Macrocyclic compounds inhibiting and inducing egfr degradation, process for their preparation and use in medicine

Abstract

The present disclosure relates to macrocyclic compounds that inhibit and induce EGFR degradation, methods of making the same, and their use in medicine. In particular, the present disclosure relates to a macrocyclic compound of general formula (I), methods of making the same, pharmaceutical compositions containing the same, and uses of the same as therapeutic agents, particularly as EGFR inhibitors and / or degraders and in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by or dependent on EGFR.

Description

Technical Field

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

[0002] Lung cancer is one of the most common malignant tumors. Statistics show that in 2018, lung cancer was the cancer with the highest incidence rate globally, with 2.094 million new cases. In China, the number of new lung cancer cases in 2018 was 868,000, with an incidence rate of 0.062%, accounting for 41.4% of the global total. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) belongs to the cell surface receptor family with tyrosine kinase activity. EGFR mutation is the most common driver gene in NSCLC, with approximately 40% of Chinese NSCLC patients having EGFR mutations, compared to 11-16% of patients in Western countries. Approximately 90% of EGFR mutations are deletions of exon 19 (Del19 mutation) and L858R point mutations in exon 21.

[0003] Several small molecule EGFR inhibitors have been approved for marketing and successfully applied to the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations, becoming one of the main treatment methods for patients with advanced NSCLC. First-generation EGFR tyrosine kinase inhibitors, represented by gefitinib and erlotinib, are reversibly binding targeted drugs that inhibit EGFR kinase activation by competitively binding to the EGFR kinase domain with ATP. However, most patients develop resistance after 10-12 months of treatment, with approximately 50% of resistance due to the development of a secondary T790M mutation. Second-generation EGFR tyrosine kinase inhibitors, represented by afatinib, are irreversible targeted drugs, but they cannot address the T790M mutation resistance problem, and their lack of selectivity for wild-type EGFR results in significant toxicity. The advent of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, overcame drug resistance caused by EGFR T790M gene mutations. It also showed strong inhibition of wild-type EGFR with good selectivity, achieving great success in clinical practice. However, new drug resistance can develop after 9-14 months of use. Studies have revealed that 6-26% of patients developed C797X or other EGFR-dependent gene mutations.

[0004] Currently, there is a lack of effective EGFR inhibitors on the market that target the EGFR C797S gene mutation as a standalone treatment. Therefore, it is necessary to develop new treatment methods for non-small cell lung cancer (NSCLC). Unlike EGFR inhibitors, PROTAC technology can degrade EGFR, which can more effectively inhibit the EGFR signaling pathway and has the potential to become a promising treatment method for NSCLC. Published patents for EGFR protein-targeted degradation include WO2024099395A1 and WO2024246838A1. Summary of the Invention

[0005] The purpose of this disclosure is to provide a compound of general formula (I), or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0009] Ring D is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups;

[0010] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0011] W is selected from bond, O, S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0012] V is N or CR 0 ;

[0013] R 0 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0014] X 4 X 5 and X 6 Whether they are the same or different, and each is independently N or CR 3 ;

[0015] R 2 R 3 and R 5The same or different, and each independently selected from hydrogen atom, oxo group, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced;

[0016] Or two Rs 3 Together with the carbon atom attached to it, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or two R groups. 5 Together with the ring atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or R 5 R 7 Together with the ring atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups; each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced;

[0017] J 1 Selected from bond, O, S(O) v NR J C(O), C(O)NR J NR J C(O), (CR) c R d ) y cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally composed of one or more R groups. 02 Replaced;

[0018] J 2 J 3 J 4 J5 and J 6 Same or different, and each is independently selected from the key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently optionally coupled with one or more R 6 Replaced;

[0019] L 1 L 2 L 3 L 4 L 5 and L 6 They may be the same or different, and each is independently selected from the bond, O, and S(O). v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L ), alkenyl, alkyneyl, cycloalkyl, heterocyclic, (CR) e R f ) u -Heterocyclic group, heterocyclic group-(CR) e R f ) u 、(CR e R f ) u -heterocyclic-(CR) e R f ) uaryl and heteroaryl; each of the alkenyl, alkyneyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally composed of one or more R 7 Replaced;

[0020] Each R a R b R c R d R e and R f The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is optionally independently bound by one or more R... 03 Replaced;

[0021] R 4 R m R 11 R 12 R 13 R 14 R J and R L The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced;

[0022] Each R 6 R 7 R 8 R 01 R 02 and R 03 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 C(O)NR 21 R 22 alkylene NR 21 R 22 alkylene C(O)NR 21 R 22 NR 23 C(O)R 24C(O)R 24 C(O)OR 24 S(O) v R 24 S(O) v OR 24 OR 24 S(O) v NR 21 R 22 =CR 15 R 16 =NR 23 , cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl;

[0023] R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, and heterocyclic groups;

[0024] Each R 21 R 22 R 23 and R 24 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

[0025] x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6;

[0026] u can be 0, 1, 2, 3, 4, 5, or 6;

[0027] a is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0028] r is 0, 1, 2, 3, 4, 5, or 6; and

[0029] v can be 0, 1, or 2.

[0030] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; in some embodiments, the ring C is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, the ring C is a 5-membered heteroaryl; in some embodiments, the ring C is pyrazolyl.

[0031] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein J 1 It is either a key or an 0; in some implementations it is an 0.

[0032] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein J 2 For key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 2 For key or (CR) c R d ) y In some implementation schemes, J 2 For bond or (CH2) y In some implementation schemes, J 2 As the key; where R c R d y, v, R J and R 6 As defined in general formula (I).

[0033] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein J 3 For key, (CR c R d ) y1 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 3 For key or (CR) c R d ) y1 In some implementation schemes, J 3 For (CR) c R d ) y1 In some implementation schemes, J 3 (CH2) y1 Where y1 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, J 3 CH2; where R c Rd v, R J and R 6 As defined in general formula (I).

[0034] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein J 4 For key, (CR c R d ) y1 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; where R c R d y, v, R J and R 6 As defined in general formula (I); in some implementations, J 4 It is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, J 4 It is a 3- to 12-membered cycloalkyl group, each of which is optionally independently converted by one or more R... 6 Replaced; in some implementations, J 4 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, J 4 The alkyl group is a 3- to 6-membered cycloalkyl group, each of which is optionally independently coupled with one or more R groups. 6 Replaced; R 6 As defined in general formula (I); in some implementations, J 4 Selected from cyclopropyl, cyclobutyl and cyclopentyl.

[0035] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein J 5 For key, (CR c R d ) y2 O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 5 For key or (CR)c R d ) y2 In some implementation schemes, J 5 For (CR) c R d ) y2 In some implementation schemes, J 5 (CH2) y2 Where y2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, J 5 CH2; where R c R d v, R J and R 6 As defined in general formula (I).

