Substituted fused heterocycle compound, preparation method thereof and application of substituted fused heterocycle compound in medicine

Abstract

The invention relates to a substituted fused heterocycle compound, a preparation method thereof and application of the substituted fused heterocycle compound in medicine. Specifically, the invention relates to a fused heterocycle compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the fused heterocycle compound as a therapeutic agent, the invention relates to the field of medicines, in particular to application as an AMPK gamma3 agonist and application in preparation of medicines for treating and / or preventing cardiovascular diseases or diseases related to skeletal muscle function decline and movement intolerance. Wherein each group in the general formula (I) is defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to substituted fused heterocyclic compounds, their preparation methods, and their pharmaceutical applications. In particular, this disclosure relates to fused heterocyclic compounds of general formula (I), their preparation methods, and pharmaceutical compositions containing such compounds, as well as their use as AMPKγ3 agonists and their use in the preparation of medicaments for the treatment and / or prevention of cardiovascular diseases or diseases related to skeletal muscle dysfunction and exercise intolerance. Background Technology

[0002] AMPK is a highly conserved intracellular energy sensor that is activated when ATP levels decrease. It consists of seven different subunits, including catalytic subunits α1 and α2, scaffold subunits β1 and β2, and AMP-binding subunits γ1, γ2, and γ3. These subunits can form 12 different heterotrimeric structures to perform downstream functions. Among them, the expression distribution of α1, β1, and γ1 subunits is relatively widespread, while α2 and β2 subunits are mainly expressed in tissues such as cardiac muscle, skeletal muscle, and liver. γ2 is mainly expressed in cardiac muscle, while γ3 is specifically expressed in skeletal muscle [Nat Rev Mol Cell Biol. 2023 Apr; 24(4):255-272.].

[0003] During exercise, AMPK is activated, and its activity is closely related to exercise endurance. AMPK-α2β2γ3 is expressed only in skeletal muscle and plays a dominant role in exercise endurance. Studies have shown that with increasing exercise intensity, the activity of AMPK-α2β2γ3 in healthy individuals increases accordingly [J Physiol. 2006 Dec 15; 577(Pt 3):1021-32.], especially after intermittent high-intensity leg training, where AMPK-α2β2γ3 activity can increase approximately 10-fold. This change is accompanied by increased glucose uptake, accelerated blood flow (indicating increased oxygen and nutrient transport to skeletal muscle), and a larger arteriovenous glucose gradient, all indicating improved glucose utilization by skeletal muscle. Furthermore, healthy individuals carrying the naturally occurring AMPKγ3-R225W enhanced mutation exhibit higher AMPK activity, muscle glycogen content, and lower muscle triglyceride content, increased mitochondrial content in muscle cells, and enhanced citrate synthase (the rate-limiting enzyme of the tricarboxylic acid cycle) activity. Electromyography data showed that AMPKγ3-R225W carriers had a stronger tolerance to exercise fatigue [PLoSOne.2007Sep 19;2(9):e903.Diabetologia.2010Sep;53(9):1986-97.]. In mice overexpressing the AMPKγ3-R225Q functional enhancement mutation, in addition to a significant increase in skeletal muscle glycogen content, skeletal muscle fatigue tolerance was also significantly improved. Skeletal muscle glycogen content was positively correlated with fatigue tolerance, and the mitochondrial content in the skeletal muscle of these mice was increased, indicating enhanced energy supply capacity [FASEB J.2005May;19(7):773-9.J BiolChem.2008Dec19;283(51):35724-34.]. However, knocking out AMPKγ3 reduces skeletal muscle glucose uptake in mice after exercise, thus decreasing exercise tolerance [Diabetes. 2023 Oct 1; 72(10):1397-1408.]. This demonstrates that AMPKγ3 plays a crucial role in regulating skeletal muscle glucose uptake and exercise tolerance.

[0004] The pan-AMPK agonist AICAR significantly improved running endurance in mice after 4 weeks of administration [Cell. 2008 Aug 8; 134(3):405-415.]. However, overactivation of AMPKγ2 promotes glycogen accumulation in the heart, leading to cardiomyopathy. Overexpression of AMPKγ2-enhancing mutations in mice also causes cardiomyopathy [Circ Res. 2007 Mar 2; 100(4):474-88.]. In addition, studies have found that 70% of individuals naturally carrying AMPKγ2-enhancing mutations exhibit symptoms of left ventricular hypertrophy [J Am Coll Cardiol 2020; 76:186-97.]. The pan-AMPK agonist MK-8722 also increases the heart weight / brain weight ratio and cardiac glycogen content in rats and monkeys, thereby inducing myocardial hypertrophy [Science. 2017; 357(6350):507-511.]. Therefore, developing selective AMPKγ3 agonists can avoid potential cardiac side effects caused by AMPKγ2 activation.

[0005] In summary, AMPKγ3 agonists can enhance muscle function and improve exercise tolerance. Therefore, they can be used clinically to treat diseases related to decreased skeletal muscle function and exercise intolerance, such as muscle wasting, obesity, metabolic syndrome, cachexia, and geriatric diseases.

[0006] The publicly disclosed patent for an AMPKγ3 agonist is WO2024084390A1. Summary of the Invention

[0007] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] X 1 For N or CR 4a ;

[0011] X 2 For N or CR 4b ;

[0012] X 3 For N or CR 4 ;

[0013] Ring A is selected from cycloalkyl, polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups;

[0014] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0015] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0016] R 4a R 4b and R 4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0017] R 2 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, OR 14 C(O)R 14 Carboxyl, cyano, nitro, amino, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0018] Each R 1 R 3 and R 5 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13 alkylene-C(O)R 14 alkylene-C(O)NR 11 R 12 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 02 Replaced;

[0019] Each R 01 and R 02 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OC(O)OR 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0020] Each R', R 11 R 12 R 13 and R 14 The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22 S(O) v R 22 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0021] R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0022] Each R * The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 alkylene NR 20 R 21 alkylene C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22Nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, and heteroarylalkyl;

[0023] Each R 20 R 21 and R 22 The same or different, and each independently selected from hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl are each independently optionally substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic and cycloalkyl;

[0024] m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6;

[0025] p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[0026] Each v is the same or different, and each is independently 0, 1 or 2.

[0027] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0028]

[0029] in:

[0030] X 1 For N or CR 4a ;

[0031] X 2 For N or CR 4b ;

[0032] X 3 For N or CR 4 ;

[0033] Ring A is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups;

[0034] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0035] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0036] R 4a R 4b and R 4The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0037] R 2 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, OR 14 C(O)R 14 Carboxyl, cyano, nitro, amino, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0038] Each R 1 R 3 and R 5 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13 alkylene-C(O)R 14 alkylene-C(O)NR 11 R 12 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 02 Replaced;

[0039] Each R 01 and R 02 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OC(O)OR 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0040] Each R', R 11 R 12 R 13 and R 14 The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22 S(O) v R 22 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0041] R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0042] Each R * The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 alkylene NR 20 R 21 alkylene C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22Nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, and heteroarylalkyl;

[0043] Each R 20 R 21 and R 22 The same or different, and each independently selected from hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl are each independently optionally substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic and cycloalkyl;

[0044] m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6;

[0045] p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

[0046] Each v is the same or different, and each is independently 0, 1 or 2.

[0047] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom.

[0048] 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:

[0049]

[0050] Among them, R 3a R 3b R 3c R 3d and R 3e They may be the same or different, and each is independently a hydrogen atom or R. 3 ;

[0051] R 2 Selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, alkenyl groups, alkynyl groups, hydroxyl groups, hydroxyalkyl groups, carboxyl groups, cyano groups, nitro groups, amino groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkylene groups, and heterocyclicalkylene groups;

[0052] Ring A, Ring C, X 1 X 2 R 1 m, R 3 R 4 R5 p is as defined in general formula (I).

[0053] 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 (III) or (IV) or a pharmaceutically acceptable salt thereof:

[0054]

[0055] Where G is N or CR 5b ;

[0056] R A For R 5 Or, two Rs A Together they form bridging alkylene groups, or R A R 5a Together they form a bridging alkylene group; the bridging alkylene group is optionally surrounded by 1, 2 or 3 R groups. 5 Replaced;

[0057] R 5a For hydrogen atoms or R 5 ;R 5b For hydrogen atoms or R 5 ;

[0058] a, b, g, e, and f may be the same or different, and each is independently 0, 1, 2, 3, 4, or 5;

[0059] c and d may be the same or different, and each can be 1, 2, 3, 4 or 5 independently;

[0060] p1 is 1, 2, 3, or 4; p3 is 0, 1, 2, 3, or 4;

[0061] Ring C, Ring D, X 1 To X 3 R 1 R 2 R 3 R 5 m and n are as defined in general formula (I).

[0062] 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 (III) or (IV) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Where G is N or CR 5b ;

[0065] Two Rs A Together they form bridging alkylene groups, or R A R5a Together they form a bridging alkylene group; the remaining R A When it exists, it is R 5 The bridging alkylene group is optionally surrounded by 1, 2, or 3 R groups. 5 Replaced;

[0066] R 5a For hydrogen atoms or R 5 ;R 5b For hydrogen atoms or R 5 ;

[0067] a, b, e, and f may be the same or different, and each is independently 0, 1, 2, 3, 4, or 5;

[0068] c and d may be the same or different, and each can be 1, 2, 3, 4 or 5 independently;

[0069] p1 is 1, 2, 3, or 4; p3 is 0, 1, 2, 3, or 4;

[0070] Ring C, Ring D, X 1 To X 3 R 1 R 2 R 3 R 5 m and n are as defined in general formula (I).

[0071] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (III), and (IIIM), or their pharmaceutically acceptable salts, are compounds represented by general formulas (V), (VI), (VI-1), and (VI-2), or their pharmaceutically acceptable salts:

[0072]

[0073] Where G is N or CR 5b ;

[0074] R 5a For hydrogen atoms or R 5 ;R 5b For hydrogen atoms or R 5 ;

[0075] p2 is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; g is 0, 1, 2, 3, 4, or 5;

[0076] a and b may be the same or different, and each is independently 0, 1, 2, 3, 4 or 5;

[0077] Ring C, R 1 m, X 1 X 2 R 4 R2 R 3a R 3b R 3c R 3d R 3e and R 5 As defined in general formula (II).

[0078] 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 (VII) or a pharmaceutically acceptable salt thereof:

[0079]

[0080] Wherein, ring B is a nitrogen-containing heterocyclic group; r is 0, 1, 2, 3, 4, 5 or 6;

[0081] L is a bond or alkylene group; the alkylene group is optionally bonded by one or more R. 02 Replaced;

[0082] R 5b For hydrogen atoms or R 5 p2 is 0, 1, 2, 3, or 4;

[0083] a, b, and g may be the same or different, and each is independently 0, 1, 2, 3, 4, or 5;

[0084] Ring C, Ring D, X 1 X 2 R 1 To R 5 , m, n, R* and R 02 As defined in general formula (I).

[0085] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein ring A is a 5- to 12-membered bicyclic or tricyclic cycloalkyl group, or a 5- to 12-membered bicyclic or tricyclic heterocyclic group; in some embodiments, ring A is a 5- to 12-membered bicyclic heterocyclic group; in some embodiments, ring A is a 5- to 12-membered spiroheterocyclic group, fused heterocyclic group, or bridged heterocyclic group; in some embodiments, ring A is a 3- to 12-membered cycloalkyl group, or a 7- to 12-membered spiroheterocyclic group, fused heterocyclic group, or bridged heterocyclic group; in some embodiments, ring A is selected from... In some implementations, ring A is selected from... In some implementations, ring A is selected from... In some implementations, ring A is In some embodiments, ring A is a 3- to 6-membered cycloalkyl group; in some embodiments, ring A is a cyclobutyl group; in some embodiments, ring A is... The right side The key is connected to N.

[0086] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein Selected from In some implementation schemes, In some implementation schemes, it is selected from

[0087] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein the two Rs A Together they form C 1-3 Bridging alkylene groups; in some embodiments, the two R groups... A Together they form a bridging ethylene group.

[0088] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for In some implementation schemes, R 2 R 3 and n are as defined in general formula (II); in some implementations, n is R 2 R 3a R 3b R 3c R 3d R 3e As defined in general formula (II).

[0089] In some embodiments of this disclosure, the compounds represented by general formulas (I), (III), (IV), and (VII), or their pharmaceutically acceptable salts, wherein ring D is phenyl or a 5- or 6-membered heteroaryl group; in some embodiments, ring D is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; in some embodiments, ring D is selected from phenyl, In some implementations, ring D is phenyl; End and R 2 The ring it belongs to is connected.

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein for R 3a R 3b R3c R 3d R 3e As defined in general formula (II); in some implementations, for R 3a R 3b and R 3c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, for

[0091] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein X 1 For CR 4a R 4a As defined in general formula (I); in some implementations, X 1 For N or CH; in some implementations, X 1 Let N be the number of elements in the array.

[0092] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein X 2 For CR 4b R 4b As defined in general formula (I); in some implementations, X 2 Selected from N, CH, and CF; in some implementations, X 2 For CF.

[0093] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein X 3 For N or CR 4 R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, X 3 For CR 4 R 4 As defined in general formula (I); in some implementations, X 3 For CH.

[0094] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein X 1 For N or CH, and / or X 2 For N or CF; in some implementations, X 1For N, and / or X 2 For CF.

