Tetracyclic compound, and preparation method therefor and use thereof in medicine

Abstract

The present disclosure relates to a tetracyclic compound, and a preparation method therefor and a use thereof in medicine. Specifically, the present disclosure relates to a tetracyclic compound represented by general formula (I), and a preparation method therefor, a pharmaceutical composition comprising the tetracyclic compound, and a use thereof as a therapeutic agent, especially a use as a STAT6 inhibitor or degrader, and a use in the preparation of a drug for treating and / or preventing STAT6-mediated or -dependent diseases or disorders. Each group in general formula (I) is as defined in the description.

Description

A tetracyclic compound, its preparation method and its pharmaceutical application Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a tetracyclic compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the tetracyclic compound, and its use as a therapeutic agent, particularly as a STAT6 inhibitor or degrader, and in the preparation of medicaments for the treatment and / or prevention of STAT6-mediated or dependent diseases or conditions. Background Technology

[0002] Type II inflammatory diseases are immune diseases primarily mediated by Th2 cells and related cytokines such as IL-4, IL-5, and IL-13, and are major pathogenic mechanisms for diseases such as asthma and atopic dermatitis (AD). Asthma is the most common chronic inflammatory lung disease, with approximately 746.4 million adults worldwide and about 63.6 million in China in 2019 (Frost & Sullivan). Atopic dermatitis, also known as eczema, has become a major contributor to the global skin disease burden. The most common characteristics of AD are itching, lichenification, and dryness. In 2019, there were approximately 390 million AD patients worldwide and about 61.5 million in China.

[0003] STAT6 belongs to the STAT (signal transducers and activators of transcription) family of transcription factors. STAT6 is mainly activated by IL-4 and IL-13, and can affect more than 80% of IL-4-regulated Th2 differentiation gene expression (Immunity. 2010 Jun 25; 32(6):852-62). The activation process of STAT6 is as follows: the binding of IL-4 / IL-13 to its receptor promotes receptor dimerization, recruits and activates JAK kinase; JAK kinase phosphorylates the intracellular terminal of the receptor, and STAT6 binds to the phosphorylated receptor through the SH2 domain, and is then phosphorylated by JAK; the phosphorylated STAT6 protein molecule forms a homodimer, enters the nucleus and activates the transcription of the target gene as a transcription factor (Expert Rev Clin Immunol. 2017 May; 13(5):425-437). STAT6 plays an important role in type II inflammatory responses. In Th2 cells, it can upregulate the expression of related inflammatory factors such as IL-4, IL-5, IL-9, and IL-13; regulate the differentiation of macrophages into M2 cells, secrete keratin, and promote epithelial damage repair; promote the switching of B cell immunoglobulin types, upregulate the expression of IgE, which can bind to receptors on the surface of mast cells and basophils, inducing allergic reactions; and promote airway smooth muscle contraction and epithelial cell mucus secretion, and upregulate the expression of chemokines, further recruiting inflammatory cells (JAKSTAT.2013Oct 1;2(4):e25301). Human genetic studies have found that activating mutations of STAT6 can lead to early-onset, severe allergic diseases, mainly atopic dermatitis and asthma (J Exp Med.2023May 1;220(5):e20221755).

[0004] Currently, three companies—Kymera, Recludix, and Nurix—are developing novel STAT6 inhibitors. Kymera's KT-621 is a STAT6 degrader for the treatment of diseases such as Alzheimer's disease (AD), Asthma, and COPD, and is in Phase 1 clinical trials. Recludix's SH2 domain-binding inhibitor is currently in the discovery stage. Nurix's STAT6 degrader is in the discovery stage and is intended for the treatment of type 2 immune diseases. Summary of the Invention

[0005] This disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0006] in:

[0007] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0008] L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O);

[0009] R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0010] X 2 For N or CH;

[0011] Ring B is selected from 3 to 12 member monocyclic or bicyclic cycloalkyl, 3 to 12 member monocyclic or bicyclic heterocyclic, 6 to 12 member monocyclic or bicyclic aryl and 5 to 12 member monocyclic or bicyclic heteroaryl;

[0012] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0013] G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0014] Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic;

[0015] V 1 For N or C;

[0016] V 2 For N or CR w1 ;

[0017] T is either N or C;

[0018] Y 1 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ;

[0019] M is selected from the bond, (CR) m1 R m2 ) e O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0020] M 1 Selected from key, (CR) m1 Rm2 ) e1 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0021] M 2 Selected from key, (CR) m1 R m2 ) e2 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0022] e can be 0, 1, 2, 3, or 4;

[0023] e1 can be 0, 1, 2, 3 or 4;

[0024] e2 is 0, 1, 2, 3 or 4;

[0025] R w3 and R m Each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and -C(O)OR 3 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. 0 replace;

[0026] R w0 R w1 R w4 R w5 R m1 R m2 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2; the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace;

[0027] Or, two Rs x Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0028] Or, two Rs y Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0029] Or, two Rs 1 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0030] Or, two Rs 2 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0031] Or, R m1 and R m2Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 replace;

[0032] x, y, n, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0033] L x -(L A ) t1 -;

[0034] L is -(L) B ) t2 -;

[0035] L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0036] R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0037] t1 is selected from integers from 0 to 10;

[0038] t2 is selected from integers from 0 to 20;

[0039] R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0040] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0041] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0042] R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0043] R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with their respective attached atoms, they form cycloalkyl or heterocyclic groups; and

[0044] v can be 0, 1, or 2.

[0045] In some implementation schemes, rings A, B, X, Y, G, and R... a R b R x R y R w0 R w1 R w3 R w4 R w5 R m R m1 R m2 R 0 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 L A and L B The groups or substituents in the group are optionally replaced by one or more substituents.

[0046] In some embodiments, ring X is a 5- or 6-membered monocyclic heterocyclic group; in other embodiments, ring X is a saturated or partially unsaturated 6-membered heterocyclic group.

[0047] In some implementation schemes, Selected from It can be a single or double bond; the + terminator and the L terminator x Connected, * end and V 2 The rings are connected, and the ++ terminal is connected to M. 1 Connected.

[0048] In some implementation schemes, for +end and L x Connected, * end and V 2 The rings are connected, and the ++ terminal is connected to M. 1 Connected.

[0049] In some embodiments, ring B is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; in some embodiments, ring B is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring B is phenyl or pyridyl; in some embodiments, ring B is phenyl.

[0050] In some implementation schemes, for B 1 B 2 B 3 B 4 and B 5 One of them is a carbon atom bonded to L, and the other four are the same or different, and each is independently either N or C. 2 ;R 2 As defined in general formula (I); in some implementations, for B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;R 2 As defined in general formula (I); in some implementations, for n1 is 0, 1, 2, 3, or 4; R 2 As defined in general formula (I); the * terminal is connected to L.

[0051] In some implementation schemes, B 3 It is a carbon atom bonded to L; B 1 B 2 B 4 and B 5 Each is independently N or CR2 ;R 2 As defined in general formula (I); in some implementations, B 2 It is a carbon atom bonded to L; B 1 B 3 B 4 and B 5 Each is independently N or CR 2 ;R 2 As defined in general formula (I).

[0052] In some implementation schemes, B 1 B 2 B 4 and B 5 Each independently for CR 2 ;R 2 As defined in general formula (I); in some implementations, B 1 B 2 B 4 and B 5 For CH.

[0053] In some implementation schemes, Selected from b1, b2, b3, and b4 are each independently 0, 1, 2, 3, or 4; b5 is 0, 1, 2, 3, or 4; B 6 and B 7 Each is independently N or CH; n1 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2 or 3; n5 is 0, 1, 2 or 3; n6 is 0, 1 or 2; R 2 As defined in the context; the * terminal is connected to L.

[0054] In some implementation schemes, Selected from

[0055] In some implementation schemes, Selected from *End with L or Z 1 Connected.

[0056] In some implementations, b1 and b2 are each independently 0, 1, or 2; in some implementations, b1 and b2 are each independently 0 or 1; in some implementations, b1 and b2 are 0; in some implementations, b1 and b2 are 1; in some implementations, b1 is 1 and b2 is 0; in some implementations, b1 is 0 and b2 is 1.

[0057] In some implementations, b3 and b4 are each independently 0, 1, or 2; in some implementations, b3 and b4 are each independently 0 or 1; in some implementations, b3 and b4 are 0; in some implementations, b3 is 0 and b4 is 0; in some implementations, b3 and b4 are 1; in some implementations, b3 is 1 and b4 is 0; in some implementations, b3 is 0 and b4 is 1.

[0058] In some implementations, b5 is 1, 2, or 3; in some implementations, b5 is 1 or 2; in some implementations, b5 is 1.

[0059] In some implementation schemes, B 6 For CH; in some implementations, B 6 Let N be the number of elements in the array.

[0060] In some implementation schemes, B 7 For CH; in some implementations, B 7 Let N be the number of elements in the array.

[0061] In some implementation schemes, B 6 For CH; B 7 For CH; in some implementations, B 6 For CH; B 7 For N; in some implementations, B 6 For N; B 7 For CH.

[0062] In some implementation schemes, R w0 -C(O)R 4 R 5 ;R 4 and R 5 As defined in general formula (I); in some implementations, R w0 Selected from In some implementation schemes, R w0 for

[0063] In some embodiments, this disclosure provides a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof.

[0064] in,

[0065] It can be a single bond or a double bond;

[0066] Y 3 Selected from NR w3 O and S;

[0067] Y4 For N or CR w4 ;

[0068] B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;

[0069] G, L x R x x, M, M 1 M 2 V 2 R w3 R w4 R 2 R 4 R 5 L, ring A, R 1 m, L 1 and X 2 As defined in general formula (I).

[0070] In some embodiments, this disclosure provides a compound of general formula (II-1) or general formula (III-1) or a pharmaceutically acceptable salt thereof.

[0071] in,

[0072] n1 is 0, 1, 2, 3 or 4;

[0073] Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 L, ring A, R 1 m, L 1 and X 2 As defined in general formula (II) or general formula (III).

[0074] In some implementations, t2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, t2 is 0, 1, 2, or 3; in some implementations, t2 is 0, 1, or 2; in some implementations, t2 is 1, 2, or 3.

[0075] In some implementations, L is -(L B )t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group; the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group; the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group; the C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B The same or different, and each independently selected from C 1-6 Alkylene and 4- to 6-membered heterocyclic groups; t2 is 0, 1, 2, or 3; in some embodiments, L is selected from alkylene, CH2, CH2CH2, CH2CH2CH2, ... In some implementations, L is selected from the bond, CH2, CH2CH2, CH2CH2CH2, *The end is connected to ring A; in some embodiments, L is selected from the bond, CH2, CH2CH2, CH2CH2CH2, * The end is connected to ring A.

[0076] In some implementations, L is Z 1 Z 2 f, g, k, R z And t3 as defined in general formula (IV) or general formula (V); in some embodiments, L is selected from *The terminal is connected to ring A; in some implementations, L is selected from... * The end is connected to ring A.

[0077] In some implementation schemes, L is selected from * The terminal is connected to ring A. In some implementations, L is... * The terminal is connected to ring A. In some implementations, L is... * The end is connected to ring A.

[0078] In some implementation schemes, V 2 For CR w1 ;R w1 As defined in general formula (I); in some implementations, V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, V 2 For N or CF; in some implementations, V 2 For CF; in some implementations, V 2 Let N be the number of elements in the array.

[0079] In some embodiments, this disclosure provides a compound of formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof.

[0080] in,

[0081] n1 is 0, 1, 2, 3 or 4;

[0082] k is 0, 1, 2, 3, 4 or 5;

[0083] f is 0, 1, 2, or 3;

[0084] g can be 0, 1, 2, or 3;

[0085] t3 is 0, 1, 2, 3, 4, or 5;

[0086] Z 1 For N and CR z1 Z 2 For N or CR z2 ;

[0087] R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0088] R z The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), oxo, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R z Together with the attached atoms, they form a cycloalkyl or heterocyclic group; or, two R groups... z Connected to form bridging alkylene groups; and

[0089] G, L x R x x M, e1, e2, R w1 Y 3 Y 4 R 4 R 5 R 2 Ring A, R 1 m, L 1 and X 2 As defined in general formula (II) or general formula (III).

[0090] In some embodiments, this disclosure provides a compound of general formula (VI) or a pharmaceutically acceptable salt thereof.

[0091] in,

[0092] Z 1 For N and CR z1 Z 2 For N or CR z2 Z 3 For N and CR z3 Z 4 For N or CR z4 ;

[0093] R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0094] f, f1, g, and g1 are each independently 0, 1, 2, or 3; and

[0095] Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, ring A, R 1 m, L 1 and X 2 As defined in general formula (II-1) or general formula (III-1).

[0096] In some embodiments, ring A is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 5- to 20-membered heterocyclic groups. In some embodiments, ring A is selected from 6- to 9-membered aryl, 9-membered heteroaryl, and 13- to 19-membered heterocyclic groups.

[0097] In some embodiments, ring A is selected from phenyl, 6-membered heteroaryl, 5-membered heteroaryl-6-membered heteroaryl, 5-membered heteroaryl-phenyl, 5-membered heterocyclic-6-membered heteroaryl, 5-membered heterocyclic-phenyl and 16 to 20-membered tetracyclic; in some embodiments, ring A is phenyl or pyridyl.

[0098] In some embodiments, ring A is selected from phenyl, 9 or 10-membered bicyclic aryl, 9 or 10-membered bicyclic heteroaryl, 13 to 15-membered tricyclic heterocyclic group, and 16 to 20-membered tetracyclic heterocyclic group.

[0099] In some implementation schemes, Selected from the following structures: *Terminal and L, (CH2)t3 or Z 4 Connected;

[0100] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom bonded to L, and the other three are the same or different, and each is independently either N or C. 1 G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom bonded to L, and the other four are the same or different, and each is independently either N or C. 1 U is CH2 or C(O);

[0101] Q is selected from O, S, NR q and CR q1 R q2 ;

[0102] a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR 1 A4 represents N or CR 1 A5 represents N or CR. 1 A6 is N or CR 1 J is selected from bond, O, (CR) j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 1 Selected from bond, O, (CR) j1 R j2 ) p S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 2 Selected from bond, O, (CR) j1 R j2 ) q S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J3 and J 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R q1 R q2 R j1 R j2 and RA The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R j1 and R j2 Together with the adjacent atoms, they form a cycloalkyl or heterocyclic group; m4 is selected from 0, 1, 2, 3, or 4; R 1 As defined in general formula (I).

[0103] In some implementation schemes, Selected from the following structures: *Terminal and L, (CH2)t3 or Z 4 Connected;

[0104] Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom bonded to L, and the other three are the same or different, and each is independently either N or C. 1 G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom bonded to L, and the other four are the same or different, and each is independently either N or C. 1 U is CH2 or C(O);

[0105] Q is selected from O, S, NR q and CR q1 R q2 ;

[0106] R q Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups;

[0107] R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0108] a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR 1 A4 represents N or CR 1 A5 represents N or CR. 1 A6 is N or CR 1 J is selected from bond, O, (CR) j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 1 Selected from bond, O, (CR) j1 R j2 ) p S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 2 Selected from bond, O, (CR) j1 R j2 ) q S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R q1 R q2 R j1 R j2 and R A The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R j1 and R j2 Together with the adjacent atoms, they form a cycloalkyl or heterocyclic group; m4 is selected from 0, 1, 2, 3, or 4; R 1As defined in general formula (I).

[0109] In some implementation schemes, Selected from In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m5 is 0, 1, or 2; m6 is 0, 1, or 2; A1 is N or CH; A2 is N or CH; J is selected from bonds, O, (CR j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); u, p, and q are each independently 0, 1, 2, 3, or 4; p1 and q1 are each independently 0, 1, 2, 3, or 4; Q is selected from O, S, and NR. q and CR q1 R q2 J 3 and J 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 Rj2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; R A R j1 R j2 R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in general formula (I).

[0110] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m5 is 0, 1, or 2; A1 is N or CH; A2 is N or CH; J is selected from bonds, O, (CR j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NRJ and NR J C(O); u, p, and q are each independently 0, 1, 2, 3, or 4; Q is selected from O, S, and NR. q and CR q1 R q2 J 3 and J 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; R A R j1 R j2 R q1 and R q2The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in general formula (I).