[0036] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein J 6 For key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups; wherein the 3 to 12-membered cycloalkyl and 3 to 12-membered heterocyclic groups are each independently optionally composed of one or more R 6 Replaced; in some implementations, J 6 For key or (CR) c R d ) y In some implementation schemes, J 6 For bond or (CH2) y In some implementation schemes, J 6 As the key; where R c R d y, v, R J and R 6 As defined in general formula (I).

[0037] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring C is a 5- to 10-membered heteroaryl group, and / or J 4 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, the ring C is a 5- or 6-membered heteroaryl, and / or J 4 Selected from cyclopropyl, cyclobutyl, and cyclopentyl; in some embodiments, ring C is pyrazolyl, and / or J 4 It is cyclobutyl.

[0038] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formulas (II), (II-1), or (II-2) or a pharmaceutically acceptable salt thereof:

[0039]

[0040]

[0041]

[0042] Wherein, ring B is a cycloalkyl or heterocyclic group;

[0043] B 1 B 2 and B 3 Whether they are the same or different, and each is independently N or CR 7a ;R 7a For hydrogen atoms or R 7 ;

[0044] R 1 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0045] s is 0, 1, 2 or 3; s1 is 0 or 1; s2 is 0 or 1;

[0046] b1 and b2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently;

[0047] m, p, q, y1 and y2 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6;

[0048] y3 and y4 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6;

[0049] Ring A, L 3 L 5 ,u,t,ring D,J 1 R 2 To R 8 And r are as defined in general formula (I).

[0050] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein for or Ring D, R 1 To R 6 , m, J 1 y1 to y4, s and t are as defined in general formula (II); in some implementations, for or Ring D, R 1 To R 6 , m, J 1 y1 to y4, s and t are as defined in general formula (II).

[0051] In some embodiments of this disclosure, for or In some implementation schemes, selected from , , and R 1 To R 6 , m, J 1 y1 to y4, s, t, Y, t1, t2, a1 and a2 are as defined in the general formula (VM).

[0052] In some embodiments of this disclosure, for or In some implementation schemes, the following options are selected: , , and ;R 1 To R 6 , m, J 1 y1 to y4, s, t, Y, t1, t2, a1 and a2 are as defined in the general formula (VM).

[0053] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein ring D is selected from... , , and In some implementation schemes, ring D is... or * Fusing to the imidazole ring at the * end, Key and L 1 Connection; X 1 and X 2 Whether they are the same or different, and each is independently N or CR 5 ;

[0054] Y is selected from bond, O, S(O). v C(O), (CR) a R b ) x C(O)O, OC(O), NR m C(O)NR m NR mC(O) and NR m C(O)NR m ; t1 and t2 are each independently 0, 1, 2, 3, 4 or 5; a1 and a2 are each independently 0, 1, 2, 3, 4 or 5; A 1 For N or CR A1 A 2 For N or CR A2 ;

[0055] R A1 and R A2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, hydroxyalkyl, haloalkyl, hydroxyl, cyano, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic and cycloalkylalkyl; R a R b x, R m R 5 And v is as defined in general formula (I);

[0056] In some implementations, ring D is selected from... , , , , , , and In some implementation schemes, ring D is selected from... , , and In some implementation schemes, ring D is selected from... , , and * Fusing to the imidazole ring at the * end, Key and L 1 Connection; in some implementations, ring D is selected from , , , , , , and The ** and +* ends fuse to the imidazole ring, with the ** end close to R. 4 , Key and L 1 Connection; in some implementations, ring D is selected from

[0057] , , , , , , , , , , , , , , , , , , , , , , and .

[0058] In some embodiments of this disclosure, ring A is a 6- to 14-membered aryl or a 5- to 14-membered heteroaryl; in some embodiments, ring A is selected from phenyl, pyridyl, indazolyl, and 1,3-dihydrospiro[indenyl-2,4'-piperidinyl]yl; in some embodiments, ring A is selected from... , and ; Key and L 5 or L 6 The * bond is connected to the W or dioxopiperidine ring.

[0059] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II), or pharmaceutically acceptable salts thereof, are compounds represented by general formulas (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof:

[0060]

[0061]

[0062]

[0063]

[0064] in,

[0065] Y is selected from bond, O, S(O). v C(O), (CR) a R b ) x C(O)O, OC(O), NR m C(O)NR m NR m C(O) and NR m C(O)NR m ;

[0066] t1 and t2 are each independently 0, 1, 2, 3, 4 or 5;

[0067] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0068] A 1 For N or CR A1 A 2 For N or CR A2 ;

[0069] R A1 and R A2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyalkyl groups, haloalkyl groups, hydroxyl groups, cyano groups, alkoxy groups, haloalkoxy groups, alkoxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups;

[0070] t is 0, 1, 2, 3, 4, 5, or 6; r is 0, 1, 2, 3, or 4;

[0071] R 2 To R 8 B 1 B 2 B 3 Ring B, L 5 , b1, b2, s1, s2, p, q, u, J 1 s, y1 to y4, m, R a R b R m x is as defined in general formula (II).

[0072] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IIIM), (IVM), (VM), (VIM), or (VII) or a pharmaceutically acceptable salt thereof:

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] Where Q is CR 8a Or N; R 8a For hydrogen atoms or R 8 ;

[0079] X is selected from bonds, O, S, and (CH2). zE 1 For CR 8b Or N; R 8b For hydrogen atoms or R 8 ;

[0080] z is 0, 1, 2, or 3; r is 0, 1, 2, or 3;

[0081] e1, e2, and e3 are each independently 0, 1, 2, or 3;

[0082] B 1 B2, ring B, B3, L5, W, s2, s1, b1, b2, u, p, q, Y, t1, t2, a1, a2, A1, A2, t, J1, R1 to R8, s, y1 to y4 and m as defined in general formulas (I), (III), (IV) or (V).

[0083] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof, wherein Y is selected from bonds, O, S, S(O), S(O)2, C(O), NR m C(O)NR m and NR m C(O); R m As defined in general formula (I); in some embodiments, Y is selected from bond, O, S, C(O), NH, N(CH3), S(O), S(O)2, C(O)NH and NHC(O); in some embodiments, Y is O.

[0084] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein t1 is 0 or 1, and / or t2 is 0 or 1; in some embodiments, t1 is 0 or 1, and / or t2 is 1; in some embodiments, t1 is 0, and / or t2 is 1.

[0085] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are wherein a1 is 0 or 1, and / or a2 is 0 or 1; in some embodiments, a1 is 1, and / or a2 is 1.

[0086] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein A 1 For CH or N; in some implementations, A 1 Let N be the number of elements in the array.

[0087] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein A 2 For CH or N; in some implementations, A2 Let N be the number of elements in the array.

[0088] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein Y is selected from O, NH, N(CH3), and S(O). v C(O)NH and NHC(O), and / or A 1 For CH or N, and / or A 2 It is CH or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1.