[0095] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; in some embodiments, the ring C is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, the ring C is a 5-membered heteroaryl; in some embodiments, the ring C is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, and tetrazolyl; in some embodiments, the ring C is selected from phenyl, pyridinyl, pyrazolyl, and imidazolyl; in some embodiments, the ring C is pyrazolyl; in some embodiments, the ring C is selected from phenyl, In some implementation schemes, The terminal is connected to N.

[0096] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein Selected from In some implementations it is In some implementations it is Q is N or CR 1g ;R 1a For hydrogen atoms or R 1 ;R 1b R 1c R 1d R 1e R 1f and R 1g They may be the same or different, and each is independently a hydrogen atom or R. 1 ;R 1 As defined in general formula (I); in some implementations, Selected from R 1a Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl, where Q is N or CR 1g ;R 1b R 1c R 1d R 1e R 1f and R 1g 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 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6Hydroxyalkyl, hydroxyl, amino, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, it is... R 1a C 1-6 Alkyl, R 1b It is a halogen;

[0097] In some implementation schemes, Selected from In some implementations it is In some implementations it is

[0098] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 1 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 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, NR 11 R 12 (CH2) j NR 11 R 12 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, j being 0, 1, 2, 3 or 4, R 11 and R 12 As defined in general formula (I); in some implementations, each R 1 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 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl; in some embodiments, each R 1 They may be the same or different, and each is independently selected from F, Cl, methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, difluoromethoxy, and amino; in some embodiments, R 1 It is F or methyl; in some embodiments, R 1 It is cyclopropyl.

[0099] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein m is 0, 1, 2, 3 or 4; in some embodiments, m is 0, 1, 2 or 3; in some embodiments, m is 1, 2 or 3; and in some embodiments, m is 2.

[0100] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and / or each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl group, and / or m is 1, 2 or 3.

[0101] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1a C 1-6 Alkyl; in some embodiments, R 1a For methyl; in some embodiments, R 1a It is cyclopropyl.

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R 1b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1b For halogen; in some implementations, R 1b It is F.

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R 1c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1c For halogen; in some implementations, R 1c It is F.

[0104] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1b R 1c R 1d R 1e R 1f and R 1g 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 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, NR 11 R 12 (CH2) j NR 11 R 12 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, j being 0, 1, 2, 3 or 4, R 11 and R 12 As defined in general formula (I).

[0105] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1c R 1d R 1e and R 1f 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 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and hydroxyl; in some embodiments, R 1c R 1d R 1e and R 1f 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; in some embodiments, R 1c R 1d R 1e and R 1f It is a hydrogen atom.

[0106] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof, wherein Q is CH or N; in some embodiments, Q is N.

[0107] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 C 1-6 Alkyl; in some embodiments, R 2 It is a methyl group.

[0108] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 2 Not a hydrogen atom; in some implementations, R 2 Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0109] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 3 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 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 3 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 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 3 They may be the same or different, and each is an independent halogen; in some implementations, each R... 3 They may be the same or different, and each is independently F or Cl.

[0110] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 3a R 3b R 3c R 3d and R 3e 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 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and hydroxyl; in some embodiments, R 3a R 3b R3c R 3d and R 3e 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; in some embodiments, R 3a R 3b R 3c R 3d and R 3e They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0111] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 3a It is a hydrogen atom or a halogen, and / or R 3b Halogen or C 1-6 Alkyl, and / or R 3c It is a hydrogen atom or a halogen, and / or R 3d It is a hydrogen atom or a halogen, and / or R 3e For hydrogen atoms; in some implementations, R 3a For F, and / or R 3b It is Cl or methyl, and / or R 3c It can be a hydrogen atom or F.

[0112] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3b For halogen; in some implementations, R 3b It is Cl.

[0113] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 3c It is a hydrogen atom.

[0114] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 3d It is a hydrogen atom or a halogen; in some implementations, R 3d For hydrogen atoms; in some implementations, R 3d For halogen; in some implementations, R 3d It is F.

[0115] In some embodiments of this disclosure, the compounds represented by general formulas (I), (III), (IV), and (VII) or their pharmaceutically acceptable salts are used, wherein n is 0, 1, 2, or 3; in some embodiments, n is 2.

[0116] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 4 Selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 4 It is a hydrogen atom.

[0117] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 4a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups.

[0118] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 4b Selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 4b For halogen; in some implementations, R 4b It is F.

[0119] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 4bSelected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 4 For hydrogen atoms, and / or R 4b It is a halogen.

[0120] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein G is N.

[0121] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 5 They may be the same or different, and each is independently selected from oxo groups, halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, NR 11 R 12 (CH2) j NR 11 R 12 C(O)R 14 C(O)OR 14 C(O)NR 11 R 12 alkylene-C(O)R 14 alkylene-C(O)NR 11 R 12 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, j being 0, 1, 2, 3 or 4, R 11 R 12 and R 14 As defined in general formula (I); in some implementations, each R 5 They may be the same or different, and each is independently selected from the oxo group and C. 1-6 Alkyl and C(O)R 14 In some implementation schemes, R 5 For C(O)R 14 R 14 As defined in general formula (I); in some implementations, R 5 Selected from methyl, In some implementation schemes, each R 5 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5 It is an oxygen group; in some embodiments, R 5Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and hydroxyl; in some embodiments, R 5 for

[0122] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 5a Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, NR 11 R 12 (CH2) j NR 11 R 12 C(O)R 14 C(O)OR 14 C(O)NR 11 R 12 alkylene-C(O)R 14 alkylene-C(O)NR 11 R 12 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, j being 0, 1, 2, 3 or 4, R 11 R 12 and R 14 As defined in general formula (I); in some implementations, R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R 14 In some implementation schemes, R 5a For C(O)R 14 , and R 14 As defined in general formula (I); in some implementations, R 5a Selected from hydrogen atoms, methyl groups, In some implementation schemes, In some implementation schemes, R 5a for In some implementation schemes, R 5a Selected from hydrogen atoms, methyl groups,

[0123] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 5b Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and hydroxyl; in some embodiments, R 5b C 1-6 Alkyl; in some embodiments, R 5b It is a methyl group.

[0124] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein p is 0, 1, 2, 3 or 4; in some embodiments, p is 0, 1 or 2; in some embodiments, p is 1.

[0125] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein p2 is 0, 1 or 2; in some embodiments, p2 is 0.

[0126] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein p3 is 0, 1 or 2; in some embodiments, p3 is 1.

[0127] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein a is 0, 1 or 2; in some embodiments, a is 1.

[0128] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein b is 0, 1 or 2; in some embodiments, b is 1.

[0129] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein c is 1 or 2; in some embodiments, c is 1.

[0130] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein d is 1 or 2; in some embodiments, d is 1.

[0131] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein e is 0, 1, 2 or 3; in some embodiments, e is 2 or 3; in some embodiments, e is 2; and in some embodiments, e is 3.

[0132] In some embodiments of this disclosure, the compound represented by general formulas (I) to (VII) or a pharmaceutically acceptable salt thereof is used, wherein f is 0, 1 or 2; in some embodiments, f is 1 or 2; in some embodiments, f is 1.

[0133] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein g is 0, 1 or 2; in some embodiments, g is 1.

[0134] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein q is 1, 2 or 3; in some embodiments, q is 2.

[0135] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein r is 0, 1 or 2; in some embodiments, r is 0.

[0136] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 5c and R 5d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 5c and R 5d It is a hydrogen atom.

[0137] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 01 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 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 groups and 3- to 6-membered cycloalkyl groups.

[0138] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 02 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 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 groups and 3- to 6-membered cycloalkyl groups.

[0139] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R * They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 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 groups and 3- to 6-membered cycloalkyl groups.

[0140] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 11 and R 12 Whether the atoms are the same or different, and each is independently a hydrogen atom, C 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, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0141] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 It is a hydrogen atom.

[0142] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl, wherein C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl groups are each independently and optionally separated by one or more R groups. * Replaced; R * As defined in general formula (I); in some implementations, R 14 C 1-6Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from oxo groups, halogens, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, NR 20 R 21 And substituted with one or more of 3- to 6-membered cycloalkyl groups; in some embodiments, R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR 20 R 21 One or more of them are replaced by R 20 and R 21 As defined in general formula (I); in some implementations, R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 The alkyl group and the 3- to 6-membered cycloalkyl group are each optionally substituted independently with one or more halogens; in some embodiments, R 14 The group is selected from methyl, ethyl, and cyclopropyl, wherein each of the methyl, ethyl, and cyclopropyl groups is independently and optionally substituted with one or more halogens;

[0143] In some implementation schemes, R 14 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl and the 3- to 6-membered heterocyclic group are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more of the haloalkoxy groups are substituted; in some embodiments, R 14 It is a 3- to 8-membered heterocyclic group; in some implementations, R 14 It is a 5- or 6-membered heterocyclic group; in some embodiments, R 14 It is a pyrroleyl group; in some embodiments, R 14 for The bond is connected to C(O).

[0144] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 15 and R16 They may be the same or different, and each is independently a hydrogen atom or F.

[0145] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 20 and R 21 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 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 20 and R 21 All are hydrogen atoms.

[0146] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 22 Selected from hydrogen atoms, 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; the 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 groups are each independently selected from halogens, C... 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted.

[0147] In some embodiments of this disclosure, the compound represented by general formulas (I) to (VII) or a pharmaceutically acceptable salt thereof is used, wherein v is 2; in some embodiments, v is 1; and in some embodiments, v is 0.

[0148] In this disclosure, formulas (I) through (VII) include formulas (I), (II), (III), (IV) and (V); formulas (I) through (VII) include formulas (I), (II), (IIIM), (III), (IV), (V), (VI), (VI-1), (VI-2) and (VII).

[0149] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... Each R 5 They may be the same or different, and each is independently selected from the oxo group and C. 1-6 Alkyl and C(O)R 14 ;R14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from oxo groups, halogens, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, NR 20 R 21 And substituted with one or more of the 3- to 6-membered cycloalkyl groups; R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0150] X 1 For N; X 2 For CR 4b R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; cyclic C is phenyl or 5 or 6-membered heteroaryl; each R 1 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 Halogenated alkyl groups and C 1-6 Haloalkoxy group; m is 0, 1, 2 or 3; R 3a R 3b R 3c R 3d and R 3e 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.

[0151] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein G is N; c is 0 or 1; d is 1; e is 1, 2, or 3; f is 1; p3 is 0, 1, or 2; and each R 5 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R14 R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR 20 R 21 One or more of them are replaced by R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; X 1 For N; X 2 For CR 4b R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; X 3 For CR 4 R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; cyclic C is phenyl or 5 or 6-membered heteroaryl; each R 1 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 Halogenated alkyl groups and C 1-6 Haloalkoxy group; m is 0, 1, 2 or 3; for R 3a R 3b R 3c R 3d and R 3e 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.

[0152] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein G is N; c is 1; d is 1; e is 1, 2, or 3; f is 1; p3 is 0, 1, or 2; and each R 5 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R 14 R 14 C1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR 20 R 21 One or more of them are replaced by R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; X 1 For N; X 2 For CR 4b R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; X 3 For CR 4 R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; cyclic C is phenyl or 5 or 6-membered heteroaryl; each R 1 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 Halogenated alkyl groups and C 1-6 Haloalkoxy group; m is 0, 1, 2 or 3; for R 3a R 3b R 3c R 3d and R 3e 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.

[0153] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein G is N; c is 1; d is 1; e is 2 or 3; f is 1; p3 is 1; R 5 It is an oxo group; R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R 14 R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR20 R 21 One or more of them are replaced by R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; X 1 For N; X 2 For CR 4b R 4b Halogen; X 3 For CH; R 2 C 1-6 Alkyl group; cyclocarbon group is pyrazolyl group; each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl group; m is 1, 2, or 3; for R 3a For halogens, R 3b For halogens, R 3c For hydrogen atoms, R 3d For hydrogen atoms, R 3e It is a hydrogen atom.

[0154] In some embodiments of this disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein G is N; a is 1, b is 1, q is 1, 2, or 3; p2 is 0, 1, or 2; and each R 5 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R 14 R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR 20 R 21 One or more of them are replaced by R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; X 1 For N; X 2 For CR 4b R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; cyclic C is phenyl or 5 or 6-membered heteroaryl; each R 1 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 Halogenated alkyl groups and C 1-6 Haloalkoxy group; m is 0, 1, 2 or 3; R 3a R 3b R 3c R 3d and R 3e 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.

[0155] In some embodiments of this disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein G is N; a is 1, b is 1, q is 2; p2 is 0; R 5a Selected from hydrogen atoms, C 1-6 Alkyl and C(O)R 14 R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy and NR 20 R 21 One or more of them are replaced by R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; X 1 For N; X 2 For CR 4b R 4b It is a halogen; R 4 For hydrogen atoms; R 2 C 1-6 Alkyl group; cyclocarbon group is pyrazolyl group; each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl; m is 1, 2 or 3; R 3a For halogens, R 3b For halogens, R 3c For hydrogen atoms, R 3d For hydrogen atoms, R 3e It is a hydrogen atom.

[0156] In some embodiments of this disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein G is N; a is 1, b is 1, q is 2; p2 is 0; R 5a For C(O)R 14 R 14 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently and optionally substituted with one or more halogens; X 1 For N; X 2 For CR 4b R 4b It is a halogen; R 4 For hydrogen atoms; R 2 C 1-6 Alkyl group; cyclocarbon group is pyrazolyl group; each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl; m is 1, 2 or 3; R 3a For halogens, R 3b For halogens, R 3c For hydrogen atoms, R 3d For hydrogen atoms, R 3e It is a hydrogen atom.