[0111] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m5 is 0, 1, or 2; A1 is N or CH; A2 is N or CH; J is selected from CH2, O, S, and NH; p and q are each independently 0, 1, 2, 3, or 4; Q is selected from O, S, and NR. q and CR q1 R q2 ;R q Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R A R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R A1 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in general formula (I).

[0112] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0113] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected. In some implementation schemes, for *Terminal and L, (CH2)t3 or Z 4 Connected. In some implementation schemes, for *Terminal and L, (CH2)t3 or Z 4 Connected.

[0114] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0115] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m5 is 0, 1, or 2; m6 is 0, 1, or 2; A1 is N or CH; A2 is N or CH; J is selected from CH2, O, S, and NH; p and q are each independently 0, 1, 2, 3, or 4; p1 and q1 are each independently 0, 1, 2, 3, or 4; Q is selected from O, S, and NR. q and CR q1 R q2 ;R q Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; RA R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R A1 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in general formula (I). In some implementations, Selected from Among them, A1, A2, Q, R 1 ,m1,m2,m5,J,p,q,R A and R A1 As defined above; *terminal and L, (CH2)t3 or Z 4 Connected.

[0116] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0117] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0118] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0119] In some implementation schemes, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

[0120] In some implementation schemes, Q 1Q is a carbon atom bonded to L. 2 Q 3 and Q 4 Whether they are the same or different, and each is independently N or CR 1 Or, Q 2 Q is a carbon atom bonded to L. 1 Q 3 and Q 4 Whether they are the same or different, and each is independently N or CR 1 ;R 1 As defined in general formula (I).

[0121] In some implementations, G 3 G is a carbon atom bonded to L. 1 G 2 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 1 Or, G 2 Carbon atom bonded to L, G 1 G 3 G 4 and G 5 Whether they are the same or different, and each is independently N or CR 1 ;R 1 As defined in general formula (I).

[0122] In some implementation schemes, R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R q C 1-6 Alkyl; in some embodiments, R q It is a methyl group.

[0123] In some implementation schemes, R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R q1 and R q2 It can be a hydrogen atom or a methyl group; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R q1 and R q2 For hydrogen atoms; in some implementations, R q1 and R q2 For methyl; in some embodiments, R q1 and Rq2 Together with the attached carbon atom, they form a cyclopropyl group.

[0124] In some implementations, Q is NR q or CR q1 R q2 ;R q R q1 and R q2 As defined above; in some implementations, Q is NR. q or CR q1 R q2 ;R q Methyl; R q1 and R q2 It can be a hydrogen atom or a methyl group; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, Q is NR. q ;R q C 1-6 Alkyl; in some embodiments, Q is selected from N-methyl, C(methyl)2 and CH2; in some embodiments, Q is N-methyl.

[0125] In some implementation schemes, R A Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R A C 1-6 Alkyl; in some embodiments, R A It is a methyl group.

[0126] In some implementation schemes, R A1 The hydrogen atom is C 1-6 Alkyl; in some embodiments, R A1 C 1-6 Alkyl; in some embodiments, R A1 It is a methyl group.

[0127] In some implementation schemes, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups and =O; or, two R groups on the same carbon atom. 1 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy and =O; in some embodiments, R 1They 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 Alkoxy; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atom, oxo group, F and methoxy group; in some embodiments, R 1 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 1 It is a hydrogen atom.

[0128] In some implementations, two R 1 Connected to form a bridge C 1-3 Alkylene; in some embodiments, the two Rs 1 They connect to form a bridge CH2CH2.

[0129] In some implementations, m is 0, 1, 2, or 3; in some implementations, m is 0, 1, or 2; in some implementations, m is 2; and in some implementations, m is 3.

[0130] In some implementations, m1 is 0, 1, or 2; in other implementations, m1 is 0 or 1.

[0131] In some implementations, m2 is 0, 1, or 2; in some implementations, m2 is 0; in some implementations, m2 is 1; and in some implementations, m2 is 2.

[0132] In some implementations, m3 is 0, 1, or 2; in some implementations, m3 is 0 or 1; in some implementations, m3 is 1; in some implementations, m3 is 0.

[0133] In some implementations, m4 is 0, 1, or 2; in some implementations, m4 is 0 or 1; in some implementations, m4 is 0.

[0134] In some implementations, m5 is 0, 1, or 2; in some implementations, m5 is 0 or 1; in some implementations, m5 is 0; in some implementations, m5 is 2.

[0135] In some implementations, m6 is 0 or 1; in other implementations, m6 is 0.

[0136] In some implementations, J is CH2 or O; in other implementations, J is O.

[0137] In some implementation schemes, J 1 For key or (CR) j1 R j2 ) p ;R j1 Rj2 And p as defined above; in some implementations, J 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, J 1 Selected from the bond, CH2 and CH2CH2; in some embodiments, J 1 It is CH2.

[0138] In some implementation schemes, J 2 For key or (CR) j1 R j2 ) q ;R j1 R j2 And q as defined above; in some implementation schemes, J 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, J 2 Selected from the bond, CH2 and CH2CH2; in some embodiments, J 2 For key.

[0139] In some implementation schemes, J 3 Selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, J 3 It can be O or CH2.

[0140] In some implementation schemes, J 4 Selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, J 4 It can be O or CH2.

[0141] In some implementation schemes, J 3 For CH2, J 4 For CH2; in some implementations, J 3 For O, J 4 For CH2; in some implementations, J 3 For CH2, J 4 For O; in some implementations, J 3 For O, J 4 It is O.

[0142] In some implementations, a1 and a2 are each independently 0 or 1; in other implementations, a1 and a2 are 1.

[0143] In some implementation schemes, R J It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R J It is a hydrogen atom.

[0144] In some implementations, k1 is 1 or 2; in other implementations, k1 is 1.

[0145] In some implementations, k2 is 0, 1, or 2; in some implementations, k2 is 0 or 1; in some implementations, k2 is 0; and in some implementations, k2 is 1.

[0146] In some implementations, k3 is 0, 1, or 2; in some implementations, k3 is 0 or 1; in some implementations, k3 is 0; and in some implementations, k3 is 1.

[0147] In some implementations, k2 is 0 and k3 is 1; in some implementations, k2 is 1 and k3 is 0; in some implementations, k2 is 0 and k3 is 0.

[0148] In some implementations, A1 is N or CH; in other implementations, A1 is N.

[0149] In some implementations, A2 is N or CH; in other implementations, A2 is N.

[0150] In some implementations, A1 is N; A2 is N.

[0151] In some implementations, u is 0, 1, or 2; in other implementations, u is 1.

[0152] In some implementations, p and q are each independently 0, 1, or 2; in other implementations, p and q are each independently 0 or 1.

[0153] In some implementations, p is 1 and q is 0; in some implementations, p is 2 and q is 0; in some implementations, p is 1 and q is 1.

[0154] In some implementations, p1 and q1 are each independently 0, 1, 2, or 3; in some implementations, p1 and q1 are each independently 1, 2, or 3; in some implementations, p1 is 1 and q1 is 3; in some implementations, p1 is 3 and q1 is 1; in some implementations, p1 is 2 and q1 is 2; in some implementations, p1 is 1 and q1 is 2; in some implementations, p1 is 2 and q1 is 1; in some implementations, p1 is 1 and q1 is 1.

[0155] In some implementations, A3 is CR 1 ;R 1 As defined in the context; in some implementations, A3 is N or CH; in some implementations, A3 is CH.

[0156] In some implementations, A4 is CR1 ;R 1 As defined in the context; in some implementations, A4 is N or CH; in some implementations, A4 is CH.

[0157] In some implementations, A5 is CR 1 ;R 1 As defined in the context; in some implementations, A5 is N or CH; in some implementations, A5 is CH.

[0158] In some implementations, A6 is CR 1 ;R 1 As defined in the context; in some implementations, A6 is N or CH; in some implementations, A6 is CH.

[0159] In some implementation schemes, R a1 It is a hydrogen atom.

[0160] In some implementation schemes, R a2 It is a hydrogen atom.

[0161] In some implementation schemes, R j1 and R j2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl; in some embodiments, R j1 and R j2 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 j1 and R j2 It is a hydrogen atom.

[0162] In some implementation schemes, R w1 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 w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w1 For halogen; in some implementations, R w1 It is F.

[0163] In some embodiments, M is selected from O, CH2, and S; in some embodiments, M is O or S; in some embodiments, M is O or CH2; in some embodiments, M is O; in some embodiments, M is S.

[0164] In some implementation schemes, M 1 For key or (CR) m1 R m2 ) e1 e1, R m1 and R m2 As defined above; in some implementation schemes, M 1 For bond or (CH2) e1 e1 is as defined above; in some implementations, M 1 Selected from the bond, CH2, CH2CH2, CH2CH2CH2 and In some implementation schemes, M 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 1 Selected from CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 1 It is CH2.

[0165] In some implementation schemes, M 2 For key or (CR) m1 R m2 ) e2 e2, R m1 and R m2 As defined above; in some implementation schemes, M 2 For bond or (CH2) e2 e2 is as defined above; in some implementations, M 2 Selected from the bond, CH2, CH2CH2, CH2CH2CH2 and In some implementation schemes, M 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 2 Selected from bonds, CH2 and In some implementation schemes, M 2 For the bond or CH2; in some implementations, M 2 For key; in some implementations, M 2 It is CH2.

[0166] In some implementations, e is 0, 1, or 2; in other implementations, e is 1.

[0167] In some implementations, e1 is 0, 1, 2, or 3; in some implementations, e1 is 1, 2, or 3; in some implementations, e1 is 1 or 2; in some implementations, e1 is 1.

[0168] In some implementations, e2 is 0, 1, 2, or 3; in some implementations, e2 is 0 or 1; in some implementations, e2 is 0; and in some implementations, e2 is 1.

[0169] In some implementations, e1 is 0, 1, 2, or 3; e2 is 0 or 1; in some implementations, e1 is 1, 2, or 3; e2 is 0 or 1; in some implementations, e1 is 1; e2 is 1; in some implementations, e1 is 1; e2 is 0; in some implementations, e1 is 2; e2 is 0; in some implementations, e1 is 3; e2 is 0.

[0170] In some implementation schemes, R m1 and R m2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Haloalkyl; or, R on the same carbon atom m1 and R m2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R m1 and R m2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl; in some embodiments, R m1 and R m2 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 m1 and R m2 Each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group; or, R on the same carbon atom m1 and R m2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R m1 and R m2 It is a hydrogen atom, or R on the same carbon atom. m1 and R m2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R m1 and Rm2 It is a hydrogen atom.

[0171] In some implementation schemes, R m It is a hydrogen atom or an alkyl group (e.g., C). 1-6 Alkyl); in some embodiments, R m It is a hydrogen atom. In some implementations, Selected from CH2O, CH2CH2O, CH2CH2CH2O, CH2CH2, CH2OCH2, CH2CH2OCH2 and CH2CH2CH2OCH2.

[0172] In some implementation schemes, Selected from *End and V 2 Or R w1 The rings they belong to are connected.

[0173] In some implementation schemes, Selected from In some implementation schemes, for In some implementation schemes, for *End and V 2 or R w1 The rings they belong to are connected.

[0174] In some embodiments, M is O or CH2; and / or e1 is 0, 1, 2 or 3; and / or e2 is 0 or 1; in some embodiments, M is O or S; and / or e1 is 0, 1, 2 or 3; and / or e2 is 0 or 1; in some embodiments, M is O or S; and / or e1 is 1, 2 or 3; and / or e2 is 0 or 1; in some embodiments, M is O or S; and / or e1 is 1; and / or e2 is 1; in some embodiments, M is O; and / or e1 is 1, 2 or 3; and / or e2 is 0; in some embodiments, M is O; and / or e1 is 1; and / or e2 is 1.

[0175] In some implementations, M is 0; and / or e1 is 1; and / or e2 is 0 or 1; and / or R m1 and R m2 It is a hydrogen atom, or R on the same carbon atom. m1 and R m2 Together with the attached carbon atom, it forms a cyclopropyl group. In some embodiments, M is O; and / or e1 is 1; and / or e2 is 1; and / or Rm1 and R m2 It is a hydrogen atom.

[0176] In some implementation schemes, Y 3 Selected from O, S, and NH; in some embodiments, Y 3 It is NH or O; in some implementations, Y 3 It is NH.

[0177] In some implementation schemes, Y 4 For N or CH; in some implementations, Y 4 For CH.

[0178] In some implementation schemes, R w3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R w3 It is a hydrogen atom.

[0179] In some implementation schemes, R w3 -C(O)OR 3 ;R 3 C 1-6 Alkyl; in some embodiments, R w3 For Boc.

[0180] In some implementation schemes, R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w4 It is a hydrogen atom.

[0181] In some implementation schemes, R w5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w5 It is a hydrogen atom.

[0182] In some implementation schemes, R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; in some embodiments, R 4 and R 5 They may be the same or different, and each is independently selected from hydrogen, methyl, ethyl, propyl, and cyclopropyl; or, R 4 and R 5 Together with the attached nitrogen atom, it forms In some implementation schemes, R 4 and R 5 C 1-6Alkyl; in some embodiments, R 4 and R 5 It is a methyl group.

[0183] In some implementation schemes, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R 2 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 Alkoxy; in some embodiments, R 2 Each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkoxy; in some embodiments, R 2 It is a hydrogen atom or a halogen; in some implementations, R 2 Selected from hydrogen atoms, F, Cl, methoxy, and difluoromethoxy; in some embodiments, R 2 Selected from hydrogen, F, Cl, and methoxy groups; in some embodiments, R 2 It is a hydrogen atom.

[0184] In some implementations, n is 0, 1, or 2; in some implementations, n is 0 or 1; in some implementations, n is 0; in some implementations, n is 1 or 2; in some implementations, n is 1; in some implementations, n is 2.

[0185] In some implementations, n1 is 0, 1, or 2; in some implementations, n1 is 0 or 1; in some implementations, n1 is 0; in some implementations, n1 is 1 or 2; in some implementations, n1 is 1; in some implementations, n1 is 2.

[0186] In some implementations, n3 is 0, 1, or 2; in some implementations, n3 is 0 or 1; in some implementations, n3 is 0.

[0187] In some implementations, n5 is 0 or 1; in other implementations, n5 is 0.

[0188] In some implementations, n6 is 0 or 1; in other implementations, n6 is 0.

[0189] In some implementations, t1 is 0, 1, 2, 3, 4 or 5; in some implementations, t1 is 0, 1, 2 or 3; in some implementations, t1 is 0, 1 or 2; in some implementations, t1 is 1, 2 or 3.

[0190] In some implementations, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4, or 5; in some embodiments, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3; L A They are the same or different, and each is independently selected from C(O) and C. 1-6 Alkylene; t1 is 1, 2, or 3; in some embodiments, L x Selected from CH2, CH2CH2, *The terminal is connected to G or ring Y; in some implementations, L x Selected from CH2, CH2CH2, *The terminal is connected to G or ring Y; in some implementations, L x for In some implementations, L x for * The terminal is connected to G or ring Y.

[0191] In some implementation schemes, R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and oxo groups; in some embodiments, R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; in some embodiments, R x It is a hydrogen atom.

[0192] In some implementations, x is 0, 1, or 2; in some implementations, x is 0 or 1; in some implementations, x is 0.

[0193] In some embodiments, ring Y is a 5- to 10-membered heteroaryl group; in some embodiments, ring Y is a 5-membered heteroaryl group; in some embodiments, ring Y is selected from pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridoneyl, imidazolyl, thiazolyl, oxazolyl, pyrroleyl, thiophenyl, isoxazolyl, and furanyl; in some embodiments, ring Y is pyrazolyl or triazolyl; in some embodiments, ring Y is selected from... In some implementation schemes, ring Y is

[0194] In some implementation schemes, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R y 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 y It is a hydrogen atom or F; in some implementations, R y It is a hydrogen atom.

[0195] In some implementations, y is 0 or 1; in some implementations, y is 0; in some implementations, y is 1.