[0089] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 For CR 5 R 5 As defined in general formula (I); in some implementations, X 1 Selected from N, CH, and CF; in some implementations, X 1 For CH.

[0090] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 2 For CR 5 R 5 As defined in general formula (I); in some implementations, X 2 Selected from N, CH, and CF; in some implementations, X 2 For CH.

[0091] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 Selected from N, CH and CF, and / or X 2 Selected from N, CH, and CF; in some implementations, X 1 For CH, and / or X 2 For CH.

[0092] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 4 For CR 3 R 3 As defined in general formula (I); in some implementations, X 4 Selected from N, CH, and CF; in some implementations, X 4 For CH.

[0093] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 5 For CR 3R 3 As defined in general formula (I); in some implementations, X 5 Selected from N, CH, and CF; in some implementations, X 5 For CH.

[0094] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 6 Let N be the number of elements in the array.

[0095] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein W is selected from bond, NH, NHC(O) and C(O)NH; in some embodiments, W is bond.

[0096] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein V is CH or N; in some embodiments, V is CH.

[0097] In some embodiments of this disclosure, Q is selected from CH, CF, and N.

[0098] In some embodiments of this disclosure, E 1 It can be CH or N.

[0099] In some embodiments of this disclosure, e1 is 0 or 1, and / or e2 is 0 or 1, and e3 is 1, 2 or 3.

[0100] In some embodiments of this disclosure, X is selected from bond, O, CH2 and CH2CH2; in some embodiments, X is CH2.

[0101] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 1 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L(CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 1 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 1 Selected from L, O, CH2, CH2CH2, CH(CH3), C(CH3)2, cyclopropyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 1 For key.

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 2 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e Rf ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 2 Selected from alkyl groups, 3- to 12-membered cycloalkyl groups, and 3- to 12-membered heterocyclic groups; in some embodiments, L 2 Selected from bonds, 5- or 6-membered cycloalkyl groups, and 5- or 6-membered heterocyclic groups; in some embodiments, L 2 For key or B 1 B 2 b1, b2 are as defined in general formula (II); in some implementations, L 2 It is piperidinyl or piperazine; in some embodiments, L 2 Selected from , or In some implementation schemes, .

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 3 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 3 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 3 Selected from bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, ethynyl, NH, N(methyl), cyclopropyl, C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 3 For key.

[0104] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 4 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 4 It is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, L 4 It is a 3- to 10-membered heterocyclic group; in some implementations, L 4 It is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; in some embodiments, L 4 for B 3 For CH or N, B 4 b3 is CH or N; b4 is 0, 1, or 2; b4 is 0, 1, or 2; in some implementations, L 4 It is piperidinyl or piperazine; in some embodiments, L 4 for or In some implementation schemes, L 4 For key.

[0105] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof, wherein ring B is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; in some embodiments, ring B is a 3- to 10-membered heterocyclic group; in some embodiments, ring B is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, ring B is... B 3 For CH or N, B 4 b3 is CH or N; b4 is 0, 1, or 2; in some embodiments, ring B is piperidinyl or piperazineyl; in some embodiments, ring B is... or In some implementation schemes, .

[0106] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein s2 is 0; in some embodiments, s2 is 1.

[0107] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 5 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u2 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u 6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5 For bond or (CH2)u2 u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5 (CH2) u2 u2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, L 5 Selected from L, O, CH2, CH2CH2, CH(CH3), C(CH3)2, cyclopropyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 5 For key.

[0108] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein L 6 Selected from bond, O, S(O) v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L C 2-6 imidene group, C 2-6 acetylenyl, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocyclic, (CR e R f ) u -3 to 12-membered heterocyclic groups, 3 to 12-membered heterocyclic groups-(CR) e R f ) u 、(CR e R f ) u -3 to 12-membered heterocyclic groups-(CR) e R f ) u6- to 10-membered aryl and 5- to 10-membered heteroaryl; the C 2-6 imidene group, C 2-6 The ynyl group, 3 to 12-membered cycloalkyl group, 3 to 12-membered heterocyclic group, 6 to 10-membered aryl group, and 5 to 10-membered heteroaryl group are each independently and optionally enclosed by one or more R groups. 7 Replaced; R e R f v, u, R L R 7 As defined in general formula (I); in some implementations, L 6 For bond or (CH2) u u is as defined in general formula (I); in some implementations, L 6 Selected from bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 6 For key.

[0109] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 L 2 L 3 L 4 L 5 or L 6 Same or different, and each independently selected from the following groups: bond, CH2, CH2CH2, CH(CH3), C(CH3)2, O, C(O), NH, NHC(O), C(O)NH, cyclopropyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and (In some embodiments, these rings are optionally selected from oxo groups, halogens, C...) 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 hydroxyalkyl).

[0110] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、 or Selected from , , , , , and In some implementation schemes, it is a key or In some implementation schemes, .

[0111] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein B 1 For CH or N, and / or B 2 For CH or N; in some implementations, B 1 For CH or N, and / or B 2 For N; in some implementations, B 1 For N, and / or B 2 Let N be the number of elements in the array.

[0112] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein B 3 For N, and / or B 4 Let N be the number of elements in the array.

[0113] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are wherein b1 is 0 or 1, and / or b2 is 0 or 1; in some embodiments, b1 is 1, and / or b2 is 1.

[0114] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are wherein b3 is 1 or 2, and / or b4 is 1 or 2; in some embodiments, b3 is 1, and / or b4 is 1.

[0115] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein s1 is 0; in some embodiments, s1 is 1.

[0116] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein B 1 For CH or N, and / or B 2 For CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1; in some implementations, B 1 For N, and / or B 2 Let N be the number of elements, and / or b1 be 1, and / or b2 be 1.

[0117] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein u is 0 or 1, and / or L 5 For bond or (CH2) u2 u2 is 0, 1, or 2, and / or ring B is a 5- or 6-membered heterocyclic group; in some embodiments, u is 0, and / or L 5 s1 is the key, and / or s2 is 0.

[0118] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein u is 0, 1 or 2; in some embodiments, u is 0.

[0119] In some embodiments of this disclosure, the compound represented by general formulas (I) to (VII) or a pharmaceutically acceptable salt thereof, wherein u2 is 0, 1 or 2; in some embodiments, u2 is 0 or 1.

[0120] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein J 1 y1 is 0, and / or y2 is 0, 1 or 2, and / or y3 is 0, 1 or 2, and / or y4 is 1 or 2.

[0121] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are wherein y1 is 0, 1, 2 or 3, and / or y2 is 0, 1, 2 or 3; in some embodiments, y1 is 1, and / or y2 is 1.

[0122] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are wherein y3 is 0, 1 or 2, and / or y4 is 1 or 2; in some embodiments, y3 is 1, and / or y4 is 1.

