Fused heterocyclic compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to fused heterocyclic compounds, processes for their preparation and their use in medicine. In particular, the present disclosure relates to a fused heterocyclic compound of general formula (I), processes for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as GLP-1 receptor agonists. In general formula (I) the various groups are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused heterocyclic compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to fused heterocyclic compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use as GLP-1 receptor agonists. Background Technology

[0002] Diabetes mellitus is a multifactorial metabolic disease characterized by chronic hyperglycemia, accompanied by disorders of glucose, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very ancient disease caused by an absolute or relative deficiency of insulin in the body, leading to elevated blood glucose levels, which in turn causes large amounts of glucose to be excreted in the urine, resulting in symptoms such as polydipsia, polyuria, polyphagia, and weight loss.

[0003] Generally, there are two types of diabetes. Type 1 diabetes, or insulin-dependent diabetes, is caused by the body producing very little or no insulin. Insulin is a hormone in the body that regulates glucose utilization. Type 2 diabetes, or insulin-independent diabetes, is caused by the body having plasma insulin levels that are the same as or higher than those of non-diabetic individuals. However, these patients develop insulin resistance, which stimulates glucose and lipid metabolism in major insulin-sensitive tissues such as muscle, liver, and adipose tissue. Even with increased plasma insulin levels, the significant insulin resistance cannot be overcome.

[0004] Insulin resistance arises not only from a reduced number of insulin receptors but also from insulin receptor defects, the mechanism of which is not yet fully understood. Insulin resistance prevents insulin from activating glucose uptake, oxidation, and storage in muscle tissue, and from effectively inhibiting lipolysis in adipose tissue and glucose production and secretion in the liver.

[0005] Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic hormone secreted by L-cells in the lower digestive tract.

[0006] GLP-1 exerts its effects by binding to its widely distributed specific receptors. Currently, GLP-1 receptors are known to exist in pancreatic islet cells, the gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and the cardiovascular system. GLP-1 receptors may also be present 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 among patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the response of β-cells to GLP-1 after eating is defective, and under certain conditions, this response is significantly enhanced after continuous GLP-1 infusion. Because the effect of human GLP-1 is very short-lived (t1 / 2 < 1.5 minutes after intravenous injection), human GLP-1 is not suitable for clinical treatment of diabetes.

[0007] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the effect of lowering fasting and postprandial glucose and improving blood glucose in patients with type 2 diabetes. However, due to the poor oral bioavailability of peptide GLP-1 and the inconvenience of administration, there is a high demand for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0008] Publicly disclosed patent applications for small molecule GLP-1 receptor agonists include CN117069743A, WO2025026270A1, and WO2022017338A1. Summary of the Invention

[0009] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] X 4 Selected from N, N + -O - and CR Z1 ;X 5 Selected from N, N + -O - and CR Z1 ;X 6 Selected from N, N + -O - and CR Z1 ;

[0013] Z 2 Selected from hydrogen atoms, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. Z2 replace;

[0014] Y is selected from C(O), S(O), S(O)2 and alkylene groups;

[0015] Q 1 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. Q1 replace;

[0016] R 1 R 2 and R 3 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, =S, NR 11a R 11b C(O)NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)OR 12 S(O) v R 12 S(O) v NR 11a R 11b OR 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced;

[0017] Ring A is selected from , , , , , , , , , , , , , , , and ;

[0018] R A for ;

[0019] Q 2Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. Q2 Replaced;

[0020] X 1 Selected from CR x1 , N and N + -O - ;X 2 Selected from CR 5 , N and N + -O - ;

[0021] X 3 Selected from CR 6 , N and N + -O - ;

[0022] Each R Z1 R 4 R 5 R 6 and R x1 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, 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)NR 11a R 11b S(O) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 P(O)R 12 R 13 OR 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 02 Replaced;

[0023] R 9 Selected from C(O)OR 12 C(O)NR 11a R 11b S(O) v R 12S(O) v NR 11a R 11b cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally composed of one or more R groups. 9a Replaced;

[0024] R 7 and R 8 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)OR 12 C(O)NR 11a R 11b OC(O)R 12 S(O) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 P(O)R 12 R 13 OR 12 cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, aryl, and heteroaryl; each of the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, aryl, and heteroaryl groups is independently and optionally selected by one or more R 02 Replaced; or

[0025] R 7 R 8 Together with the atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 78 Replaced;

[0026] n1 is 0, 1, 2, 3, 4 or 5; n2 is 0, 1, 2, 3, 4 or 5;

[0027] Each R Q1 R 01 R Z2 R Q2 R 02 R 9a and R 78They may be the same or different, and each is independently selected from deuterium, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, nitro, hydroxy, 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) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 (CH2) x P(O)R 12 R 13 S(O) v OR 12 OR 12 =CR 12a R 13a =NR 00 C(=NR) 00 )R 12 S(=NR) 00 )R 12 S(=NR) 00 )(O)R 12 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently and optionally selected by one or more R * Replaced;

[0028] Each R * The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, nitro, hydroxyl, oxo, =S, NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)NR 11a R 11b C(O)OR12 S(O) v R 12 S(O) v NR 11a R 11b OR 12 The alkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, and heterocyclic oxy groups, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, and heterocyclic oxy groups is independently and optionally substituted by one or more identical or different substituents selected from deuterium, oxo, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0029] R 11a R 11b R 00 R 12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxyalkyl, C(O)R 15 C(O)OR 15 NR 14a R 14b C(O)NR 14a R 14b NR 0 C(O)R 15 S(O) v R 15 OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl and heteroarylalkyl; or R 11a and R 11b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0030] R 12a and R 13a They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic groups;

[0031] R 0 R 15 R 14a and R14b The same or different, and each independently selected from hydrogen atom, deuterium atom, alkyl, alkoxy, hydroxyalkyl, haloalkyl, C(O)alkyl, amino, amide, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from deuterium atom, halogen, cyano, nitro, amino, hydroxy, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic;

[0032] x is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1 or 2.

[0033] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof.

[0034]

[0035] Among them, X 4 X 5 X 6 Z 2 Q 1 R 1 To R 4 R A X 1 X 2 R 6 and Q 2 As defined in general formula (I).

[0036] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0037]

[0038] Among them, R za R zc R zd R ze and R zf They may be the same or different, and each is independently a hydrogen atom or R. Z2 ; or R za R zf Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... Z2 Replaced;

[0039] R 7a and R 8aThey may be the same or different, and each is independently a hydrogen atom or R. 78 ;R 9a 'For hydrogen atoms or R 9a ;

[0040] q is 0, 1, 2, 3, 4, 5, or 6; a is 0, 1, or 2;

[0041] X 5 R Z1 Q 1 R 1 To R 4 X 1 X 2 R 6 R Q2 R Z2 R 78 and R 9a As defined in general formula (I).

[0042] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or pharmaceutically acceptable salts thereof are compounds represented by general formula (IV) or pharmaceutically acceptable salts thereof.

[0043]

[0044] Where T is selected from bond, O, and S(O). v C(O), (CR) Z2c R Z2d ) y O(CR) Z2c R Z2d ) y NR cc 、(CR Z2c R Z2d ) y NR cc 、(CR Z2c R Z2d ) y C(O)NR cc and (CR) Z2c R Z2d ) y NR cc C(O);

[0045] T 0 Selected from bond, O, S(O) v C(O), (CR) Z2c R Z2d ) y 、(CR Z2c R Z2d ) y O, NR cc NRcc (CR Z2c R Z2d ) y C(O)NR cc (CR Z2c R Z2d ) y and NR cc C(O)(CR Z2c R Z2d ) y ;

[0046] R Z2a R Z2b R Z2c R Z2d and R cc They may be the same or different, and each is independently a hydrogen atom or R. Z2 ; or R Z2a R Z2b R Z2c R Z2d and R cc The two atoms in the group and the atoms attached to them together form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R groups. Z2 Replaced;

[0047] m is 0, 1, 2, 3, or 4; y is 0, 1, 2, 3, or 4;

[0048] R zc R zd R ze R Z2 X 5 R Z1 a, Q 1 R 1 To R 4 R 7a R 8a R 9a '、X 1 X 2 R 6 R Q2 And q are as defined in general formula (III).

[0049] In some embodiments of this disclosure, Y is C(O).

[0050] In some embodiments disclosed herein, X 4 Selected from C-methyl, CF, CH, and N; in some embodiments, X 4 For CH or N; in some implementations, X 4 For CH.

[0051] In some embodiments disclosed herein, X5 For N or CR Z0 R Z0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, X 5 Selected from C-methyl, CF, CH, and N; in some embodiments, X 5 For CH or N; in some implementations, X 5 Let N be the number of elements in the array.

[0052] In some embodiments disclosed herein, X 6 Selected from C-methyl, CF, CH, and N; in some embodiments, X 6 For CH or N; in some implementations, X 6 For CH.

[0053] In some embodiments disclosed herein, X 4 For CH or N; and / or X 5 For CH or N; and / or X 6 It can be CH or N.

[0054] In some embodiments disclosed herein, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 hydroxyalkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, each R Z1 They may be the same or different, and each is independently selected from hydrogen, F, cyano, methyl, methoxy, cyclopropyl, difluoromethyl, difluoroethyl, trifluoroethyl, and methoxymethyl; in some embodiments, each R... Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, or carbon atoms. 1-6 alkyl.

[0055] In some embodiments of this disclosure, a is 0 or 1; in other embodiments, a is 0.

[0056] In some implementation schemes disclosed herein, for or In some implementation schemes, for R 1 R2 and R 3 As defined in general formula (I).

[0057] In some embodiments disclosed herein, ring A is X 1 X 2 Q 2 R A R 4 and R 6 As defined in general formula (I); in some implementations, ring A is In some implementation schemes, ring A is X 1 X 2 R A R 4 R 6 R Q2 And q are as defined in general formula (IIII);

[0058] In some implementations, ring A is or X 1 Q 2 R A R 4 R 5 and R 6 As defined in general formula (I); in some implementations, ring A is In some implementation schemes, ring A is In some implementation schemes, ring A is X 1 R A R 4 R 5 R 6 R Q2 And q are as defined in general formula (III).

