N=, -NR aa -L 2A - and -NR aa -C(O)-NR bb -L 2A -, wherein each of heterocyclyl and heteroaryl is independently and optionally substituted with one or more R Z1 ; L 2A selected from the group consisting of a bond, alkyl, deuterioalkyl, heteroalkyl, and -N=; represents Y is selected from the group consisting of C(O), S(O), S(O)2, deuterioalkylene and alkylene; R 1 , R 2 and R 3 are the same or different and each of them is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, -(CH2) x NR 11a R 11b , -(CH2) x C(O)NR 11a R 11b , -NR 00 C(O)R 12 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R12 , -S(O) t R 12 , -S(O) t NR 11a R 11b , -NR 00 S(O) t R 12 , -(CH2) x P(O)R 12 R 13 , -S(O) t OR 12 , -OS(O) t R 12 , -OR 12 , =CR 12a R 13a , =NR 00 , C(=NR 00 )R 12 , S(=NR 00 )(O)R 12 , S(=NR 00 )R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R 01 ; ring A is selected from the group consisting of and a bicyclic heteroaryl substituted with R A and Q 2 ; the bicyclic heteroaryl is optionally substituted with one or more R 01 ; R A represents Q 2 selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted with one or more R Q2 ; X 1 represents CR x1 or N; R 4 , R 5 , R 6 and R x1 , if present, are the same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, -(CH2) x NR 11a R 11b , -NR 00 C(O)R 12 , -C(O)R 12 , -C(O)OR 12 , -(CH2) x C(O)NR 11a R 11b , -OC(O)R 12 , -S(O) t R 12 , -S(O) t NR 11a R11b , -NR 00 S(O) t R 12 , -(CH2) x P(O)R 12 R 13 , -S(O) t OR 12 , -OS(O) t R 12 , -OR 12 , C(=NR 00 )R 12 , S(=NR 00 )(O)R 12 , S(=NR 00 )R 12 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R 01 ; or Q 2 and R 6 together with the carbon atoms to which they are attached, they form a ring B, or Q 2 and R 5 together with the carbon atoms to which they are attached, form a ring B; or R Q2 and R 6 together with the atoms of the ring to which they are attached, they form ring B 0 , or R Q2 and R 5together with the atoms of the ring to which they are attached, they form ring B 0 ; each ring B is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and ring B is optionally substituted with one or more R B ; each ring B 0 independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and ring B 0 optionally substituted by one or more R B ; R 9 selected from the group consisting of -C(O)OR 12 , -C(O)NR 11a R 11b , -S(O) t R 12 , -S(O) t NR 11a R 11b , heterocyclyl and heteroaryl, wherein each of heterocyclyl and heteroaryl is independently and optionally substituted with one or more R 9a ; R 7 and R 8are the same or different and each of them is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, -(CH2) x NR 11a R 11b , -(CH2) x C(O)NR 11a R 11b , -NR 00 C(O)R 12 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O) t R 12 , -S(O) t NR 11a R 11b , -NR 00 S(O) t R 12 , -(CH2) x P(O)R 12 R 13 , -S(O) t OR 12 , -OS(O) t R 12 , -OR 12 , =CR 12a R 13a , =NR 00 , C(=NR 00 )R 12 , S(=NR 00 )(O)R 12 , S(=NR 00 )R 12, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R 01 ; or R 7 and R 8 together with the atoms to which they are attached, form a 3- to 5-membered cycloalkyl or heterocyclyl, wherein each of the 3- to 5-membered cycloalkyl and heterocyclyl is independently and optionally substituted with one or more R 78 ; n1 is 0, 1, 2, 3, 4, or 5; n2 is 0, 1, 2, 3, 4, or 5; each of R Q1 , R Z2 , R Z1 , R 01 , R Q2 , R B , R 9a and R 78is the same or different and each is independently selected from the group consisting of deuterium atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuterioalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, =S, -(CH2) x NR 11a R 11b , -NR 00 C(O)R 12 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -(CH2) x C(O)NR 11a R 11b , -S(O) t R 12 , -S(O) t NR 11a R 11b , -NR 00 S(O) t R 12 , -(CH2) x P(O)R 12 R 13 , -S(O) t OR 12 , -OS(O) t R 12 , -OR 12 ,=CR 12a R 13a ,=NR 00 , C(=NR 00 )R 12 , S(=NR 00 )(O)R 12 , S(=NR 00 )R 12, cycloalkyl, heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl is independently and optionally substituted with one or more R * ; or R Z2 and R Z1 together with the atoms of the ring to which they are attached, they form ring C; ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and ring C is optionally substituted with one or more R c ; each of R * and R c is the same or different and each is independently selected from the group consisting of deuterium atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, =S, -(CH2) x NR 11a R 11b , -NR 00 C(O)R 12 , -C(O)R 12 , -C(O)OR 12 , -(CH2)x C(O)NR 11a R 11b , -S(O) t R 12 , -S(O) t NR 11a R 11b , -NR 00 S(O) t R 12 , -(CH2) x P(O)R 12 R 13 , -OC(O)R 12 , -S(O) t OR 12 , -OS(O) t R 12 , -OR 12 , =CR 12a R 13a , =NR 00 , C(=NR 00 )R 12 , S(=NR 00 )(O)R 12 , S(=NR 00 )R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted with one or more identical or different substituents selected from the group consisting of deuterium atom, oxo, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; each of R 11a , R 11b, R 12 and R 13 is the same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, alkyl, alkoxy, hydroxyalkyl, haloalkyl, -C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -(CH2) y NR 14a R 14b , -(CH2) y C(O)NR 14a R 14b , -NR 0 C(O)R 15 , -S(O) t R 15 , -S(O) t NR 14a R 14b , -NR 0 S(O) t R 15 , -S(O) t OR 15 , - OS(O) t R 15 , -OR 15 , 4-12-membered cycloalkyl and heterocyclyl; or R 11a and R 11btogether with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of a deuterium atom, oxo, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; each of R aa , R bb , R 00 and R 0 is the same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, hydroxyalkyl, haloalkyl, C(O)alkyl, amido, cycloalkyl and heterocyclyl; each of R 12a and R 13a is the same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl; or R 12a and R 13atogether with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is independently and optionally substituted with one or more identical or different substituents selected from the group consisting of deuterium, halogen, cyano, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl; each of R 15 , R 14a and R 14bis the same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, alkyl, alkoxy, hydroxyalkyl, haloalkyl, C(O)alkyl, amino, amido, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently and optionally substituted with one or more identical or different substituents selected from the group consisting of a deuterium atom, halogen, cyano, nitro, amino, hydroxyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclyl; x is 0, 1, 2, 3, 4, 5, or 6; y is equal to 0, 1, 2, 3, 4, 5, or 6; and t is equal to 0, 1, or 2.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, Where represents a single bond or a double bond; X is selected from the group consisting of the bond, CR Z2c R Z2d CR Z2c R Z2d , CR Z2c R Z2d , Oh, NR CC , CR Z2c R Z2d O, OCR Z2c R Z2d and C(O); X 5 selected from the group consisting of communication, CR Z2e R Z2f CR Z2e R Z2f , CR Z2e R Z2f , Oh, NR CC , CR Z2e R Z2f O, OCR Z2e R Z2f and C(O); R Z2a , R Z2c , R Z2d , R Z2e and R Z2f are the same or different and each independently represents a hydrogen atom or R Z2 ; R Za and R Zd are the same or different and each independently represents a hydrogen atom or R Z2 ; ring D is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; R cc selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and cycloalkyl; c is 0, 1, 2, 3, 4, 5 or 6; and ring A, Y, R 1 , R 2 , R 3 , Q 1 and R Z2 are as defined in paragraph 1.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring A is and X 1 , Q 2 , R A , R 4 , R 5 and R 6 are as defined in paragraph 1.

4. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, where Q 2 is tetrahydropyranyl, optionally substituted by one or more R Q2 , and R Q2 is as defined in paragraph 1; preferably Q 2 represents and q is 1, 2, 3, 4, 5, or 6, and R Q2 is as defined in paragraph 1.

5. A compound or pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein ring D is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, preferably 5-membered heteroaryl and more preferably pyrazolyl.

6. A compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs 2-5, wherein selected from the group consisting of R cc represents a hydrogen atom or C 1-6 alkyl (preferably hydrogen or methyl); and preferably selected from the group consisting of .

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein the compound or pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, where X 2 , X 3 and X4 are the same or different, and each independently represents a CR z1a or N; R z1a represents a hydrogen atom or R Z1 ; And ring A, Y, R 1 , R 2 , R 3 , Q 1 , Z 2 and R Z1 are as defined in paragraph 1.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein the compound or pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or (IV'), or a pharmaceutically acceptable salt thereof, Where m is 0, 1, 2, 3, 4, 5, or 6; and ring B, X 1 , Q 1 , Z 1 , Z 2 , R 1 -R 4 , R 5 , R 6 , R A and R B are as defined in paragraph 1.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein ring B is a 3- to 12-membered heterocyclyl.

10. The compound or its pharmaceutically acceptable salt according to claim 8, where Z 1 is a 3- to 12-membered heterocyclyl, optionally substituted with one or more R Z1 , and R Z1 is as defined in paragraph 1.

11. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 7-10, where Z 2 represents a hydrogen atom or a 5- to 10-membered heteroaryl, optionally substituted by one or more R Z2 , and R Z2 is as defined in paragraph 1; preferably Z 2 represents a hydrogen atom or and R Z2b represents a hydrogen atom, R Zd selected from the group consisting of a hydrogen atom, a halogen and C 1-6 alkyl, and R cc selected from the group consisting of a hydrogen atom, C 1-6alkyl, 3-6 membered cycloalkyl and C 1-6 deuterioalkyl.

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, where Q 1 represents phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted with one or more R Q1 , and R Q1 is as defined in paragraph 1.

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, where R A represents and R 7a and R 8a are the same or different and each independently represents a hydrogen atom or R 78 ; R 9a ' represents a hydrogen atom or C 1-6 alkyl, and R 78 is as defined in paragraph 1; and preferably R A represents more preferably R A represents 14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, where R 1 represents a hydrogen atom, and / or R 2 represents a hydrogen atom, and / or R 3 represents C 1-6 alkyl, and / or R 4 , R 5 and R 6 represent hydrogen atoms, and / or X 1 is a CH.

15. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:

16. A compound represented by the general formula (IA) or a salt thereof, Where Q 1 , Z 1 , Z 2 , R 1 , R 2 and R 3 are as defined in paragraph 1.

17. A compound represented by the general formula (IVB) or (IV'B), or a salt thereof, where R L selected from the group consisting of halogen, hydroxyl and alkoxy, preferably hydroxyl, and ring B, X 1 , R A , R 4 , R 5 , R 6 , R B and m are as defined in paragraph 8.

18. A compound represented by the general formula (INA) or a salt thereof, Where Q 1 , R 1 , R 2 , R 3 , R Z2a , , X, X 5 , R Za , R Zd , ring D, R Z2 and c are as defined in paragraph 2.

19. A compound or its salt, wherein the structure of the compound or its salt is as follows:

20. A method for producing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the method comprises: subjecting a compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof to a condensation reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, where R L selected from the group consisting of halogen, hydroxyl and alkoxy, preferably hydroxyl; Y is C(O); and ring A, Q 1 , Z 1 , Z 2 , R 1 , R 2 and R 3 are as defined in paragraph 1.

21. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15 and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15 or a pharmaceutical composition according to claim 21 in the preparation of a medicinal product for agonistic action on the GLP-1 receptor.

23. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 21 in the preparation of a medicinal product for the treatment and / or prevention of type I diabetes, type II diabetes, diabetes associated with malnutrition, complications of diabetes, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular diseases, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance and liver insulin resistance, and preferably in the preparation of a medicinal product for the treatment and / or prevention of type I diabetes, type II diabetes, obesity, complications of diabetes, non-alcoholic steatohepatitis and cardiovascular diseases.

24. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15 or a pharmaceutical composition according to claim 21 in the preparation of a medicinal product for the treatment and / or prevention of idiopathic diabetes type I, latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension and ischemic heart disease.

Images