[0123] In some embodiments of this disclosure, y3 is 1 and y4 is 1, or y3 is 1 and y4 is 2.

[0124] In some implementation schemes disclosed herein, Selected from , , , , and .

[0125] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1 C 1-6 Alkyl; in some embodiments, R 1 It is a methyl group.

[0126] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyl alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 2 Selected from hydrogen atoms, halogens, C1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 2 It is a hydrogen atom or a methyl group; in some embodiments, R 2 It is a hydrogen atom.

[0127] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

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

[0129] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0130] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, oxo groups, and C atoms. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5 It is a hydrogen atom.

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

[0132] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; and / or R 1 C 1-6 Alkyl, and / or R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 5 It is a hydrogen atom.

[0133] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 1 C 1-6 Alkyl, and / or R 2 For hydrogen atoms, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 5 It is a hydrogen atom.

[0134] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

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

[0136] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl.

[0137] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 7a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 7a It is a hydrogen atom.

[0138] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein p is 0, 1 or 2; in some embodiments, p is 0.

[0139] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein q is 0, 1 or 2; in some embodiments, q is 0.

[0140] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 8 They may be the same or different, and each is independently a halogen; in some implementations, R 8 It is F.

[0141] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof are used, wherein r is 0, 1, 2, 3 or 4; in some embodiments, r is 0, 1 or 2; in some embodiments, r is 2.

[0142] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein v is 0; in some embodiments, v is 2.

[0143] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R a and R b It is a hydrogen atom.

[0144] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or pharmaceutically acceptable salts thereof are used, wherein x is 0, 1, 2, 3 or 4; in some embodiments, x is 0, 1 or 2.

[0145] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R m It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0146] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 0 It is a hydrogen atom.

[0147] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R A1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R A1 It is a hydrogen atom.

[0148] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R A2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R A2 It is a hydrogen atom.

[0149] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for or .

[0150] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for or .

[0151] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0152] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 13 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0153] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0154] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R J It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0155] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R c and R d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R c and R d It is a hydrogen atom.

[0156] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts are used, wherein y is 0, 1, 2, 3 or 4; in some embodiments, y is 0, 1 or 2.

[0157] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein R L It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0158] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R e and R f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; in some embodiments, R e and R f It is a hydrogen atom.

[0159] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 01 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano and 3 to 6-membered cycloalkyl.

[0160] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 02 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano and 3 to 6-membered cycloalkyl.

[0161] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (VII) or their pharmaceutically acceptable salts, wherein each R 03 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano and 3 to 6-membered cycloalkyl.

[0162] In this disclosure, the general formulas (I) to (VII) include general formulas (I), (II), (II-1), (II-2), (III), (IV), (V) and (VI).

[0163] In some embodiments of this disclosure, the compounds represented by general formulas (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, wherein Y is selected from bonds, O, S, C(O), NH, N(CH3), S(O), S(O)2, C(O)NH and NHC(O), A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; s is 0, 1 or 2; R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, oxo groups, and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; t is 0, 1 or 2; each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1, or 2; u is 0 or 1, s1 is 1; B 1 For CH or N, B 2For CH or N, b1 is 0 or 1, b2 is 0 or 1, B 3 For CH or N, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; s2 is 0 or 1; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; p is 0, 1, or 2; q is 0, 1, or 2; L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group; r is 0, 1 or 2.

[0164] In some embodiments of this disclosure, the compounds represented by general formulas (III), (IV), (V) or (VI), or pharmaceutically acceptable salts thereof, wherein Y is selected from O, S, C(O), NH, N(CH3), S(O), S(O)2, C(O)NH, and NHC(O), and A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; J 1 For y1, y2, y3, y4, and y1 are all 0, 1, or 2; for y2, y3, y4 are all 1 or 2; for y4, y1 is 0; for y3, y4 is 1 or 2; for y4, y3 is 0; for y4, y4 is 1 or 2. 1 C 1-6 Alkyl; R 2 For hydrogen atoms; each R 3 The same or different, and each independently is C. 1-6 Alkyl; s is 1; R 4 For hydrogen atoms; R 5 For hydrogen atoms; t is 0, u is 0, B 1 For CH or N, B 2 For CH or N, b1 is 0 or 1, b2 is 0 or 1, s1 is 1; s2 is 0; L 5 For bond or (CH2) u2 u2 is 0, 1, or 2; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1 or 2; each R 8 They may be the same or different, and each is an independent halogen; r is 0, 1 or 2.

[0165] In some embodiments of this disclosure, the compound represented by general formula (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof, wherein Y is O, A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; J 1 For y1, y2, y3, y4, and y1 are all 0, 1, or 2; for y2, y3, y4 are all 1 or 2; for y4, y1 is 0; for y3, y4 is 1 or 2; for y4, y3 is 0; for y4, y4 is 1 or 2. 1 C 1-6 Alkyl; R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 3 The same or different, and each independently is C. 1-6 Alkyl; s is 1; R 4 For hydrogen atoms; R 5 For hydrogen atoms; t is 0, u is 0, B 1 For CH or N, B 2 For CH or N, b1 is 0 or 1, b2 is 0 or 1, s1 is 0 or 1; s2 is 0 or 1; ring B is a 3- to 12-membered heterocyclic group; L 5 For the key; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, hydroxyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; each R 8 They may be the same or different, and each is an independent halogen; r is 0, 1 or 2.

[0166] In some embodiments of this disclosure, the compound represented by general formula (VM) or (VII) or a pharmaceutically acceptable salt thereof, wherein Y is O, A 1 For N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; J 1 For y1, y2, y3, y4, and y1 are all 0, 1, or 2; for y2, y3, y4 are all 1 or 2; for y4, y1 is 0; for y3, y4 is 1 or 2; for y4, y3 is 0; for y4, y4 is 1 or 2. 1 C 1-6 Alkyl; R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 3 The same or different, and each independently is C. 1-6 Alkyl; s is 1; R 4 For hydrogen atoms; R 5 For hydrogen atoms; t is 0, u is 0, B 1 For CH or N, B 2For CH or N, b1 is 0 or 1, b2 is 0 or 1, s1 is 0 or 1; ring B is a 3- to 12-membered heterocyclic group; B 3 For CH or N; s2 is 0 or 1; L 5 For the key; each R 7 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, hydroxyl and C 1-6 Haloalkyl; p is 0, 1, or 2; q is 0, 1, or 2; Q is selected from CH, CF, and N; each R 8 They may be the same or different, and each is an independent halogen; r is 0, 1, or 2; W is a bond or NH; E 1 It is CH or N; e1 is 0 or 1; e2 is 0 or 1; e3 is 1 or 2; X is selected from bond, O and CH2.