[0059] In some embodiments disclosed herein, Z 2 It 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 selected from C. 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group, and / or Q 2 The heterocyclic group is a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 One or more of the haloalkoxy groups are substituted; in some embodiments, Z2 It is an indazole group or a tetrahydroxyheptan[4,3,2-cd]indazole group, wherein the indazole group and the tetrahydroxyheptan[4,3,2-cd]indazole group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group, and / or Q 2 It is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally surrounded by one or more C16 groups. 1-6 Alkyl groups are substituted.

[0060] In some embodiments disclosed herein, Q 2 It 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 and optionally converted by one or more R Q2 Replaced by, R Q2 As defined in general formula (I); in some implementations, Q 2 For optional use by one or more R Q2 The replaced 3 to 10-membered heterocyclic groups, R Q2 As defined in general formula (I); in some implementations, Q 2 For optional use by one or more R Q2 The substituted tetrahydropyranyl group, R Q2 As defined in general formula (I);

[0061] In some implementation schemes, Q 2 for In some implementation schemes, Q 2 for R Q2 And q are as defined in general formula (III).

[0062] In some implementation schemes disclosed herein, for or In some implementation schemes, ;R Q2 And q as defined in general formula (III);

[0063] In some implementation schemes, Q 2 or for ;R Qa and R Qb Different, and each independently selected from hydrogen atoms, halogens, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, hydroxyl, cycloalkyl, and heterocyclic groups; in some embodiments, Q 2 or for or .

[0064] In some embodiments disclosed herein, each R Q2 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; in some embodiments, each R Q2 The same or different, and each independently is C. 1-6 Alkyl; in some embodiments, R Q2 It is a methyl group.

[0065] In some embodiments of this disclosure, q is 0, 1, 2 or 3; in some embodiments, q is 0, 1 or 2; in some embodiments, it is 0; and in some embodiments, it is 2.

[0066] In some embodiments disclosed herein, R Qa Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R Qb Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R Qa C 1-6 Alkyl, and / or R Qb C 1-6 Alkyl; in some embodiments, R Qa Methyl, and / or R Qb It is a methyl group.

[0067] In some embodiments disclosed herein, Z 2 It 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 and optionally converted by one or more R Z2 Replaced; in some implementations, Z 2 For optional use by one or more R Z2 The 6 to 14 aryl groups are replaced; in some embodiments, Z 2The indazole group is an indazole group or a tetrahydroxyheptan[4,3,2-cd]indazole group, wherein the indazole group and the tetrahydroxyheptan[4,3,2-cd]indazole group are each independently and optionally converted by one or more R groups. Z2 Replace; in some implementations, Z 2 For optional use by one or more R Z2 Substituted indazole group; R Z2 As defined in general formula (I);

[0068] In some implementation schemes, Z 2 for R Za R Zc and R Zd They may be the same or different, and each is independently a hydrogen atom or R. Z2 Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; c is 0, 1, 2, 3, 4, 5, or 6; R Z2 As defined in general formula (I);

[0069] In some implementation schemes, Z 2 for ;R za R zc R zd R ze and R zf As defined in general formula (III); in some implementations, Z 2 Selected from , , , , and In some implementation schemes, Z 2 for or .

[0070] In some embodiments of this disclosure, 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 5- to 10-membered heteroaryl group; in some embodiments, ring D is a 5- or 6-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... , , and In some implementation schemes, ring D is... ; All of these are fusion sites with phenyl groups.

[0071] In some embodiments of this disclosure, c is 0, 1, or 2; in other embodiments, it is 1.

[0072] In some embodiments disclosed herein, R za R zc R zd and R zf They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, 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 As defined in general formula (I); in some implementations, R za R zc R zd and R zf They may be the same or different, and each is independently selected from hydrogen atoms, F, methylamino groups, and .

[0073] In some implementation schemes, R za R zc R zd and R zf They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy, or R za R zf Together with the carbon atom attached thereto, it forms a 5- to 12-membered cycloalkyl group or a 5- to 12-membered heterocyclic group, wherein each of the 5- to 12-membered cycloalkyl group and the 5- to 12-membered heterocyclic group is independently selected independently from an oxo group, a halogen, or a C-aryl group. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl groups and one or more of 3- to 6-membered cycloalkyl groups are substituted; in some embodiments, R za R zc R zd and R zf They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R za Rzf Together with the carbon atom attached thereto, they form a 5- to 8-membered cycloalkyl group or a 5- to 8-membered heterocyclic group; in some embodiments, R za R zc R zd and R zf They may be the same or different, and each is independently a hydrogen atom or a halogen, or R za R zf Together with the carbon atom attached thereto, they form 5, 6, 7, or 8-membered heterocyclic groups; in some embodiments, R za R zc R zd and R zf They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0074] In some embodiments disclosed herein, R zc and R zd They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R zc and R zd They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R zc and R zd It is a hydrogen atom.

[0075] In some embodiments disclosed herein, R za Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R za It is a hydrogen atom.

[0076] In some embodiments disclosed herein, R zc Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R zc It is a hydrogen atom.

[0077] In some embodiments disclosed herein, R zd Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R zd It is a hydrogen atom or a halogen; in some implementations, R zdIt is a halogen; in some embodiments, it is F; in some embodiments, it is R. zd It is a hydrogen atom.

[0078] In some embodiments disclosed herein, each R Z2 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 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 groups, 3- to 10-membered cycloalkyl groups, and 3- to 10-membered heterocyclic groups are each independently selected from deuterium, oxo groups, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 The R group is substituted with one or more of alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups. 11a R 11b R 12 and R 13 As defined in general formula (I); in some implementations, each R Z2 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 hydroxyalkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, each R Z2 They may be the same or different, and each is independently selected from F, cyano, methyl, methoxy, trideuterated methyl, cyclopropyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxymethyl, tert-butyl and -CH2cyclopropyl;

[0079] In some implementation schemes, each R Z2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R Z2 C 1-6Alkyl or 3- to 6-membered cycloalkyl; in some embodiments, R Z2 C 1-6 Alkyl; in some embodiments, R Z2 It is a methyl group.

[0080] In some embodiments disclosed herein, R ze Selected from hydrogen atoms, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic and 3- to 10-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R ze Selected from hydrogen atoms, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 1-6 Deuterated alkyl groups and 3- to 6-membered cycloalkyl groups;

[0081] In some implementation schemes, R ze C 1-6 Alkyl or 3- to 6-membered cycloalkyl; in some embodiments, R ze Selected from hydrogen atom, methyl, cyclopropyl, deuterated methyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxymethyl, methoxyethyl, isopropyl, tert-butyl, and -CH2cyclopropyl; in some embodiments, R ze It is methyl or cyclopropyl; in some embodiments, R ze C 1-6 Alkyl; in some embodiments, R ze It is CD3.

[0082] In some embodiments disclosed herein, R zf Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R Zf It is a hydrogen atom.

[0083] In some embodiments disclosed herein, X 5 For N or CR Z1 ; and / or each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R za Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C1-6 Halogenated alkyl groups, and / or R zc Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R zd Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R zf Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R ze Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, or R za R zf Together with the carbon atom attached thereto, they form a 5- to 7-membered cycloalkyl group or a 5- to 7-membered heterocyclic group; in some embodiments, X 5 For CH or N, and / or each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R za For hydrogen atoms, and / or R zc For hydrogen atoms, and / or R zd It is a hydrogen atom or a halogen; and / or R zf For hydrogen atoms, and / or R ze C 1-6 Alkyl or 3- to 6-membered cycloalkyl, or R za R zf Together with the carbon atom attached to it, they form a 7-membered heterocyclic group.

[0084] In some embodiments of this disclosure, T is selected from bonds, O, S, S(O), S(O)2, C(O), (CH2). y O(CH2) y NH, (CH2) y NH, (CH2) y C(O)NH and (CH2) y NR cc C(O); in some implementations, T is O.

[0085] In some embodiments disclosed herein, T 0 Selected from bonds, O, S, S(O), S(O)2, C(O), (CH2) y (CH2) y O, NH, NH(CH2) y C(O)NH(CH2) y and NR ccC(O)(CH2) y In some implementation schemes, T 0 Selected from O, NH and CH2; in some embodiments, T 0 It is CH2.

[0086] In some embodiments of this disclosure, y is 0, 1, or 2; in other embodiments, y is 1.

[0087] In some embodiments of this disclosure, m is 0, 1, or 2; in other embodiments, m is 1.

[0088] In some embodiments of this disclosure, T is selected from O, NH and CH2, and / or T 0 Selected from O, NH and CH2, and / or m is 0 or 1, and / or R Z2a and R Z2b It is a hydrogen atom; in some embodiments, T is O, and / or T 0 It is NH or CH2, and / or m is 1.

[0089] In some embodiments disclosed herein, Q 1 It 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 and optionally converted by one or more R Q1 Replace; in some implementations, Q 1 It is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally surrounded by one or more R groups. Q1 Replace; in some implementations, Q 1 For optional use by one or more R Q1 Substituted phenyl, R Q1 As defined in general formula (I); in some implementations, Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The substituted group is one or more of a haloalkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclic group; in some embodiments, Q 1 for In some implementation schemes, Q 1 for or ;

[0090] In some implementation schemes, Q 1 for ;R Q1a R Q1b R Q1cThey may be the same or different, and each is independently a hydrogen atom or R. Q1 R Q1 As defined in general formula (I); in some implementations, Q 1 for R Q1a R Q1b and R Q1c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups.

[0091] In some embodiments disclosed herein, each R Q1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl C 1-6 Alkyl groups and 3 to 10-membered heterocyclic C groups 1-6 Alkyl; in some embodiments, each R Q1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, and 3- to 10-membered cycloalkyl groups; in some embodiments, each R Q1 They may be the same or different, and each is independently a halogen or a carbon. 1-6 Alkyl; in some embodiments, each R Q1 They may be the same or different, and each is independently F or methyl.