[0157] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered cycloalkyl group; each R 5 They may be the same or different, and each is independently selected from the oxo group and C. 1-6 Alkyl and C(O)R 14 p is 0, 1, or 2; R 14 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl and the 3- to 6-membered heterocyclic group are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more of the haloalkoxy groups are substituted; R ’ For hydrogen atoms, X 1 For N; X 2 For CR 4b R 4b Halogen; X 3 CH; ring C is a 5- or 6-membered heteroaryl group; each R 1 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 Halogenated alkyl groups and C 1-6 Haloalkoxy; R 2 C 1-6Alkyl; ring D is phenyl; each R 3 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 Halogenated alkyl groups and C 1-6 Haloalkoxy; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3.

[0158] In some embodiments of this disclosure, the compound represented by general formula (VI), (VI-1) or (VI-2) or a pharmaceutically acceptable salt thereof, wherein a is 0, b is 0; g is 1; p2 is 0; R 5b C 1-6 Alkyl; R 5a For C(O)R 14 R 14 It is a 3- to 6-membered heterocyclic group; X 1 For N; X 2 For CR 4b R 4b It is a halogen; R 4 For hydrogen atoms; R 2 C 1-6 Alkyl; cyclic C is 5 or 6-membered heteroaryl; each R 1 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; m is 0, 1, 2, or 3; R 3a R 3b R 3c R 3d and R 3e They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0159] Table A lists typical compounds disclosed herein, including but not limited to:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0169]

[0170] in,

[0171] Rings A and R 5 p, R', X 1 To X 3 , ring D, R 2 R 3 And n is as defined in general formula (I).

[0172] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof.

[0173]

[0174] in,

[0175] Rings A and R 5 p, X 1 X 2 R 2 R 4 R 3a R 3b R 3c R 3d and R 3e As defined in general formula (II).

[0176] Another aspect of this disclosure relates to compounds of general formula (IIIA) or (IVA) or salts thereof.

[0177]

[0178] Among them, rings D and R 2 R 3 , n, X 1 To X 3 R A p1, G, R 5a a, b, R 5 p3, c, d, e and f are as defined in general formula (III) or (IV).

[0179] Another aspect of this disclosure relates to compounds of general formula (VA) or salts thereof.

[0180]

[0181] in,

[0182] X 1 X 2 R2 R 3a R 3b R 3c R 3d R 3e R 4 R 5 R 5a G, p2, a, b and q are as defined in general formula (V).

[0183] Another aspect of this disclosure relates to compounds of general formula (VIIA) or (VIIA-2) or salts thereof.

[0184]

[0185] Among them, R P Selected from OH, halogens, and alkoxy groups; in some embodiments, OH;

[0186] Ring B, Ring C, Ring D, X 1 X 2 R 1 To R 5 p2, a, b, g, R 5b L, m, n, R* and r are as defined in general formula (VII).

[0187] Another aspect of this disclosure relates to compounds of the general formula (IC)-(IF) or salts thereof.

[0188]

[0189] Among them, R P2 Selected from OH, halogens and OR 14 ;

[0190] R A1 and R A2 They may be the same or different, and each is independently an alkyl group;

[0191] Rings A and R 5 p, R', X 1 To X 3 , ring D, R 2 R 3 , n and R 14 As defined in general formula (I).

[0192] In some implementation schemes, R A1 It is isopropyl; in some embodiments, R A2 It is a methyl group.

[0193] In some implementation schemes, R 14The cyclopentyl or cyclohexyl group is optionally substituted with one or more alkyl groups; in some embodiments, R 14 It is cyclopentyl or cyclohexyl, wherein the cyclopentyl or cyclohexyl is optionally substituted by one or more selected from methyl, ethyl, propyl and isopropyl.

[0194] Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0203]

[0204] A compound of general formula (IA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0205] Wherein, X is a halogen, and in some implementations it is Br;

[0206] Ring A, Ring C, Ring D, X 1 To X 3 R 1 To R 3 m, n, R ’ R 5 p is as defined in general formula (I).

[0207] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0208] A compound of general formula (IIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0209] Wherein, X is a halogen, and in some implementations it is Br;

[0210] Ring A, Ring C, X 1 X 2 R 1 m, R 2 R 3a R 3b R 3c R 3d R 3e R 4 R 5 p is as defined in general formula (II).

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

[0212] A compound of general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0213] Wherein, X is a halogen, and in some implementations it is Br;

[0214] Ring C, Ring D, X 1 To X 3 R 1 To R 3 m, n, R A p1, G, R 5a a and b are as defined in general formula (III).

[0215] Another aspect of this disclosure relates to a method for preparing a compound of the above general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0216] A compound of general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (IV) or a pharmaceutically acceptable salt thereof.

[0217] Wherein, X is a halogen, and in some implementations it is Br;

[0218] Ring C, Ring D, X 1 To X 3 R 1 To R 3 m, n, G, R 5a R 5 p3, c, d, e and f are as defined in general formula (IV).

[0219] Another aspect of this disclosure relates to a method for preparing a compound of the above general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0220] A compound of general formula (VA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (V) or a pharmaceutically acceptable salt thereof.

[0221] Wherein, X is a halogen, and in some implementations it is Br;

[0222] Ring C, X 1 X 2 R 1 m, R 2 R 3a R 3b R 3c R 3d R 3e R 4 R 5 p2, G, R 5a a, b, and q are as defined in general formula (V).

[0223] Another aspect of this disclosure relates to a method for preparing a compound of the above general formula (VII) or a pharmaceutically acceptable salt thereof, the method comprising:

[0224] A compound of general formula (VIIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (VIIB) or a salt thereof to yield a compound of general formula (VII) or a pharmaceutically acceptable salt thereof; or a compound of general formula (VIIA-2) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IB) or a salt thereof to yield a compound of general formula (VII) or a pharmaceutically acceptable salt thereof.

[0225] Among them, R P Selected from OH, halogens, and alkoxy groups; in some embodiments, OH;

[0226] X is a halogen, which is Br in some implementations;

[0227] Ring B, Ring C, Ring D, X 1 X 2 R 1 To R 5 p2, a, b, g, R 5b L, R*, r, m and n are as defined in general formula (VII).

[0228] The condensation reaction described above occurs under alkaline conditions. In some embodiments, the condensation reaction optionally occurs under alkaline conditions in the presence of a condensing agent. The condensing agent includes, but is not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, and O-benzotriazole-N,N,N',N'-tetramethylurea hexamethylurea. Fluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-(7-oxobenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolylphosphonium hexafluorophosphate; preferably HATU.

[0229] The above-mentioned nucleophilic substitution reaction occurs under basic conditions.

[0230] In some embodiments of this disclosure, in the preparation methods of general formulas (I) to (VII), the nucleophilic substitution reaction is optionally carried out in the presence of a catalyst, which is a metal catalyst; including but not limited to copper catalysts, CuI (cuprous iodide), cuprous iodide and N,N'-dimethylethylenediamine, NaI, KI, palladium acetate, diphenylphosphine ferrocene palladium dichloride, tetraphenylphosphine palladium, dichlorodiphenylphosphine palladium, palladium on carbon, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, etc.; in some embodiments, it is cuprous iodide and N,N'-dimethylethylenediamine.

[0231] The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to, N,N'-dimethylethylenediamine, diisopropylethylamine, triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, 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, potassium phosphate or diisopropylethylamine is used.

[0232] The reactions described above can be carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.

[0233] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (VII) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0234] This disclosure further relates to the use of compounds of general formulas (I) to (VII) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments that stimulate AMPKγ3 activity.

[0235] This disclosure further relates to the use of compounds of general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on AMPKγ3.

[0236] This disclosure further relates to the use of compounds of general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of cardiovascular disease or diseases associated with skeletal muscle dysfunction and exercise intolerance; in some embodiments, the use in the preparation of medicaments for the treatment and / or prevention of heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association class I-IV symptoms, heart failure with reduced left ventricular function, heart failure with preserved left ventricular function, heart failure with moderate ejection fraction, cardiovascular death, heart failure in patients with type II diabetes, coronary artery disease, unstable angina, peripheral vascular disease, renal vascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, and altered cardiovascular risk; and in some embodiments, the use in the preparation of medicaments for the treatment and / or prevention of heart failure or peripheral artery disease.

[0237] This disclosure further relates to a method of activating AMPKγ3 activity, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0238] This disclosure further relates to a method of treating and / or preventing diseases or conditions mediated or dependent on AMPKγ3, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0239] This disclosure further relates to a method for treating and / or preventing cardiovascular disease or diseases associated with skeletal muscle dysfunction and exercise intolerance, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0240] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament; in some embodiments, it is used as a medicament that activates AMPKγ3 activity; in some embodiments, it is used as an AMPKγ3 agonist.

[0241] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on AMPKγ3.

[0242] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for activating AMPKγ3 activity.

[0243] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on AMPKγ3.

[0244] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of cardiovascular disease or diseases associated with skeletal muscle dysfunction and exercise intolerance.

[0245] The diseases or conditions described in this disclosure are treated and / or prevented by stimulating AMPKγ3.

[0246] In some embodiments, the AMPKγ3-mediated or dependent diseases or conditions described in this disclosure are cardiovascular diseases or diseases associated with decreased skeletal muscle function and exercise intolerance; in some embodiments, they are selected from heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with moderate ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with type II diabetes mellitus, coronary heart disease, unstable angina, and peripheral vascular disease (e.g., peripheral artery disease). Diseases including renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndromes, and modification of cardiovascular risk.

[0247] In some embodiments, the disease or condition described in this disclosure is heart failure; in other embodiments, it is peripheral artery disease.

[0248] In some embodiments, the diseases associated with decreased skeletal muscle function and exercise intolerance described in this disclosure include obesity, metabolic syndrome, diabetes, heart failure, peripheral artery disease, cachexia, frailty, and certain musculoskeletal disorders. [Pedersen, BK & Saltin, B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports 25 Suppl 3, 1-72 (2015)]; in some embodiments, obesity and obesity-related conditions (e.g., overweight, weight gain, or weight maintenance); and in some embodiments, obesity with coexisting conditions such as metabolic syndrome. Metabolic syndrome includes diseases, conditions, or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., type 2 diabetes), coronary artery disease, and heart failure.

[0249] In some implementations, the disease or condition is diabetes or diabetes-related conditions, including type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, kidney disease, hypertension, neuropathy, and retinopathy.

[0250] The active compound can be formulated in a form suitable for administration via any appropriate route, either in a unit dose or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0251] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0252] 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.

[0253] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0254] 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.

[0255] 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.

[0256] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation 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.

[0257] 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.

[0258] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions 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.

[0259] Oil suspensions are formulated 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.

[0260] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, 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.

[0261] 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.

[0262] 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 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 can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0263] 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.

[0264] 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 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, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0265] Terminology Explanation

[0266] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0267] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 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 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-10 Alkyl groups, in some embodiments 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.

[0268] 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). 1-20Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), alkylenes having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), alkylenes having 2 to 7 carbon atoms (i.e., C464-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker.

[0269] The term "bridged alkylene" refers to an alkylene ring formed by the connection of two non-adjacent atoms, as defined above. Non-limiting examples include: bridged ethylene (-CH2CH2-), bridged propylene (-CH2CH2-), and bridged methylene (-CH2-).

[0270] For example, the fragment in general formula (III) Two R A When connected to form a bridging ethylene group, it is... p4 is 0, 1, or 2.

[0271] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0272] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12).2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0273] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0274] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 5 or 6 ring atoms.

[0275] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0276] The polycyclic alkyl groups include: spirocyclic alkyl, fused cyclic alkyl, and bridged cyclic alkyl; further including 5 to 12-membered bicyclic or tricyclic alkyl groups.

[0277] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, 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 spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0278] Its connection point can be anywhere;

[0279] wait.

[0280] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0281] Its connection point can be anywhere; wait.

[0282] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0283] Its connection point can be anywhere.

[0284] 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... wait.

[0285] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0286] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) 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-), and having 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). In some embodiments, the heterocyclic group has 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic groups), 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic groups), 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic groups), 5 to 12-membered heterocyclic groups, or 7 to 12-membered heterocyclic groups; in some embodiments, it has 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic groups); in some embodiments, it has 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic groups), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups); in some embodiments, it has 5 or 6 ring atoms.

[0287] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, azacyclic butyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0288] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups; further including 5- to 12-membered bicyclic or tricyclic heterocyclic groups.

[0289] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms within its ring, as defined above. In some embodiments, it is a 3- to 12-membered nitrogen-containing heterocyclic group or a 3- to 10-membered nitrogen-containing heterocyclic group; in some embodiments, it is a 4- to 7-membered nitrogen-containing heterocyclic group; and in some embodiments, it is a 5- or 6-membered nitrogen-containing heterocyclic group.

[0290] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments, it is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered mono-spiroheterocyclic group. Non-limiting examples include:

[0291] wait.

[0292] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, it is a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0293]

[0294] wait.

[0295] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized 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 bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0296]

[0297] wait.

[0298] 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:

[0299] wait.

[0300] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0301] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl). In some embodiments, the aryl group has 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, it has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Monocyclic aryl groups include, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthracene, phenanthrene, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0302]

[0303] wait.

[0304] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0305] 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).

[0306] 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.

[0307] 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:

[0308]

[0309] wait.

[0310] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0311] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0312] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0313] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0314] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0321] 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.

[0322] 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.

[0323] 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, they are -alkyl-alkoxy groups; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.

[0324] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0325] The term "hydroxyl group" refers to -OH.

[0326] The term "amino" refers to -NH2.

[0327] The term "cyano" refers to -CN.

[0328] The term "nitro" refers to -NO2.