[0167] In some embodiments of this disclosure, the compound represented by the general formula (IIIM), (IVM), (VM), or (VIM), or a pharmaceutically acceptable salt thereof, wherein Y is O, A 1 For CH or N, A 2 For CH or N, a1 is 0 or 1, a2 is 0 or 1, t1 is 0 or 1, t2 is 0 or 1; J 1 For y1, y2, y3, y4, and y4, y1 is 0, 1, or 2; for y2, y3 is 0, 1, or 2; for y4, y4 is 1 or 2. 1 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; s is 0, 1 or 2; R 4 For hydrogen atoms; each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, oxo groups, and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; t is 0, 1 or 2; each R 6 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Haloalkyl; m is 0, 1, or 2; u is 0, s1 is 1; B 1 For CH or N, B 2 For CH or N, b1 is 0 or 1, b2 is 0 or 1, B 3 For CH or N, ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; s2 is 0 or 1; each R 7They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; p is 0, 1, or 2; q is 0, 1, or 2; L 5 For the key; each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group; r is 0, 1 or 2; Q is CH or N; W is a bond; for or .

[0168] Typical compounds disclosed herein include, but are not limited to:

[0169] , ,

[0170] , ,

[0171] , ,

[0172] , ,

[0173] , ,

[0174] , ,

[0175] , ,

[0176] , ,

[0177] , ,

[0178] , ,

[0179] , ,

[0180] , , , 、 、 、

[0181] 、 、

[0182] 、 、

[0183] 、 、

[0184] 、 、 、

[0185] 、 、

[0186] 、 、

[0187] 、 、

[0188] 、 、

[0189] 、 、 、 、 、 、 、 、 、 、

[0190] 、 、

[0191] 、 、 、 、 、 、 、 、 、 、

[0192] 、 、

[0193] 、 、 、 、 、 、 、 、 、 、

[0194] 、 、

[0195] 、 、

[0196] 、 、

[0197] 、 、

[0198] 、 、

[0199] 、 、 、 、 、 、 、 、 、 、

[0200] 、 、

[0201] 、 、 、 、 、 、 、 、 、 、

[0202] 、 、

[0203] 、 、 、 、 、 、 、 、 、 、

[0204] 、 、

[0205] 、 、 、 、 、 、 、 、 、 、

[0206] 、 、

[0207] 、 、

[0208] 、 、

[0209] 、 、

[0210] 、 、

[0211] 、 、

[0212] 、 、

[0213] 、 、

[0214] 、 、

[0215] 、 、

[0216] 、 、

[0217] 、 、

[0218] 、 、

[0219] 、 、

[0220] 、 、

[0221] 、 、

[0222] 、 、

[0223] 、 、

[0224] 、 、

[0225] 、 、

[0226] 、 、

[0227] 、 、

[0228] 、 、

[0229] 、 、

[0230] 、 、

[0231] 、 、 、 、 、

[0232] 、 、

[0233] 、 、

[0234] 、 、 、 、

[0235] 、 、 、

[0236] 、 、 、 、 、 、 、 、 、 、 、

[0237] 、 、

[0238] 、 、 、 、 、 、 、 、 、

[0239] 、 、 、 、

[0240] 、 、

[0241] 、 、

[0242] 、 、

[0243] 、 、

[0244] 、 、

[0245] 、 、

[0246] 、 、 、

[0247] 、 、 、 、

[0248] 、 、

[0249] 、 、

[0250] 、 、

[0251] 、 、

[0252] 、 、

[0253] 、 、

[0254] 、 、 、

[0255] 、 、 、 、 、 、 、 、 、

[0256] 、 、 、 、 、

[0257] 、 、 、 、 、 、 、 、 、 、 、 、 、

[0258] 、 、

[0259] 、 、

[0260] 、 、

[0261] 、 、 、

[0262] 、 、 、 、 、 、 、 、 、

[0263] 、 、 、 、 , , , , , , , , ,

[0264] , , , , , , ,

[0265] , ,

[0266] , , .

[0267] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof:

[0268]

[0269] Among them, R P The protecting group is selected from hydrogen atoms, amino protecting groups, OH and O-hydroxy protecting groups; in some embodiments, the amino protecting group is Boc;

[0270] Ring C, Ring D, J 1 To J 6 X 4 X 5 X 6 R 2 To R 5 , t and a are as defined by general formula (I).

[0271] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IIIA-2), (IVA-2), (VA-2), (VA-4), and (VIA-2):

[0272]

[0273] Among them, R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc.

[0274] Y, t1, t2, a1, a2, A 1 A 2 J 1 R 1 To R 7 、u、B 1 B 2 b1, b2, p, s, t, y1 to y4 and m are as defined by general formulas (IIIM), (IVM), (VM) or (VIM).

[0275] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IIIA-1), (IVA-1), or (VA-1):

[0276]

[0277]

[0278] Among them, R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc.

[0279] Y, t1, t2, a1, a2, A 1 J 1 R 1 To R 7 , s, t, y1 to y4 and m are as defined by general formulas (III), (IV) or (V).

[0280] Typical intermediate compounds or salts thereof disclosed herein include, but are not limited to:

[0281] , ,

[0282] , , , , , ,

[0283] , , , , , 、 、 、

[0284] 、 、 、 、

[0285] 、 、 、 、

[0286] 、 、 、 、 、 、 、 、 、 、

[0287] 、 、 、 、 、 、 、 、

[0288] 、 、 、 、 、 、

[0289] 、 、 、 、 、 、 、 、

[0290] 、 、 、 、 、 、

[0291] 、 、 、 、 、 、

[0292] 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0293] 、 、 、 、 、 、 、 、 、 、

[0294] 、 、 、 、 、 、 、 、 、 、

[0295] 、 、 、 、 、 、

[0296] 、 、 、 、 、 。

[0297] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (III), (IV) or (V) or pharmaceutically acceptable salts thereof, the method comprising:

[0298]

[0299] A compound of general formula (IIIA) or a salt thereof undergoes a reductive amination reaction with a compound of general formula (IIIB) or a salt thereof to yield a compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0300] The compound of general formula (IVA) or its salt reacts with the compound of general formula (IIIB) or its salt via a reductive amination reaction to yield the compound of general formula (IV) or its pharmaceutically acceptable salt.

[0301] A compound of general formula (VA) or a salt thereof undergoes a reductive amination reaction with a compound of general formula (IIIB) or a salt thereof to yield a compound of general formula (V) or a pharmaceutically acceptable salt thereof.

[0302] Among them, A 2 N is 0, u is 0, B 1 It is CH and s1 is 1;

[0303] B 2 Ring B, B 3 L 5 ,s2,b1,b2,p,q,r,Y,t1,t2,a1,a2,A 1 ,t,J 1 R 1 To R 8 , s, y1 to y4 and m are as defined in general formulas (III), (IV) or (V).

[0304] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IIIM), (IVM), (VM), and (VIM) or pharmaceutically acceptable salts thereof, the method comprising:

[0305]

[0306] The compound of general formula (IIIA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (IIIM) CH or their pharmaceutically acceptable salts.