[0196] In some implementations, G is a hydrogen atom or Ring Y, R y and y are as defined in the context; in some implementations, G is Ring Y, R y and y as defined in the context; in some implementations, G is a hydrogen atom or Cycloyl Y is a 5-membered heteroaryl group; R y Selected from hydrogen atoms, halogens and C 1-6 Alkyl; y is 0 or 1; in some embodiments, G is a hydrogen atom; in some embodiments, G is selected from hydrogen atoms, In some implementations, G is selected from hydrogen atoms,

[0197] In some implementations, cycloy is a 5-membered heteroaryl group; Ry They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; in some embodiments, for

[0198] In some implementations, G or Selected from

[0199] In some implementations, G or Selected from In some implementations, G or for

[0200] In some implementation schemes, Z 1 For N or CH; in some implementations, Z 1 Let N be the number of elements in the array.

[0201] In some implementation schemes, Z 2 For N or CH; in some implementations, Z 2 For N; in some implementations, Z 2 For CH.

[0202] In some implementation schemes, Z 3 For N or CH; in some implementations, Z 3 Let N be the number of elements in the array.

[0203] In some implementation schemes, Z 4 For N or CH; in some implementations, Z 4 Let N be the number of elements in the array.

[0204] In some implementation schemes, R z1 and R z2 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 z1 and R z2 Each is an independent hydrogen atom.

[0205] In some implementation schemes, R z3 and R z4 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 z3 and R z4 Each is an independent hydrogen atom.

[0206] In some implementations, f and g are each independently 0, 1, or 2; in some implementations, f and g are each independently 0 or 1; in some implementations, f is 1 and g is 1; in some implementations, f is 0 and g is 0; in some implementations, f is 1 and g is 0.

[0207] In some implementations, f1 and g1 are each independently 0, 1, or 2; in some implementations, f1 and g1 are each independently 0 or 1; in some implementations, f1 is 1 and g1 is 1; in some implementations, f1 is 0 and g1 is 0; in some implementations, f1 is 1 and g1 is 0.

[0208] In some implementation schemes, R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and oxo groups; in some embodiments, R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and oxo groups; in some embodiments, R z It is a hydrogen atom.

[0209] In some implementations, two R z Connected to form a bridge C 1-3 Alkylene; in some embodiments, the two Rs z They connect to form a bridge CH2CH2.

[0210] In some implementations, two R atoms on the same carbon atom z Together with the attached carbon atom, they form a cyclopropyl group.

[0211] In some implementations, k is 0, 1, or 2; in some implementations, k is 0 or 1; in some implementations, k is 0.

[0212] In some implementations, t3 is 0, 1, 2, or 3; in some implementations, t3 is 0; in some implementations, t3 is 2; and in some implementations, t3 is 3.

[0213] In some implementation schemes, Z 1 For N or CH; and / or Z 2 For N or CH; and / or f and g are each independently 0 or 1; and / or R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; and / or k is 0 or 1; and / or t3 is 0, 1, 2 or 3.

[0214] In some implementation schemes, X 2 For CH.

[0215] In some implementations, L 1 It is a bond or NH.

[0216] In some implementation schemes, R a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R a It is a hydrogen atom.

[0217] In some implementation schemes, V 1 The answer is C.

[0218] In some implementations, T stands for C.

[0219] In some implementation schemes, V 1 C is C; T is C.

[0220] In some implementation schemes, V 1 N is N; T is C.

[0221] In some implementation schemes, V 1 C is C; T is N.

[0222] In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for

[0223] In some implementation schemes, R b It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R b For hydrogen atoms; in some implementations, R b It can be a hydrogen atom or a methyl group.

[0224] In some implementation schemes, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is tert-butyl.

[0225] In some implementation schemes, R 6 It is a hydrogen atom.

[0226] In some implementation schemes, R 7 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C1-6 Alkyl group.

[0227] In some implementation schemes, R 8 and R 9 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0228] In some implementation schemes, R 0 Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy and cyano groups; in some embodiments, R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, Selected from * The terminal is connected to ring X; + The terminal is connected to M. 2 Connected; The end is connected to ring B; Y 3 Y 4 V 2 and R w0 As defined above.

[0229] In some implementation schemes, Y 1 and Y 2 The ring is a 5-membered heteroaryl group; in some implementation schemes, Y 1 and Y 2 The ring is selected from pyrrole, furanyl, thiophene, imidazole, pyrazolyl, oxazolyl, thiazolyl, and triazolyl; in some embodiments, Y 1 and Y 2 The ring is selected from pyrrole, furanyl, and imidazolyl; in some embodiments, Y 1 and Y 2 The ring it belongs to is pyrrole.

[0230] In some implementation schemes, Y 1 Selected from N, O, S, CH and NH; in some embodiments, Y 1 Selected from N, O, CH and NH; in some embodiments, Y 1 For CH.

[0231] In some implementation schemes, Y 2 Selected from N, O, S, CH and NH; in some embodiments, Y 2 Selected from O, CH and NH; in some implementations, Y 2It is NH or O; in some implementations, Y 2 It is NH.

[0232] In some embodiments, the compound represented by general formula (IV) or general formula (V) or its pharmaceutically acceptable salt, G is a hydrogen atom or Cycloyl Y is a 5-membered heteroaryl group; R y Selected from hydrogen atoms, halogens and C 1-6 Alkyl group; y is 0 or 1; It can be a single or double bond; R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; x is 0 or 1; L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2, or 3; M is O or CH2; e1 is 0, 1, 2, or 3; e2 is 0 or 1; R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 3 For NH or O; Y 4 For N or CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form 3 to 8-membered heterocyclic groups; R 2 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 alkoxy group; n1 is 0, 1, or 2; Z 1 For N or CH; Z 2 For N or CH; R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; k is 0, 1, or 2; f and g are each independently 0, 1, or 2; t3 is 0, 1, 2, or 3; L 1 For bond or NH; X 2 For CH; Selected from *The terminal is connected to (CH2)t3; Q is NR. q or CR q1 R q2 ;R q Methyl; R q1 and R q2It can be a hydrogen atom or a methyl group; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group; R 1 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 Alkyl group; m1 is 0 or 1; m2 is 0, 1 or 2; m3 is 0, 1 or 2; m5 is 0 or 1; J is CH2 or O; A1 is N or CH; A2 is N or CH; R A C 1-6 Alkyl; R A1 C 1-6 Alkyl group; and p and q are each independently 0, 1 or 2.

[0233] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0234] Among them, ring Y is a 5-membered heteroaryl group; R y It represents a hydrogen atom or a halogen; y is 0 or 1; L x for *The end is connected to ring Y; R x For hydrogen atoms; M is O or S; R m1 and R m2 Each is independently a hydrogen atom or a carbon atom. 1- 6-alkyl; or, R on the same carbon atom m1 and R m2 Together with the adjacent carbon atom, they form a cyclopropyl group; e1 is 0, 1, 2, or 3; e2 is 0 or 1; R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 3 For NH or O; Y 4 For N or CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form 3 to 8-membered heterocyclic groups; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy group; n1 is 0, 1 or 2; L is -(L B ) t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C1-6 Alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group, wherein the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted by one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; Selected from * The terminal is connected to L; L 1 For bonds or NH; and X 2 For CH.

[0235] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0236] Among them, ring Y is a 5-membered heteroaryl group; R y It represents a hydrogen atom or a halogen; y is 0 or 1; L x for *The end is connected to ring Y; R x For hydrogen atoms; M is O or S; R m1 and R m2 Each is independently a hydrogen atom or a carbon atom. 1- 6-alkyl; or, R on the same carbon atom m1 and R m2 Together with the adjacent carbon atom, they form a cyclopropyl group; e1 is 0, 1, 2, or 3; e2 is 0 or 1; R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 3 For NH or O; Y 4 For N or CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form 3 to 8-membered heterocyclic groups; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy group; n1 is 0, 1 or 2; L is -(L B ) t2 -;L BThey may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group, wherein C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted by one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; Selected from *The terminal is connected to L; L 1 For bonds or NH; and X 2 For CH.

[0237] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0238] in, Selected from L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; M is O or S; R m1 and R m2 It is a hydrogen atom, or R on the same carbon atom. m1 and R m2 Together with the adjacent carbon atom, they form a cyclopropyl group; e1 is 1, 2, or 3; e2 is 0 or 1; R w1 It is a halogen; Y 3 For NH; Y 4 For CH; R 4 and R 5 Methyl; n1 is 0, 1, or 2; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; L is *The end is connected to ring A; for *The terminal is connected to L; L 1 As the key; and X 2 For CH.

[0239] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0240] in, Selected from L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; M is O or S; R m1 and R m2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl group, or R on the same carbon atom m1 and R m2 Together with the adjacent carbon atom, they form a cyclopropyl group; e1 is 1, 2, or 3; e2 is 0 or 1; R w1 It is a halogen; Y 3 For NH; Y 4 For CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form 3 to 8-membered heterocyclic groups; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy group; n1 is 0, 1 or 2; L is -(L B ) t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group, wherein the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted by one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; for * The terminal is connected to L; A1 is N; p1 and q1 are each independently 0, 1, 2 or 3; R 1 For hydrogen atoms; m6 is 0; L 1 As the key; and X 2 For CH.

[0241] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0242] in, Selected from L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; M is O; R m1 and R m2 It is a hydrogen atom, or R on the same carbon atom. m1 and R m2 Together with the adjacent carbon atom, they form a cyclopropyl group; e1 is 1; e2 is 0 or 1; R w1 It is a halogen; Y 3 For NH; Y 4 For CH; R 4 and R 5 C 1-6 Alkyl; R 2 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 alkoxy group; n1 is 0, 1, or 2; L is selected from... *The end is connected to ring A; Selected from * The terminal is connected to L; L 1 For bonds or NH; and X 2 For CH.

[0243] Group A: Typical compounds disclosed herein include, but are not limited to:

[0244] This disclosure provides a compound of general formula (II-1A) or general formula (III-1A) or a salt thereof.

[0245] in,

[0246] R P Selected from halogens, -B(OH)2 and

[0247] Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 and R 5 As defined in general formula (II-1) or general formula (III-1).

[0248] This disclosure provides a compound of general formula (IVA) or general formula (VA) or a salt thereof.

[0249] in,

[0250] R L It is a hydrogen atom or an amino protecting group;

[0251] G, L x R x x, M, e1, e2, R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1 f, g, R z And k is as defined in general formula (IV) or general formula (V).

[0252] In some implementation schemes, R L It is a hydrogen atom or Boc; in some implementations, R L For hydrogen atoms; in some implementations, R L For Boc.

[0253] This disclosure provides a compound of general formula (VIA) or a salt thereof.

[0254] in,

[0255] Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1f and g are as defined in general formula (IV).

[0256] Group B: Typical intermediate compounds include, but are not limited to:

[0257] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0258] The compound of general formula (II-1A) or its salt reacts with the compound of general formula (IIB) or its salt to give the compound of general formula (II-1) or its pharmaceutically usable salt.

[0259] The compound of general formula (III-1A) or its salt reacts with the compound of general formula (IIB) or its salt to give the compound of general formula (III-1) or its pharmaceutically usable salt.

[0260] in,

[0261] R P It is a halogen; R T -B(OH)2 or Or, R P -B(OH)2 or R T It is a halogen;

[0262] Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, L, ring A, R 1 m, L 1 and X 2 As defined in general formula (II-1) or general formula (III-1).

[0263] In some implementation schemes, R P For halogen; in some implementations, R P For Cl; in some implementations, R P for

[0264] In some implementation schemes, R T For halogen; in some implementations, RT For Br; in some implementations, R T for

[0265] In some implementation schemes, R P It is a halogen; R T for In some implementation schemes, R P For Cl; R T for

[0266] In some implementation schemes, R P for R T For halogen; in some implementations, R P for R T It is Br.

[0267] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0268] The compound represented by general formula (IVA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0269] in,

[0270] R L It is a hydrogen atom;

[0271] t4 can be 0, 1, 2, 3, or 4;

[0272] t3 is 1, 2, 3, 4 or 5, and t3 is t4+1;

[0273] Z 2 Let N be the number of people in the group.

[0274] G, L x R x x, M, e1, e2, R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1 f, g, R z , k, ring A, R 1 m, L 1 and X 2 As defined in general formula (IV).

[0275] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0276] The compound represented by general formula (VA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (IVB) or its salt to give the compound represented by general formula (V) or its pharmaceutically usable salt.

[0277] in,

[0278] R L It is a hydrogen atom;

[0279] t4 can be 0, 1, 2, 3, or 4;

[0280] t3 is 1, 2, 3, 4 or 5, and t3 is t4+1;

[0281] Z 2 Let N be the number of people in the group.

[0282] G, L x R x x, M, e1, e2, R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1 f, g, R z , k, ring A, R 1 m, L 1 and X 2 As defined in general formula (V).

[0283] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0284] The compound of general formula (VIA) or its salt undergoes a reductive amination reaction with the compound of general formula (VIB) or its salt to give the compound of general formula (VI) or its pharmaceutically usable salt.

[0285] in,

[0286] Z 2 CH; Z 3 Let N be the number of people in the group.

[0287] Ring Y, R y y, L x R x x, M, e1, e2, R m1 Rm2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1 Z 4 , f, f1, g, g1, ring A, R 1 m, L 1 and X 2 As defined in general formula (VI).

[0288] In some embodiments, the reaction in the preparation method of general formula (II-1) or general formula (III-1) is a coupling reaction. In some embodiments, the coupling reaction is carried out under alkaline conditions and with the aid of a catalyst.

[0289] In some embodiments, the reagent providing alkaline conditions includes organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide. In some embodiments, the reagent providing alkaline conditions is potassium phosphate.

[0290] In some embodiments, the catalyst includes, but is not limited to, palladium methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)

[0291] In some embodiments, in the preparation method of general formula (IV) or general formula (V), t4 is 2; t3 is 3; in some embodiments, t4 is 1; t3 is 2; in some embodiments, t4 is 0; t3 is 1.

[0292] In some embodiments, in the preparation methods of general formula (IV), general formula (V) or general formula (VI), the reductive amination reaction occurs in the presence of a reducing agent; in some embodiments, the reductive amination reaction occurs under acidic conditions and in the presence of a reducing agent; in some embodiments, the reagents providing the acidic conditions include, but are not limited to, acetic acid, glacial acetic acid, Ti(i-PrO)3 ​​and BF3·Et2O; furthermore, the acidic environment may also be generated during the reaction, for example, by reacting the hydrochloride salt or trifluoroacetate of an amine with sodium acetate to generate acetic acid in situ.

[0293] In some embodiments, the reducing agent includes, but is not limited to, sodium borohydride acetate, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium acetylborohydride; in some embodiments, the reducing agent is sodium cyanoborohydride; in some embodiments, the reducing agent is sodium triacetoxyborohydride.

[0294] In some embodiments, the above preparation method is carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0295] Another aspect of this disclosure relates to a pharmaceutical composition comprising the above-described general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) of this disclosure or a compound thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0296] This disclosure further relates to the use of the above-mentioned general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting or degrading STAT6.

[0297] This disclosure further relates to the use of the above-described general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0298] This disclosure further relates to the use of the above-mentioned general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0299] This disclosure further relates to the above-described general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), and (VI) or compounds of this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of drugs for the treatment and / or prevention of cancer, inflammatory diseases (e.g., type 2 inflammatory diseases), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, etc. Use in medicines for the treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, and dermatomyositis. Hepatitis, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury. Use in medications for acute respiratory distress syndrome, allergic reactions, sinusitis, pulmonary hypertension, cataracts, myasthenia gravis, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

[0300] This disclosure also relates to a method for regulating the ubiquitination and degradation of STAT6 protein in a subject, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0301] This disclosure also relates to a method of inhibiting or degrading STAT6 in a subject, comprising administering to a desired patient the above-described general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0302] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on STAT6, comprising administering to a desired patient the above-described general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0303] This disclosure also relates to a method for treating and / or preventing cancer, inflammatory diseases (e.g., type 2 inflammatory diseases), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T-cell activation, cardiovascular diseases, or central nervous system diseases, comprising administering the above general formulas (I), (II), (III), (II-1), and (III-1) to a desired patient. Compounds of formula (IV), formula (V), formula (VI) or those disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, are used in some embodiments to treat and / or prevent asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, and other similar conditions. Inflammation, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute Lung injury, acute respiratory distress syndrome, allergic reaction, sinusitis, pulmonary hypertension, cataract, myasthenia gravis, thyroiditis, appendicitis, allergy, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

[0304] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicine.