[0329] The term "oxo" or "oxo group" refers to "=O".

[0330] The term "carbonyl" refers to C=O.

[0331] TBS refers to tert-butyldimethylsilyl.

[0332] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0333] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0334] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. They also include 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.

[0335] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0336]

[0337] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0338]

[0339] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0340] 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) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0341] 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.

[0342] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0343] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0344] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, such as 1, 2, or 3, meaning that 1 to 3 hydrogen atoms are independently replaced 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).

[0345] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, 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.

[0346] "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. They 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.

[0347] 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.

[0348] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0349] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more 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

[0350] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0351] Example

[0352] 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 determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0353] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0354] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0355] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0356] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLCe2695-2489 HPLC system.

[0357] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0358] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0359] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0360] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0361] 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 diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0362] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0363] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0364] 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, AccelaChemBio Inc, and Darui Chemicals.

[0365] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0366] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0367] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0368] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0369] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0370] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0371] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0372] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0373] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0374] Example 1

[0375] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-((8-((1S,2S)-2-fluorocyclopropane-1-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0376]

[0377] (8-((1S,2S)-2-fluorocyclopropane-1-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)tert-butyl carbamate 1b

[0378] (1S,2S)-2-fluorocyclopropane-1-carboxylic acid 1a (100 mg, 0.961 mmol, BIDE) and 3-tert-butoxycarbonylaminodemethyltropane 1b (217 mg, 0.959 mmol, BIDE) were dispersed in N,N-dimethylformamide (5 mL), followed by the addition of diisopropylethylamine (373 mg, 2.89 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (402 mg, 1.06 mmol, SHAOYUAN), and stirred at room temperature for 8 hours. Quenching with water (15 mL), extraction with ethyl acetate (30 mL × 3), combining the organic phases, washing with saturated sodium chloride solution (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography with eluent system A to give title compound 1c (280 mg, yield: 93.3%).

[0379] MS m / z(ESI): 313.4 [M+1].

[0380] Step 2

[0381] (3-amino-8-azabicyclo[3.2.1]oct-8-yl)((1S,2S)-2-fluorocyclopropyl)methyl ketone 1d

[0382] Compound 1c (280 mg, 0.896 mmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) was added. The mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated, and the residue was purified by high performance liquid chromatography (Waters 2545, column: Atlantis T3 prep OBD C18; 30*150 mm, 5 μm; mobile phase: water (0.1% formic acid) and acetonitrile; flow rate: 30 mL / min, 27 min gradient, ratio: acetonitrile 10%-95%) to give the title compound 1d (150 mg, yield 78.7%).

[0383] MS m / z(ESI):213.4[M+1].

[0384] Step 3

[0385] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((8-(((1S,2S)-2-fluorocyclopropane-1-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)nicotinic acid ester 1f

[0386] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-(methylthio)nicotinate 1e (4.1 g, 8.09 mmol, prepared by the method disclosed in compound C5 on page 59 of patent application "WO2024084390")) was dissolved in dichloromethane (60 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (1.81 g, 8.92 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (70 mL) and saturated sodium bicarbonate solution (50 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (80 mL) and saturated sodium chloride solution (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a solid crude product (4 g). The crude product (200 mg) and compound 1d (100 mg, 0.471 mmol) were dissolved in dimethyl sulfoxide (3 mL), and diisopropylethylamine (124 mg, 0.959 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 1f (140 mg, yield 54.5%).

[0387] MS m / z(ESI): 671.2 [M+1].

[0388] Step 4

[0389] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-6-((8-((1S,2S)-2-fluorocyclopropane-1-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 1g

[0390] Compound 1f (210 mg, 0.313 mmol) was dissolved in a dry mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and Raney nickel (200 mg, 3.41 mmol) and glacial acetic acid (188 mg, 3.13 mmol) were added. The mixture was purged with hydrogen three times, and the mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The reaction solution was directly concentrated, and the residue was purified by column chromatography using eluent system A to give 1 g (65 mg, 40.0%) of the title compound. MS m / z (ESI): 519.2 [M+1].

[0391] Step 5

[0392] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-((8-((1S,2S)-2-fluorocyclopropane-1-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0393] 1 g (51 mg, 0.098 mmol) of compound 1, 3-bromo-4-fluoro-1-methylpyrazole (26 mg, 0.145 mmol, Acon Biotech), potassium phosphate (63 mg, 0.297 mmol), cuprous iodide (38 mg, 0.199 mmol), and N,N'-dimethylethylenediamine (35 mg, 0.397 mmol) were dispersed in xylene (2 mL), purged with nitrogen, and microwaved to 130 °C. The mixture was stirred for 5 hours, cooled, and concentrated. The residue was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate, acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give title compound 1 (15 mg, 24.7%).

[0394] MS m / z(ESI): 617.2 [M+1].

[0395] 1 H NMR(500MHz,DMSO-d6)δ8.53(d,1H),7.83(d,1H),7.58(t,1H),7.43-7.36(m,1H),7.33-7.16(m,2H),4.99-4.77(m,1H),4.70-4.43(m ,3H),4.20(d,1H),3.72(s,3H),3.69(d,1H),2.10-1.93(m,3H),1.92-1.85(m,2H),1.84(s,3H),1.82-1.48(m,5H),1.06-0.94(m,1H).

[0396] Example 2

[0397] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 2-1

[0398] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 2-2

[0399]

[0400]

[0401] first step

[0402] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((3-(methoxycarbonyl)-3-methylcyclobutyl)amino)nicotinate 2a

[0403] Compound 1e (200 mg, 0.38 mmol) was cooled to 0 °C, and m-chloroperoxybenzoic acid (98 mg, 0.46 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid crude product (200 mg). The crude product was dissolved in dimethyl sulfoxide (3 mL) with methyl 3-amino-1-methylcyclobutane-1-carboxylic acid (83 mg, 0.58 mmol, prepared by the method disclosed in compound 305-1 on page 187 of patent application “US20190352271”). Diisopropylethylamine (124 mg, 0.959 mmol) was added, and the mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give title compound 2a (227 mg, yield 97.7%).

[0404] MS m / z(ESI): 602.2 [M+1].

[0405] Step 2

[0406] (R)-3-((5-(3-chloro-2-fluorophenyl)-4-fluoro-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino)-1-methylcyclobutane-1-carboxylic acid methyl ester 2b

[0407] Compound 2a (220 mg, 0.36 mmol) was dissolved in a dry mixture of tetrahydrofuran (10 mL) and methanol (10 mL), and Raney nickel (200 mg, 3.41 mmol) and glacial acetic acid (110 mg, 1.83 mmol) were added. The mixture was purged with hydrogen three times, and the mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The reaction solution was directly concentrated, and the residue was purified by column chromatography using eluent system A to give title compound 2b (130 mg, 79.1%). MS m / z (ESI): 450.4 [M+1].

[0408] Step 3

[0409] (R)-3-((5-(3-chloro-2-fluorophenyl)-4-fluoro-7-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino)-1-methylcyclobutane-1-carboxylic acid methyl ester 2c

[0410] Compound 2b (50 mg, 0.11 mmol), 3-bromo-4-fluoro-1-methylpyrazole (26 mg, 0.145 mmol, Acon Biotech), potassium phosphate (63 mg, 0.297 mmol), cuprous iodide (38 mg, 0.199 mmol), and N,N'-dimethylethylenediamine (35 mg, 0.397 mmol) were dispersed in xylene (2 mL), purged with nitrogen, microwaved to 130 °C, stirred for 5 hours, cooled and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 2c (40 mg, 66.7%).

[0411] MS m / z(ESI): 546.2 [M-1].

[0412] Step 4

[0413] (R)-3-((5-(3-chloro-2-fluorophenyl)-4-fluoro-7-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino)-1-methylcyclobutane-1-carboxylic acid 2d

[0414] Compound 2c (40 mg, 0.11 mmol) and lithium hydroxide monohydrate (9.3 mg, 0.21 mmol) were dissolved in methanol (5 mL), and the mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water (5 mL), the pH was adjusted to 5-6 by dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated to obtain crude product 2d (38 mg). The crude product was used directly in the next step without purification.

[0415] MS m / z(ESI): 534.3 [M+1].

[0416] Step 5

[0417] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 2-1

[0418] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 2-2

[0419] Compound 2d (38 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of tetrahydropyrrole (16 mg, 0.22 mmol), diisopropylethylamine (30 mg, 0.23 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (43 mg, 0.11 mmol, Shaoyuan). The mixture was stirred at room temperature for 16 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 30%-50%) to obtain the title compound (5 mg, 5 mg).

[0420] Preparation of compounds with a retention time of 20.52 min:

[0421] MS m / z(ESI): 587.2 [M+1].

[0422] 1 H NMR(500MHz,DMSO-d6)δ8.47(s,1H),7.82(dd,1H),7.64(d,1H),7.58(t,1H),7.40(t,1H),7.30-7.25(m,1H),4.30-4.15(m,2 H),3.71(s,3H),3.70(s,1H),2.94-2.82(m,2H),2.04-1.91(m,4H),1.83(s,3H),1.81-1.71(m,4H),1.34(s,3H),1.24(s,2H).

[0423] Preparation of compounds with a retention time of 22.12 min:

[0424] MS m / z(ESI): 587.2 [M+1].

[0425] 1 H NMR(500MHz,DMSO-d6)δ8.51(s,1H),7.82(d,1H),7.61-7.56(m,1H),7.52(d,1H),7.41-7.36(m,1H),7.27(t,1H),4.62-4.53(m,1H),4.19 (d,1H),3.72(s,3H),3.70(d,1H),3.31-3.26(m,4H),2.37(ddd,2H),2.30-2.22(m,2H),1.87-1.81(m,5H),1.77-1.70(m,2H),1.36(s,3H).

[0426] Example 3

[0427] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0428] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 3-2

[0429]

[0430] first step

[0431] (R)-3-((5-(3-chloro-2-fluorophenyl)-4-fluoro-7-(3-fluoropyridin-2-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino)-1-methylcyclobutane-1-carboxylic acid methyl ester 3a

[0432] Compound 2b (64 mg, 0.142 mmol), 2-bromo-3-fluoropyridine (25 mg, 0.145 mmol, Adamas), potassium phosphate (90 mg, 0.424 mmol), cuprous iodide (54 mg, 0.283 mmol), and N,N'-dimethylethylenediamine (50 mg, 0.567 mmol) were dispersed in xylene (2 mL), purged with nitrogen, microwaved to 130 °C, stirred for 5 hours, cooled, filtered, and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 3a (38 mg, yield: 49.3%).

[0433] MS m / z(ESI): 545.2 [M+1].

[0434] Step 2

[0435] (R)-3-((5-(3-chloro-2-fluorophenyl)-4-fluoro-7-(3-fluoropyridin-2-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino)-1-methylcyclobutane-1-carboxylic acid 3b

[0436] Compound 3a (38 mg, 0.07 mmol) and lithium hydroxide monohydrate (9.3 mg, 0.21 mmol) were dissolved in methanol (5 mL), and the mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water (5 mL), the pH was adjusted to 5-6 by dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated to obtain crude product 3b (37 mg). The crude product was used directly in the next step without purification.

[0437] MS m / z(ESI): 531.2 [M+1].

[0438] Step 3

[0439] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0440] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 3-2

[0441] Compound 2d (37 mg, crude product) was dissolved in N,N-dimethylformamide (1.5 mL), followed by the sequential addition of tetrahydropyrrole (13 mg, 0.176 mmol), diisopropylethylamine (23 mg, 0.178 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (34 mg, 0.089 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: Boston ODS-BIO C18; Prep 250*30 mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 30%-70%) to obtain the title compound (6 mg, 6 mg).

[0442] Preparation of compounds with a retention time of 16.17 min:

[0443] MS m / z(ESI): 584.4 [M+1].

[0444] 1 H NMR(500MHz,DMSO-d6)δ8.55(s,1H),8.30(d,1H),7.80(dd,1H),7.61-7.55(m,2H),7.46-7.39(m,2H),7.28(dd,1H),4.62-4.53(m,1H),4.32( d,1H),3.82(d,1H),3.31-3.25(m,4H),2.43-2.33(m,2H),2.31-2.22( m,2H),1.86(s,3H),1.85-1.81(m,2H),1.77-1.70(m,2H),1.36(s,3H).

[0445] Preparation of compounds with a retention time of 17.12 min:

[0446] MS m / z(ESI): 584.4 [M+1].

[0447] 1H NMR(500MHz,DMSO-d6)δ8.53(s,1H),8.30(d,1H),7.80(dd,1H),7.70(d,1H),7.59(dd,1H),7.47-7.40(m,2H),7.28(dd,1H),4.34(d,1H),4.30-4 .21(m,1H),3.82(d,1H),2.94-2.85(m,4H),2.05-1.99(m,2H),1.98-1.9 1(m,2H),1.87(s,3H),1.86-1.81(m,2H),1.80-1.73(m,2H),1.35(s,3H).

[0448] Example 4

[0449] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2r,4S)-6-methyl-5-oxo-6-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 4-1

[0450] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2s,4R)-6-methyl-5-oxo-6-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 4-2

[0451]

[0452] first step

[0453] 2-(cyanomethyl)-5,8-dioxane[3,4]octane-2-carboxylic acid methyl ester 4b

[0454] Compound 4a (10 g, 58.08 mmol) was dissolved in dry tetrahydrofuran (300 mL), cooled in a dry ice-ethanol bath, and then diisopropylaminolithium (6.30 g, 63.48 mmol, 2 M in THF) was added. After stirring for 30 minutes, bromoacetonitrile (8.35 g, 69.61 mmol) was added, and the reaction was stirred for another 2 hours. The reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography using eluent system B to give the title compound 4b (4 g, yield 32.6%).