[0307] The compound of general formula (IVA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (IVM) CH or their pharmaceutically acceptable salts,

[0308]

[0309] The compound of general formula (VA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (VM) CH or pharmaceutically acceptable salts thereof, or

[0310]

[0311] The compound of general formula (VA-4) or its salt reacts with the compound of general formula (VB-2) or its salt in a reductive amination reaction to give A. 2 For CH and B 1 Compounds of the general formula (VM) for N or their pharmaceutically acceptable salts,

[0312]

[0313] The compound of general formula (VIA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (VIM) CH or their pharmaceutically usable salts.

[0314] Where u is 0 and s1 is 1;

[0315] B 2 Ring B, B 3 L 5 ,Q,W,s2,b1,b2,p,q,r,Y,t1,t2,a1,a2,A 1 ,t,J 1 R 1 To R 8 , s, y1 to y4 and m are as defined in general formulas (IIIM), (IVM), (VM) or (VIM).

[0316] In some embodiments, the reductive amination reaction described above may optionally occur under acidic or basic conditions; in some embodiments, the reductive amination reaction described above occurs under acidic conditions; in some embodiments, the reductive amination reaction occurs under basic conditions.

[0317] Reagents providing acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, acetic acid, glacial acetic acid, Ti(i-PrO)3 ​​and BF3·Et2O, TiCl4, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, titanium tetrachloride, Me3SiCl, and TMSOTf. In some embodiments, the reagent providing acidic conditions is an added acidic reagent, and / or an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the hydrochloride salt of the reactants.

[0318] The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to, N,N'-dimethylethylenediamine, triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, N,N-diisopropylethylamine is used.

[0319] In the above synthesis scheme, the above-mentioned reductive amination reaction occurs in the presence of a reducing agent; in some embodiments, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and sodium acetylborohydride; in some embodiments, it is sodium triacetoxyborohydride.

[0320] The reactions described above can be carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.

[0321] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formulas (I) to (VII) of this disclosure and those shown in Table A, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0322] This disclosure further relates to the use of compounds of general formulas (I) to (VII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for regulating EGFR ubiquitination and degradation.

[0323] This disclosure further relates to the use of compounds of general formulas (I) to (VII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on EGFR.

[0324] This disclosure further relates to the use of compounds of general formulas (I) to (VII) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of cancer; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal carcinoma, bronchial neoplasms, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0325] This disclosure also relates to a method for regulating the ubiquitination and degradation of EGFR protein in a subject, comprising administering to a desired patient a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0326] This disclosure also relates to a method for inhibiting and / or degrading EGFR protein, comprising administering to a desired patient a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0327] This disclosure also relates to a method of treating and / or preventing EGFR-mediated or dependent diseases or conditions, comprising administering to a desired patient a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0328] This disclosure also relates to a method of treating and / or preventing cancer, comprising administering to a desired patient a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0329] This disclosure further relates to a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0330] This disclosure further relates to a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for regulating the ubiquitination and degradation of EGFR protein in a subject.

[0331] This disclosure further relates to a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which serves as an EGFR inhibitor and / or degrader.

[0332] This disclosure further relates to a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine for treating and / or preventing diseases or conditions mediated or dependent on EGFR.

[0333] This disclosure further relates to compounds of the above general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating EGFR protein ubiquitination and degradation in a subject.

[0334] This disclosure further relates to compounds of the above general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for inhibiting and / or degrading EGFR protein.

[0335] This disclosure further relates to compounds of the above general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on EGFR.

[0336] This disclosure further relates to a compound of the above general formulas (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, for the treatment and / or prevention of cancer; in some embodiments, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0337] In some embodiments, the EGFR-mediated or dependent diseases or conditions described in this disclosure are cancers; in some embodiments, the diseases or conditions are selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; in some embodiments, lung cancer; in some embodiments, non-small cell lung cancer.

[0338] In some embodiments, the lung cancer is small cell lung cancer or non-small cell lung cancer; in some embodiments, the non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or large cell lung cancer; in some embodiments, the head and neck cancer is head and neck squamous cell carcinoma; in some embodiments, the esophageal cancer is esophageal squamous cell carcinoma; and in some embodiments, the glioblastoma is glioblastoma multiforme.

[0339] In some embodiments, the cancer described in this disclosure is an EGFR protein with an L858R mutation.

[0340] In some embodiments, the cancer described in this disclosure is an EGFR protein with a 19del mutation.

[0341] In some embodiments, the cancer described in this disclosure is an EGFR protein with a T790M mutation.

[0342] In some embodiments, the cancer described in this disclosure is an EGFR protein with a C797X mutation.

[0343] In some embodiments, the cancer described in this disclosure is an EGFR protein with L858R and T790M mutations. In some embodiments, the cancer is an EGFR protein with 19del and T790M mutations. In some embodiments, the cancer is an EGFR protein with L858R and C797X mutations. In some embodiments, the cancer is an EGFR protein with 19del and C797X mutations. In some embodiments, the cancer is an EGFR protein with T790M and C797X mutations.

[0344] In some embodiments, the cancer is an EGFR protein with mutations L858R, T790M, and C797X. In some embodiments, the cancer is an EGFR protein with mutations 19del, T790M, and C797X. In some embodiments, the C797X mutation is a C797S mutation; where X represents any amino acid including S.

[0345] The active compound can be formulated in a form suitable for administration via any appropriate route, either in a unit dose or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0346] As a general guideline, a suitable unit dose can be 0.1 to 1000 mg.

[0347] 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.

[0348] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0349] 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.

[0350] 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.

[0351] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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 disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] Terminology Explanation

[0361] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0362] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-10 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C164 ... 1-6 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0363] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 alkylene), C 1-8 Alkylene, C 2-7 Alkylene or C 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker.

[0364] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C64-64 carbon atoms). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0365] 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 (Alkyne group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0366] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0367] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28) ring atoms (i.e., 3 to 28 membered cycloalkyl). In some embodiments, the cycloalkyl group has 3 to 16 ring atoms (i.e., 3 to 16-membered cycloalkyl); in some embodiments, the cycloalkyl group has 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl) or 3 to 10 ring atoms (i.e., 3 to 10-membered cycloalkyl); in some embodiments, it has 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl); in some embodiments, it has 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl), 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl), or 5 or 6 ring atoms (i.e., 5 or 6-membered cycloalkyl); in some embodiments, it has 5 or 6 ring atoms.

[0368] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0369] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0370] The term "spirocycloalkyl" refers to a polycyclic system in which the rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or the ring may contain 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 the full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28) ring atoms (i.e., 5 to 28 membered spirocycloalkyl). In some embodiments, the spirocycloalkyl group is a spirocycloalkyl group having 6 to 16 ring atoms (i.e., a 6 to 16-membered spirocycloalkyl group) or a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spirocycloalkyl group), and in some embodiments, a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). The spirocycloalkyl group includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), and in some embodiments is a monospirocycloalkyl or bispirocycloalkyl 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 monospirocycloalkyl group. Non-limiting examples include:

[0371] Its connection point can be anywhere;

[0372] wait.