[0305] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or the compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0306] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III), general formula (II-1), general formula (III-1), general formula (IV), general formula (V), general formula (VI) or the compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on STAT6.

[0307] This disclosure further relates to the above-mentioned general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the purpose of regulating STAT6 protein ubiquitination and degradation in a subject.

[0308] This disclosure further relates to the above-described general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the purpose of inhibiting or degrading STAT6 in a subject.

[0309] This disclosure further relates to the above-mentioned general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), (VI) or compounds of this disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0310] This disclosure further relates to the above-described general formulas (I), (II), (III), (II-1), (III-1), (IV), (V), and (VI), or compounds of this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of cancer, inflammatory diseases (e.g., type 2 inflammatory diseases), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, and thrombin-induced platelet aggregation. Aggregates, liver disease, pathological immune conditions involving T-cell activation, cardiovascular disease, or central nervous system disease; in some implementations, for the treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, liver disease. Inflammation, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute Lung injury, acute respiratory distress syndrome, allergic reaction, sinusitis, pulmonary hypertension, cataract, myasthenia gravis, thyroiditis, appendicitis, allergy, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, and prostatitis.

[0311] In some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases; in some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related diseases, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases; in some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from S… TAT6-mediated or dependent diseases or conditions include asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, and Stevens-Johnson syndrome. Inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome. Allergic reactions, sinusitis, pulmonary hypertension, cataracts, myasthenia gravis, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, and prostatitis.

[0312] In some implementation schemes, cancer includes, but is not limited to, benign or malignant tumors, solid tumors, fluid-filled tumors, brain cancer, kidney cancer, liver cancer (hepatocellular carcinoma), adrenal cancer, bladder cancer, breast cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreas cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, larynx cancer, skin cancer, bone or thyroid cancer, sarcoma cancer, glioblastoma cancer, neuroblastoma cancer, multiple myeloma cancer, gastrointestinal cancer, especially colorectal cancer (colon cancer or colorectal cancer), adenoma cancer, neck and head cancer, and epidermal cancer. Proliferative disorders, psoriasis, benign prostatic hyperplasia, tumors, epithelial tumors, adenomas, adenocarcinomas, pancreatic ductal carcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, uveal melanoma, lymphoma, Hodgkin's and non-Hodgkin's cancers, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disease, MyD88-driven disease, indolent multiple myeloma, smoking or hematologic malignancies (including leukemia, diffuse large B-cell lymphoma), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intraangiocarcinoma (intravascular large B-cell lymphoma); in some implementations, the cancer to be treated is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma, ovarian cancer, malignant peripheral nerve schwannoma (MPNST), and pancreatic cancer. In some implementations, the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma, ovarian cancer, malignant peripheral nerve healthy tumor (MPNST), pancreatic cancer, and non-small cell carcinoma.

[0313] In some implementations, the cancer is selected from solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma, etc.), hematologic malignancies (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.

[0314] In some implementations, the neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by cerebral ischemia and trauma.

[0315] In some implementations, the cardiovascular diseases include, but are not limited to, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, post-angioplasty restenosis, post-angioplasty restenosis, post-coronary artery bypass grafting restenosis, post-coronary artery bypass grafting restenosis, stroke, transient ischemic attack, peripheral artery occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0316] In some embodiments, the asthma includes intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced or exacerbated by bacterial or viral infection. In some embodiments, the asthma is eosinophilic asthma (EA).

[0317] In some embodiments, the urticaria described in this disclosure is chronic urticaria or acute urticaria; in some embodiments, the urticaria described in this disclosure is chronic urticaria.

[0318] In some embodiments, the urticaria described in this disclosure is chronic spontaneous urticaria (CSU) or chronic inducible urticaria; in some embodiments, the urticaria described in this disclosure is chronic spontaneous urticaria. In some embodiments, the multiple sclerosis described in this disclosure is relapsing-remitting multiple sclerosis (RMS).

[0319] In some embodiments, the allergy described in this disclosure is an allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites, or cockroach calyxes, etc.

[0320] In some implementations, the diabetes described in this disclosure is type 1 diabetes.

[0321] In some implementations, the thyroiditis is Hashimoto's thyroiditis or autoimmune thyroiditis.

[0322] In some implementations, the bronchitis includes, but is not limited to, acute bronchitis, peanut bronchitis, catarrhal bronchitis, croup bronchitis, chronic bronchitis, or smoke-like bronchitis.

[0323] The active compound can be formulated in a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as 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.

[0324] As a general guideline, the active compounds of this disclosure are presented in some embodiments in a unit dose manner, or in a manner that a patient can self-administer as a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg. In some embodiments, a suitable unit dose may be 0.1 to 1000 mg.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0329] Pharmaceutical compositions containing active ingredients may 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 may 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.

[0330] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] Terminology Explanation

[0340] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0341] 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). The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C164 ... 1-6Alkyl 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, and when substituted, they can be substituted at any usable connection point. In some embodiments, 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.

[0342] The term "heteroalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2, and the nitrogen atom may optionally be quaternized, wherein the alkyl group is as defined above; in some embodiments, the heteroalkyl group is a C14 alkyl group in which one, two, or three carbon atoms are replaced by heteroatoms selected from N, O, S, S(O), and S(O)2. 1-6 Alkyl (i.e., 1 to 6-membered heteroalkyl); in some embodiments, the heteroalkyl is 2 to 6-membered heteroalkyl. The heteroalkyl can be substituted or unsubstituted, and when substituted, it can be substituted at any usable link. The substituent in some embodiments is 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.

[0343] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). The alkylene is, in some embodiments, an alkylene having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is 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.

[0344] 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-) and bridged methylene (-CH2-).

[0345] 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). The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, 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.

[0346] 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 The alkynyl group (in some embodiments) 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. In some embodiments, 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.

[0347] 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. In some embodiments, the substituent is 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.

[0348] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (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., 3 to 12 membered cycloalkyl) or a cycloalkyl group having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl), in some embodiments, a cycloalkyl group having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and in some embodiments, a cycloalkyl group having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0349] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0350] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0351] 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 with 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl with 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: Its connection point can be anywhere; wait.

[0352] 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 has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it has 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: Its connection point can be anywhere; wait.

[0353] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system sharing two non-directly linked carbon atoms between rings, 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) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 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 or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0354] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0355] 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 is a heterocyclic group with 5 to 20 ring atoms (i.e., a 5 to 20-membered heterocyclic group); in some embodiments, the heterocyclic group is a heterocyclic group with 13 to 19 ring atoms (i.e., a 13 to 19-membered heterocyclic group); in some embodiments, the heterocyclic group is a heterocyclic group with 5 to 15 ring atoms (i.e., a 5 to 15-membered heterocyclic group); in some embodiments, a heterocyclic group with 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group with 4 to 12 ring atoms (i.e., a 4 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group with 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in one In some embodiments, the heterocyclic group has 4 to 8 ring atoms (i.e., 4 to 8-membered heterocyclic group); in some embodiments, the heterocyclic group has 4 to 6 ring atoms (i.e., 4 to 6-membered heterocyclic group); in some embodiments, the heterocyclic group has 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic group); in some embodiments, the heterocyclic group has 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic group); in some embodiments, the heterocyclic group has 6 ring atoms (i.e., 6-membered heterocyclic group); in some embodiments, the heterocyclic group has 13 to 15 ring atoms (i.e., 13 to 15-membered heterocyclic group); and in some embodiments, the heterocyclic group has 14 ring atoms (i.e., 14-membered heterocyclic group).

[0356] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0357] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0358] 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). The spiroheterocyclic group has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered spiroheterocyclic groups), and 7 to 11 ring atoms in some embodiments (i.e., 7 to 11-membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), and in some embodiments is a monospirocyclic or bispirocyclic 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 group. Non-limiting examples include: wait.

[0359] 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). The fused heterocyclic group is, in some embodiments, a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, 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 is a bicyclic or tricyclic fused heterocyclic 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 bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0360] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain 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: wait.

[0361] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0362] 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 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point 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: wait.

[0363] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0364] 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 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., 5 to 15-membered heteroaryl). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0365] 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, etc.

[0366] 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: wait.

[0367] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0368] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0369] When a polycyclic system is divalent, and the monocyclic ring connected to the parent ring is a heterocyclic ring, then the polycyclic system is a heterocyclic base, for example... The *terminus is connected to the parent compound, therefore it belongs to a heterocyclic group; when the monocyclic ring connected to the parent compound is a cycloalkyl group, then the polycyclic system is a cycloalkyl group, for example... The *terminus is attached to the parent compound, therefore it belongs to the cycloalkyl group; when the monocyclic ring attached to the parent compound is a heteroaryl group, then the polycyclic system is a heteroaryl group, for example... The *terminus is connected to the parent compound, therefore it belongs to the heteroaryl group;

[0370] When the monocyclic ring connected to the parent compound is aryl, the polycyclic system is aryl (except where the monocyclic ring connected to the parent compound is aryl, and all other monocyclic rings are heteroaryl or aryl, with at least one monocyclic ring being heteroaryl; in this case, it is classified as heteroaryl). For example... The *terminus is connected to the parent compound, therefore it belongs to the aryl group. And... Although the *terminus is connected to the parent compound, it belongs to the heteroaryl group.

[0371] The term "tetracyclic" refers to a polycyclic ring system having four rings containing 0 to 5 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 15 to 24 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) ring atoms (i.e., 15 to 24-membered tetracyclic). Each monocyclic ring in the tetracyclic is independently selected from saturated rings, partially unsaturated rings, and aromatic rings, and the monocyclic rings may be joined together in a fused, bridged, or helical manner; in some embodiments, the tetracyclic is a 16 to 20-membered tetracyclic; in some embodiments, the tetracyclic is a 17 or 18-membered tetracyclic; in some embodiments, the tetracyclic is a 17-membered tetracyclic; non-limiting examples of "tetracyclic" include, but are not limited to: wait.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0377] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0378] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0379] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0380] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0381] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0382] 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.

[0383] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0384] 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.

[0385] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0386] The term "hydroxyl group" refers to -OH.

[0387] The term "thiol" refers to -SH.

[0388] The term "amino" refers to -NH2.

[0389] The term "cyano" refers to -CN.

[0390] The term "nitro" refers to -NO2.

[0391] The term "oxo" or "oxo group" refers to "=O".

[0392] The term "carbonyl" refers to C=O.

[0393] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0394] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0395] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0396] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0397] The term "tricyclic" refers to a polycyclic ring system having three rings containing 0 to 5 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 9 to 24 ring atoms (i.e., 9 to 24-membered tricyclic), each monocyclic ring being independently selected from saturated rings, partially unsaturated rings, and aromatic rings, and the monocyclic rings may be joined together in a fused, bridged, or helical manner; in some embodiments, the tricyclic ring is a 14- or 15-membered tricyclic ring; in some embodiments, the tricyclic ring is a 14-membered tricyclic ring; non-limiting examples of "tricyclic" include, but are not limited to: wait.

[0398] The optional substituents described in this disclosure include: deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 22 -NR 23 R 24 -C(O)R 22 -C(O)OR 22 -C(O)NR 23 R 24 -OC(O)NR 23 R 24 -OC(O)R 22 -OC(O)OR 22 -NR 25 C(O)R 22 -NR 25 C(O)OR 22 -S(O) v R 22 -S(O) v NR 23 R 24 , oxo group, =S and =CR 26 R 27 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally influenced by one or more R groups. t replace;

[0399] R 22 R 23 and R 24 The same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, deuteralkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms.t Replace; or R 23 and R 24 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. t Substituted heterocyclic groups;

[0400] R 25 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuteralkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0401] R 26 and R 27 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, deuteralkyl, alkoxy, hydroxyl, and cycloalkyl; or, R 26 and R 27 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0402] R t Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0403] Or, two Rs t Together with the atoms attached thereto, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, deuteralkoxy and oxo.

[0404] v can be 0, 1, or 2.

[0405] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), trichloroacetyl, triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0406] The term "leaving group," or simply leaving group, refers to an atom or functional group that breaks off from a larger molecule in a chemical reaction. It is used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa of the conjugate acid means that the corresponding leaving group does not need to combine with other atoms, and its tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, -OTf, or -OH.

[0407] 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.

[0408] 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.

[0409] In the chemical structure of the compounds described in this disclosure, the bonds... Indicates forward or reverse.

[0410] 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:

[0411] 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:

[0412] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0413] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of spatial interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0414] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, include solvates (e.g., hydrates, non-aqueous solvates) or non-solvents of the compounds thereof or pharmaceutically acceptable salts thereof.

[0415] 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.

[0416] 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.

[0417] 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.

[0418] "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 will 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.

[0419] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0420] "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.

[0421] "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.

[0422] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0423] 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.

[0424] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0425] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0426] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0427] Example

[0428] 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. -6The 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).

[0429] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS); a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO QExactive).

[0430] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0431] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0432] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0433] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0434] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0435] 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.

[0436] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0437] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0438] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0439] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0440] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0441] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0442] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0443] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0444] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0445] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0446] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0447] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and D: dichloromethane / 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.

[0448] Example 1

[0449] 2-(3-(1H-1,2,3-triazol-1-yl)propionyl)-7-(4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)phenyl)-N,N-dimethyl-1,2,3,4,5,10-hexahydropyrido[3',4':4,5]pyrano[2,3-f]indole-9-carboxamide1

[0450] first step

[0451] (5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)methanol 1b

[0452] Under nitrogen atmosphere, lithium borohydride (172 mg, 7.90 mmol) was added to a tetrahydrofuran (10 mL) solution of 1-(tert-butyl)-4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridine-1,4(2H)-dicarbonate 1a (3 g, 7.87 mmol, Shanghai Shaoyuan). The mixture was heated to 50 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration under reduced pressure was dissolved in dichloromethane (20 mL). A 1,4-dioxane solution of hydrogen chloride (6 mL) was added, and the mixture was stirred for 2 hours. The mixture was then concentrated under reduced pressure to obtain the title compound 1b (0.61 g).

[0453] MS m / z(ESI):240.2[M+1].

[0454] Step 2

[0455] 1-(4-(hydroxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,4-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one 1d

[0456] 3-(1H-1,2,3-triazol-1-yl)propionic acid 1c (0.34 g, 2.41 mmol, Shanghai Haohong) and compound 1b (0.61 g, 2.21 mmol) were dispersed in N,N-dimethylformamide (6 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1 g, 2.63 mmol) and diisopropylethylamine (1.5 g, 11.60 mmol) were added sequentially to the above system, and the mixture was stirred for 12 hours. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 1d (0.39 g).

[0457] MS m / z(ESI): 363.2 [M+1].

[0458] Step 3

[0459] 1g of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde

[0460] 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione 1e (2.5 g, 7.40 mmol, Shanghai Haohong), 2-(bromomethyl)-1,3-dioxapentane 1f (1.6 g, 9.62 mmol, Beijing Bailingwei) were dispersed in ethylene glycol dimethyl ether (10 mL). Then, di[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (0.83 g, 0.74 mmol) and [4,4] [-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel dichloride (0.15 g, 0.37 mmol), tris(trimethylsilyl)silane (1.85 g, 7.40 mmol) and 2,6-dimethylpyridine (1.58 g, 14.8 mmol) were reacted under nitrogen atmosphere and blue light irradiation for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain crude product. The crude product was dissolved in dichloromethane (5 mL), and 1,4-dioxane solution of hydrogen chloride (1 mL) was added. The mixture was stirred for 1 hour and concentrated under reduced pressure to 1 g (260 mg) of the title compound.

[0461] MS m / z(ESI):302.1[M+1].

[0462] Step 4

[0463] methyl 4-bromo-6-chloro-5-fluoro-1H-indole-2-carboxylate 1i

[0464] 2-Bromo-4-chloro-3-fluorobenzaldehyde 1h (9.7g, 40.7mmol, Shanghai Haohong) was dissolved in methanol (50mL), cooled to -60℃, and sodium methoxide solution (29.3g, 162.7mmol) was added in portions. Ethyl diazonate (21g, 162.7mmol) was added dropwise. The reaction was carried out at this temperature for 1 hour, allowed to rise naturally to room temperature, and stirred for another 12 hours. The mixture was then cooled to 0℃, filtered, and the filter cake was dried. The crude product was dispersed in xylene (80mL), reacted at 160℃ for 2 hours, cooled to 0℃, filtered, and the filter cake was dried to give the title compound 1i (1.26g).