[0455] MS m / z(ESI): 212.0 [M+1]

[0456] Step 2

[0457] 1,4-Dioxa-9-azabispirol [4.1.4] 7 .1 5 Dodecane-8-one 4c

[0458] Compound 4b (4 g, 18.94 mmol) was dissolved in a mixed solvent of dry tetrahydrofuran (40 mL) and methanol (40 mL), Raney nickel (22.2 g, 0.34 mol) and glacial acetic acid (11.3 g, 0.19 mmol) was added, and hydrogen was purged three times. The mixture was heated to 60 °C and stirred for 16 hours under a hydrogen atmosphere. The reaction solution was concentrated and the residue was purified by column chromatography with eluent system B to give the title compound 4c (1.2 g, yield 34.7%).

[0459] MS m / z(ESI): 184.2 [M+1].

[0460] Step 3

[0461] 9-Methyl-1,4-dioxa-9-azabispiro[4.1.4] 7 .1 5 Dodecane-8-one 4d

[0462] Compound 4c (50 mg, 0.27 mmol) was dissolved in dry tetrahydrofuran (2 mL), sodium hydride (7 mg, 0.30 mol) was added under an ice-water bath, and the reaction was stirred for 30 minutes. Iodomethane (40 mg, 0.28 mol) was added dropwise, and the mixture was brought to room temperature and stirred for another 2 hours. The reaction was quenched by adding water (5 mL), and the mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system A to give the title compound 4d (50 mg, 92.9% yield).

[0463] MS m / z(ESI):198.2[M+1].

[0464] Step 4

[0465] 6-Methyl-6-azaspiro[3.4]octane-2,5-dione 4e

[0466] Compound 4d (300 mg, 1.35 mmol) was dissolved in tetrahydrofuran (4 mL), sulfuric acid (4 mL, 2 M) was added, and the mixture was stirred at 50 °C for 3 hours. The pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (3 mL × 3). The organic phases were combined and concentrated to give the title compound 4e (250 mg, crude product). The product was directly proceeded to the next step without purification.

[0467] Step 5

[0468] 2-Amino-6-methyl-6-azaspiro[3.4]octane-5-one 4f

[0469] Compound 4e (250 mg, crude product) was dissolved in a mixed solvent of ethanol (5 mL) and water (5 mL), sodium carbonate (620 mg, 5.88 mmol) and hydroxylamine hydrochloride (270 mg, 3.92 mmol) were added, and the mixture was heated at 100 °C for 2 hours. The mixture was extracted with ethyl acetate (3 mL × 3), the organic phases were combined, and the mixture was concentrated to obtain the crude product. The crude product was dissolved in ammonia-methanol solution (5 mL, 7.0 M), Raney nickel (222 mg, 3.40 mmol) was added, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was concentrated and the residue was purified by column chromatography with eluent system B to obtain the title compound 4f (150 mg, yield 56.4%, a pair of cis-trans isomers).

[0470] MS m / z(ESI): 155.2 [M+1].

[0471] 1 H NMR(400MHz, CDCl3)δ:3.51-3.86(m,1H),3.25-3.33(m,2H),3.10(s,2H),2.91(s ,3H),2.65-2.68(m,1H),2.23-2.28(m,1H),2.09-2.19(m,3H),1.80-1.85(m,1H).

[0472] Step 6

[0473] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((6-methyl-5-oxo-6-aza-6-azaspiro[3.4]oct-2-yl)amino)nicotinic acid ester 4g

[0474] Compound 1e (200 mg, 0.38 mmol) was cooled to 0 °C, and m-chloroperoxybenzoic acid (98 mg, 0.46 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid crude product (200 mg). The crude product was dissolved in dimethyl sulfoxide (3 mL) along with 4f (50 mg, 0.32 mmol), and diisopropylethylamine (130 mg, 1.01 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and purified by column chromatography with eluent system B to give 4 g (130 mg, yield 65.4%) of the title compound.

[0475] MS m / z(ESI): 613.5 [M+1].

[0476] Step 7

[0477] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-4-methyl-6-((6-methyl-5-oxo-6-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 4h

[0478] 4 g (130 mg, 0.21 mmol) of the compound was dissolved in a dry mixture of tetrahydrofuran (10 mL) and methanol (10 mL), Raney nickel (100 mg, 1.70 mmol) and glacial acetic acid (120 mg, 2.00 mmol) were added, and hydrogen was purged three times. The mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The reaction solution was then directly concentrated to give the title compound 4h (60 mg, yield 61.4%).

[0479] MS m / z(ESI):461.3[M+1].

[0480] Step 8

[0481] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2r,4S)-6-methyl-5-oxo-6-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 4-1

[0482] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2s,4R)-6-methyl-5-oxo-6-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 4-2

[0483] Compound 4h (18 mg, 0.039 mmol), 3-bromo-4-fluoro-1-methylpyrazole (14 mg, 0.078 mmol, Acon Biotech), potassium phosphate (26 mg, 0.12 mmol), cuprous iodide (18 mg, 0.094 mmol), and N,N'-dimethylethylenediamine (20 mg, 0.23 mmol) were dispersed in xylene (5 mL), purged with nitrogen, and microwaved to 130 °C. The mixture was stirred for 5 hours, cooled, and concentrated. The concentrate was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate, acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to obtain the title compound (3 mg, 3 mg).

[0484] MS m / z(ESI): 559.2 [M+1].

[0485] MS m / z(ESI): 559.2 [M+1].

[0486] Example 5

[0487] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0488]

[0489]

[0490] first step

[0491] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)amino)nicotinate 5a

[0492] Compound 1e (200 mg, 0.38 mmol) was cooled to 0 °C, and m-chloroperoxybenzoic acid (98 mg, 0.46 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid crude product (200 mg). The crude product (84 mg) was dissolved in dimethyl sulfoxide (3 mL) with 5,6,7,8-tetrahydroimidazolo[1,2-a]pyridine-7-amine (60 mg, 0.024 mmol, prepared by the method disclosed on page 27 of patent application “US20220304990, compound 5”), and diisopropylethylamine (104 mg, 0.080 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and purified by column chromatography with eluent system B to give title compound 5a (38 mg, yield 39.7%, a pair of diastereomers).

[0493] MS m / z(ESI): 596.5 [M+1].

[0494] Step 2

[0495] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-4-methyl-6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)amino)-3,4-dihydro-2,7-naphthidin-1(2H)-one 5b

[0496] Compound 5a (38 mg, 0.064 mmol) was dissolved in a dry mixture of tetrahydrofuran (5 mL) and methanol (5 mL). Raney nickel (50 mg, 0.085 mmol) and glacial acetic acid (38 mg, 0.63 mmol) were added, and the mixture was purged with hydrogen three times. The mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The solid was removed by filtration, and the reaction solution was directly concentrated to give the title compound 5b (28 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 444.2 [M+1].

[0497] Step 3

[0498] (4R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one

[0499] Compound 5b (28 mg, crude product), 3-bromo-4-fluoro-1-methylpyrazole (23 mg, 0.13 mmol, Acon Biotech), potassium phosphate (40 mg, 0.19 mmol), cuprous iodide (24 mg, 0.13 mmol), and N,N'-dimethylethylenediamine (22 mg, 0.25 mmol) were dispersed in xylene (3 mL), purged with nitrogen, and microwaved to 130 °C. The mixture was stirred for 5 hours, cooled, and concentrated. The concentrate was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give title compound 5 (0.53 mg, yield 1.6%, a pair of diastereomers).

[0500] MS m / z(ESI): 542.2 [M+1].

[0501] Example 6

[0502] (R)-4-(3-chloro-5-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 6-1

[0503] (R)-4-(3-chloro-5-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 6-2

[0504]

[0505]

[0506] first step

[0507] 4-[(3-chloro-5-fluorophenyl)(cyano)methyl]-5-fluoro-6-(methylthio)nicotinic acid ethyl ester 6c

[0508] Compound 6a (100 mg, 0.59 mmol, BIDE) was dissolved in dry toluene (5 mL), and NaHMDS (0.35 mL, 2 M in THF) was added dropwise under an ice-water bath. After stirring for 30 minutes, 6b (176 mg, 0.70 mmol, prepared by the method disclosed on page 76 of patent application "WO2024084390, compound C8") was added. The mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched by adding water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 6c (180 mg, 79.7%).

[0509] MS m / z(ESI):383.0[M+1].

[0510] Step 2

[0511] 4-[1-(3-chloro-5-fluorophenyl)-1-cyanoethyl]-5-fluoro-6-(methylthio)nicotinic acid ethyl ester 6d

[0512] Compound 6c (50 mg, 0.13 mmol) was dissolved in dry tetrahydrofuran (2 mL), and NaHMDS (0.087 mL, 2 M in THF) was added dropwise under an ice-water bath. After stirring continuously for 30 minutes, iodomethane (37 mg, 0.26 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched by adding water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 6d (25 mg, 48.2%).

[0513] MS m / z(ESI): 397.0 [M+1].

[0514] Step 3

[0515] 4-[1-(3-chloro-5-fluorophenyl)-1-cyanoethyl]-5-fluoro-6-(methylsulfinyl)nicotinic acid ethyl ester 6e

[0516] 6d (30 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (26 mg, 0.15 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (2 mL) and saturated sodium bicarbonate solution (2 mL) sequentially. The organic phase was washed sequentially with saturated sodium bicarbonate solution (2 mL) and saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid crude product 6e (30 mg). The product was used directly in the next step without purification.

[0517] Step 4

[0518] 4-[1-(3-chloro-5-fluorophenyl)-1-cyanoethyl]-5-fluoro-6-[[3-(methoxycarbonyl)-3-methylcyclobutyl]amino]-nicotinic acid ethyl 6f

[0519] The crude product 6e (30 mg) and methyl 3-amino-1-methylcyclobutane-1-carboxylic acid (10 mg, 0.070 mmol, Shaoyuan) were dissolved in dimethyl sulfoxide (1 mL), and diisopropylethylamine (18 mg, 0.14 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (2 mL), and the mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined, concentrated, and purified by column chromatography with eluent system B to give the title compound 6f (25 mg, yield 72.6%, a pair of diastereomers).

[0520] MS m / z(ESI):492.1[M+1].

[0521] Step 5

[0522] (R)-3-[[5-(3-chloro-5-fluorophenyl)-4-fluoro-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl]-amino]-1-methylcyclobutane-1-carboxylic acid methyl ester 6g

[0523] Compound 6f (25 mg, 0.051 mmol) was dissolved in a dry mixture of tetrahydrofuran (2 mL) and methanol (2 mL), Raney nickel (3 mg, 0.051 mmol) and glacial acetic acid (10 mg, 0.17 mmol) were added, and hydrogen was purged three times. The mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The solid was filtered off, and the remaining reaction solution was directly concentrated to give the title compound 6 g (20 mg, 87.5%, a pair of diastereomers).

[0524] MS m / z(ESI): 450.1 [M+1].

[0525] Step 6

[0526] (R)-3-[[5-(3-chloro-5-fluorophenyl)-4-fluoro-7-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl]amino]-1-methylcyclobutane-1-carboxylic acid methyl ester 6h

[0527] 6 g (25 mg, 0.056 mmol) of compound, 3-bromo-4-fluoro-1-methylpyrazole (20 mg, 0.11 mmol, Acon Biotech), potassium phosphate (35 mg, 0.16 mmol), cuprous iodide (21 mg, 0.11 mmol), and N,N'-dimethylethylenediamine (20 mg, 0.21 mmol) were dispersed in xylene (2 mL), purged with nitrogen, microwaved to 130 °C, stirred for 5 hours, cooled and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 6h (23 mg, 42.0%, a pair of diastereomers).

[0528] MS m / z(ESI): 548.2 [M+1].

[0529] Step 7

[0530] (R)-3-[[5-(3-chloro-5-fluorophenyl)-4-fluoro-7-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl]-amino]-1-methylcyclobutane-1-carboxylic acid 6i

[0531] Compound 6h (15 mg, 0.027 mmol) and lithium hydroxide monohydrate (2 mg, 0.047 mmol) were dissolved in methanol (2 mL), and the mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (2 mL), the pH was adjusted to 5-6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined and concentrated to obtain crude product 6i (14 mg). The crude product was used directly in the next step without purification.

[0532] MS m / z(ESI): 534.3 [M+1].

[0533] Step 8

[0534] (R)-4-(3-chloro-5-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 6-1

[0535] (R)-4-(3-chloro-5-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 6-2

[0536] Compound 6i (14 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of tetrahydropyrrole (4 mg, 0.041 mmol), diisopropylethylamine (7 mg, 0.054 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (10 mg, 0.29 mmol, succinate). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to obtain the title compound (2 mg, 13.0%). Compounds with shorter retention times:

[0537] MS m / z(ESI): 587.4 [M+1].

[0538] 1 H NMR(500MHz, CDCl3)δ8.80(s,1H),7.22(d,1H),7.08(d,1H),7.01(dt,1H),6.90(dt,1H),4.08(d,1H),3.81(d,1H),3.76(s,3H),3.4 7(t,2H),3.33(t,3H),2.61-2.50(m,1H),2.43-2.30(m,1H),2.22(s,1H),2.01(d,1H),1.90(q,2H),1.86-1.78(m,5H),1.49(s,3H).

[0539] Compounds with longer retention times:

[0540] MS m / z(ESI): 587.4 [M+1].