[0092] In some embodiments disclosed herein, R Q1a R Q1b and R Q1c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R Q1a It is a hydrogen atom or a carbon atom. 1-6 Alkyl, and / or R Q1b For halogen, and / or R Q1c C 1-6 Alkyl or 3- to 6-membered cycloalkyl; in some embodiments, R Q1a C 1-6 Alkyl, and / or R Q1b For halogen, and / or R Q1c C 1-6Alkyl; in some embodiments, R Q1a Methyl, and / or R Q1b For F, and / or R Q1c For methyl; in some embodiments, R Q1a R Q1b and R Q1c They may be the same or different, and each is independently selected from hydrogen, F, methyl and cyclopropyl.

[0093] In some embodiments disclosed herein, Q 1 It is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally surrounded by one or more R groups. Q1 Replace, R Q1 As defined in general formula (I), and / or each R Q2 The same or different, and each independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of haloalkyl and 3 to 6-membered cycloalkyl groups, and / or each R Q2 The same or different, and each independently of halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, Q 1 The phenyl group is optionally selected from halogens and C. 1-6 One or more of the alkyl groups are substituted, and / or each R Q2 The same or different, and each independently is C. 1-6 alkyl.

[0094] In some embodiments disclosed herein, R 9 The heterocyclic group 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 and optionally converted by one or more R groups. 9a Replaced by, R 9a As defined in general formula (I); in some implementations, R 9 For optional use by one or more R 9a The replaced 5-membered heterocyclic group, R 9a As defined in general formula (I); in some implementations, R 9 For optional use by one or more R 9a The replaced 5-membered heterocyclic group, at least one R 9a It is an oxygen group; in some embodiments, R 9 for R 9a 'For hydrogen atoms or C 1-6 Alkyl; in some embodiments, R 9 For optional use by one or more R 9a The replaced 5-membered heteroaryl group, R 9a As defined in general formula (I); in some implementations, R 9 for In some implementation schemes, R 9 for or In some implementation schemes, R 9 for .

[0095] In some embodiments disclosed herein, R 7 R 8 Together with the atoms attached thereto, they form a 3- to 10-membered cycloalkyl group, wherein the 3- to 10-membered cycloalkyl group is optionally bonded by one or more R... 78 Replaced by, R 78 As defined in general formula (I); in some implementations, R 7 R 8 Together with the atoms attached to it, it forms an optional structure controlled by one or more R atoms. 78 The substituted cyclopropyl group, R 78 As defined in general formula (I); in some implementations, R 7 R 8 Together with the atoms attached to it, it forms a cyclopropyl group that can be optionally substituted with a methyl group.

[0096] In some embodiments of this disclosure, n1 is 0 or 1, and / or n2 is 0 or 1; in other embodiments, n1 is 0, and / or n2 is 0.

[0097] In some embodiments disclosed herein, R A for In some implementation schemes, R A for R 7a R 8a R 9a As defined in general formula (III); in some implementations, R A for or In some implementation schemes, In some implementation schemes, In some implementation schemes, In some implementation schemes, R A for ;R 7a Selected from hydrogen atoms, C1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 Alkyne group.

[0098] In some embodiments disclosed herein, R 7a and R 8a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 Alkyne group. In some embodiments of this disclosure, R 7a and R 8a They are different and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 Alkyne group.

[0099] In some embodiments disclosed herein, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, OR 12 3 to 10-membered cycloalkyl groups and 3 to 10-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl groups, 3- to 10-membered cycloalkyl groups, and 3- to 10-membered heterocyclic groups are each independently and optionally enclosed by one or more R groups. * Replaced; in some implementations, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, OR 12 C 1-6 Alkylene-OR 12 C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 alkynyl-R ** , oxo-group, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic group, 3- to 10-membered cycloalkyl C 1-6 Alkyl groups and 3 to 10-membered heterocyclic C groups 1-6 Alkyl, R ** For hydrogen atoms or R * ;

[0100] In some implementation schemes, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, CH2-OR 12 and C≡CR ** ;R ** For hydrogen atoms or R * In some implementation schemes, R 7a C 1-6 Alkyl or C 2-6 Alkyne group; in some implementations, R 7a C 1-6 Alkyl; in some embodiments, R 7a It is methyl;

[0101] In some implementation schemes, R 7a Selected from C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups; in some embodiments, R 7a Selected from C 1-6 Alkyl, CH2-OR 12 and C≡CR ** R 12 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6Alkyl; in some embodiments, R 7a Selected from methyl, propynyl, , , and acetylene group;

[0102] In some implementation schemes, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, OR 12 CH2-OR 12 CD2-OR 12 3 to 10-membered cycloalkyl groups and 3 to 10-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl groups, 3- to 10-membered cycloalkyl groups, and 3- to 10-membered heterocyclic groups are each independently and optionally influenced by one or more R groups. * Replaced;

[0103] In some implementation schemes, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, CH2-OR 12 CD2-OR 12 and C≡CR ** ;R ** For hydrogen atoms or R * ;

[0104] In some implementation schemes, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 CD2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups; in some embodiments, R 7a Selected from methyl, propynyl, , , , ethynyl, methoxymethyl, CH2-O-CHF2, CH2-O-CH2 cyclopropyl and CD2-O-cyclopropyl.

[0105] In some embodiments disclosed herein, R 8a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 8a It is a hydrogen atom.

[0106] In some embodiments disclosed herein, each R 78 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 2-6 Alkyne group; 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.

[0107] In some embodiments disclosed herein, each R 78 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, CH2-OR 12 and C≡CR ** ;R ** For hydrogen atoms or R *.

[0108] In some embodiments disclosed herein, R 9a’ Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 9a’ It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 9a’ It is a hydrogen atom.

[0109] In some embodiments disclosed herein, each R 9a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; 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.

[0110] In some embodiments disclosed herein, R 9a 'is a hydrogen atom, and / or R 7a Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 CD2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups, and / or R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 9a 'is a hydrogen atom, and / or R 7a Selected from C 1-6 Alkyl, C 2-6Alkyne group, CH2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups, and / or R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 7a Selected from C 1-6 Alkyl, CH2-OR 12 and C≡CR ** R 12 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6 Alkyl, and / or R 8a It is a hydrogen atom.

[0111] In some embodiments disclosed herein, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or X 1 For CH or N, and / or X 2 For CH or N; in some implementations, R 1 For hydrogen atoms, and / or R2 For hydrogen atoms, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 6 For hydrogen atoms, and / or X 1 For CH, and / or X 2 It can be CH or N.

[0112] In some embodiments disclosed herein, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1 It is a hydrogen atom.

[0113] In some embodiments disclosed herein, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 2 It is a hydrogen atom.

[0114] In some embodiments disclosed herein, R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0115] In some embodiments disclosed herein, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0116] In some embodiments disclosed herein, R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5 It is a hydrogen atom.

[0117] In some embodiments disclosed herein, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6 It is a hydrogen atom.

[0118] In some embodiments disclosed herein, X1 For CH or N; in some implementations, X 1 For CH.

[0119] In some embodiments disclosed herein, R x1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R x1 It is a hydrogen atom.

[0120] In some embodiments disclosed herein, X 2 For CR 5 Or N; in some implementations, X 2 For CH or N; in some implementations, X 2 For CH; in some implementations, X 2 Let N be the number of elements in the array.

[0121] In some embodiments disclosed herein, X 1 For CH or N, and / or X 2 For CH or N; in some implementations, X 1 For CH, and / or X 2 It can be CH or N.

[0122] In some embodiments disclosed herein, R Z2a R Z2b R Z2c and R Z2d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyl, cyano, oxo, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; in some embodiments, R Z2c and R Z2d It is a hydrogen atom.

[0123] In some implementation schemes, R Z2a and R Z2b It is a hydrogen atom.

[0124] In some embodiments disclosed herein, R cc Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; in some embodiments, R cc It is a hydrogen atom.

[0125] In some embodiments disclosed herein, R 11a and R 11b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 11a and R 11b They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 11a and R 11b All are hydrogen atoms; in some implementations, R 11a For hydrogen atoms, and / or R 11b It is a methyl group.

[0126] In some embodiments disclosed herein, R 00 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 00 It can be a hydrogen atom or a methyl group.

[0127] In some embodiments disclosed herein, R 0 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 0 It can be a hydrogen atom or a methyl group.

[0128] In some embodiments disclosed herein, R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; in some embodiments, R 12 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 12 C 1-6 Alkyl; in some embodiments, R 12 For methyl; in some embodiments, R 12 For hydrogen atoms; in some implementations, R 12Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 12 Selected from hydrogen atom, methyl, CHF2, cyclopropyl and cyclopropylmethyl.

[0129] In some embodiments disclosed herein, R 15 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 15 It is a hydrogen atom.

[0130] In some embodiments disclosed herein, R 14a and R 14b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0131] In some embodiments of this disclosure, x is 0, 1, or 2; in other embodiments, x is 0.

[0132] In some embodiments disclosed herein, each R 01 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 01 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0133] In some embodiments disclosed herein, each R 02 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl, OC 1-6 Alkoxy C 1-6 Alkyl, C(O)NR 11a R 11b alkylene C(O)NR 11a R 11bC(O)R 12 S(O) v R 12 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic and 5 or 6-membered heteroaryl, wherein each of the 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic and 5 or 6-membered heteroaryl is independently selected independently from halogen, C 1-6 Alkyl and C 1-6 One or more of the alkoxy groups are substituted.

[0134] In some embodiments disclosed herein, each R * They may be the same or different, and each is independently selected from deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl, oxo, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl, 3- to 6-membered cycloalkyloxy, and 3- to 6-membered heterocyclic alkyloxy; in some embodiments, each R * They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl, oxo, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, OR 12 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 alkyl.

[0135] In some embodiments of this disclosure, v is 2.

[0136] In some embodiments of this disclosure, the compound is not a compound listed in Table A of application number PCT / CN2024 / 133436.

[0137] In some embodiments disclosed herein, R ze Not methyl, or R 7a It is not methyl.