[0465] MS m / z(ESI):308.0[M+1].

[0466] Step 5

[0467] 4-Bromo-6-chloro-5-fluoro-N,N-dimethyl-1H-indole-2-carboxamide

[0468] Compound 1i (1 g, 3.26 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL), water (1.5 mL), and methanol (1.5 mL). Lithium hydroxide (800 mg, 19.06 mmol) was added, and the mixture was stirred at 40 °C for 12 hours. The pH was adjusted to 4 with 2 M dilute hydrochloric acid, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude intermediate and dimethylamine hydrochloride (0.28 g, 3.43 mmol) dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (2.7 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.36 g, 3.58 mmol) were added sequentially to the above system. The mixture was stirred at 0 °C for 2 hours, and the reaction solution was poured into water, filtered, and the filter cake was dried to obtain the title compound 1j (0.83 g).

[0469] MS m / z(ESI): 319.1 [M+1].

[0470] Step 6

[0471] 4-(4-(6-chloro-2-(dimethylaminocarbonyl)-5-fluoro-1H-indol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1k

[0472] Compound 1j (0.83 g, 2.60 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 g, 2.83 mmol, Shanghai Haohong), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.1 g, 0.14 mmol) were dissolved in 1,4-dioxane (10 mL), and water (2 mL) and potassium carbonate (1.1 g, 7.96 mmol) were added. The mixture was reacted at 90 °C for 3 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with water and ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 1k (0.92 g).

[0473] MS m / z(ESI): 501.2 [M+1].

[0474] Step 7

[0475] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-4-(hydroxymethyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(dimethylaminocarbonyl)-5-fluoro-1H-indole-1-carboxylic acid tert-butyl ester 1l

[0476] Compound 1k (0.25 g, 0.49 mmol), compound 1c (0.18 g, 0.49 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl), palladium (50 mg, 0.06 mmol), and potassium phosphate (0.37 g, 1.74 mmol) were dissolved in 1,4-dioxane (10 mL) and water. In a mixed solvent of (2 mL), the mixture was stirred at 80 °C for 6 hours under nitrogen atmosphere, concentrated under reduced pressure, and purified by column chromatography using eluent system B. The residue was dissolved in dichloromethane (10 mL), and diisopropylethylamine (0.1 mL) and ditert-butyl dicarbonate (75 mg, 0.34 mmol) were added. The mixture was stirred for 12 hours, concentrated under reduced pressure, and purified by column chromatography using eluent system A to obtain the title compound 1l (0.25 g).

[0477] MS m / z(ESI): 801.2[M+1].

[0478] Step 8

[0479] 2-(3-(1H-1,2,3-triazol-1-yl)propionyl)-N,N-dimethyl-7-(4-(piperazin-1-yl)phenyl)-1,2,3,4,5,10-hexahydropyrido[3',4':4,5]pyrano[2,3-f]indole-9-carboxamide 1m

[0480] Compound 1l (0.25 g, 0.31 mmol) was dispersed in N,N-dimethylformamide (5 mL). Sodium hydrogen (16 mg, 0.40 mmol) was added sequentially to the above system, and the mixture was heated to 70 °C and stirred for 1 hour. The mixture was extracted with water and ethyl acetate, and the organic phases were combined and washed with saturated sodium chloride solution. The organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography using eluent system A. The crude product was dissolved in dichloromethane (8 mL), and a solution of 1,4-dioxane hydrogen chloride (1 mL) was added. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain the title compound 1m (60 mg).

[0481] MS m / z(ESI): 581.2 [M+1].

[0482] Step 9

[0483] 2-(3-(1H-1,2,3-triazol-1-yl)propionyl)-7-(4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)phenyl]-N,N-dimethyl-1,2,3,4,5,10-hexahydropyrido[3',4':4,5]pyrano[2,3-f]indole-9-carboxamide1

[0484] Compound 1m (60 mg, 0.10 mmol) and compound 1g (33 mg, 0.11 mmol) were dispersed in a mixed solvent of methanol (1 mL) and dichloromethane (2 mL). Triethylamine (20 mg, 0.2 mmol) and sodium cyanoborohydride (12 mg, 0.2 mmol) were added sequentially to the above system. The mixture was stirred for 2 hours, the reaction was quenched with acetone, filtered, and the filtrate was subjected to high performance liquid chromatography (column: ODS-BIO C). 18 The title compound 1 (16 mg, yield: 17.8%) was purified by a mobile phase consisting of aqueous phase (0.1% ammonium bicarbonate) and acetonitrile, with a gradient ratio of acetonitrile 20%-95%.

[0485] MS m / z(ESI): 866.2 [M+1].

[0486] Example 2

[0487] 8-(2-chloro-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2

[0488] 8-(2-chloro-4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2-1

[0489] 8-(2-chloro-4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2-2

[0490] first step

[0491] 3-Bromo-5-chloro-2-fluoro-4-iodoaniline 2b

[0492] 3-Bromo-5-chloro-2-fluoroaniline 2a (45.30 g, 201.82 mmol, Shanghai Hanhong) was dissolved in acetic acid (200 mL), and N-iodosuccinimide (45.40 g, 201.79 mmol) was added. The mixture was stirred at 40 °C for 1 hour. After the reaction solution cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 2b (50 g, yield: 70.7%).

[0493] MS m / z(ESI): 349.8 [M+1].

[0494] Step 2

[0495] (3-Bromo-5-chloro-2-fluoro-4-iodophenyl)hydrazine 2c

[0496] Compound 2b (30 g, 85.63 mmol) was mixed with concentrated hydrochloric acid (150 mL), and an aqueous solution of sodium nitrite (6.20 g, 89.95 mmol) (15 mL) was slowly added dropwise at -5 °C. After stirring for 1 hour, a concentrated hydrochloric acid solution of stannous chloride dihydrate (58 g, 257.04 mmol) (100 mL) was added dropwise, and the reaction was stirred for 2 hours. The pH of the reaction solution was adjusted to 9-10 with 30% sodium hydroxide solution, diluted with ethyl acetate, filtered, and the filtrate was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 2c (25.5 g). The product was used directly in the next reaction without purification.

[0497] MS m / z(ESI): 362.9 [M-1].

[0498] Step 3

[0499] 2-(2-(3-bromo-5-chloro-2-fluoro-4-iodophenyl)hydrazylmethylene)-N,N-dimethylpropionamide 2d

[0500] The crude compound 2c (25.50 g, 69.79 mmol) was dissolved in methanol (200 mL), and N,N-dimethyl-2-oxopropionamide (8.4 g, 72.96 mmol, Jiangsu Aikon) was added dropwise. The mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2d (32 g). The product was used directly in the next reaction without purification.

[0501] MS m / z(ESI):462.0[M+1].

[0502] Step 4

[0503] 6-Bromo-4-chloro-7-fluoro-5-iodo-N,N-dimethyl-1H-indole-2-carboxamide 2e

[0504] The crude compound 2d (11.70 g, 25.30 mmol) was mixed with polyphosphoric acid (100 mL), and N-iodosuccinimide (45.40 g, 201.79 mmol) was added. The mixture was stirred at 125 °C for 1.5 h. After the reaction solution cooled to room temperature, it was poured into ice water, filtered, and the filter cake was dissolved in ethyl acetate and washed with water. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the title compound 2e (3.5 g, yield: 31.06%).

[0505] MS m / z(ESI):445.0[M+1].

[0506] Step 5

[0507] 6-Bromo-4-chloro-7-fluoro-5-formyl-N,N-dimethyl-1H-indole-2-carboxamide 2f

[0508] Compound 2e (1.8 g, 4.04 mmol) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere at -78 °C, a 2 M tetrahydrofuran solution of magnesium isopropyl chloride (4.5 mL) was added dropwise. After stirring for 2 hours while maintaining the temperature, a tetrahydrofuran solution of N,N-dimethylformamide (440 mg, 6.02 mmol) (2 mL) was added dropwise. The reaction was slowly brought back to room temperature and stirred for 1 hour. Water was then added to quench the reaction mixture. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system D to give the title compound 2f (320 mg, yield: 22.8%).

[0509] MS m / z(ESI): 347.0 [M+1].

[0510] Step 6

[0511] 3-(3-fluoro-1H-pyrazole-1-yl)methyl propionate 2h

[0512] 2 g of 3-fluoro-1H-pyrazole (3.5 g, 40.66 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (11.22 g, 81.33 mmol) and methyl 3-bromopropionate (10.19 g, 61 mmol) were added, and the mixture was stirred for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 2h (6.1 g, yield: 87.1%).

[0513] MS m / z(ESI): 173.0 [M+1].

[0514] Step 7

[0515] 3-(3-Fluoro-1H-pyrazol-1-yl)propionic acid 2i

[0516] Compound 2h (6 g, 34.85 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide monohydrate (2.92 g, 69.70 mmol) was added. The mixture was stirred for 1 hour, diluted with water, and the pH was adjusted to about 5 with 1 M hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 2i (5.5 g). The product was used directly in the next step of the reaction without purification.

[0517] MS m / z(ESI):159.0[M+1].

[0518] Step 8

[0519] 4-(hydroxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2k

[0520] 1-(tert-butyl)4-ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-3,6-dihydropyridine-1,4(2H)-dicarbonate 2j (3 g, 7.87 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (172 mg, 7.90 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 50 °C for 12 hours. After the reaction solution was cooled to room temperature, it was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2k (1.6 g, yield: 60%).

[0521] MS m / z(ESI): 340.2 [M+1].

[0522] Step 9

[0523] 5-(4-chloro-2-(dimethylaminocarbonyl)-7-fluoro-5-formyl-1H-indol-6-yl)-4-(hydroxymethyl)-3,6-dihydropyridine

[0524] -1(2H)-tert-butyl carboxylate 2l

[0525] Compound 2k (500 mg, 1.47 mmol), compound 2f (509 mg, 1.47 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (108 mg, 147 μmol), and anhydrous potassium carbonate (406 mg, 2.94 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The mixture was purged with nitrogen and stirred at 80 °C for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 2l (570 mg, yield: 81%).

[0526] MS m / z(ESI): 480.2 [M+1].

[0527] Step 10

[0528] 5-(4-chloro-2-(dimethylaminocarbonyl)-7-fluoro-5-(hydroxymethyl)-1H-indol-6-yl)-4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2m

[0529] Compound 2l (500 mg, 1.04 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (45 mg, 2.08 mmol) was added under a nitrogen atmosphere in an ice bath. The mixture was allowed to return to room temperature naturally with stirring for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 2m (375 mg, yield: 75%).

[0530] MS m / z(ESI):482.2[M+1].

[0531] Step 11

[0532] 8-Chloro-12-fluoro-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole

[0533] -10-Formamide 2o

[0534] Compound 2m (350 mg, 727 μmol) was dissolved in tetrahydrofuran (3 mL), and 50% sulfuric acid (2 mL) was added. The mixture was stirred at 70 °C for 2 hours. After the reaction solution cooled to room temperature, the pH was adjusted to >7 with 2M sodium hydroxide solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The solution was dried over saturated anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2o (270 mg). The product was used directly in the next reaction without purification.

[0535] MS m / z(ESI): 364.2 [M+1].

[0536] Step Twelve

[0537] 8-Chloro-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 2p

[0538] Compound 2i (130 mg, 822 μmol) and compound 2o (200 mg, 551 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (142 mg, 1.10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (251 mg, 661 μmol) were added. The mixture was stirred for 16 hours, the reaction solution was poured into water, and extracted with ethyl acetate (15 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 2p (252 mg, yield: 91%).

[0539] MS m / z(ESI): 504.2 [M+1].

[0540] Step Thirteen

[0541] 12-Fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentanyl)-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2q

[0542] Compound 2p (250 mg, 497 μmol), pinacol diborate (252 mg, 994 μmol), potassium acetate (98 mg, 998 μmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (37 mg, 50 μmol) were mixed in 1,4-dioxane (5 mL), purged with nitrogen, and stirred at 100 °C for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 2q (220 mg, yield: 74%).

[0543] MS m / z(ESI): 596.2 [M+1].

[0544] Step Fourteen

[0545] 6-Bromo-7-methoxy-1H-indazole 2s

[0546] 4-Bromo-2-fluoro-3-methoxybenzaldehyde 2r (9 g, 38.62 mmol, Shanghai Biotech) was dissolved in ethylene glycol dimethyl ether (100 mL), and 85% hydrazine hydrate (16 g, 271.67 mmol) was added. The reaction mixture was reacted at 100 °C for 48 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2s (950 mg, yield: 10.8%).

[0547] MS m / z(ESI):227.1[M+1].

[0548] Step 15

[0549] 6-Bromo-3-iodo-7-methoxy-1H-indazole 2t

[0550] Compound 2S (1.10 g, 4.84 mmol) was dissolved in N,N-dimethylformamide (15 mL), and N-iodosuccinimide (1.42 g, 6.30 mmol, Shanghai Titan) was added. The mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2T (1.41 g, yield: 82.4%).

[0551] MS m / z(ESI): 353.0 [M+1].

[0552] Step Sixteen

[0553] 6-Bromo-3-iodo-7-methoxy-1-methyl-1H-indazole 2u

[0554] Compound 2t (1.41 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.10 g, 8.0 mmol) and methyl iodide (1.13 g, 8.0 mmol, Shanghai Titan) were added. The mixture was stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2u (900 mg, yield: 61.3%).

[0555] MS m / z(ESI): 367.1 [M+1].

[0556] Step Seventeen

[0557] 6-Bromo-3-iodo-1-methyl-1H-indazole-7-phenol 2v

[0558] Compound 2u (900 mg, 2.45 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium ethanethiol (2.06 g, 24.52 mmol, Shanghai Titan) was added. The reaction mixture was reacted at 80 °C for 30 min. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The aqueous phases were combined, and the pH was adjusted to 6-7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2v (800 mg, yield: 92.4%).

[0559] MS m / z(ESI): 353.0 [M+1].

[0560] Step 18

[0561] 4-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2x

[0562] 2w of 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50 g, 234.44 mmol, prepared according to the method disclosed in the literature "Journal of Medicinal Chemistry, 2013, vol. 56, #22, p. 9275-9295") was dissolved in dichloromethane (500 mL), and triphenylphosphine (79.93 g, 304.74 mmol) and carbon tetrabromide (101.07 g, 304.77 mmol) were added under ice bath. The reaction mixture was stirred for 30 min while maintaining the temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2x (64 g, yield: 98.8%). MS m / z (ESI): 220.0 [M-55].

[0563] Step 19

[0564] 4-(((6-bromo-3-iodo-1-methyl-1H-indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2y

[0565] Compound 2v (20 g, 56.66 mmol) and compound 2x (16.43 g, 59.49 mmol) were dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (15.66 g, 113.31 mmol) was added. The mixture was stirred for 0.5 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 2y (26.8 g, yield: 86.2%).

[0566] MS m / z(ESI):492.1[M-55].

[0567] Step 20

[0568] 4-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2z

[0569] Compound 2y (10 g, 18.24 mmol) was dissolved in 1,4-dioxane (200 mL) and water (40 mL), and 2,6-bisbenzyloxypyridine-3-boronic acid pinacol ester (11.41 g, 27.34 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.33 g, 1.82 mmol), and potassium carbonate (5.04 g, 36.48 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 3 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 2z (7 g, yield: 83.9%).

[0570] MS m / z(ESI): 711.6 [M+1].

[0571] Step Twenty-One

[0572] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-2',3'-dihydro-1H,1'H,7H-spiro[furano[3,2-g]indazole-6,4'-pyridine]-1'-carboxylic acid tert-butyl ester 2aa

[0573] Compound 2z (10 g, 14.05 mmol) was dissolved in 1,4-dioxane (300 mL), and sodium formate (1.91 g, 28.08 mmol), sodium acetate (2.30 g, 28.04 mmol), bis(tert-tert-butylphosphine)palladium (1.07 g, 2.09 mmol), and tetraethylammonium chloride (4.65 g, 28.06 mmol) were added. The reaction mixture was reacted at 95 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2aa (5.5 g, yield: 62.05%).

[0574] MS m / z(ESI): 631.6 [M+1].