[0541] 1 H NMR (500MHz, CDCl3) δ8.81(s,1H),7.24(d,1H),7.13(d,1H),7.04(dt,1H),6.95(dt,1H),4.38(q,1H),4.12(d,1 H),3.83(d,1H),3.79(s,3H),3.53(t,2H),3.39(t,2H),3.23(ddd,2H),1.93(dt,6H),1.88(s,3H),1.50(s,3H).

[0542] Example 7

[0543] (R)-4-(3-chloro-2-fluorophenyl)-2-(1-cyclopropyl-4-fluoro-1H-pyrazole-3-yl)-5-fluoro-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 7-1

[0544] (R)-4-(3-chloro-2-fluorophenyl)-2-(1-cyclopropyl-4-fluoro-1H-pyrazole-3-yl)-5-fluoro-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 7-2

[0545]

[0546] first step

[0547] 4-Fluoro-3-iodo-1H-pyrazole 7b

[0548] Compound 7a (1.50 g, 17.4 mmol, Leyan) was dissolved in dry chloroform (30 mL), and N-iodosuccinimide (4.31 g, 19.2 mmol) was added to replace hydrogen three times. The mixture was heated to 80 °C and stirred for 7 hours under a hydrogen atmosphere. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate, acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to obtain title compound 7b (1.08 g, 29.3%) MS m / z (ESI): 213.1 [M+1].

[0549] Step 2

[0550] 1-Cyclopropyl-4-fluoro-3-iodo-1H-pyrazole 7c

[0551] Compound 7b (515 mg, 2.43 mmol), cyclopropylboronic acid (418 mg, 4.87 mmol, BIDE), sodium carbonate (773 mg, 7.29 mmol), copper acetate (883 mg, 4.86 mmol), and 2,2'-bipyridine (1.13 g, 7.23 mmol) were dispersed in dichloroethane (20 mL), heated to 50 °C, stirred for 16 hours, cooled and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 7c (403 mg, 65.8%).

[0552] 1H NMR (500MHz, CDCl3) δ7.25(d,1H),3.58(tt,1H),1.16-1.09(m,2H),1.06-0.98(m,2H).

[0553] Step 3

[0554] (R)-3-[[5-(3-chloro-2-fluorophenyl)-7-(1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-4-fluoro-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl]amino]-1-methylcyclobutane-1-carboxylic acid methyl ester 7d

[0555] Compounds 2b (23 mg, 0.051 mmol), 7c (26 mg, 0.10 mmol), potassium phosphate (33 mg, 0.16 mmol), cuprous iodide (20 mg, 0.11 mmol), and N,N'-dimethylethylenediamine (18 mg, 0.20 mmol) were dispersed in xylene (2 mL), purged with nitrogen, microwaved to 130 °C, stirred for 5 hours, cooled and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 7d (23 mg, 78.4%, a pair of diastereomers).

[0556] MS m / z(ESI): 574.2 [M+1].

[0557] Step 4

[0558] (R)-3-[[5-(3-chloro-2-fluorophenyl)-7-(1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)-4-fluoro-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl]amino]-1-methylcyclobutane-1-carboxylic acid 7e

[0559] Compound 7d (23 mg, 0.040 mmol) and lithium hydroxide monohydrate (17 mg, 0.40 mmol) were dissolved in methanol (2 mL), and the mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water (2 mL), the pH was adjusted to 5-6 by dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined and concentrated to obtain crude product 7e (22 mg). The crude product was used directly in the next step without purification.

[0560] MS m / z(ESI): 560.2 [M+1].

[0561] Step 5

[0562] (R)-4-(3-chloro-2-fluorophenyl)-2-(1-cyclopropyl-4-fluoro-1H-pyrazole-3-yl)-5-fluoro-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 7-1

[0563] (R)-4-(3-chloro-2-fluorophenyl)-2-(1-cyclopropyl-4-fluoro-1H-pyrazole-3-yl)-5-fluoro-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 7-2

[0564] Compound 7e (22 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of tetrahydropyrrole (14 mg, 0.20 mmol), diisopropylethylamine (16 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (16 mg, 0.060 mmol, Shaoyuan). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to obtain the title compound (10 mg, 40.8%). Compounds with shorter retention times:

[0565] MS m / z(ESI): 613.4 [M+1]. 1 H NMR(500MHz, CDCl3)δ8.80(s,1H),7.22(d,1H),7.08(d,1H),7.01(dt,1H) ,6.90(dt,1H),4.66(q,1H),4.08(d,1H),3.81(d,1H),3.76(s,3H),3.47( t,2H),3.33(t,2H),2.59-2.49(m,2H),2.43-2.31(m,2H),2.22(t,1H),2. 07-1.97(m,1H),1.94-1.87(m,2H),1.87-1.79(m,5H),1.37-1.26(m,4H).

[0566] Compounds with longer retention times:

[0567] MS m / z(ESI): 613.4 [M+1].

[0568] 1 H NMR(500MHz, CDCl3)δ8.78(s,1H),7.22(d,1H),7.11(d,1H),7.01(dt,1H),6.93(dt,1H),4.36(tt,1H),4.09(d, 1H),3.80(d,1H),3.76(s,3H),3.51(t,2H),3.37(t,2H),3.21(ddd,2H),1.95-1.80(m,11H),1.37-1.26(m,4H).

[0569] MS m / z(ESI): 613.2 [M+1].

[0570] MS m / z(ESI): 613.2 [M+1].

[0571] Example 8

[0572] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2r,4S)-5-methyl-6-oxo-5-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 8-1

[0573] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((2s,4R)-5-methyl-6-oxo-5-azaspiro[3.4]oct-2-yl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 8-2

[0574]

[0575] MS m / z(ESI): 559.2 [M+1].

[0576] MS m / z(ESI): 559.2 [M+1].

[0577] Example 9

[0578] (R)-6-[[(1s,3S)-3-(5-azaspiro[2,4]heptane-5-carbonyl)cyclobutyl]amino]-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 9-1

[0579] (R)-6-[[(1r,3R)-3-(5-azaspiro[2,4]heptane-5-carbonyl)cyclobutyl]amino]-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 9-2

[0580]

[0581] Referring to Example 2, the raw material 3-amino-1-methylcyclobutane-1-carboxylic acid methyl ester in the first step was replaced with 3-aminocyclobutane-1-carboxylic acid methyl ester (Yaoshi), and the raw material tetrahydropyrrole in the fifth step was replaced with 5-azaspiro[2.4]heptane hydrochloride (Biode) to obtain the title compound (12 mg, 43.4%) and (10 mg, 36.2%).

[0582] Compounds with shorter retention times:

[0583] MS m / z(ESI): 599.2 [M+1].

[0584] 1 H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,1H),7.67(t,1H),7.59(s,1H),7.41(t,1H),7.28(t,1H),4.49(d,1H),4.26-4.09(m, 1H),3.85-3.65(m,5H),3.65-3.39(m,1H),3.29-3.15(m,3H),3.06-2.79(m,1H),2.22(d,2H),1.91-1.66(m,6H),0.58(dt,4H).

[0585] Compounds with longer retention times:

[0586] MS m / z(ESI): 599.2 [M+1].

[0587] 1H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,1H),7.67(t,1H),7.59(s,1H),7.41(t,1H),7.28(t,1H),4.68-4.55(m,1H),4.21(d,1H),3.72(s,3 H),3.70(d,1H),3.47(q,2H),3.23(d,2H),3.19-3.01(m,1H),2.49-2. 41(m,2H),2.28(tq,2H),1.85(s,3H),1.77(dt,2H),0.64-0.48(m,4H).

[0588] Example 10

[0589] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-[[(1s,3S)-3-(morpholin-4-carbonyl)cyclobutyl]amino]-3,4-dihydro-2,7-naphthidium-1(2H)-one 10-1

[0590] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-[[(1r,3R)-3-(morpholin-4-carbonyl)cyclobutyl]amino]-3,4-dihydro-2,7-naphthidium-1(2H)-one 10-2

[0591]

[0592] Referring to Example 2, the raw material 3-amino-1-methylcyclobutane-1-carboxylic acid methyl ester in the first step was replaced with 3-aminocyclobutane-1-carboxylic acid methyl ester (Yaoshi), and the raw material tetrahydropyrrole in the fifth step was replaced with morpholine (Guoyao) to obtain title compound 10-1 (12mg, 53.0%) and title compound 10-2 (10mg, 45.2%).

[0593] Compounds with shorter retention times:

[0594] MS m / z(ESI): 589.2 [M+1].

[0595] 1H NMR(500MHz,DMSO)δ8.50(s,1H),7.82(d,1H),7.64(dd,1H),7.58(ddd,1H),7.39(td,1H),7.27(t,1H),4.53-4.40(m,1H),4.19(d,1H), 3.71(s,3H),3.70(d,1H),3.56-3.49(m,5H),3.42(t,2H),3.38(t,2H),3.09-2.97(m,1H),2.49-2.42(m,2H),2.20(dd,1H),1.84(s,3H).

[0596] Compounds with longer retention times:

[0597] MS m / z(ESI): 589.2 [M+1].

[0598] 1 H NMR(500MHz,DMSO)δ8.50(s,1H),7.82(d,1H),7.64(dd,1H),7.58(ddd,1H),7.39(td,1H),7.27(t,1H),4.53-4.40( m,1H),4.19(d,1H),3.71(s,3H),3.70(d,1H),3.62-3.42(m,7H),3.27-3.13(m,3H),2.41-2.14(m,3H),1.84(s,3H).

[0599] Example 11

[0600] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-[[(1s,3S)-3-(4-hydroxypiperidin-1-carbonyl)-3-methylcyclobutyl]amino]-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 11-1

[0601] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-[[(1r,3R)-3-(4-hydroxypiperidin-1-carbonyl)-3-methylcyclobutyl]amino]-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 11-2

[0602]

[0603] Referring to Example 2, the raw material tetrahydropyrrole in step 5 was replaced with 4-hydroxypiperidine (Shaoyuan) to obtain title compound 11-1 (10 mg, 17.3%) and title compound 11-2 (20 mg, 34.6%).

[0604] Compounds with shorter retention times:

[0605] MS m / z(ESI): 617.3 [M+1].

[0606] 1 H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,1H),7.67(t,1H),7.59(t,1H),7.40(d,1H),7.29(d,1H),4.69-4.54(m,1H),4.28-4.17(m,1H),3.61 -3.41(m,1H),3.40-3.35(m,5H),3.30-3.15(m,3H),3.07-2.78(m,1H) ,2.49-2.38(m,3H),2.23(d,2H),1.92-1.66(m,5H),0.66-0.47(m,4H).

[0607] Compounds with longer retention times:

[0608] MS m / z(ESI): 617.3 [M+1].

[0609] 1 H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,1H),7.67(t,1H),7.59(t,1H),7.40(d,1H),7.29(d,1H),4.69-4.54(m,1H),4.21(d,1H),3.72(s,3H) ,3.70(d,1H),3.47(q,2H),3.23(d,2H),3.19-3.01(m,2H),2.49-2.41( m,2H),2.38-2.16(m,2H),1.85(s,3H),1.77(dt,2H),0.62-0.50(m,4H).

[0610] Example 12

[0611] (R)-4-(3-chloro-2-fluorophenyl)-6-(((1s,3S)-3-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylcyclobutyl)amino)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 12-1

[0612] (R)-4-(3-chloro-2-fluorophenyl)-6-(((1r,3R)-3-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylcyclobutyl)amino)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 12-1

[0613]

[0614] Referring to Example 2, the raw material tetrahydropyrrole in step 5 was replaced with 3,3-difluoropyrrole (Shaoyuan) to obtain title compound 12-1 (10 mg, 16.5%) and title compound 12-2 (15 mg, 24.7%).

[0615] Compounds with shorter retention times:

[0616] MS m / z(ESI): 623.2 [M+1].

[0617] 1 H NMR(500MHz,DMSO)δ8.51(s,1H),7.83(d,1H),7.59(t,1H),7.55(d,1H),7.39(t,1H),7.27(t,H),4.5 9(t,1H),4.19(d,1H),3.83-3.65(m,7H),3.55(dt,2H),2.49-2.24(m,5H),1.84(s,3H),1.38(d,3H).

[0618] Compounds with longer retention times:

[0619] MS m / z(ESI): 623.2 [M+1].

[0620] 1 H NMR(500MHz,DMSO)δ8.49(s,1H),7.83(d,1H),7.67(d,1H),7.59(s,1H),7.41(t,1H),7.28(t,1H),4.33-4.25(m,2 H),4.21(d,1H),3.88-3.67(m,5H),3.65-3.56(m,2H),3.01-2.81(m,2H),2.02(ddd,3H),1.85(s,4H),1.36(d,3H).

[0621] Example 13

[0622] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 13-1

[0623] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 13-2

[0624]

[0625]

[0626] first step

[0627] ((3,3-Dimethoxycyclobutanediyl)(methoxy)methoxy)trimethylsilane 13b

[0628] Compound 13a (25 g, 0.14 mol) was dissolved in dry tetrahydrofuran (150 mL). Diisopropylaminolithium (LDA) (0.079 L, 2 M in THF) was added dropwise under a dry ice-ethanol bath. After stirring for 30 minutes, trimethylchlorosilane (27 g, 0.25 mol) was added. The mixture was slowly heated to room temperature and stirred overnight. The mixture was concentrated under reduced pressure at low temperature. Hexane (100 mL) was added and stirred to form a suspension. The suspension was poured into ice water (200 mL) and extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated to obtain the title compound 13b (26 g, crude product). The product was used directly in the next step without purification.