[0373] 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, 20, 21, 22, 23, 24, 25, 26, 27, or 28) ring atoms (i.e., 5 to 28-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 16 ring atoms (i.e., 6 to 16-membered fused cycloalkyl) or a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quaternary, ternary / pentary, ternary / hexaternary, quaternary / quaternary, quaternary / pentary, quaternary / hexaternary, pentary / pentary, pentary / pentary, pentary / pentary, pentary / hexatern ... or pentary / hexaternary bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0374] Its connection point can be anywhere; wait.

[0375] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the rings may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28) carbon atoms (i.e., 5 to 28-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 bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0376] Its connection point can be anywhere.

[0377] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... , , wait.

[0378] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0379] 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 has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28) ring atoms (i.e., 3 to 28-membered heterocyclic group). In some embodiments, the heterocyclic group has 3 to 16 ring atoms (i.e., 3 to 16-membered heterocyclic group); in some embodiments, the heterocyclic group has 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic group), or 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic group), or 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic group); in some embodiments, it has 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic group); in some embodiments, it has 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic group), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic group), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic group); in some embodiments, it has 5 or 6 ring atoms.

[0380] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, azacyclic butyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0381] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0382] 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 it contains at least one monocyclic heterocyclic group with a connecting point 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, 20, 21, 22, 23, 24, 25, 26, 27, or 28) ring atoms (i.e., 5 to 28-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 16 ring atoms (i.e., a 6 to 16-membered spiroheterocyclic group) or a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), and in some embodiments, it is a monospirocyclic or bispirocyclic group, and 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 monospirocyclic group. Non-restrictive examples include:

[0383] wait.

[0384] 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 connecting 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, 20, 21, 22, 23, 24, 25, 26, 27, or 28) ring atoms (i.e., 5 to 28-membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 16 ring atoms (i.e., a 6 to 16-membered fused heterocyclic group) or 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:

[0385] wait.

[0386] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two atoms are shared between the rings, 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, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28) ring atoms (i.e., 5 to 20-membered bridged heterocyclic group). In some embodiments, the bridged heterocyclic group is a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered bridged heterocyclic group), and in some embodiments, it is a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclic group). Based on the number of constituent rings, they can be classified as bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), and in some embodiments, they are bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0387] wait.

[0388] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0389] , , and wait.

[0390] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0391] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28) ring atoms (i.e., 6 to 28-membered aryl). In some embodiments, the aryl group is an aryl group having 6 to 16 ring atoms (i.e., 6 to 16-membered aryl) or an aryl group having 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, an aryl group having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Monocyclic aryl groups include, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthraceneyl, phenanthryl, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0392] wait.

[0393] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28) ring atoms (i.e., 5 to 28-membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 16 ring atoms (i.e., a 5 to 16-membered heteroaryl group) or a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0394] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.

[0395] 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:

[0396]

[0397] wait.

[0398] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0399] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0400] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0401] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0402] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0409] 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.

[0410] The term "hydroxyalkoxy" refers to an alkoxy group that is substituted with one or more hydroxyl groups, where the alkoxy group is as defined above.

[0411] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl group and the alkoxy group are as defined above; in some embodiments, it is -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.

[0412] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0413] The term "hydroxyl group" refers to -OH.

[0414] The term "amino" refers to -NH2.

[0415] The term "cyano" refers to -CN.

[0416] The term "nitro" refers to -NO2.

[0417] The term "oxo" or "oxo group" refers to "=O".

[0418] The term "carbonyl" refers to C=O.

[0419] TBS refers to tert-butyldimethylsilyl.

[0420] 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, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), etc.

[0421] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, trans-block 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.

[0422] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and the E-type are included."

[0423] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. Also included are transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. For example, some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0424] 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:

[0425] .

[0426] 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:

[0427] .

[0428] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0429] 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 I In some implementation schemes, it is deuterium.

[0430] 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.

[0431] When a position is specifically designated as deuterium D, the position 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.

[0432] "Optional" or "optional" means that the event or situation subsequently described 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 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.

[0433] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, such as 1, 2, or 3, meaning that 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0434] "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.

[0435] "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.

[0436] 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.

[0437] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0438] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0439] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0440] Example

[0441] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0442] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0443] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0444] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0445] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0446] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0447] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0448] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0449] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0450] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0451] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0452] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0453] The known starting materials of this invention can be synthesized using or according to 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.

[0454] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0455] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0456] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0457] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0458] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0459] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0460] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0461] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0462] In the examples, the reaction process 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 C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0463] Example 1

[0464] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 59 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 3 -yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0465]

[0466] Exact Mass: 846.38

[0467] Example 2

[0468] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 3 -yl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0469]

[0470]

[0471] first step

[0472] 3-((2-bromo-4-fluoro-5-nitrophenoxy)methyl)-4-(4-methoxybenzyl)piperazine-1-carboxylic acid tert-butyl ester 2c

[0473] 2-Bromo-4-fluoro-5-nitrophenol 2a (2.0 g, 8.47 mmol, Biotin), 3-(hydroxymethyl)-4-(4-methoxybenzyl)piperazine-1-carboxylic acid tert-butyl ester 2b (3.14 g, 9.32 mmol, prepared by the method disclosed in compound 3a on page 40 of patent application WO2022247816A1), and triphenylphosphine (3.33 g, 12.7 mmol) were dissolved in tetrahydrofuran (50 mL), and diisopropyl azodicarboxylic acid (2.57 g, 12.7 mmol, 2.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 2c (3.0 g, yield: 64%).

[0474] MS m / z (ESI): 554.2 [M+1].

[0475] Step 2

[0476] 3-((2-bromo-4-fluoro-5-nitrophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 2d

[0477] Compound 2c (3.0 g, 5.42 mmol) was dissolved in acetonitrile (50 mL) and water (5 mL), and cerium ammonium nitrate (17.2 g, 32.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (100 mL × 2), 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 elution system B to give the title compound 2d (2.0 g, yield: 85%).

[0478] MS m / z (ESI): 434.1 [M+1].

[0479] Step 3

[0480] 9-Fluoro-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 2e

[0481] Compound 2d (2.0 g, 4.60 mmol) was dissolved in 1,4-dioxane (20 mL), and cesium carbonate (3.0 g, 9.2 mmol) and methanesulfonic acid [(R)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (437 mg, 0.46 mmol, adamas) were added. The mixture was purged with nitrogen three times and heated to 120 °C for 16 h. The reaction solution was cooled to room temperature, poured into 30 mL of water, and 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 using system C as the elution point to give the title compound 2e (830 mg, yield: 51%).

[0482] MS m / z (ESI): 354.2 [M+1].