[0138] In some embodiments disclosed herein, R 78 Not methyl, or R Z2 It is not methyl.

[0139] In some embodiments of this disclosure, the compound represented by general formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R ze Selected from hydrogen atoms, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 1-6 Deuterated alkyl groups and 3- to 6-membered cycloalkyl groups, R zf It is a hydrogen atom or a halogen; R za For hydrogen atoms, R zc For hydrogen atoms, R zd It is a hydrogen atom or a halogen; T is CH2 or O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 0 or 1;

[0140] Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 4 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 Halogenated alkyl, X 1 For CH, X 2 For CH or N; R 9a 'For hydrogen atoms or C 1-6 Alkyl, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, CH2-OR 12 CD2-OR 12 and C≡CR ** ;R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl; R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups; R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, 2 or 3.

[0141] In some embodiments of this disclosure, the compound represented by general formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R ze Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl, R zf It is a hydrogen atom or a halogen; R za For hydrogen atoms, R zc For hydrogen atoms, R zd It is a hydrogen atom or a halogen; T is CH2 or O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 0 or 1;

[0142] Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 Selected from hydrogen atoms, halogens, C1-6 Alkyl and C 1-6 Haloalkyl, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 4 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 Halogenated alkyl, X 1 For CH, X 2 For CH or N; R 9a 'For hydrogen atoms or C 1-6 Alkyl, R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, 2 or 3.

[0143] In some embodiments of this disclosure, the compound represented by general formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R za For hydrogen atoms, R zc For hydrogen atoms, R zd R is a hydrogen atom or a halogen. ze C 1-6 Alkyl or 3- to 6-membered cycloalkyl, R zf T is a hydrogen atom; T is O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 1; Q 1 The phenyl group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1 For CH, X 2 For N; R 9a ' is a hydrogen atom, R 7a Selected from C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups, R 8a For hydrogen atoms; each R Q2 The same or different, and each independently is C. 1-6 Alkyl group; q is 0, 1, 2 or 3.

[0144] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R ze C 1-6 Alkyl or 3- to 10-membered cycloalkyl, R zc For hydrogen atoms, R zd It is a hydrogen atom or a halogen; T is CH2 or O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 0 or 1;

[0145] Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1 For CH, X 2 For CH or N; R 9a ' is a hydrogen atom, R 7a Selected from C 1-6 Alkyl, CH2-OR 12 and C≡CR ** R 12 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 8a For hydrogen atoms; each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, 2 or 3.

[0146] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R ze C 1-6 Alkyl or 3- to 10-membered cycloalkyl, R zc For hydrogen atoms, R zd It is a hydrogen atom or a halogen; T is CH2 or O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 0 or 1;

[0147] Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1For CH, X 2 For N; R 9a ' is a hydrogen atom, R 7a Selected from C 1-6 Alkyl, CH2-OR 12 and C≡CR ** R 12 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 8a For hydrogen atoms; each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, 2 or 3.

[0148] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R ze C 1-6 Alkyl or 3- to 10-membered cycloalkyl, R zc For hydrogen atoms, R zd It is a hydrogen atom or a halogen; T is CH2 or O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 0 or 1;

[0149] Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1 For CH, X 2 For CH or N; R 9a ' is a hydrogen atom, R 7a CH2-OR 12 Or C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6 Alkyl, R 8a For hydrogen atoms; each R Q2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 0, 1, 2 or 3.

[0150] In some embodiments of this disclosure, the compound represented by general formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R za For hydrogen atoms, R zc For hydrogen atoms, R zd R is a hydrogen atom or a halogen. ze C 1-6 Deuterated alkyl or 3- to 6-membered cycloalkyl, R zf T is a hydrogen atom; T is O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 1; Q 1 The phenyl group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1 For CH, X 2 For CH or N; R 9a ' is a hydrogen atom, R 7a Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 CD2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, R **Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 8a For hydrogen atoms; each R Q2 The same or different, and each independently is C. 1-6 Alkyl group; q is 0, 1, 2 or 3.

[0151] In some embodiments of this disclosure, the compound represented by general formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein X 5 For CH or N, each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; a is 0 or 1; R za For hydrogen atoms, R zc For hydrogen atoms, R zd R is a hydrogen atom or a halogen. ze Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl groups and 3- to 6-membered cycloalkyl groups, R zf T is a hydrogen atom; T is O; T 0 It is CH2 or NH; R Z2a and R Z2b For a hydrogen atom, m is 1; Q 1 The phenyl group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group; R 1 For hydrogen atoms, R 2 For hydrogen atoms, R 3 C 1-6 Alkyl, R 4 For hydrogen atoms, R 6 For hydrogen atoms, X 1 For CH, X 2 For CH or N; R 9a ' is a hydrogen atom, R 7a CH2-OR 12 or CD2-OR 12 R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, R 8a For hydrogen atoms; each RQ2 The same or different, and each independently is C. 1-6 Alkyl group; q is 0, 1, 2 or 3.

[0152] Group A: Typical compounds disclosed herein, or their pharmaceutically acceptable salts, include, but are not limited to:

[0153] , ,

[0154] , ;

[0155] , ;

[0156] , ,

[0157] , ;

[0158] , ,

[0159] , ;

[0160] , ,

[0161] , ;

[0162] , ,

[0163] , ;

[0164] , ;

[0165] , ;

[0166] , ,

[0167] , ;

[0168] , ;

[0169] 、 、

[0170] 、 ；

[0171] 、 ；

[0172] 、 、

[0173] 、 ；

[0174] 、 ；

[0175] 、 、

[0176] 、 ；

[0177] 、 ；

[0178] 、 ；

[0179] 、 ；

[0180] 、 ；

[0181] 、 ；

[0182] 、 ；

[0183] 、 ；

[0184] 、 ；

[0185] 、 ；

[0186] 、 ；

[0187] 、 ；

[0188] , ;

[0189] , ;

[0190] , ;

[0191] and .

[0192] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof.

[0193]

[0194] Among them, R W It is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc;

[0195] Z 2 X 4 X 5 X 6 Q 1 and R 1 To R 3 As defined in general formula (II).

[0196] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof.

[0197]

[0198] Among them, R W It is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc;

[0199] R za R zc R zd R ze R zf X 5 R Z1 a, Q 1 and R 1 To R 3 As defined in general formula (III).

[0200] Another aspect of this disclosure relates to compounds of general formula (IVA) or salts thereof.

[0201]

[0202] Among them, R WIt is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc;

[0203] T, T 0 R Z2a R Z2b m, R zc R zd R ze X 5 R Z1 a, Q 1 and R 1 To R 3 As defined in general formula (IV).

[0204] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IC), (ID), (IE), and (IF).

[0205] R P It is selected from OH, halogens and alkoxy groups, and in some embodiments is OH.

[0206] In some implementation schemes, R 11a It is a hydrogen atom or a carbon atom. 1-6 Alkyl, in some embodiments, R 11a It is methyl. In some embodiments, R 11b Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; in some embodiments, R 11b It is a phenyl group.

[0207] Group B: Typical intermediate compounds or salts thereof disclosed herein include, but are not limited to:

[0208] , , , ;

[0209] , , , ;

[0210] , , , , , , , , and .

[0211] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0212]

[0213] A compound of general formula (IIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIB) or a salt thereof to give a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0214] Among them, R W For hydrogen atoms; R P Selected from OH, halogens, and alkoxy groups, with OH being the preferred form in some embodiments;

[0215] Z 2 X 4 X 5 X 6 Q 1 R 1 To R 4 R A X 1 X 2 R 6 and Q 2 As defined in general formula (II).

[0216] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0217] A compound of general formula (IIIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIIB) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0218] Among them, R W For hydrogen atoms; R P Selected from OH, halogens, and alkoxy groups, with OH being the preferred form in some embodiments;

[0219] R za R zc R zd R ze R zf X 5 R Z1 a, Q 1 R 1 To R 4 R 7a R 8a R 9a '、X 1 X2 R 6 R Q2 And q are as defined in general formula (III).

[0220] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0221] The compound of general formula (IVA) or its salt reacts with the compound of general formula (IIIB) or its salt to give the compound of general formula (IV) or its pharmaceutically usable salt.

[0222] Among them, R W For hydrogen atoms; R P Selected from OH, halogens, and alkoxy groups, with OH being the preferred form in some embodiments;

[0223] T, T 0 R Z2a R Z2b m, R zc R zd R ze X 5 R Z1 a, Q 1 R 1 To R 4 R 7a R 8a R 9a '、X 1 X 2 R 6 R Q2 And q are as defined in general formula (IV).

[0224] In some embodiments, the condensation reaction described above occurs under alkaline conditions; in some embodiments, the condensation reaction described above occurs under alkaline conditions in the presence of a condensing agent.

[0225] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, 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, N,N-diisopropylethylamine is used.

[0226] The condensing agents mentioned 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'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, and O-(7-azabenzotriazole-1 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole-1-yloxytripyrrolylphosphonium hexafluorophosphate; in some embodiments, HATU.

[0227] In some embodiments, the reaction of the above steps is carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, trifluoroacetic 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 mixtures thereof.

[0228] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (IV) or group A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0229] This disclosure further relates to the use of compounds of formulas (I) to (IV) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for activating GLP-1 receptors.

[0230] This disclosure further relates to the use of compounds of formulas (I) to (IV) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of GLP-1 receptor agonists.

[0231] This disclosure further relates to the use of compounds of formulas (I) to (IV) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, malnutrition-associated diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, 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, the use in the preparation of medicaments for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease;

[0232] In some embodiments, the use is permitted in the preparation of medicaments for the treatment and / or prevention of idiopathic type 1 diabetes, latent immune diabetes mellitus in adults (LADA), young adult-onset diabetes mellitus (MODY), gestational diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary artery disease.

[0233] This disclosure further relates to a method of activating a GLP-1 receptor, comprising administering to a desired patient a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0234] This disclosure further relates to a method of treating and / or preventing diseases or conditions mediated by GLP-1 receptors, comprising administering to a desired patient a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0235] This disclosure further relates to a method for treating and / or preventing type 1 diabetes, type 2 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, comprising administering to a desired patient a compound of formula (I), (II), or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0236] This disclosure further relates to a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0237] This disclosure further relates to a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as a GLP-1 receptor agonist.