[0629] Step 2

[0630] 3,3-Dimethoxy-1-(trifluoromethyl)cyclobutane-1-carboxylic acid methyl ester 13c

[0631] Compound 13b (26 g, crude product) was dissolved in dry dichloromethane (800 mL). N-trimethylsilyl-bis(trifluoromethanesulfonic acid)imide (0.40 g, 1.13 mmol) was added under ice-water bath. After stirring for 5 minutes, 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodoxapentane (25 g, 0.076 mol) was added. The mixture was slowly heated to room temperature and stirred overnight. The solution was quenched with saturated sodium bicarbonate aqueous solution (200 mL), and extracted with dichloromethane (150 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography using eluent system B to give the title compound 13c (5.10 g, 19.9%).

[0632] Step 3

[0633] 3,3-Dimethoxy-1-(trifluoromethyl)cyclobutane-1-carboxylic acid 13d

[0634] Compound 13c (280 mg, 1.16 mmol) and lithium hydroxide monohydrate (50 mg, 1.16 mmol) were dissolved in tetrahydrofuran (10 mL) and water (3 mL). The mixture was stirred at room temperature for 1.5 hours. The pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated to give compound 13d (263 mg, crude product), which was used directly in the next step without purification.

[0635] MS m / z(ESI):228.3[M+1].

[0636] Step 4

[0637] (3,3-Dimethoxy-1-(trifluoromethyl)cyclobutyl)(pyrrolidin-1-yl)methyl ketone 13e

[0638] Compound 13d (260 mg, crude product) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of tetrahydropyrrole (120 mg, 1.69 mmol), diisopropylethylamine (450 mg, 3.48 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (650 mg, 1.71 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give the title compound 13e (120 mg, 37.4%).

[0639] 1H NMR (500MHz, CDCl3) δ3.58(t,2H),3.46-3.41(m,2H),3.19(s,3H),3.15(s,3H),2.85(d,2H),2.71-2.66(m,2H),1.94-1.85(m,4H).

[0640] Step 5

[0641] (3,3-Dimethoxy-1-(trifluoromethyl)cyclobutyl)(pyrrolid-1-yl)methyl ketone 13f

[0642] Compound 13e (330 mg, 1.17 mmol) was dissolved in acetone (5 mL) and 6N hydrochloric acid (3 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain compound 13f (220 mg, crude product). The product was used directly in the next step without purification.

[0643] Step 6

[0644] 3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobut-1-one 13g

[0645] Compound 13f (450 mg, crude product) was dissolved in water (10 mL) and ethanol (10 mL), followed by the addition of hydroxylamine hydrochloride (270 mg, 3.89 mmol) and sodium carbonate (610 mg, 5.76 mmol). The reaction mixture was heated to 100 °C and stirred for 2 hours. After concentration, the mixture was dissolved in dichloromethane (10 mL), and the solid was filtered off. The filtrate was concentrated, and ammonia-methanol solution (10 mL) and Raney nickel (50 mg, 0.85 mmol) were added. Hydrogen was purged three times, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The solid was filtered off, and the remaining reaction mixture was directly concentrated. The residue was purified by column chromatography using eluent system B to give the title compound 13 g (120 mg, 28.2%). MS m / z (ESI): 237.2 [M+1].

[0646] Step 7

[0647] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl-4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)nicotinate 13h

[0648] Compound 1e (200 mg, 0.38 mmol) was cooled to 0 °C, and m-chloroperoxybenzoic acid (98 mg, 0.46 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid crude product (200 mg). The crude product (150 mg) and compound 13 g (102 mg, 0.43 mmol) were dissolved in dimethyl sulfoxide (3 mL), and diisopropylethylamine (112 mg, 0.87 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 13h (95 mg, yield 47.7%, a pair of diastereomers).

[0649] MS m / z(ESI): 695.2 [M+1].

[0650] Step 8

[0651] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-4-methyl-6-((3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 13i

[0652] Compound 13h (95 mg, 0.14 mmol) was dissolved in a dry mixture of tetrahydrofuran (2 mL) and methanol (2 mL), Raney nickel (3 mg, 0.051 mmol) and glacial acetic acid (10 mg, 0.17 mmol) were added, hydrogen was purged three times, and the mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The solid was filtered off, and the remaining reaction solution was directly concentrated to give the title compound 13i (42 mg, 56.6%, a pair of diastereomers).

[0653] MS m / z(ESI): 543.2 [M+1].

[0654] Step 9

[0655] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1s,3S)-3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 13-1

[0656] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-4-methyl-6-(((1r,3R)-3-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 13-2

[0657] Compound 13i (60 mg, 0.11 mmol), 3-bromo-4-fluoro-1-methylpyrazole (40 mg, 0.22 mmol), potassium phosphate (70 mg, 0.33 mmol), cuprous iodide (41 mg, 0.22 mmol), and N,N'-dimethylethylenediamine (30 mg, 0.34 mmol) were dispersed in xylene (5 mL), purged with nitrogen, and microwaved to 130 °C. The mixture was stirred for 3 hours, cooled, and concentrated. The concentrate was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate, acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give the title compound (2 mg, 4.2%) and (3 mg, 6.4%).

[0658] Compounds with shorter retention times:

[0659] MS m / z(ESI): 641.2 [M+1].

[0660] Compounds with longer retention times:

[0661] MS m / z(ESI): 641.2 [M+1].

[0662] 1 H NMR(500MHz,MeOD)δ8.61(s,1H),7.59(d,1H),7.52-7.45(m,1H),7.38-7.31(m,1H),7.21(t,1H),4.45(t,1H), 4.36(d,1H),3.79(s,3H),3.71(d,1H),3.60-3.51(m,5H),3.26-3.13(m,2H),2.60(ddd,2H),1.99-1.90(m,6H).

[0663] Example 14

[0664] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1s,3S)-3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 14-1

[0665] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1r,3R)-3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 14-2

[0666]

[0667] first step

[0668] (3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)carbamate tert-butyl ester 14b

[0669] Compound 14a (101 mg, 0.44 mmol, Leyan) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of tetrahydropyrrole (58 mg, 0.82 mmol), diisopropylethylamine (175 mg, 1.35 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (188 mg, 0.49 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to obtain title compound 14b (95 mg, 76.5%).

[0670] MS m / z(ESI):285.2[M+1].

[0671] Step 2

[0672] (3-amino-1-hydroxycyclobutyl)(pyrrolid-1-yl)methyl ketone 14c

[0673] Compound 14c (92 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL) and 4N dioxane hydrochloride (3 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain compound 14c (71 mg, crude product). The product was used directly in the next step without purification.

[0674] Step 3

[0675] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl-4-((R)-1-(3-chloro-2-fluorophenyl)-1-cyanoethyl)-5-fluoro-6-((3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)nicotinate 14d

[0676] Compound 1e (200 mg, 0.38 mmol) was cooled to 0 °C, and m-chloroperoxybenzoic acid (98 mg, 0.46 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 10 hours. The reaction was quenched by adding saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) in sequence. The organic phase was washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid crude product (200 mg). The crude product (168 mg) and compound 14c (71 mg, 0.32 mmol) were dissolved in dimethyl sulfoxide (3 mL), and diisopropylethylamine (112 mg, 0.87 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 14d (124 mg, yield 59.9%, a pair of diastereomers).

[0677] MS m / z(ESI):463.3[M+1].

[0678] Step 4

[0679] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-6-((3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 14e

[0680] Compound 14d (124 mg, 0.19 mmol) was dissolved in a dry mixture of tetrahydrofuran (5 mL) and methanol (5 mL), Raney nickel (130 mg, 2.21 mmol) and glacial acetic acid (120 mg, 1.99 mmol) were added, hydrogen was purged three times, and the mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The solid was filtered off, and the remaining reaction solution was directly concentrated to give the title compound 14e (70 mg, 74.0%, a pair of diastereomers).

[0681] MS m / z(ESI):491.2[M+1].

[0682] Step 5

[0683] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1s,3S)-3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 14-1

[0684] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1r,3R)-3-hydroxy-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 14-2

[0685] Compound 14e (70 mg, 0.14 mmol), 3-bromo-4-fluoro-1-methylpyrazole (53 mg, 0.30 mmol), potassium phosphate (96 mg, 0.45 mmol), cuprous iodide (42 mg, 0.22 mmol), and N,N'-dimethylethylenediamine (41 mg, 0.47 mmol) were dispersed in xylene (3 mL), purged with nitrogen, and microwaved to 130 °C. The mixture was stirred for 3 hours, cooled, and concentrated. The concentrate was purified by high-performance liquid chromatography (HPLC) (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate, acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give the title compound (10 mg, 11.9%) and (15 mg, 17.9%). Compounds with shorter retention times:

[0686] MS m / z(ESI): 589.2 [M+1].

[0687] 1 H NMR(500MHz,DMSO)δ8.51(s,1H),7.82(d,1H),7.58(d,2H),7.39(t,1H),7.27(t,1H),5.83(s,1H),4.72 (q,1H),4.19(d,1H),3.72(s,5H),3.48(t,2H),3.31-3.23(m,2H),2.47-2.31(m,3H),1.94-1.70(m,7H).

[0688] Compounds with longer retention times:

[0689] MS m / z(ESI): 589.2 [M+1].

[0690] 1H NMR(500MHz,DMSO)δ8.49(s,1H),7.82(d,1H),7.69-7.55(m,2H),7.40(t,1H),7.28(t,1H),5.87(s,1H),4.20(d,1 H),4.03(q,1H),3.80-3.63(m,4H),3.52(t,2H),3.35-3.33(m,2H),2.93(q,2H),2.13(dt,2H),1.89-1.71(m,7H).

[0691] Example 15

[0692] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1s,3S)-3-fluoro-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 15-1

[0693] (R)-4-(3-chloro-2-fluorophenyl)-5-fluoro-2-(4-fluoro-1-methyl-1H-pyrazol-3-yl)-6-(((1r,3R)-3-fluoro-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-4-methyl-3,4-dihydro-2,7-naphthidium-1(2H)-one 15-2

[0694]

[0695] Compound 14e (60 mg, 0.10 mmol) was dispersed in dichloromethane (10 mL), purged with nitrogen, and diethylaminotrifluoride (50 mg, 0.31 mmol) was added dropwise under an ice-water bath. The reaction was stirred continuously for 3 hours, quenched with saturated sodium bicarbonate aqueous solution (5 mL), and extracted with dichloromethane (5 mL × 3). The organic phases were combined, and the concentrate was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give the title compound (3 mg, 5.0%, a mixture of two diastereomers).

[0696] MS m / z(ESI): 591.2 [M+1].

[0697] 1H NMR(500MHz,CD3OD)δ8.63(s,1H),7.59(d,1H),7.48(t,1H),7.35(t,1H),7.21(t,1H),4.36(d,1H),3.79(s,3H),3.70(d,1H),3.6 5-3.57(m,2H),3.52-3.44(m,3H),2.97-2.66(m,2H),2.25-2.16(m,1H),2.07-2.03(m,2H),2.01-1.93(m,4H),1.92-1.83(m,2H).

[0698] Example 16

[0699] (R)-4-(3-chloro-2-fluoro-4-methylphenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 16-1

[0700] (R)-4-(3-chloro-2-fluoro-4-methylphenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 16-2

[0701]

[0702] first step

[0703] 4-[(3-chloro-2-fluoro-4-methylphenyl)(cyano)methyl]-5-fluoro-6-(methylthio)nicotinic acid ethyl ester 16b

[0704] Compound 16a (155 mg, 0.84 mmol, WuXi AppTec) was dissolved in dry toluene (5 mL), and NaHMDS (0.52 mL, 2 M in THF) was added dropwise under an ice-water bath. After stirring continuously for 30 minutes, 6b (230 mg, 0.92 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched by adding water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography with eluent system B to give the title compound 16b (100 mg, 29.9%).

[0705] MS m / z(ESI): 397.0 [M+1].

[0706] Step 2

[0707] 4-[1-(3-chloro-2-fluoro-4-methylphenyl)-1-cyanoethyl]-5-fluoro-6-(methylthio)nicotinic acid ethyl ester 16c

[0708] Compound 16b (190 mg, 0.48 mmol) was dissolved in dry tetrahydrofuran (5 mL), and sodium bis(trimethylsilyl)amino (NaHMDS) (0.095 mL, 2 M in THF) was added dropwise under an ice-water bath. After stirring for 30 minutes, iodomethane (210 mg, 1.48 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and purified by column chromatography with eluent system B to give the title compound 16c (165 mg, 83.9%).

[0709] MS m / z(ESI):411.3[M+1].

[0710] Step 3

[0711] 4-[1-(3-chloro-2-fluoro-4-methylphenyl)-1-cyanoethyl]-5-fluoro-6-(methylsulfinyl)nicotinic acid ethyl ester 16d

[0712] 16c (165 mg, 0.40 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 °C, and m-chloroperoxybenzoic acid (88 mg, 0.43 mmol, 85% wt) was added in portions. The mixture was then brought to room temperature and stirred for 1 hour. The reaction was quenched by adding saturated sodium thiosulfate solution (2 mL) and saturated sodium bicarbonate solution (2 mL) sequentially. The organic phase was washed sequentially with saturated sodium bicarbonate solution (2 mL) and saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give solid crude product 16d (170 mg). This was used directly in the next step.

[0713] MS m / z(ESI):427.0[M+1].