[0575] Step Twenty-Two

[0576] 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-carboxylic acid tert-butyl ester 2bb

[0577] Compound 2aa (5.50 g, 8.72 mmol) was dissolved in tetrahydrofuran (70 mL) and methanol (30 mL), and 10% palladium on carbon (2.78 g) and palladium hydroxide (3.67 g) were added. The reaction was carried out at 70 °C for 48 hours under a hydrogen atmosphere at 30 atm. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2bb (3.5 g). The product was used directly in the next reaction without purification.

[0578] MS m / z(ESI): 455.6 [M+1].

[0579] Step Twenty-Three

[0580] 3-(1-Methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate 2cc

[0581] The crude compound 2bb (6.2 g, 13.64 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (20 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether, filtered, and the filter cake was dried to obtain the crude title compound 2cc (6.5 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 355.1 [M+1].

[0582] Step Twenty-Four

[0583] 8-(5-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 2ee

[0584] 3-Bromo-4-fluorochlorobenzene 2dd (5 g, 23.87 mmol, Shanghai Bide), 4-piperidinone ethylene glycol (2.76 g, 26.26 mmol, Shanghai Shaoyuan) were dissolved in 1,4-dioxane (50 mL), and sodium tert-butoxide (4.58 g, 47.66 mmol), tris(dibenzylideneacetone)dipalladium (1.09 g, 1.19 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.49 g, 2.39 mmol) were added. The mixture was purged with nitrogen and stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2ee (2.8 g, yield: 43.1%). MS m / z (ESI): 272.21 [M+1].

[0585] Step Twenty-Five

[0586] 8-(4-bromo-5-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 2ff

[0587] Compound 2ee (2.8 g, 10.30 mmol) was dissolved in N-methylpyrrolidone (30 mL), and N-bromosuccinimide (2.01 g, 11.29 mmol) was added at -10 °C. The mixture was stirred and reacted for 0.5 hours. The reaction solution was poured into ice water, and a solid precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 2ff (3.6 g). The product was used directly in the next reaction without purification.

[0588] MS m / z(ESI): 350.1 [M+1].

[0589] Step Twenty-Six

[0590] 1-(4-bromo-5-chloro-2-fluorophenyl)piperidin-4-one 2gg

[0591] The crude compound 2ff (3.6 g, 10.27 mmol) was dissolved in tetrahydrofuran (25 mL), and 2M sulfuric acid (25 mL) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 2gg (2.4 g, yield: 76.2%).

[0592] MS m / z(ESI): 305.9 [M+1].

[0593] Step Twenty-Seven

[0594] 3-(1'-(1-(4-bromo-5-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-3-yl)piperidin-2,6-dione2hh

[0595] Compound 2gg (400 mg, 1.30 mmol) and compound 2cc (611 mg, 1.30 mmol) were dissolved in 1,2-dichloroethane (10 mL), and tetraethyl titanate (893 mg, 3.91 mmol) was added. The mixture was stirred at 65 °C for 2 hours, then cooled to 0 °C, and sodium cyanoborohydride (156 mg, 2.61 mmol) was added. The mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with dichloromethane (15 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2hh (430 mg, yield: 51%).

[0596] MS m / z(ESI): 644.3 [M+1].

[0597] Step Twenty-Eight

[0598] 8-(2-chloro-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2

[0599] 8-(2-chloro-4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2-1

[0600] 8-(2-chloro-4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 2-2

[0601] Compound 2hh (80 mg, 124 μmol), compound 2q (90 mg, 151 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl), palladium (20 mg, 24 μmol), and potassium phosphate (65 mg, 306 μmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was purged with nitrogen and stirred at 100 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep). C18, C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20-55%, flow rate: 30mL / min) to obtain title compound 2 (2mg, yield: 1.3%). Compound 2 was resolved by chiral column to obtain title compounds 2-1 and 2-2.

[0602] MS m / z(ESI): 1033.7 [M+1].

[0603] 1 H NMR (500MHz, CDCl3): δ9.52(d,1H),7.94(s,1H),7.49(s,1H),7.35(dt,1H),7.20(s,1H),7.10-7.03(m,2H ),6.44(d,1H),5.73(td,2H),5.38–5.20(m,1H),4.59(s,2H),4.40(q,2H),4.30(d,2H),4.19(s,2H),3.86 -3.78(m,2H),3.70–3.66(m,4H),3.35(s,3H),3.21(s,3H),3.01–2.99(m,4H),2.87–2.71(m,3H),2.68–2. 60(m,2H),2.53–2.46(m,4H),2.38–2.30(m,3H),2.07-2.03(m,3H),1.85-1.78(m,2H),1.69-1.65(m,4H).

[0604] Example 3

[0605] 8-(2-chloro-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 3

[0606] Title compound 3 was prepared by referring to this application and known technical methods.

[0607] MS m / z(ESI):1006.7[M+1].

[0608] Example 4

[0609] 2-(3-(1H-pyrazol-1-yl)propionyl)-8-(2-chloro-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12-fluoro-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 4

[0610] Title compound 4 was prepared by referring to this application and known technical methods.

[0611] MS m / z(ESI):1015.7[M+1].

[0612] Example 5

[0613] 8'-(2-chloro-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluorophenyl)-12'-fluoro-2'-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1',2',3',4',5',11'-hexahydrospiro[cyclopropane-1,7'-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole]-10'-formamide 5

[0614] Title compound 5 was prepared by referring to this application and known technical methods.

[0615] MS m / z(ESI):1059.7[M+1].

[0616] Example 6

[0617] 8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-

[0618] (S)-8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazole-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 6-1

[0619] (R)-8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazole-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 6-2

[0620] first step

[0621] 8-(4-bromo-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 6b

[0622] 4-Bromo-2-fluoro-1-iodobenzene 6a (1 g, 3.32 mmol, Shanghai Bide) and 4-piperidinone ethylene glycol (523 mg, 3.66 mmol, Shanghai Shaoyuan) were dissolved in toluene (5 mL). Sodium tert-butoxide (383 mg, 3.99 mmol), tris(dibenzylacetone)dipalladium (304 mg, 332 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (621 mg, 997 μmol) were added. The mixture was purged with nitrogen and stirred in a microwave at 130 °C for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6b (580 mg, yield: 55.1%).

[0623] MS m / z(ESI): 316.1 [M+1].

[0624] Step 2

[0625] 1-(4-bromo-2-fluorophenyl)piperidin-4-one 6c

[0626] Compound 6b (550 mg, 1.74 mmol) was dissolved in tetrahydrofuran (5 mL), and 2 M sulfuric acid (5 mL) was added. The mixture was stirred at 80 °C for 16 hours. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6c (300 mg, yield: 63.3%).

[0627] MS m / z(ESI):272.0[M+1].

[0628] Step 3

[0629] 3-(1'-(1-(4-bromo-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-3-yl)piperidin-2,6-dione 6d

[0630] Compound 6c (1.4 g, 5.14 mmol) and compound 2cc (2.41 g, 5.14 mmol) were dissolved in 1,2-dichloroethane (20 mL), and tetraethyl titanate (3.52 g, 14.43 mmol) was added. The mixture was stirred at 65 °C for 2 hours, then cooled to 0 °C, and sodium cyanoborohydride (615 mg, 10.28 mmol) was added. The mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6d (1.9 g, yield: 60.5%).

[0631] MS m / z(ESI): 610.2 [M+1].

[0632] Step 4

[0633] 3-(1'-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-4-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-3-yl)piperidin-2,6-dione 6e

[0634] Compound 6d (500 mg, 819 μmol), pinacol diboronate (416 mg, 1.64 mmol), potassium acetate (161 mg, 1.64 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (139 mg, 164 μmol) were mixed in 1,4-dioxane (10 mL), purged with nitrogen, stirred at 100 °C for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 6e (380 mg, yield: 70.5%).

[0635] MS m / z(ESI): 658.5 [M+1].

[0636] Step 5

[0637] 8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 6

[0638] (S)-8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazole-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 6-1

[0639] (R)-8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazole-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 6-2

[0640] Compound 2p (15 mg, 30 μmol) and compound 6e (25 mg, 38 μmol) were dissolved in 1,4-dioxane (10 mL) and water (0.5 mL), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (5 mg, 4.3 μmol), and potassium phosphate (19 mg, 89 μmol). The mixture was purged with nitrogen and reacted at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20-55%, flow rate: 30mL / min) to obtain title compound 6 (2mg, yield: 6.7%). Title compounds 6-1 and 6-2 could be obtained by resolution by chiral column chromatography.

[0641] MS m / z(ESI): 999.6 [M+1].

[0642] 1 H NMR (500MHz, CDCl3): δ9.50(d,1H),7.93(s,1H),7.49(s,1H),7.35(dt,1H),7.28-7.19(m,2H),7.12-7. 03(m,2H),6.68(d,1H),5.73(td,2H),5.26–5.20(m,1H),4.59(s,2H),4.40(q,2H),4.30(d,2H),4.19(s, 2H),3.87(s,2H),3.71(t,4H),3.49-3.40(m,3H),3.36(s,3H),3.21(s,3H),3.03–2.97(m,3H),2.93–2.7 9(m,4H),2.70–2.60(m,2H),2.58–2.48(m,3H),2.42–2.34(m,2H),2.07-2.02(m,4H),1.70-1.66(m,4H).

[0643] Example 7

[0644] 8-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 7

[0645] 8-(4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 7-1

[0646] 8-(4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 7-2

[0647] Using the synthetic route in Example 6, the title compound 7 was prepared by replacing the first-step starting compound 6a with 1-chloro-5-fluoro-4-iodo-2-methoxybenzene (Shanghai Bide). The title compounds 7-1 and 7-2 were obtained by chiral column resolution.

[0648] MS m / z(ESI):1029.7[M+1].

[0649] Example 8

[0650] 8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 8

[0651] (S)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 8-1

[0652] (R)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 8-2

[0653] first step

[0654] 8-(4-bromo-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 8b

[0655] Using steps 24 to 26 of the synthetic route in Example 2, the starting compound 2dd in step 24 was replaced with o-fluoroiodobenzene 8a to prepare the title compound 8b (17.8 g, yield: 61%).

[0656] MS m / z(ESI):316.0[M+1].

[0657] Step 2

[0658] 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-4-one 8c

[0659] Compound 8b (2 g, 7.35 mmol), pinacol diborate (2.1 g, 8.27 mmol), potassium acetate (1.5 g, 15.28 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (528 mg, 735 μmol) were mixed in 1,4-dioxane (30 mL), purged with nitrogen, and stirred at 100 °C for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 8c (2.3 g, yield: 98%).

[0660] MS m / z(ESI): 320.2 [M+1].

[0661] Step 3

[0662] 12-Fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-8-(3-fluoro-4-(4-oxopiperidin-1-yl)phenyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 8d

[0663] Compound 8c (194 mg, 615 μmol), compound 2p (258 mg, 512 μmol), potassium phosphate (220 mg, 1.04 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (65 mg, 77 μmol) were mixed in 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 8d (250 mg, yield: 74%).

[0664] MS m / z(ESI): 661.3 [M+1].

[0665] Step 4

[0666] 8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 8

[0667] (S)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 8-1

[0668] (R)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 8-2

[0669] Compound 8d (40 mg, 60 μmol) and 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (33 mg, 91 μmol, prepared by the method disclosed in Example 106 on page 322 of patent application "WO2023083194") were dissolved in 1,2-dichloroethane (0.5 mL) and dimethyl sulfoxide (0.5 mL). Sodium acetate (15 mg, 181 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (26 mg, 121 μmol) was added, and the mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). C18, 30×150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30mL / min), yielded title compound 8 (5mg, yield: 8.5%), which was resolved by chiral column to give title compounds 8-1 and 8-2.

[0670] Compound 8:

[0671] MS m / z(ESI): 972.8 [M+1].

[0672] 1H NMR (500MHz, DMSO-d6): δ12.30(s,1H),10.85(s,1H),7.65(dt,1H),7.50(d,1H),7.19(dd,3H),6 .94(dd,1H),6.85(d,1H),6.55(dd,1H),5.87(ddd,1H),4.25(td,4H),3.90(s,3H),3.71(d,4H),3 .54(d,2H),3.24(d,5H),3.20–2.87(m,9H),2.82–2.69(m,5H),2.65–2.58(m,2H),2.44(s,2H),2 .30(dtd,1H),2.21–2.12(m,1H),2.08(s,1H),2.03–1.93(m,3H),1.65(q,2H),1.49–1.40(m,1H).

[0673] Example 9

[0674] 8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 9

[0675] (S)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 9-1

[0676] (R)-8-(4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 9-2

[0677] Using the synthetic route in Example 8, the starting material 3-(1-methyl-6-(piperazin-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione hydrochloride in step four was replaced with 3-(1-methyl-7-(piperazin-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione hydrochloride (prepared using the method disclosed in Example 23 on page 417 of patent application "WO2025101588"). The formate of title compound 9 (5 mg, yield: 11.3%) was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-60%, flow rate: 30 mL / min). Resolution by a chiral column yielded title compounds 9-1 and 9-2.

[0678] Compound 9:

[0679] MS m / z(ESI): 972.7 [M+1].

[0680] 1 H NMR (500MHz, CDCl3): δ9.63(d,1H),8.01(s,1H),7.43(dd,1H),7.35(dt,1H ),7.21(d,2H),7.15–7.04(m,3H),6.68(dt,1H),5.72(td,1H),4.42–4.23( m,8H),3.87(s,3H),3.71(t,4H),3.32(d,11H),3.00(qd,3H),2.86(s,4H), 2.77–2.63(m,2H),2.61–2.48(m,3H),2.44–2.37(m,1H),2.27–2.02(m,6H).

[0681] Example 10

[0682] 8-(4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide10

[0683] (R)-8-(4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 10-1

[0684] (S)-8-(4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 10-2

[0685] Using the synthetic route in Example 8, the fourth-step starting material 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (prepared using the method disclosed in intermediate AWS on page 657 of patent application "WO2020264499"), and purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate). The formate of title compound 10 (2 mg, yield: 4.4%) was prepared by a C18 column (30×150 mm, 5 μm); mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-60%, flow rate: 30 mL / min). The formate of title compound 10 was obtained by chiral column resolution to give title compounds 10-1 and 10-2.

[0686] Compound 10:

[0687] MS m / z(ESI): 988.7 [M+1].

[0688] 1H NMR (500MHz, CDCl3): δ9.54(d,1H),8.06(s,1H),7.35(dt,1H),7.21(d,2H),7.11–7.06(m,1H),6.73(s,1H ),6.71–6.65(m,2H),5.72(td,1H),5.22(dd,1H),4.40(q,2H),4.34-4.24(m,2H),3.87(s,3H),3.74-3.65 (m,3H),3.44(m,2H),3.40-3.26(m,6H),3.25-3.15(m,3H),3.06–2.93(m,5H),2.91–2.78(m,4H),2.77–2. 68(m,2H),2.59-2.52(m,2H),2.30-2.20(m,3H),2.16-2.09(m,2H),2.07-2.01(m,3H),1.97-1.88(m,3H).

[0689] Example 11

[0690] 8-(4-(4-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide11

[0691] (S)-8-(4-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 11-1

[0692] (R)-8-(4-(4-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 11-2

[0693] Using the synthetic route in Example 8, the starting material 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride was replaced with 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (prepared by the method disclosed in Example 2 on page 165 of patent application "WO2022032026") to obtain title compound 11 (8 mg, yield: 18%), which was then resolved by chiral column chromatography to obtain title compounds 11-1 and 11-2.

[0694] Compound 11:

[0695] MS m / z(ESI): 981.6 [M+1].

[0696] 1 H NMR (500MHz, DMSO-d6): δ12.31(d,1H),10.85(s,1H),7.65(d,1H),7.18(dt,3H),6.67–6.47(m,3H),5.87(t,1H),5.09(d,1H),4.63–4.12(m ,6H),3.76(d,8H),3.52–3.37(m,5H),3.08(d,6H),2.95(d,5H),2.82–2.59(m,5H),2.42(d,3H),2.12(dd,1H),1.96(ddq,4H),1.63(q,2H).

[0697] Example 12

[0698] 8-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide12

[0699] (R)-8-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 12-1

[0700] (S)-8-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 12-2

[0701] Using the synthetic route in Example 8, the starting material 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (prepared by the method disclosed in Example 4 on page 44 of patent application "CN119431448A"). The formate of title compound 12 (3 mg, yield: 6.9%) was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-60%, flow rate: 30 mL / min). Resolution by a chiral column yielded title compounds 12-1 and 12-2.