[0238] This disclosure further relates to a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for activating GLP-1 receptors.

[0239] This disclosure further relates to a compound of formula (I) to (IV) or group A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, malnutrition-associated diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, hyperlipidemia, cerebral infarction, stroke, non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, glaucoma, diarrhea, insulin resistance, and hepatic insulin resistance.

[0240] In some embodiments, the GLP-1 receptor-mediated diseases or conditions described in this disclosure are selected from type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, 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, they are type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, and cardiovascular disease; in some embodiments, they are selected from idiopathic type 1 diabetes, latent immune diabetes mellitus (LADA) in adults, young adult-onset diabetes mellitus (MODY), gestational diabetes, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, and coronary heart disease.

[0241] In some embodiments, the cardiovascular disease is heart failure; in other embodiments, the cardiovascular disease is heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

[0242] In some implementations, the obesity is obesity associated with heart failure with preserved ejection fraction.

[0243] "Diabetic complications" are complications arising from diabetes or hyperglycemia, and can be either acute or chronic complexes. The term "acute complex" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), while "chronic complex" includes, for example, microvascular diseases (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory nerve disorders, motor nerve disorders, autonomic nerve disorders), and gangrene. Major diabetic complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0244] Coronary heart disease includes myocardial infarction and angina pectoris.

[0245] "Dementia" includes, for example, Alzheimer's disease, early-onset dementia (EOD), vascular dementia, and diabetic dementia.

[0246] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this 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.

[0247] As a general guideline, the active compounds disclosed herein are presented in unit dose form or in a manner that allows patients to self-administer a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0248] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0249] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0250] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0251] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0252] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These 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, thus providing sustained release over a longer period.

[0253] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0254] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These 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 sweeteners.

[0255] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0256] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. 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, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0257] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0258] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0259] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0260] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0261] 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 activity of the specific compound used, the severity of the disease, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal treatment mode, such as the treatment regimen, the daily dosage of the compound, or the type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0262] Terminology Explanation

[0263] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0264] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, and in some embodiments is 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., C12). 1-12 Alkyl), in some embodiments of which are alkyl groups having 1 to 6 carbon atoms (i.e., C164 ... 1-6 Alkyl groups). Non-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 their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0265] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 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., C2). 1-20 Alkylene). In some embodiments, the alkylene is an alkylene having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes), in some embodiments having 1 to 6 carbon atoms (i.e., C164-C ... 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0266] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0267] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in a molecule, wherein the definition of an alkyl group is as described 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., C64, C74, C84, C9 ... 2-12 alkenyl), in some embodiments alkenyl groups having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0268] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in a molecule, where the definition of alkyl is as described above. In some embodiments, it 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 ynyl group), in some embodiments 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, and when substituted, the substituent is selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0269] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, in some embodiments containing 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl), in some embodiments containing 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl) or containing 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, and 10) carbon atoms (i.e., 3 to 10-membered cycloalkyl), and in some embodiments containing 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups.

[0270] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings and may contain one or more double bonds. In some embodiments, it is 6 to 14-membered, and in others, it is 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (e.g., bispirocycloalkyl) based on the number of shared spiro atoms between the rings, and in some embodiments, they are both monospirocycloalkyl and bispirocycloalkyl. In some embodiments, they are 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 3-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 5 / 7-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, 6 / 6-membered, 6 / 7-membered, 7 / 5-membered, or 7 / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0271] Its connection point can be anywhere;

[0272] wait.

[0273] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. In some embodiments, it is 6 to 14-membered, and in some embodiments, it is 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, it can be classified as bicyclic or polycyclic fused-ring alkyl (e.g., tricyclic, tetracyclic), in some embodiments bicyclic or tricyclic, and in some embodiments 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0274] Its connection point can be anywhere; wait.

[0275] The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. In some embodiments, it is 6 to 14-membered, and in some embodiments, it is 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Based on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl, which in some embodiments is bicyclic, tricyclic, or tetracyclic, and in some embodiments is bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0276] Its connection point can be anywhere.

[0277] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... , , etc.; in some implementation schemes, it is and .

[0278] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0279] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. In some embodiments, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., 3 to 14-membered heterocyclic groups), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; in some embodiments, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered heterocyclic groups) or 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, and 10) ring atoms. Monocyclic heterocyclic groups (i.e., 3 to 10-membered heterocyclic groups) or containing 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14) (i.e., 6 to 14-membered heterocyclic groups), wherein 1-3 are heteroatoms (e.g., 1, 2, and 3); in some embodiments, containing 3 to 8 ring atoms, wherein 1-3 (e.g., 1, 2, and 3) are heteroatoms; in some embodiments, containing 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclic groups), wherein 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0280] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. In some embodiments, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered spiroheterocyclic groups), and in some embodiments, it is 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic groups). Spiroheterocyclic groups are classified as monospirocyclic or polyspirocyclic (e.g., bispirocyclic) groups based on the number of shared spiro atoms between the rings; in some embodiments, both monospirocyclic and bispirocyclic groups are used. In some implementations, the spirocyclic group is 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6. Non-limiting examples of spirocyclic groups include:

[0281] .

[0282] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with 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 optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. In some embodiments, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered fused heterocyclic groups), and in some embodiments, it is 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered fused heterocyclic groups). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic or multicyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups. In some embodiments, they are bicyclic or tricyclic; in others, they are 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:

[0283] .

[0284] The term "bridged heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It 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 optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. In some embodiments, it is 6 to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered bridged heterocyclic groups), and in some embodiments, it is 7 to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, and in some embodiments, it is bicyclic, tricyclic, or tetracyclic, and in some embodiments, it is bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0285] .

[0286] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0287] and wait.

[0288] The heterocyclic group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0289] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, and in some embodiments is 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0290] .

[0291] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0292] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.

[0293] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0294] wait.

[0295] The heteroaryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0296] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl residues include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0297] The term "amino protecting group" is used to protect the amino group by an easily removable group so that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonyl (Ts), and p-methoxybenzyl (PMB), etc. These groups may optionally be substituted with 1-3 substituents selected from halogens, alkoxy groups, and nitro groups; in some embodiments, the amino protecting group is Boc.

[0298] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0299] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0300] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0301] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0302] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0303] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0304] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0305] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0306] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0307] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0308] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0309] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0310] The term "hydroxyalkoxy" refers to an alkoxy group that is substituted with one or more hydroxyl groups, where the alkoxy group is as defined above.

[0311] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; in some embodiments, it is -alkyl-alkoxy; including but not limited to methoxyethyl, methoxypropyl, etc.

[0312] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0313] The term "hydroxyl group" refers to -OH.

[0314] The term "thiol" refers to -SH.

[0315] The term "amino" refers to -NH2.

[0316] The term "cyano" refers to -CN.

[0317] The term "nitro" refers to -NO2.

[0318] The term "oxo" or "oxo" refers to "=O".

[0319] The term "carbonyl" refers to C=O.

[0320] The term "carboxyl group" refers to -C(O)OH.

[0321] The term "amide group" refers to -C(O)NH2.

[0322] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. Also included are transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. For example, some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0323] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of keto-enol equilibrium are shown below:

[0324]

[0325] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0326] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, trans-blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both Z-type and E-type 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. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0327] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations; bond" "No configuration is specified, which means it can be Z configuration or E configuration, or both configurations at the same time."

[0328] The compounds disclosed herein include all suitable isotopic derivatives 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 may be introduced into the compounds of this 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) 2c , 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., are deuterium in some implementation schemes.

[0329] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0330] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6"Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0331] "Substituted" refers to one or more hydrogen atoms in a group, such as 1 to 6, or in some embodiments, 1 to 3 hydrogen atoms being independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0332] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0333] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or 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 both inorganic and organic acids.

[0334] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0335] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0336] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0337] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0338] Example

[0339] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0340] MS measurements were performed using the following instruments: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0341] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0342] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0343] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0344] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0345] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0346] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0347] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0348] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0349] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0350] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0351] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0352] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0353] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0354] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0355] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0356] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0357] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0358] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0359] Example 1

[0360] 3-((1S,2S)-1-(5-(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]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0361]

[0362] first step

[0363] (S)-3-bromo-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 1b

[0364] (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 1a (1.0 g, 2.67 mmol, Biotin) was dissolved in acetonitrile (20 mL), and copper bromide (596 mg, 2.67 mmol) was added. The reaction mixture was cooled to 0 °C, and isoamyl nitrite (469 mg, 4.00 mmol) was added dropwise. The mixture was stirred at 0 °C for 0.5 hours, then heated to 60 °C and stirred for another 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give title compound 1b (350 mg, yield: 29.9%).

[0365] MS m / z (ESI): 438.3 [M+1].

[0366] Step 2

[0367] (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 1c

[0368] Compound 1b (500 mg, 1.14 mmol) was dissolved in tetrahydrofuran (10 mL), purged with nitrogen, and n-butyllithium (0.92 mL, 2.5 M, Adamas) was added dropwise at -78°C with stirring for 1 hour. Trimethyl borate (475 mg, 4.57 mmol, Adamas) was then added, and the reaction was continued at -78°C with stirring for 0.5 hours. The reaction mixture was quenched with 20 mL of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were 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 give title compound 1c (220 mg, yield: 47.8%).

[0369] MS m / z (ESI): 404.4 [M+1].

[0370] Step 3

[0371] 5-Iodo-3-(1-methyl-1H-indazol-5-yl)pyrimidin-4(3H)-one 1e

[0372] 5-Iodopyrimidine-4(3H)-one 1d (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 openly at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to obtain a crude product. This crude product was then slurried with dichloromethane to give the title compound 1e (500 mg, yield: 31.5%).

[0373] MS m / z (ESI): 353.1 [M+1].