[0714] Step 4

[0715] 4-[1-(3-chloro-2-fluoro-4-methylphenyl)-1-cyanoethyl]-5-fluoro-6-[(3-methoxycarbonyl-3-methylcyclobutyl)amino] ethyl nicotinate 16e

[0716] The crude product 16d (1700 mg) and methyl 3-amino-1-methylcyclobutane-1-carboxylic acid (110 mg, 0.77 mmol) were dissolved in dimethyl sulfoxide (5 mL), and diisopropylethylamine (155 mg, 1.20 mmol) was added. The mixture was heated to 80 °C and stirred for 8 hours. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, concentrated, and purified by column chromatography with eluent system B to give the title compound 16e (130 mg, yield 64.5%, a mixture of two diastereomers).

[0717] MS m / z(ESI): 506.4 [M+1].

[0718] Step 5

[0719] (R)-3-[(5-(3-chloro-2-fluoro-4-methylphenyl)-4-fluoro-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino]-1-methylcyclobutane-1-carboxylic acid methyl ester 16f

[0720] Compound 16e (130 mg, 0.26 mmol) was dissolved in a dry mixture of tetrahydrofuran (8 mL) and methanol (8 mL), Raney nickel (15 mg, 0.26 mmol) and glacial acetic acid (45 mg, 0.75 mmol) were added, and hydrogen was purged three times. The mixture was heated to 50 °C and stirred for 8 hours under a hydrogen atmosphere. The solid was filtered off, and the remaining reaction solution was directly concentrated to give the title compound 16f (75 mg, 62.9%, a mixture of two diastereomers).

[0721] MS m / z(ESI):464.2[M+1].

[0722] Step 6

[0723] (R)-3-[(5-(3-chloro-2-fluoro-4-methylphenyl)-4-fluoro-7-(3-fluoropyridin-2-yl)-5-methyl-8-oxo-5,6,7,8-tetrahydro-2,7-naphthidin-3-yl)amino]-1-methylcyclobutane-1-carboxylic acid methyl ester 16g

[0724] Compound 16f (35 mg, 0.075 mmol), 2-bromo-3-fluoropyridine (30 mg, 0.17 mmol, Acon Biotech), potassium phosphate (48 mg, 0.23 mmol), cuprous iodide (15 mg, 0.079 mmol), and N,N'-dimethylethylenediamine (7 mg, 0.079 mmol) were dispersed in xylene (5 mL), purged with nitrogen, microwaved to 130 °C, stirred for 5 hours, cooled and concentrated. The concentrate was purified by column chromatography using eluent system B to obtain the title compound 16 g (12 mg, 21.5%, a pair of diastereomers).

[0725] MS m / z(ESI): 559.3 [M+1].

[0726] Step 7

[0727] (R)-4-(3-chloro-2-fluoro-4-methylphenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-((3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 16h

[0728] 16 g (40 mg, 0.071 mmol) of the compound and lithium hydroxide monohydrate (3 mg, 0.072 mmol) were dissolved in methanol (2 mL). The mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water (2 mL). The pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined and concentrated to obtain crude product 16 h (39 mg). The crude product was used directly in the next step without purification.

[0729] MS m / z(ESI): 545.3 [M+1].

[0730] Step 8

[0731] (R)-4-(3-chloro-2-fluoro-4-methylphenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1s,3S)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 16-1

[0732] (R)-4-(3-chloro-2-fluoro-4-methylphenyl)-5-fluoro-2-(3-fluoropyridin-2-yl)-4-methyl-6-(((1r,3R)-3-methyl-3-(pyrrolidine-1-carbonyl)cyclobutyl)amino)-3,4-dihydro-2,7-naphthidium-1(2H)-one 16-2

[0733] Compound 16h (38 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of tetrahydropyrrole (15 mg, 0.21 mmol), diisopropylethylamine (27 mg, 0.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (40 mg, 0.10 mmol, Shaoyuan). The mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high performance liquid chromatography (Waters 2545, column: BostonPhlex ODS C18; Prep 150*30 mm, 5 μm; mobile phase: water 0.1% ammonium bicarbonate), acetonitrile; flow rate: 30 mL / min, 27 min gradient: 40%-95%) to give title compound 16-1 (20 mg, 49.1%) and title compound 16-2 (20 mg, 49.1%).

[0734] Compounds with shorter retention times:

[0735] MS m / z(ESI): 598.2 [M+1].

[0736] 1 H NMR(500MHz,DMSO)δ8.52(s,1H),8.31(d,1H),7.81(ddd,1H),7.68(d,1H),7.43(dt,1H),7.35(t,1H),7.26(d,1H),4.34(d,1H),4.29-4 .19(m,1H),3.78(d,1H),2.96-2.84(m,2H),2.37(s,3H),2.01(dd,2H),1.95(dd,1H),1.88-1.81(m,8H),1.81-1.72(m,2H),1.35(s,3H).

[0737] Compounds with longer retention times:

[0738] MS m / z(ESI): 598.2 [M+1].

[0739] 1H NMR(500MHz,DMSO)δ8.55(s,1H),8.31(d,1H),7.81(ddd,1H),7.55(d,1H),7.43(dt,1H),7.33(t,1H),7.25(d,1H),4.57(h,1H),4.32(d,1H) ,3.78(d,1H),3.31-3.26(m,2H),2.44-2.33(m,7H),2.29-2.21(m,2H) ,2.06-1.94(m,2H),1.87-1.81(m,3H),1.79-1.70(m,2H),1.36(s,3H).

[0740] Biological evaluation

[0741] Test Example 1: The agonistic effect of the disclosed compound on AMPK (A2 / B2 / G3) enzyme activity.

[0742] This experiment used the STK-S1 (Revvity, 62ST1PEC) kit (including experimental buffer, S1-Biotin, STK-Eu). 3+ Antibodies, detection buffers, streptavidin-XL665, etc. were used to evaluate the activation effect of compounds on the activity of recombinant human AMPK (A2 / B2 / G3) heterotrimeric protease by detecting phosphorylation of STK substrate S1.

[0743] I. Experimental Procedure

[0744] Experimental buffer: Dilute the 5× buffer in the kit to 1×, then add 5mM MgCl2 and 1mM DTT (Sigma, D0632) to a final concentration.

[0745] The test compounds were dissolved in DMSO (20 mM stock solution). The initial concentration was set at 2 mM, and then serially diluted 3-fold with DMSO to well 11. DMSO was added only to well 12. Compound AMP (MCE, HY-A0181) was diluted to 6 mM. The diluted compounds were then diluted 50-fold with experimental buffer and mixed thoroughly. 2.5 μL was added to each well of a 384-well plate, with each sample prepared in duplicate.

[0746] The enzyme AMPK A2 / B2 / G3 (SignalChem, P46-10GH) was diluted to 0.7 nM using experimental buffer. 3.5 μL was added to each well. The compounds and enzyme were incubated in a biochemical incubator at 25 °C for 10 min. The substrate S1-biotin was diluted to 5 μM using experimental buffer, and 2 μL was added to each well. ATP (Sigma, A7699) was diluted to 150 μM using experimental buffer, and 2 μL was added to each well. All were incubated at 25 °C for a total of 90 min.

[0747] STK-Eu 3+ Antibody was prepared into a 1× working solution using detection buffer, and 5 μL was added to each well. Streptavidin-XL665 was prepared into a 1 μM working solution using detection buffer, and 5 μL was added to each well. The mixture was incubated at 25 °C for 60 min. After the reaction, the HTRF signal value was read using a microplate reader.

[0748] Data processing: Using the activation effect of 30 μM AMP as a 100% reference, the relative maximum activation effect (Relative Emax%) of each compound on the enzyme was calculated; the agonist-effect four-parameter equation curve was fitted using GraphPad Prism 10 software, and the EC50 was calculated. 50 Values ​​are shown in Table 1.

[0749] Table 1. Agonistative effects of the disclosed compounds on AMPK (A2 / B2 / G3) enzyme activity

[0750] Example number <![CDATA[EC 50 (nM)]]> 1 1～40 Compounds with a retention time of 20.52 min were prepared in 2-1 and 2-2. 4.2 Compounds with a retention time of 16.17 min were prepared in 3-1 and 3-2. 3.1

[0751] Conclusion: The disclosed compound has a strong activating effect on the enzyme activity of recombinant human AMPK (A2 / B2 / G3) heterotrimeric protein.

[0752] Test Example 2: The agonistic effect of the disclosed compound on AMPK (A2 / B2 / G2) enzyme activity

[0753] This experiment used the STK-S1 (Revvity, 62ST1PEC) kit to evaluate the activation effect of compounds on the activity of recombinant human AMPK (A2 / B2 / G2) heterotrimeric protease by detecting phosphorylation of STK substrate S1, and to determine whether the compounds are selective for AMPK (A2 / B2 / G2).

[0754] II. Experimental Procedure

[0755] Experimental buffer: Dilute the 5× buffer in the kit to 1×, then add 5mM MgCl2 and 1mM DTT to a final concentration.

[0756] The test compounds were dissolved in DMSO (20 mM stock solution). The initial concentration was set at 20 mM, and DMSO was used for 3-fold serial dilutions up to well 11. DMSO was added only to well 12. Compound AMP (MCE, HY-A0181) was diluted to 6 mM. The diluted compounds were then diluted 50-fold with experimental buffer and mixed thoroughly. 2.5 μL was added to each well of a 384-well plate, and each sample was prepared in duplicate.

[0757] The enzyme AMPK A2 / B2 / G2 (SignalChem, P54-10GH) was diluted to 0.115 nM using experimental buffer. 3.5 μL was added to each well. The compounds and enzyme were incubated in a biochemical incubator at 25 °C for 10 min. The substrate S1-biotin was diluted to 5 μM using experimental buffer, and 2 μL was added to each well. ATP (Sigma, A7699) was diluted to 75 μM using experimental buffer, and 2 μL was added to each well. All were incubated at 25 °C for a total of 90 min.

[0758] STK-Eu 3+ Antibody was prepared into a 1× working solution using detection buffer, and 5 μL was added to each well. Streptavidin-XL665 was prepared into a 1 μM working solution using detection buffer, and 5 μL was added to each well. The mixture was incubated at 25 °C for 60 min. After the reaction, the HTRF signal value was read using a microplate reader.

[0759] Data processing: Using the activation effect of 30 μM AMP as a 100% reference, the relative maximum activation effect (Relative Emax%) of each compound on the enzyme was calculated; the agonist-effect four-parameter equation curve was fitted using GraphPad Prism 10 software, and the EC50 was calculated. 50 value.

[0760] Conclusion: The disclosed compound has no activating effect on the enzymatic activity of recombinant human AMPK (A2 / B2 / G2) heterotrimeric protein and exhibits very good selectivity.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: X 1 For N or CR 4a ; X 2 For N or CR 4b ; X 3 For N or CR 4 ; Ring A is selected from cycloalkyl, polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups; The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 4a R 4b and R 4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced; R 2 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, OR 14 C(O)R 14 Carboxyl, cyano, nitro, amino, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced; Each R 1 R 3 and R 5 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13 alkylene-C(O)R 14 alkylene-C(O)NR 11 R 12 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 02 Replaced; Each R 01 and R 02 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OC(O)OR 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced; Each R', R 11 R 12 R 13 and R 14 The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22 S(O) v R 22 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced; R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; Each R * The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 alkylene NR 20 R 21 alkylene C(O)NR 20 R 21 C(O)R 22 C(O)OR 22 OR 22 Nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, and heteroarylalkyl; Each R 20 R 21 and R 22 The same or different, and each independently selected from hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl are each independently optionally substituted by one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic and cycloalkyl; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each v is the same or different, and each is independently 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, R 3a R 3b R 3c R 3d and R 3e They may be the same or different, and each is independently a hydrogen atom or R. 3 ; R 2 Selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, alkenyl groups, alkynyl groups, hydroxyl groups, hydroxyalkyl groups, carboxyl groups, cyano groups, nitro groups, amino groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkylene groups, and heterocyclicalkylene groups; Ring A, Ring C, X 1 X 2 R 1 m, R 3 R 4 R 5 p as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 12-membered cycloalkyl group or a 7- to 12-membered spiroheterocyclic group, a fused heterocyclic group, or a bridged heterocyclic group; preferably, ring A is selected from...

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and / or each R 1 They may be the same or different, and each is independently selected from halogens and C. 1-6 Alkyl group, and / or m is 1, 2 or 3; and / or R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or each R 3 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 Halogenated alkyl and C 1-6 Haloalkoxy; and / or R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, and / or R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or each R 5 They may be the same or different, and each is independently selected from the oxo group and C. 1-6 Alkyl and C(O)R 14 Preferably, the ring C is phenyl or a 5- or 6-membered heteroaryl group; and / or R 2 C 1-6 Alkyl groups; and / or each R 3 They may be the same or different, and each is independently a halogen; and / or R 4 For hydrogen atoms, and / or R 4b It is a halogen; more preferably, the ring C is a pyrazolyl group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

6. A compound of general formula (IA) or a salt thereof: in, Rings A and R 5 p, R', X 1 To X 3 , ring D, R 2 R 3 and n as defined in claim 1.

7. A compound or a salt thereof, selected from the following compounds:

8. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for activating AMPKγ3 activity.

10. Use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 8 in the preparation of a medicament for the treatment and / or prevention of cardiovascular disease or diseases related to skeletal muscle dysfunction and exercise intolerance; preferably in the preparation of a medicament for the treatment and / or prevention of heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association class I-IV symptoms, heart failure with reduced left ventricular function, heart failure with preserved left ventricular function, heart failure with moderate ejection fraction, cardiovascular death, heart failure in patients with type II diabetes, coronary artery disease, unstable angina, peripheral vascular disease, renal vascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, and altered cardiovascular risk; more preferably in the preparation of a medicament for the treatment and / or prevention of heart failure or peripheral artery disease.

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