[0702] Compound 12:

[0703] MS m / z(ESI): 954.6 [M+1].

[0704] 1 H NMR (500MHz, CDCl3): δ9.64(d,1H),8.00(s,1H),7.35(dt,1H),7.24–7.15(m,2H),7.08(td,1H),6.68(dt, 1H),6.46(dd,2H),5.72(td,1H),4.40(q,2H),4.33-4.24(m,2H),4.00(dt,1H),3.87(s,3H),3.72-3.64(m, 3H),3.40-3.28(m,5H),3.26-3.14(m,3H),3.03-2.96(m,2H),2.91–2.79(m,5H),2.74–2.63(m,2H),2.59-2 .51(m,2H),2.39-2.30(m,2H),2.20-2.14(m,1H),2.10-2.03(m,2H),2.02-1.92(m,5H),1.91-1.84(d,2H).

[0705] Example 13

[0706] 8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 13

[0707] (R)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 13-1

[0708] (S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 13-2

[0709] first step

[0710] 4-((2,4-difluoro-6-iodophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 13a

[0711] Compound 2x (1.13 g, 4.09 mmol) and 2,4-difluoro-6-iodophenol (800 mg, 3.12 mmol, Bailingwei Chemical) were dissolved in N,N-dimethylformamide (20 mL), and anhydrous potassium carbonate (864 mg, 6.25 mmol) was added. The reaction mixture was reacted for 30 min. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 13a (1.0 g, yield: 71%). MS m / z (ESI): 396.0 [M-55].

[0712] Step 2

[0713] 5,7-Difluoro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 13b

[0714] Compound 13a (700 mg, 1.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and palladium acetate (70 mg, 0.31 mmol), sodium formate (317 mg, 4.66 mmol), sodium acetate (382 mg, 4.65 mmol), and tetraethylammonium chloride (772 mg, 4.66 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 12 hours. The reaction solution was cooled to room temperature, and a saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 13b (400 mg, yield: 80%).

[0715] MS m / z(ESI):268.0[M-55].

[0716] Step 3

[0717] 5,7-Difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13c

[0718] Compound 13b (700 mg, 2.17 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (231 mg) and 20% palladium hydroxide on carbon (305 mg) were added. The mixture was purged with hydrogen and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 13c (350 mg, yield: 50%).

[0719] MS m / z(ESI):270.1[M-55].

[0720] Step 4

[0721] 5,7-Difluoro-6-iodo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13d

[0722] Compound 13c (350 mg, 1.08 mmol) was dissolved in tetrahydrofuran (10 mL). A 2 M solution of diisopropylaminolithium in tetrahydrofuran (0.81 mL) was slowly added dropwise at -78 °C. After reacting for 2 hours, iodine (547 mg, 2.15 mmol) was added, and the mixture was slowly heated to room temperature and reacted for 3 hours. Saturated sodium thiosulfate and sodium carbonate solutions were added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 13d (450 mg, yield: 93%). MS m / z (ESI): 396.0 [M-55].

[0723] Step 5

[0724] 6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0725] 13e

[0726] Compound 13d (450 mg, 0.99 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (417 mg, 0.99 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), followed by the addition of [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (65 mg, 0.10 mmol) and anhydrous potassium carbonate (414 mg, 2.99 mmol). The mixture was purged with nitrogen and heated to 100 °C for 16 hours. The reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 13e (581 mg, yield: 95%).

[0727] MS m / z(ESI): 615.2 [M+1].

[0728] Step 6

[0729] 6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 13f

[0730] Compound 13e (90 mg, 0.15 mmol) was dissolved in ethyl acetate (5 mL), followed by the addition of 10% palladium on carbon (24 mg) and 20% palladium hydroxide on carbon (32 mg). The mixture was then purged with hydrogen and heated to 60 °C for 6 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 13f (40 mg, yield: 62%).

[0731] MS m / z(ESI):381.1[M-55].

[0732] Step 7

[0733] 13g of 3-(5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-6-yl)piperidine-2,6-dione hydrochloride

[0734] Compound 13f (40 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise under ice bath conditions. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 13 g (40 mg). The product was used directly in the next reaction without purification.

[0735] MS m / z(ESI): 337.3 [M+1].

[0736] Step 8

[0737] 8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 13

[0738] (R)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptanecyclo[3,4-f]indole-10-carboxamide 13-1

[0739] (S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-

[0740] 1,3,4,5,7,11-hexahydro-2H-pyrido[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 13-2

[0741] Compound 8d (30 mg, 45 μmol) and compound 13g (19 mg, 50 μmol) were dissolved in 1,2-dichloroethane (1 mL) and dimethyl sulfoxide (0.5 mL), sodium acetate (11 mg, 136 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (29 mg, 136 μmol) was added, and the mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to give title compound 13 (10 mg, yield: 22.4%), which was resolved by chiral column to give title compounds 13-1 and 13-2.

[0742] Compound 13:

[0743] MS m / z(ESI): 981.9 [M+1].

[0744] 1 H NMR (500MHz, DMSO-d6): δ12.31(d,1H),10.95(s,1H),7.65(dt,1H),7.24–7.07( m,4H),6.54(d,1H),5.87(ddd,1H),4.52(s,2H),4.28–4.10(m,4H),3.79–3.64( m,4H),3.58–3.49(m,4H),3.08(d,6H),2.94(dt,4H),2.76(dt,3H),2.50(p,4H) ,2.24(t,2H),2.10(td,1H),2.06–1.94(m,2H),1.89(h,4H),1.78–1.54(m,4H).

[0745] Example 14

[0746] 8-(4-(4-((4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14

[0747] 8-(4-(4-((4aR)-8-((S)-2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14-1

[0748] 8-(4-(4-((4aR)-8-((R)-2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14-2

[0749] first step

[0750] 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester 14b

[0751] (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester 14a (3.0 g, 13.90 mmol, Shanghai Shaoyuan) was dissolved in ethyl acetate (25 mL), water (25 mL) was added, the mixture was cooled to 0 °C, sodium bicarbonate (3.5 g, 41.70 mmol) was added, and benzyl chloroformate (3.55 g, 20.80 mmol) was added dropwise. The reaction mixture was reacted for 16 hours. The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 14b (4.3 g, yield: 88%).

[0752] MS m / z(ESI): 349.2 [M-1].

[0753] Step 2

[0754] 1-Benzyl 4-(tert-butyl)(R)-2-((2,4,6-trifluorophenoxy)methyl)piperazine-1,4-dicarboxylic acid ester 14c

[0755] 2,4,6-Trifluorophenol (700 mg, 4.7 mmol) and compound 14b (1.68 g, 4.78 mmol) were dissolved in tetrahydrofuran (50 mL). Triphenylphosphine (2.45 g, 9.34 mmol) and diisopropyl azodicarbonate (1.89 g, 9.35 mmol) were added under nitrogen protection. The mixture was stirred for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 14c (2.3 g, yield: 100%). MS m / z (ESI): 425.2 [M-55].

[0756] Step 3

[0757] (R)-3-((2,4,6-trifluorophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 14d

[0758] Compound 14c (2.3 g, 4.79 mmol) was dissolved in methanol (40 mL), and 10% palladium on carbon hydrogenation catalyst (100 mg) and 20% palladium hydroxide on carbon hydrogenation catalyst (100 mg) were added. The mixture was purged with hydrogen and stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14d (1.86 g). The product was used directly in the next reaction without purification.

[0759] MS m / z(ESI): 347.2 [M+1].

[0760] Step 4

[0761] (R)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 14e

[0762] The crude compound 14d (1.76 g, 5.08 mmol) was dissolved in dimethyl sulfoxide (40 mL), and sodium hydride (230 mg, 5.75 mmol, 60% purity) was added. The reaction was carried out for 30 minutes, and then the temperature was raised to 120 °C and reacted for another 30 minutes. The reaction was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 14e (340 mg, yield: 21%).

[0763] MS m / z(ESI):271.2[M-55].

[0764] Step 5

[0765] (R)-8-bromo-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 14f

[0766] Compound 14e (155 mg, 475 μmol) was dissolved in dichloromethane (7.5 mL), and N-bromosuccinimide (95 mg, 534 μmol) was added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 14f (148 mg, yield: 77%).

[0767] MS m / z(ESI):349.0[M-55].

[0768] Step 6

[0769] (4aR)-8-(2,6-bis(benzyloxy)pyridin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 14g

[0770] Compound 14f (148 mg, 365 μmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (155 mg, 371 μmol) were dissolved in 6.5 mL of a mixture of 1,4-dioxane and water (V / V = 10 / 3). [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (26 mg, 40 μmol) and anhydrous potassium carbonate (116 mg, 839 μmol) were added. The reaction was purged with nitrogen and carried out at 100 °C for 16 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give 14 g (160 mg, yield: 71%) of the title compound.

[0771] MS m / z(ESI): 616.2 [M+1].

[0772] Step 7

[0773] (4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 14h

[0774] 14 g (160 mg, 260 μmol) of compound was dissolved in ethyl acetate (10 mL), and 30 mg (10 mg) of wet palladium on carbon and 40 mg (20 mg) of palladium hydroxide on carbon were added. The mixture was purged with hydrogen and heated to 60 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14h (113 mg). The product was used directly in the next reaction without purification.

[0775] Step 8

[0776] 3-((R)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidine-2,6-dione hydrochloride 14i

[0777] The crude compound 14h (113 mg, 258 μmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (1 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 14i (100 mg). The product was used directly in the next reaction without purification.

[0778] MS m / z(ESI): 338.2 [M+1].

[0779] Step 9

[0780] 8-(4-(4-((4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14

[0781] 8-(4-(4-((4aR)-8-((S)-2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14-1

[0782] 8-(4-(4-((4aR)-8-((R)-2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-3-fluorophenyl)-12-fluoro-2-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-1,3,4,5,7,11-hexahydro-2H-pyridino[3',4':5,6]oxaheptane[3,4-f]indole-10-carboxamide 14-2

[0783] Compound 8d (30 mg, 45 μmol) and compound 14i (17 mg, 45 μmol) were dissolved in 1,2-dichloroethane (1 mL) and dimethyl sulfoxide (0.5 mL), sodium acetate (11 mg, 136 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (29 mg, 136 μmol) was added, and the mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-45%, flow rate: 30 mL / min) to obtain the formate of title compound 14 (10 mg, yield: 11.2%), which was resolved by chiral column to obtain title compounds 14-1 and 14-2.

[0784] Compound 14:

[0785] MS m / z(ESI): 981.9 [M+1].

[0786] 1 H NMR (500MHz, CDCl3): δ9.51(d,1H),7.92(s,1H),7.32(dt,1H),7.17(d,2H),7.08–7.03(m,1H),6 .67–6.63(m,1H),6.36(d,1H),5.70(td,1H),4.37(q,2H),4.29(d,2H),3.99(dq,2H),3.84(s,2H) ,3.73–3.50(m,5H),3.25(d,6H),3.07(s,1H),3.00–2.93(m,2H),2.81(dd,3H),2.73–2.62(m,2H) ,2.52(s,3H),2.34(d,2H),2.25-2.18(m,2H),2.17–2.10(m,2H),2.07–1.90(m,4H),1.82(s,3H).

[0787] Biological evaluation

[0788] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0789] Test Example 1-1: Degradation Activity Test of the Compounds Disclosed on Total STAT6 Protein in THP-1 Cells

[0790] I. Experimental Objective

[0791] The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 The Dmax value is used to evaluate the in vitro activity of the compound.

[0792] II. Experimental Principle

[0793] This experiment uses The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies for detection, one of which is conjugated to [specific antibody name missing]. TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that laser excitation (615 nm or 620 nm) triggers FRET energy transfer to the receptor, causing it to fluoresce at a specific wavelength (665 nm). The intensity of this specific signal is proportional to the total STAT6 protein level in the cell. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[0794] III. Experimental Materials

[0795] 1. Instruments

[0796] 2. Reagents and consumables

[0797] IV. Experimental Methods

[0798] On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, cells were seeded at 30,000 cells / 16 μL / well in 384-well cell culture microplates. The test compound (final concentration range: 10,000-0.5 nM, 3-fold serial dilution, DMSO final concentration 0.25%) was added using a TECAN D300e micro-volume separator, and the cells were incubated at 37°C in a 5% CO2 cell culture incubator for 48 hours.

[0799] On the third day, first prepare 5× lysis buffer, then remove the 384-well plate after incubation. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes to lyse. Prepare 1× detection buffer, then add 5 μL of the premixed detection antibody pair to each well of the 384-well cell culture microplate according to the kit instructions, vortex at room temperature for 2 minutes, centrifuge, and incubate overnight at 25°C in the dark.

[0800] On the third day, the luminescence values ​​at 620nm and 665nm were read using an Envision microplate reader.

[0801] V. Data Analysis

[0802] Calculate the ratio of acceptor to donor emission signals per well: Ratio = 665nm fluorescence signal value / 620nm fluorescence signal value × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, degradation rate (%) = 100 × (ratio compound - ratio blank control) / (ratio solvent control - ratio blank control).

[0803] Table 1-1 Degradation activity of the disclosed compounds on total STAT6 protein in THP-1 cells.

[0804] Among them, for DC 50 DC 50 <500nM is A; DC 50 B is present in the range of 500 nM to 5000 nM; DC 50 >5000nM is C;

[0805] Dmax > 70% is A; Dmax between 50% and 70% is B; Dmax between 30% and 50% is C.

[0806] Conclusion: The compound disclosed herein exhibits good degradation activity against total STAT6 protein in THP-1 cells.

[0807] Test Examples 1-2: Degradation Activity Tests of the Disclosed Compounds on Total STAT6 Protein in THP-1 Cells I. Experimental Objectives

[0808] The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 The Dmax value is used to evaluate the in vitro activity of the compound.

[0809] II. Experimental Principle

[0810] This experiment uses The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies for detection, one of which is conjugated to [specific antibody name missing]. TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp (320 or 340 nm) or laser (337 nm) triggers a resonance energy transfer (FRET) between the donor and receptor molecules, which emit a TR FRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate allows for signal intensity detection at 615 nm or 620 nm, which can serve as an internal standard for homogenizing the signal intensity at 665 nm. The total protein level can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[0811] III. Experimental Materials

[0812] 1. Instruments

[0813] 2. Reagents and consumables

[0814] IV. Experimental Methods

[0815] On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, the cells were seeded at 30,000 cells / 16 μL / well in columns 3-24 of a 384-well cell culture microplate. Columns 1 and 2 were filled with the same volume of medium as control wells. The test compound (final concentration range: 30 nM-0.001524 nM or 1-0.000051 nM, 3-fold serial dilution, DMSO final concentration 0.25%) was added using a TECAN D300e microfluidic analyzer and incubated at 37°C in a 5% CO2 cell culture incubator for 24 hours.

[0816] On the second day, first prepare 5× lysis buffer, then remove the incubated 384-well plate. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes. Prepare 1× detection buffer, then prepare the premixed detection antibody pair according to the kit instructions. Add 5 μL of antibody to each well of the 384-well cell culture microplate, vortex at room temperature for 2 minutes, centrifuge, and incubate overnight at 25°C in the dark.

[0817] On the third day, the total protein level can be determined by reading the luminescence values ​​at 620nm and 665nm using an Envision microplate reader and calculating the signal intensity of the 665nm / 620nm ratio.

[0818] V. Data Analysis

[0819] Calculate the ratio of acceptor to donor emission signals per well: Ratio = 665nm fluorescence signal value / 620nm fluorescence signal value × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, degradation rate (%) = 100 × (ratio compound - ratio blank control) / (ratio solvent control - ratio blank control).

[0820] Reference compound 1: (WO2025049820A1 compound I-677)

[0821] Reference compound 2: (Compound I-733 in WO2025049820A1)

[0822] Table 1-2 Degradation activities of the disclosed compounds on total STAT6 protein in THP-1 cells.

[0823] Conclusion: The compound disclosed herein exhibits good degradation activity against total STAT6 protein in THP-1 cells.

[0824] Table 1-3 Degradation activities of the disclosed compounds on total STAT6 protein in THP-1 cells.