[0374] Step 4

[0375] (S)-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-carboxylic acid tert-butyl ester 1f

[0376] Compound 1e (150 mg, 0.43 mmol), compound 1c (210 mg, 0.52 mmol), anhydrous potassium carbonate (177 mg, 1.28 mmol), and tetraphenylphosphine palladium (132 mg, 0.043 mmol, BIDE) were dissolved in dioxane (8 mL) and water (2 mL), purged with nitrogen, and the reaction was stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give crude title compound 1f (20 mg).

[0377] MS m / z (ESI): 584.4 [M+1].

[0378] Step 5

[0379] (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 1g

[0380] Compound 1f (20 mg, 0.034 mmol) was dissolved in dichloromethane (1 mL), and a 4M dioxane solution (2 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title compound 1 g (17 mg). The product was used directly in the next reaction without purification.

[0381] MS m / z (ESI): 484.4 [M+1].

[0382] Step 6

[0383] 3-((1S,2S)-1-(5-(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]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0384] 1 g (17 mg, 0.035 mmol) of compound and 1 h (22 mg, 0.053 mmol, prepared by the method disclosed in Example 1, page 17 of patent application CN117069743A) of 5-(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-pyrrolo[3,2-b]pyridine-2-carboxylic acid (prepared by the method disclosed in Example 1, page 17 of patent application CN117069743A) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (14.2 mg, 0.11 mmol) was added. After complete dissolution of the raw materials, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (15 mg, 0.039 mmol) was added. The mixture was stirred at room temperature for 16 hours (mmol). 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 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 title compound 1 (15 mg, yield: 48.6%).

[0385] MS m / z (ESI): 878.4 [M+1].

[0386] Example 2

[0387] 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-(2-methyl-2,7,8,9-tetrahydrooxoheptan[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 2

[0388]

[0389]

[0390] first step

[0391] (2-Methyl-2,7,8,9-tetrahydrooxoheptancyclo[4,3,2-cd]indazol-5-yl)boronic acid 2b

[0392] 5-Bromo-2-methyl-2,7,8,9-tetrahydrooxaheptane[4,3,2-cd]indazole 2a (500 mg, 1.87 mmol, prepared by the method disclosed in the intermediate of Example 35 on page 111 of patent application WO2025026270A1) was dissolved in tetrahydrofuran (10 mL), purged with nitrogen, and n-butyllithium (1.5 mL, 2.5 M, Adamas) was added dropwise at -78°C with stirring for 1 hour. Trimethyl borate (583 mg, 5.61 mmol, Adamas) was then added, and the reaction was continued with stirring at -78°C for 0.5 hours. The reaction solution was quenched with 20 mL of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give title compound 2b (150 mg, yield: 34.5%).

[0393] MS m / z (ESI): 233.1 [M+1].

[0394] Step 2

[0395] 5-Iodo-3-(2-methyl-2,7,8,9-tetrahydrooxaheptane[4,3,2-cd]indazol-5-yl)pyrimidin-4(3H)-one 2c

[0396] Compound 1d (1.0 g, 4.50 mmol, Adamas), compound 2b (1.58 g, 6.82 mmol), 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 the mixture was stirred open at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give title compound 2c (300 mg, yield: 16.3%).

[0397] MS m / z (ESI): 409.1 [M+1].

[0398] Step 3

[0399] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxoheptanecyclo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 2d

[0400] Compound 2c (175 mg, 0.43 mmol), compound 1c (210 mg, 0.52 mmol), anhydrous potassium carbonate (177 mg, 1.28 mmol), and tetraphenylphosphine palladium (132 mg, 0.043 mmol, BIDE) were dissolved in dioxane (8 mL) and water (2 mL), purged with nitrogen, and the reaction was stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the crude title compound 2d (25 mg).

[0401] MS m / z (ESI): 640.3 [M+1].

[0402] Step 3

[0403] (S)-5-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2-methyl-2,7,8,9-tetrahydrooxaheptanecyclo[4,3,2-cd]indazol-5-yl)pyrimidin-4(3H)-one 2e

[0404] Compound 2d (25 mg, 0.039 mmol) was dissolved in dichloromethane (1 mL), and a 4M dioxane solution (2 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title compound 2e (20 mg). The product was used directly in the next reaction without purification.

[0405] MS m / z (ESI): 540.3 [M+1].

[0406] Step 4

[0407] 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-(2-methyl-2,7,8,9-tetrahydrooxoheptan[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 2

[0408] Compound 2e (20 mg, 0.037 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 2f (23 mg, 0.056 mmol, prepared by the method disclosed in Intermediate 47 on page 185 of patent application WO2022017338A1) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (15 mg, 0.12 mmol) was added, and after complete dissolution of the reactants, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (16 mg, 0.041 mmol) was added. The mixture was stirred at room temperature for 16 hours (mmol). 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 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 title compound 2 (10 mg, yield: 29.0%).

[0409] MS m / z (ESI): 933.5 [M+1].

[0410] Example 3

[0411] 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxoheptanecyclo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one3

[0412]

[0413]

[0414] Compound 2e (20 mg, 0.037 mmol) and compound 1h (23 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (15 mg, 0.12 mmol) was added. After the raw materials were completely dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (16 mg, 0.041 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture 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 high-performance liquid chromatography (HPLC) (instrument: 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 title compound 3 (12 mg, yield: 34.7%).

[0415] MS m / z (ESI): 934.5 [M+1].

[0416] Example 4

[0417] 3-(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]pyridin-5-carbonyl)-1H-indol-1-yl)-2-(prop-1-yn-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one4

[0418]

[0419]

[0420] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-(prop-1-yn-1-yl)cyclopropyl)-1H-indole-2-carboxylic acid 4a (27 mg, 0.062 mmol, prepared by the method disclosed in Example 144, intermediate, on page 150 of patent application WO2025026270) and 1 g (20 mg, 0.041 mmol) of compound were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (16 mg, 0.12 mmol) was added. After the raw materials were completely dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (17 mg, 0.045 mmol) was added. The mixture was stirred at room temperature for 16 hours (mmol). 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 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 title compound 4 (13 mg, yield: 35.2%).

[0421] MS m / z (ESI): 901.4 [M+1].

[0422] Example 5

[0423] 3-((1S,2R)-1-(5-(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]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(prop-1-yn-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one5

[0424]

[0425] MS m / z (ESI): 902.4 [M+1].

[0426] Example 6

[0427] 3-((1S,2R)-1-(5-(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]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-ethynylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one6

[0428]

[0429] MS m / z (ESI): 888.4 [M+1].

[0430] Example 7

[0431] 3-((1S,2R)-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]pyridin-5-carbonyl)-1H-indol-1-yl)-2-ethynylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one7

[0432]

[0433] MS m / z (ESI): 887.4 [M+1].

[0434] Example 8

[0435] 3-((1S,2R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-(prop-1-yn-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one8

[0436]

[0437] MS m / z (ESI): 957.5 [M+1].

[0438] Example 9

[0439] 3-((1S,2R)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(prop-1-yn-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one9

[0440] Exact Mass: 957.41

[0441]

[0442] MS m / z (ESI): 958.5 [M+1].

[0443] Example 10

[0444] 3-((1S,2R)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-ethynylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one10

[0445]

[0446] MS m / z (ESI): 943.4 [M+1].

[0447] Example 11

[0448] 3-((1S,2R)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-ethynylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one11

[0449]

[0450] MS m / z (ESI): 944.4 [M+1].

[0451] Example 12

[0452] 3-((1S,2S)-2-(cyclopropoxymethyl)-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]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 12

[0453]

[0454] MS m / z (ESI): 933.5 [M+1].

[0455] Example 13

[0456] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(5-(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]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 13

[0457]

[0458] MS m / z (ESI): 934.5 [M+1].

[0459] Example 14

[0460] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 14

[0461]

[0462] MS m / z (ESI): 989.5 [M+1].

[0463] Example 15

[0464] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 15

[0465]

[0466] MS m / z (ESI): 990.5 [M+1].

[0467] Example 16

[0468] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 16

[0469]

[0470] MS m / z (ESI): 961.5 [M+1].

[0471] Example 17

[0472] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 17

[0473] Exact Mass: 961.40

[0474]

[0475] MS m / z (ESI): 962.4 [M+1].

[0476] Example 18

[0477] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 18

[0478]

[0479] MS m / z (ESI): 905.4 [M+1].

[0480] Example 19

[0481] 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(1-(2-methyl-2,7,8,9-tetrahydrooxo[4,3,2-cd]indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 19

[0482]

[0483] MS m / z (ESI): 906.4 [M+1].

[0484] Example 20

[0485] 3-((1S,2S)-1-(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]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one20

[0486]

[0487] MS m / z (ESI): 850.4 [M+1].

[0488] Example 21

[0489] 3-((1S,2R)-2-ethynyl-1-(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-tetrahydro2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 21

[0490]

[0491] MS m / z (ESI): 859.4 [M+1].

[0492] Example 22

[0493] 3-((1S,2R)-2-ethynyl-1-(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]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 22

[0494]

[0495] MS m / z (ESI): 860.4 [M+1].

[0496] Example 23

[0497] 3-((1S,2S)-2-(cyclopropoxymethyl)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 23

[0498]

[0499] MS m / z (ESI): 959.5 [M+1].

[0500] Example 24

[0501] 3-((1S,2S)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-(methoxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 24

[0502]

[0503] MS m / z (ESI): 933.5 [M+1].

[0504] Example 25

[0505] 3-((1S,2S)-2-((difluoromethoxy)methyl)-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]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 25

[0506]

[0507] MS m / z (ESI): 943.4 [M+1].

[0508] Example 26

[0509] 3-((1S,2S)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-((difluoromethoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one26

[0510]

[0511] MS m / z (ESI): 969.4 [M+1].

[0512] Example 27

[0513] 3-((1S,2S)-2-((cyclopropylmethoxy)methyl)-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]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 27

[0514]

[0515] MS m / z (ESI): 947.5 [M+1].

[0516] Example 28

[0517] 3-((1S,2S)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-((cyclopropylmethoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 28

[0518]

[0519]

[0520]

[0521] first step

[0522] (R)-4-((cyclopropylmethoxy)methyl)-2,2-dimethyl-1,3-dioxapentane 28b

[0523] (R)-(-)-glycerol acetone 28a (2.0 g, 15.1 mmol, Shanghai Bide Pharmaceutical) was dissolved in N,N-dimethylformamide (300 mL), sodium hydride (1.2 g, 30.0 mmol, 60%) was added, and the mixture was stirred at room temperature for 30 minutes. Bromomethylcyclopropane (3.1 g, 22.96 mmol) was then added, and the reaction was carried out at 70°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution (600 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), 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 B to give the title compound 28b (2.3 g, yield: 81.6%).

[0524] 1H NMR (500 MHz, CDCl3): δ 4.33-4.28 (m, 1H), 4.10-4.07 (m, 1H), 3.77-3.74 (m, 1H), 3.60-3.56 (m, 1H), 3.49-3.45 (m, 1H), 3.39-3.30 (m, 2H), 1.44 (s, 3H), 1.38 (s, 3H), 1.11-1.05 (m, 1H), 0.57-0.53 (m, 2H), 0.23-0.20 (m, 2H).

[0525] Step 2

[0526] (S)-3-(cyclopropylmethoxy)propane-1,2-diol 28c

[0527] Compound 28b (2.3 g, 12.35 mmol) was dissolved in tetrahydrofuran (20 mL), and water (5.0 mL) and concentrated hydrochloric acid (1.0 mL) were added. The reaction mixture was reacted at 60 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give crude title compound 28c (1.6 g). The product was used directly in the next reaction without purification.

[0528] 1 H NMR (500 MHz, CDCl3): δ 3.92-3.89 (m, 1H), 3.77-3.74 (m, 1H), 3.69-3.66 (m, 1H), 3.61-3.59 (m, 1H), 3.57-3.54 (m, 1H), 3.34 (d, 2H), 2.73 (brs,1H), 2.29(brs, 1H), 1.11-1.05 (m, 1H), 0.59-0.55 (m, 2H), 0.25-0.22 (m, 2H).

[0529] Step 3

[0530] (R)-4-((cyclopropylmethoxy)methyl)-1,3,2-dioxapentane-2,2-dioxide 28d

[0531] Compound 28c (1.6 g, 10.95 mmol) was dissolved in tetrahydrofuran (20 mL), and thionyl chloride (2.0 g, 16.81 mmol) was added dropwise under ice bath conditions. The mixture was stirred at 60 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product for later use.

[0532] The crude product was dissolved in acetonitrile (15 mL) and water (15 mL), and sodium periodate (3.0 g, 14.02 mmol) and ruthenium trichloride hydrate (50 mg, 0.22 mmol) were added. The mixture was reacted at room temperature for 3 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), 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 B to give the title compound 28d (2.2 g, yield: 96.5%).

[0533] 1 H NMR (500 MHz, CDCl3): δ 5.10-5.05 (m, 1H), 4.78-4.75 (m, 1H), 4.66-4.63 (m, 1H), 3.86-3.83 (m, 1H), 3.81-3.78 (m, 1H), 3.45-3.38 (m, 2H), 1.11-1.05 (m, 1H), 0.61-0.57 (m, 2H), 0.26-0.23 (m, 2H).

[0534] Step 4

[0535] 1-((1S,2S)-1-cyano-2-((cyclopropylmethoxy)methyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide 28f

[0536] Compound 28d (1.6 g, 7.68 mmol) and compound (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide 28e (1.0 g, 2.45 mmol, prepared by the method disclosed in intermediate 47-D on page 185 of patent application WO2022017338A1) were dissolved in N,N-dimethylpropenylurea (12.8 g, 99.9 mmol). Under nitrogen protection, bis(trimethylsilylaminolithium) (20.3 mL, 20.3 mmol, 1.0 M, Adamas) was added dropwise at -20°C. After the addition was complete, the reaction was continued at -20°C for 2 hours. The reaction solution was quenched with formic acid (5.0 mL), diluted with ethyl acetate (300 mL), and the organic phase was washed with water (200 mL × 3), then washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 28f (800 mg, yield: 62.9%).

[0537] MS m / z (ESI): 512.5 [M+1].

[0538] Step 5

[0539] 1-((1S,2S)-2-((cyclopropylmethoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide 28g

[0540] Compound 28f (300 mg, 0.59 mmol), sodium bicarbonate (500 mg, 5.95 mmol), and hydroxylamine hydrochloride (410 mg, 5.90 mmol) were dissolved in dimethyl sulfoxide (5 mL) and reacted at 60 °C for 3.5 h. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product for later use.

[0541] The crude product was dissolved in dimethyl sulfoxide (5 mL), and bicyclo[5.4.0]-1,8-diaza-7-nonene (225 mg, 1.48 mmol) and N,N'-carbonyldiimidazole (200 mg, 1.23 mmol) were added. The mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to give 28 g (100 mg, yield: 29.9%) of the title compound.

[0542] MS m / z (ESI): 571.6 [M+1].

[0543] Step 6

[0544] 1-((1S,2S)-2-((cyclopropylmethoxy)methyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid 28h

[0545] 28 g (100 mg, 0.18 mmol) of the compound was dissolved in tetrahydrofuran (5 mL), and tert-butanol (600 mg, 5.34 mmol) and water (30 mg, 1.67 mmol) were added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 3-4 with 1 M dilute hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product of the title compound 28 h (100 mg). The product was used directly in the next reaction without purification.

[0546] MS m / z (ESI): 482.5 [M+1].

[0547] Step 7

[0548] 5-Bromo-1-cyclopropyl-1H-indazole 28j

[0549] 5-Bromo-1H-indazole 28i (5.0 g, 25.37 mmol), cyclopropylboronic acid (2.8 g, 32.94 mmol), anhydrous copper acetate (6.9 g, 38.09 μmol), 2,2'-bipyridine (5.9 g, 38.03 mmol), and cesium carbonate (6.7 g, 63.4 mmol) were dissolved in 1,2-dichloroethane (100 mL) and reacted at 70°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (100 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (50 mL), 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 B to give the title compound 28j (5.0 g, yield: 83.1%).

[0550] MS m / z (ESI): 236.9 [M+1].

[0551] Step 8

[0552] 1-Cyclopropyl-5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indazole 28k

[0553] Compound 28j (3.0 g, 12.65 mmol), potassium acetate (2.5 g, 25.27 mmol), pinacol diborate (4.8 g, 18.98 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.85 g, 2.53 mmol) were dissolved in dioxane (100 mL), purged three times with nitrogen, and reacted at 85 °C for 16 h. The reaction mixture was cooled to room temperature, extracted with water (100 mL) and ethyl acetate (60 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 28k (3.0 g, yield: 99.3%).

[0554] MS m / z (ESI): 285.0 [M+1].

[0555] Step 9

[0556] 3-(1-Cyclopropyl-1H-indazol-5-yl)-5-iodopyrimidine-4(3H)-one 28l

[0557] Compound 1d (200 mg, 0.90 mmol), compound 28k (0.38 g, 1.35 mmol), 2,2'-bipyridine (0.28 g, 1.8 mmol), copper acetate (0.33 g, 1.8 mmol), and sodium carbonate (0.28 g, 2.7 mmol) were dissolved in 1,2-dichloroethane (30 mL). The mixture was stirred open at 70 °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 elution system B to give the title compound 28l (150 mg, yield: 44%).

[0558] MS m / z (ESI): 378.9 [M+1].

[0559] Step 10

[0560] (S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-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 28m

[0561] Compound 28l (140 mg, 0.37 mmol), compound 1c (220 mg, 0.55 mmol), anhydrous potassium carbonate (153 mg, 1.11 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (50.5 mg, 0.07 mmol, BIDE) were dissolved in dioxane (20 mL) and water (4 mL), purged with nitrogen, and the reaction was stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the crude title compound 28m (130 mg, yield: 57.6%).

[0562] MS m / z (ESI): 610.4 [M+1].

[0563] Step 11

[0564] (S)-3-(1-Cyclopropyl-1H-indazol-5-yl)-5-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidin-4(3H)-one 28n

[0565] Compound 28m (38 mg, 62.33 μmol) was dissolved in ethyl acetate (2 mL), and a solution of 1,4-dioxane in 4 M hydrogen chloride (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 28n (40 mg). The product was used directly in the next reaction without purification.

[0566] MS m / z (ESI): 510.3 [M+1].

[0567] Step Twelve

[0568] 3-((1S,2S)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-((cyclopropylmethoxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 28

[0569] Compound 28h (40 mg, 0.083 mmol) and compound 28n (30 mg, 0.059 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (30 mg, 0.23 mmol) was added. After the raw materials were completely dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (30 mg, 0.079 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 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 (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: Gilson-GX-281, column: Boston Phlex, Prep 30 × 150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40-70%, flow rate: 30 mL / min) to give title compound 28 (15 mg, yield: 26.2%).

[0570] MS m / z (ESI): 974.0 [M+1].

[0571] 1 H NMR (500 MHz, CDCl3): δ 11.48 (br, 1H), 8.33-8.19 (m, 1H), 8.06-7.80 (m, 3H), 7.71-7.31 (m, 5H), 7.11-7.00 (m, 2H), 6.73-6.68 (m, 1H), 5.85-5.81 (m, 1H), 4.45-4.41 (m, 1H), 3.91-3.84 (m, 2H), 3.74-3.62 (m, 2H), 3.30-3.01(m, 5H), 2.29-2.25 (m, 6H), 2.07-1.75 (m, 4H), 1.67-1.52 (m, 5H), 1.37-1.24 (m, 12H), 1.02-0.89 (m, 2H), 0.55-0.45 (m, 2H), 0.22-0.12 (m, 2H).

[0572] Example 29

[0573] 3-((1S,2S)-2-(cyclopropoxymethyl-d2)-1-(2-((S)-3-(1-(1-cyclopropyl-1H-indazol-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 29

[0574]

[0575] MS m / z (ESI): 961.5 [M+1].