[0825] Among them, for DC 50 DC 50 <0.005nM is A; DC 50 B is defined as B in the range of 0.005 nM to 0.010 nM; DC 50 C is present in the range of 0.01 nM to 0.015 nM;

[0826] For Dmax, Dmax > 95% is A; Dmax between 90% and 95% is B; Dmax < 90% is C. Test Example 2: Inhibitory Activity Test of the Compounds Disclosed on STAT6 Phosphorylation Levels in PBMC Cells. I. Experimental Objective

[0827] The purpose of this experiment was to test the inhibitory effect of the compound on STAT6 phosphorylation levels in PBMC cells, based on IC50. 50 Size is used to evaluate the in vitro activity of compounds.

[0828] II. Experimental Principle

[0829] The TR-FRET phosphorylated protein kit is based on the principle of traditional sandwich immunoassay. First, cells are pretreated by lysis. Then, a pair of specific antibodies conjugated to either a TR-FRET Solar Eu fluorescent resonance energy transfer donor or a TR-FRET LA fluorescent resonance energy transfer receptor are added to the sample. When these two antibodies bind to different epitopes of the phosphorylated protein, the donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp or laser triggers resonance energy transfer (FRET) between the donor and receptor molecules, which emits a TR-FRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate can be detected at 615 nm or 620 nm, and this signal can be used as an internal standard for homogenizing the signal intensity at 665 nm. The level of total phosphorylated protein can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio.

[0830] III. Experimental Materials

[0831] 1. Instruments

[0832] 2. Reagents and consumables

[0833] IV. Experimental Methods

[0834] On the first day, frozen PBMC cells were resuspended in IMDM medium containing 10% inactivated fetal bovine serum and seeded at 50,000 cells / 14 μL / well in 384-well plates. The test compound was added to each well using an ultra-micro pipette to achieve 10 concentration points with a 3-fold serial dilution starting from 10 μM (final concentration range: 10,000-0.5 nM or 30 nM-0.001524 nM or 1-0.000051 nM, depending on the properties of different series of compounds). The well plates were incubated at 37°C in a cell culture incubator with 5% CO2 for 48 hours.

[0835] On the third day, after 48 hours of incubation, 2 μL of IL-4 (final concentration 3 ng / mL) was added to each well of the cell plate, and the plate was placed in an incubator for 10 minutes of stimulation. After incubation, 4 μL of IL-4 was added to each well. Use the 5× lysis buffer from the TR-FRET Phospho STAT6 (Y641) Kit, and lyse at room temperature (400 rpm) for 30 minutes; then proceed as follows. The recommended procedure for the TR-FRET Phospho STAT6(Y641) Kit is as follows: Prepare 4× premixed detection antibody pairs (detection buffer + Ab1-Solar Eu + Ab2-LA), add 5 μL of antibody per well to a 384-well cell culture microplate, vortex at room temperature for 2 minutes, centrifuge, and incubate overnight at 25°C in the dark.

[0836] On the fourth day, the level of phosphorylated protein can be determined by reading the 665nm and 620nm wavelengths using an Envision microplate reader and calculating the signal intensity of the 665nm / 620nm ratio.

[0837] V. Data Analysis

[0838] The IC50 of the compound's inhibitory activity was calculated using Xlfit software. 50 value.

[0839] Conclusion: The compound disclosed herein exhibits good inhibitory activity against STAT6 phosphorylation levels in PBMC cells.

[0840] Test Example 3: Pharmacokinetic Evaluation

[0841] I. SD Rat Experiment

[0842] 1. Abstract

[0843] Using SD rats as test animals, the plasma drug concentration of the disclosed compound at different time points after gavage (ig) administration to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[0844] 2. Test Plan

[0845] 2.1 Test Drugs

[0846] This compound is disclosed.

[0847] 2.2 Experimental Animals

[0848] SD rats were provided by Viton Lever Laboratories. After fasting overnight, the drugs were administered via gavage.

[0849] 2.3 Drug Preparation

[0850] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.2 mg / mL.

[0851] 2.4 Administration

[0852] The dosage is 2.0 mg / kg, and the administration volume is 10.0 mL / kg.

[0853] 3. Operation

[0854] Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0855] The levels of the target compound in the plasma of SD rats were determined after administration of different concentrations of the drug.

[0856] Conclusion: The compound disclosed herein has a high exposure level in SD rats and exhibits pharmacokinetic advantages.

[0857] II. C57 Mouse Experiment

[0858] 1. Abstract

[0859] Using C57 mice as test animals, the plasma drug concentrations of the disclosed compound at different time points after administration by gavage (ig) / intravenous injection (iv) in C57 mice were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in C57 mice was investigated to evaluate its pharmacokinetic characteristics.

[0860] 2. Test Plan

[0861] 2.1 Test Drugs

[0862] This disclosed compound

[0863] 2.2 Experimental Animals

[0864] C57 mice were provided by Viton Lever Laboratories. The drugs were administered via gavage and intravenous injection, respectively.

[0865] 2.3 Drug Preparation

[0866] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a 0.1 mg / mL colorless clear solution (gavage administration group) and a 0.1 mg / mL colorless clear solution (intravenous injection group).

[0867] 2.4 Administration

[0868] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g.

[0869] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 0.1 mL / 10 g.

[0870] 3. Operation

[0871] In the gavage administration group: 0.1 mL of blood was collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The blood collection and centrifugation process was performed under ice bath conditions.

[0872] Intravenous injection group: Blood samples were collected before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration. The treatment was the same as that of the gavage group.

[0873] The levels of the target compound in the plasma of C57 mice were determined after administration of different concentrations of the drug.

[0874] Conclusion: The compound disclosed herein exhibits high exposure levels in C57 mice and demonstrates pharmacokinetic advantages.

[0875] Test Example 4: Degradation Activity Test of the Compounds of this Disclosure on STAT6 Protein in Human Whole Blood

[0876] I. Experimental Objective

[0877] The purpose of this experiment was to test the degradation effect of the disclosed compound on STAT6 protein in human whole blood, based on DC... 50 Size is used to evaluate the in vitro activity of compounds.

[0878] II. Experimental Materials

[0879] 1. Instruments

[0880] 2. Reagents and consumables

[0881] III. Experimental Methods

[0882] On day 1, 95 μL of human whole blood was plated into each well of a 96-well U-bottom cell culture plate. The test compound was then added to each well using a micro-liquid separator. The overall dimethyl sulfoxide (DMSO) concentration was set at 0.25%, with initial compound concentrations of 100 nM, 10 nM, or 1 nM (column 2), and 3-fold or 4-fold gradients (columns 3-11). Columns 1 and 12 were treated with DMSO only as negative and positive controls, respectively. The culture plates were then incubated at 37°C in a 5% CO2 cell culture incubator for 24 hours.

[0883] On the second day, 15 minutes before the end of whole blood incubation, the PB-conjugated anti-CD3 (anti-CD3-Pacific Blue) antibody was diluted 10-fold with complete culture medium (IMDM medium + 10% inactivated FBS) and added to whole blood at a rate of 5 μL per well. After brief mixing, the wells were incubated in a cell culture incubator for 15 minutes. After incubation, whole blood from the 96-well cell culture plate was transferred to 2 mL deep-well plates, 1 mL of 1× lysis / fixation buffer was added and mixed, and the plates were incubated at 37°C for 20 minutes to fully lyse and fix the red blood cells. The plates were then washed three times with staining buffer. Next, 400 μL of pre-chilled permeation buffer III was added to each well, mixed, and incubated on ice for 30 minutes. After washing three times with staining buffer, add 200 μL of Alexa Fluor 647-conjugated anti-STAT6 antibody (1:125 ratio) to each well in columns 2-12, and add 200 μL of Alexa Fluor 647-conjugated isotype control antibody (1:125 ratio) to each well in column 1. Incubate overnight at 4°C in the dark.

[0884] On the third day, after centrifuging to remove the antibodies, the cells were washed twice with staining buffer and then resuspended in 200 μL of staining buffer. Subsequently, whole-plate fluorescence detection (detecting Pacific Blue and Alexa Fluor 647 fluorescence channels) was performed on a flow cytometer.

[0885] V. Data Analysis

[0886] The proportion of STAT6-positive cells and their average fluorescence intensity in the CD3-positive single-cell population were analyzed using Flowjo software. The proportion of STAT6-positive cells in the negative control group was set at approximately 0.5%.

[0887] Calculate the relative fluorescence unit, where the relative fluorescence unit = the proportion of STAT6-positive cells in CD3 cells × the average fluorescence intensity.

[0888] Calculate the degradation rate, degradation rate = (relative fluorescence units) 阳性对照 -Relative fluorescence unit 化合物 ) / (Relative fluorescence unit) 阳性对照 -Relative fluorescence unit 阴性对照 The maximum degradation rate (Dmax) of the compound was determined by multiplying the degradation rate by 100% and setting the maximum degradation rate at each concentration as the maximum degradation rate (Dmax). A dose-response curve was plotted using XLfit, and DC was calculated. 50 .

[0889] Conclusion: The compound disclosed herein exhibits good degradation activity against STAT6 protein in human whole blood.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O); R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; X 2 For N or CH; Ring B is selected from 3 to 12 member monocyclic or bicyclic cycloalkyl, 3 to 12 member monocyclic or bicyclic heterocyclic, 6 to 12 member monocyclic or bicyclic aryl and 5 to 12 member monocyclic or bicyclic heteroaryl; Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; G is selected from hydrogen atom, halogen, and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic; V 1 For N or C; V 2 For N or CR w1 ; T is either N or C; Y 1 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ; M is selected from the bond, (CR) m1 R m2 ) e O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); M 1 Selected from key, (CR) m1 R m2 ) e1 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); M 2 Selected from key, (CR) m1 R m2 ) e2 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); e can be 0, 1, 2, 3, or 4; e1 can be 0, 1, 2, 3 or 4; e2 is 0, 1, 2, 3 or 4; R w3 and R m Each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and -C(O)OR 3 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally converted by one or more R groups. 0 replace; R w0 R w1 R w4 R w5 R m1 R m2 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2; the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace; Or, two Rs x Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs y Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 1 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 2 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, R m1 and R m2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 replace; x, y, n, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7; L x -(L A ) t1 -; L is -(L) B ) t2 -; L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally converted by one or more R 0 replace; R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; t1 is selected from integers from 0 to 10; t2 is selected from integers from 0 to 20; R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups; R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with their respective attached atoms, they form cycloalkyl or heterocyclic groups; and v can be 0, 1, or 2.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; Y 3 Selected from NR w3 O and S; Y 4 For N or CR w4 ; B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ; G, L x R x x, M, M 1 M 2 V 2 R w3 R w4 R 2 R 4 R 5 L, ring A, R 1 m, L 1 and X 2 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (II-1) or general formula (III-1) or a pharmaceutically acceptable salt thereof. in, n1 is 0, 1, 2, 3 or 4; Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 L, ring A, R 1 m, L 1 and X 2 As defined in claim 2.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is -(L B ) t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1- 6-alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group, wherein the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1- The alkyl group is substituted with one or more substituents in the 6-haloalkyl group and the =O group; t2 is 0, 1, 2, 3, 4, 5 or 6; Preferably, L is selected from the following: CH2, CH2CH2, CH2CH2CH2, * The end is connected to ring A.

5. A compound of formula (I) according to any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof. in, n1 is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3, 4 or 5; f is 0, 1, 2, or 3; g can be 0, 1, 2, or 3; t3 is 0, 1, 2, 3, 4, or 5; Z 1 For N and CR z1 Z 2 For N or CR z2 ; R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl; R z The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), oxo, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R z Together with the attached atoms, they form a cycloalkyl or heterocyclic group; or, two R groups... z They connect to form bridging alkylene groups; G、L x 、R x 、x、 M, e1, e2, R w1 Y 3 Y 4 R 4 R 5 R 2 Ring A, R 1 m, L 1 and X 2 As defined in claim 2.

6. The compound of general formula (I) according to any one of claims 1 to 4, wherein it is the compound of general formula (VI) or a pharmaceutically acceptable salt thereof. in, Z 1 For N and CR z1 Z 2 For N or CR z2 Z 3 For N and CR z3 Z 4 For N or CR z4 ; R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl; f, f1, g, and g1 are each independently 0, 1, 2, or 3; and Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, ring A, R 1 m, L 1 and X 2 As defined in claim 3.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, 9- or 10-membered bicyclic aryl, 9- or 10-membered bicyclic heteroaryl, 13- to 15-membered tricyclic heterocyclic, and 16- to 20-membered tetracyclic heterocyclic; and / or R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups and =O; or, two R groups on the same carbon atom. 1 Together with the attached carbon atom, it forms a cyclopropyl group; and / or m is 0, 1, 2 or 3.

8. The compound of formula (I) according to any one of claims 1 to 6, wherein... Selected from *Terminal and L, (CH2)t3 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m5 is 0, 1, or 2; m6 is 0, 1, or 2; A1 is N or CH; A2 is N or CH; J is selected from bonds, O, (CR j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); u, p, and q are each independently 0, 1, 2, 3, or 4; p1 and q1 are each independently 0, 1, 2, 3, or 4; Q is selected from O, S, and NR. q and CR q1 R q2 J 3 and J 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; R A R j1 R j2 R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in claim 1; Preferably, Selected from *Terminal and L, (CH2)t3 or Z 4 Connected.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R w1 It is F.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein M is O or S; and / or e1 is 1, 2 or 3; and / or e2 is 0 or 1; and / or R m1 and R m2 Each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, or R on the same carbon atom m1 and R m2 Together with the attached carbon atom, they form a cyclopropyl group; Preferably, M is 0; and / or e1 is 1; and / or e2 is 0 or 1; and / or R m1 and R m2 It is a hydrogen atom.

11. The compound of general formula (I) according to any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 3 Selected from O, S and NH; preferably, Y 3 For NH; and / or Y 4 It is N or CH; preferably, Y 4 For CH.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the connected nitrogen atom, they form a 3- to 8-membered heterocyclic group; preferably, R 4 and R 5 C 1-6 alkyl.

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 2 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 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy group; and / or n or n1 is 0, 1 or 2.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3; preferably, L x Selected from CH2, CH2CH2, More preferably, L x for * The terminal is connected to G or ring Y.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein G is a hydrogen atom or Cycloyl Y is a 5-membered heteroaryl group; R y Selected from hydrogen atoms, halogens and C 1- 6 alkyl; y is 0 or 1; preferably, G is selected from hydrogen atoms, 16. The compound of formula (I) according to any one of claims 5 to 15, or a pharmaceutically acceptable salt thereof, wherein Z 1 For N or CH; and / or Z 2 For N or CH; and / or f and g are each independently 0 or 1; and / or R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; and / or k is 0 or 1; and / or t3 is 0, 1, 2 or 3.

17. The compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: And all compounds or their pharmaceutically usable salts mentioned in Group A of the instructions.

18. A compound of general formula (II-1A) or general formula (III-1A), or a salt thereof, in, R P Selected from halogens, -B(OH)2 and Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 and R 5 As defined in claim 3.

19. A compound of general formula (VIA) or a salt thereof, in, Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, Z 1 f and g are as defined in claim 6.

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

21. A method for preparing a compound of general formula (II-1) or general formula (III-1) as claimed in claim 3, the method comprising: The compound of general formula (II-1A) or its salt reacts with the compound of general formula (IIB) or its salt to give the compound of general formula (II-1) or its pharmaceutically usable salt. The compound of general formula (III-1A) or its salt reacts with the compound of general formula (IIB) or its salt to give the compound of general formula (III-1) or its pharmaceutically usable salt. in, R P It is a halogen; R T -B(OH)2 or Or, R P -B(OH)2 or R T It is a halogen; Ring Y, R y y, L x R x x, M, e1, e2, R m1 R m2 R w1 Y 3 Y 4 R 4 R 5 R 2 n1, L, ring A, R 1 m, L 1 and X 2 As defined in claim 3.

22. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, and one or more pharmaceutically acceptable carriers, diluents or excipients.

23. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22 in the preparation of a medicament for inhibiting or degrading STAT6.

24. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on STAT6.

25. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, in the preparation of a medicament for the treatment and / or prevention of cancer, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases. Used for the treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, and inflammation. Gastrointestinal disorders, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, systemic sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome, and so on. Uses in medications for allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

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