[0576] Example 30

[0577] 3-((1S,2S)-2-(cyclopropoxymethyl-d2)-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]pyridin-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one 30

[0578]

[0579] MS m / z (ESI): 935.5 [M+1].

[0580] Biological evaluation

[0581] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0582] I. Purpose of the Test

[0583] The purpose of this experiment was to test the agonistic activity of the compound molecule on the hGLP-1 receptor, according to EC... 50Size was used to evaluate the in vitro activity of the molecule. This experiment used the ONE-Glo™ Luciferase Assay System (Promega, E6110). Under the influence of the compound molecule, the downstream signaling pathway of GLP-1R was activated, leading to an increase in cAMP levels. cAMP binds to the CRE, initiating the transcriptional expression of the downstream luciferase gene. Luciferase reacts with its substrate to emit fluorescence. The fluorescence signal was measured using the ONE-Glo™ reagent to reflect the compound's activity in activating the GLP-1 receptor.

[0584] II. Experimental Methods

[0585] A stable CHO-K1 / CRE-luc / hGLP-1 receptor cell line was constructed (hGLP-1 receptor plasmid was self-constructed; CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / hGLP-1 receptor cells were digested, centrifuged, and resuspended. The single-cell suspension was mixed thoroughly and the viable cell density was adjusted to 2.78 × 10⁻⁶ cells / mL using cell culture medium (DME / F-12 + 10% FBS). 5 Cells / ml were added to a 96-well cell culture plate (Corning, #3903) at a rate of 90 µL / well. The plate was incubated for 16 hours at 37°C and 5% CO2.

[0586] The compound was dissolved in DMSO to prepare a stock solution with an initial concentration of 20 mM. The initial concentration of the small molecule compound was 0.02 mM, diluted 3-fold, and diluted 10 times, with the 11th spot being DMSO. In a separate 96-well plate, 95 µL of cell culture medium (DME / F-12 + 10% FBS) was added to each well. Then, 5 µL of the test sample at different concentrations was added to each well, and the mixture was stirred. Next, 10 µL / well of the test sample at different concentrations was added to the cell culture plate, with two replicates for each sample. The culture plate was incubated in an incubator for 5 hours (37°C). o (C, 5% CO2). Remove the 96-well cell culture plate, add 100 µL of ONE-Glo™ reagent to each well, and incubate at room temperature for 10 minutes. Measure the chemiluminescence using a microplate reader (PHERAstar FS, BMG Labtech).

[0587] III. Data Analysis

[0588] The data was processed and analyzed using Microsoft Excel and Graphpad Prism 10. The EC50 values ​​of the compounds were obtained. 50 The values ​​are shown in Table 1.

[0589] Table 1. Agonistaltic activity of the compounds disclosed herein against hGLP-1 receptors.

[0590]

[0591] Conclusion: The compound disclosed herein exhibits high agonistic activity against the GLP-1 receptor.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: X 4 Selected from N, N + -O - and CR Z1 ;X 5 Selected from N, N + -O - and CR Z1 ;X 6 Selected from N, N + -O - and CR Z1 ; Z 2 Selected from hydrogen atoms, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. Z2 replace; Y is selected from C(O), S(O), S(O)2 and alkylene groups; Q 1 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. Q1 replace; R 1 R 2 and R 3 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, oxo, =S, NR 11a R 11b C(O)NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)OR 12 S(O) v R 12 S(O) v NR 11a R 11b OR 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced; Ring A is selected from , , , , , , , , , , , , , , , and ; R A for ; Q 2 Selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. Q2 Replaced; X 1 Selected from CR x1 , N and N + -O - ;X 2 Selected from CR 5 , N and N + -O - ; X 3 Selected from CR 6 , N and N + -O - ; Each R Z1 R 4 R 5 R 6 and R x1 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkenyl, 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)NR 11a R 11b S(O) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 P(O)R 12 R 13 OR 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 02 Replaced; R 9 Selected from C(O)OR 12 C(O)NR 11a R 11b S(O) v R 12 S(O) v NR 11a R 11b cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally composed of one or more R groups. 9a Replaced; R 7 and R 8 The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, oxo, NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)OR 12 C(O)NR 11a R 11b OC(O)R 12 S(O) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 P(O)R 12 R 13 OR 12 cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, aryl, and heteroaryl; each of the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic alkyl, aryl, and heteroaryl groups is independently and optionally selected by one or more R 02 Replaced; or R 7 R 8 Together with the atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 78 Replaced; n1 is 0, 1, 2, 3, 4 or 5; n2 is 0, 1, 2, 3, 4 or 5; Each R Q1 R 01 R Z2 R Q2 R 02 R 9a and R 78 They may be the same or different, and each is independently selected from deuterium, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, nitro, hydroxy, 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) v R 12 S(O) v NR 11a R 11b NR 00 S(O) v R 12 (CH2) x P(O)R 12 R 13 S(O) v OR 12 OR 12 =CR 12a R 13a =NR 00 C(=NR) 00 )R 12 S(=NR) 00 )R 12 S(=NR) 00 )(O)R 12 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently and optionally selected by one or more R * Replaced; Each R * The same or different, and each independently selected from deuterium, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, cyano, amino, nitro, hydroxyl, oxo, =S, NR 11a R 11b NR 00 C(O)R 12 C(O)R 12 C(O)NR 11a R 11b C(O)OR 12 S(O) v R 12 S(O) v NR 11a R 11b OR 12 The alkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, and heterocyclic oxy groups, wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, and heterocyclic oxy groups is independently and optionally substituted by one or more identical or different substituents selected from deuterium, oxo, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 11a R 11b R 00 R 12 and R 13 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxyalkyl, C(O)R 15 C(O)OR 15 NR 14a R 14b C(O)NR 14a R 14b NR 0 C(O)R 15 S(O) v R 15 OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl and heteroarylalkyl; or R 11a and R 11b Together with the nitrogen atom attached thereto, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy. R 12a and R 13a They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic groups; R 0 R 15 R 14a and R 14b The same or different, and each independently selected from hydrogen atom, deuterium atom, alkyl, alkoxy, hydroxyalkyl, haloalkyl, C(O)alkyl, amino, amide, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from deuterium atom, halogen, cyano, nitro, amino, hydroxy, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl and heterocyclic; x is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: in, X 4 X 5 X 6 Z 2 Q 1 R 1 To R 4 R A X 1 X 2 R 6 and Q 2 As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z 2 It 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 selected from C. 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group, and / or Q 2 The heterocyclic group is a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 One or more of the haloalkoxy groups are substituted; preferably, Z 2 It is an indazole group or a tetrahydroxyheptan[4,3,2-cd]indazole group, wherein the indazole group and the tetrahydroxyheptan[4,3,2-cd]indazole group are each independently and optionally selected from C. 1-6 Alkyl, C 1-6 Substituted with one or more of a haloalkyl group and a 3- to 6-membered cycloalkyl group, and / or Q 2 It is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally surrounded by one or more C16 groups. 1-6 Alkyl groups are substituted.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof: in, R za R zc R zd R ze and R zf They may be the same or different, and each is independently a hydrogen atom or R. Z2 ; or R za R zf Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... Z2 Replaced; R 7a and R 8a They may be the same or different, and each is independently a hydrogen atom or R. 78 ;R 9a 'For hydrogen atoms or R 9a ; q is 0, 1, 2, 3, 4, 5, or 6; a is 0, 1, or 2; X 5 R Z1 Q 1 R 1 To R 4 X 1 X 2 R 6 R Q2 R Z2 R 78 and R 9a As defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: X 5 For N or CR Z1 ; and / or each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R za Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R zc Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R zd Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R zf Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R ze Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, or R za R zf Together with the carbon atom attached thereto, they form a 5- to 7-membered cycloalkyl group or a 5- to 7-membered heterocyclic group; preferably, X 5 For CH or N, and / or each R Z1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or R za For hydrogen atoms, and / or R zc For hydrogen atoms, and / or R zd It is a hydrogen atom or a halogen; and / or R zf For hydrogen atoms, and / or R ze C 1-6 Alkyl or 3- to 6-membered cycloalkyl, or R za R zf Together with the carbon atom attached to it, they form a 7-membered heterocyclic group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or X 1 For CH or N, and / or X 2 It is CH or N; preferably, R 1 For hydrogen atoms, and / or R 2 For hydrogen atoms, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 6 For hydrogen atoms, and / or X 1 For CH, and / or X 2 It can be CH or N.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Q 1 It is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally surrounded by one or more R groups. Q1 Replace, R Q1 As defined in claim 1, and / or each of the R Q2 The same or different, and each independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, Q 1 It is phenyl or pyridyl, wherein the phenyl and pyridyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substituted with one or more of haloalkyl and 3 to 6-membered cycloalkyl groups, and / or each R Q2 The same or different, and each independently of halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, Q 1 The phenyl group is optionally selected from halogens and C. 1-6 One or more of the alkyl groups are substituted, and / or each R is substituted. Q2 The same or different, and each independently is C. 1-6 alkyl.

8. The compound according to any one of claims 4 to 7, or a pharmaceutically acceptable salt thereof, wherein R 9a 'is a hydrogen atom, and / or R 7a Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 CD2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered cycloalkyl C 1-6 Alkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups, and / or R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 9a 'is a hydrogen atom, and / or R 7a Selected from C 1-6 Alkyl, C 2-6 Alkyne group, CH2-OR 12 and C≡CR ** R 12 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl, R ** Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl and 3- to 6-membered cycloalkyloxy groups, and / or R 8a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 7a Selected from C 1-6 Alkyl, CH2-OR 12 and C≡CR ** R 12 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, R ** Selected from hydrogen atoms, halogens and C 1-6 Alkyl, and / or R 8a It is a hydrogen atom.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , and .

10. Compounds or salts thereof represented by general formula (IIA): in, R W It is a hydrogen atom or an amino protecting group, preferably Boc; Z 2 X 4 X 5 X 6 Q 1 and R 1 To R 3 As defined in claim 2.

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