[0483] Step 4

[0484] 9-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 2g

[0485] Compound 2e (600 mg, 1.70 mmol), ((1s,3s)-3-(aminomethyl)cyclobutyl)methanol 2f (215 mg, 1.87 mmol, prepared by the method disclosed in Example 1 on page 35 of patent application WO2024099402A1) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (440 mg, 3.40 mmol, 0.6 mL) was added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, quenched with water (30 mL), 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 elution system C to give 2 g (580 mg, yield: 76%) of the title compound.

[0486] MS m / z (ESI): 449.3 [M+1].

[0487] Step 5

[0488] 9-((((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 2i

[0489] 2 g (250 mg, 0.56 mmol) of compound 2 h, methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid 2 h (110 mg, 0.45 mmol, prepared by the method disclosed in Example 1 on page 22 of patent application CN114163454A), and triphenylphosphine (177 mg, 0.68 mmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (136 mg, 0.68 mmol, 135 μL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give title compound 2i (209 mg, yield: 69%).

[0490] MS m / z (ESI): 678.4 [M+1].

[0491] Step 6

[0492] 8-Amino-9-((((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 2j

[0493] Compound 2i (209 mg, 0.31 mmol) was dissolved in ethyl acetate (5 mL), and palladium on carbon (50 mg, 0.05 mmol, 10% wt) was added. Hydrogen was purged three times, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 2j (180 mg). The product was used directly in the next reaction without purification.

[0494] MS m / z (ESI): 648.4 [M+1].

[0495] Step 7

[0496] 9-Amino-10-(((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 2k

[0497] Compound 2j (180 mg, 0.28 mmol) was dissolved in methanol (5 mL), and cyanogen bromide (45 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (20 mL × 2), 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 elution system A to give the title compound 2k (140 mg, yield: 75%).

[0498] MS m / z (ESI): 673.5 [M+1].

[0499] Step 8

[0500] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 3 -tert-butyl carboxylate 2l

[0501] Compound 2k (140 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5 mL), and bis(trimethylsilylaminolithium) (0.6 mL, 1 M tetrahydrofuran solution) was added dropwise at 0 °C. The mixture was stirred for 30 minutes after returning to room temperature. The reaction solution was poured into 20 mL of ethyl acetate and washed successively with saturated ammonium chloride solution (10 mL × 2) and saturated sodium chloride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 2l (110 mg, yield: 83%).

[0502] MS m / z (ESI): 641.4 [M+1].

[0503] Step 9

[0504] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclobutazine-3-one 2m

[0505] Compound 2l (62 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane in 4 M hydrogen chloride (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 2), 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 to give crude title compound 2m (47 mg). The product was used directly in the next reaction without purification.

[0506] MS m / z (ESI): 541.4 [M+1].

[0507] Step 10

[0508] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,26 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 3 -yl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0509] Compound 2m (47 mg, 0.09 mmol) and 3-(2,6-difluoro-4-(4-oxopiridin-1-yl)phenyl)piperidin-2,6-dione 2n (42 mg, 0.13 mmol, prepared by the method disclosed in intermediate 7 on page 102 of patent application WO2024246838A1) were dissolved in 1,2-dichloroethane (5 mL), sodium triacetoxyborohydride (55 mg, 0.26 mmol) were added, and the mixture was heated to 50 °C and reacted overnight. After the reaction was completed, water (5 mL) was added to quench the reaction, followed by extraction with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (instrument model: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give title compound 2 (22 mg, yield: 30%).

[0510] MS m / z (ESI): 847.5 [M+1].

[0511] 1H NMR (500 MHz, CDCl3): δ 11.57 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.59 (s, 1H), 6.84 (s, 1H), 6.54 (d, 1H), 6.45 (d, 1H), 4.67-4.58 (m, 1H), 4.33-4.28 (m, 1H), 4.24-4.16 (m, 1H), 4.11-4.06 (m, 3H), 3.88-3.80 (m, 2H), 3.74 (s, 3H), 3.71-2.95 (m, 5H), 2.90-2.51 (m, 15H), 2.13-1.78 (m, 6H), 1.68-1.57 (m, 2H), 0.94-0.86 (m, 1H).

[0512] Example 3

[0513] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 7 5 9 5 10 5 11 -Decahydrogen-1 1 H-9-oxa-4-aza-5(10,11)-imidazo[4',5':4,5]benzo[1,2-e]pyrido[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridane-1(4,5)-pyrazola-7(1,3)-cyclobutane-cyclononafen-5 3 -yl)piperazine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 3

[0514]

[0515] Exact Mass: 860.39

[0516] Example 4

[0517] 3-(2,6-difluoro-4-(4-((7) 1 s,7 3 s,E)-1 1,2 6 5 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 6 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(9,10)-imidazo[4,5-g]pyrido[1,2-a]quinoxalo-2(2,4)-pyrido-1(4,5)-pyrazola-7(1,3)-cyclobutanecyclononafen-5 3 -yl)piperazine-1-yl)phenyl)piperidine-2,6-dione

[0518]

[0519] Exact Mass: 859.41

[0520] Example 5

[0521] (7 1 s,7 3 s,E)-5 3 -(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)-1 1 ,2 6 -Dimethyl-5 1 5 2 5 3 5 4 5 4a 5 5 5 6 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(9,10)-imidazo[4,5-g]pyrido[1,2-a]quinoxalo-2(2,4)-pyrido-1(4,5)-pyrazola-7(1,3)-cyclobutanecyclononafen-5 5 3-Diketone-5

[0522]

[0523] Exact Mass: 859.37

[0524] Example 6

[0525] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 5 6 -3-oxo-5-dioxide 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrido[1,2-d][1,4]thiazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 3 -yl)piperazine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0526]

[0527] Exact Mass: 894.34

[0528] Example 7

[0529] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthol-5 7 -yl)piperazine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0530]

[0531] Exact Mass: 846.38

[0532] Example 8

[0533] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)cyclobutanecyclononafen-5 7 -yl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0534]

[0535]

[0536] first step

[0537] 6-Bromo-2-fluoro-3-nitrophenol 8b

[0538] 3-Fluoro-2-nitrophenol 8a (500 mg, 3.18 mmol, BIDE) was dissolved in chloroform (20 mL), and N-bromosuccinimide (1.13 g, 6.36 mmol) was added in portions at 0 °C. The mixture was heated to room temperature and reacted for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with dichloromethane (50 mL × 2), 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 elution system B to give the title compound 8b (438 mg, yield: 58%).

[0539] MS m / z (ESI): 236.0 [M+1].

[0540] Step 2

[0541] 3-((6-bromo-2-fluoro-3-nitrophenoxy)methyl)-4-(4-methoxybenzyl)piperazine-1-carboxylic acid tert-butyl ester 8c

[0542] Compound 8b (438 mg, 1.86 mmol), compound 2b (690 mg, 2.04 mmol), and triphenylphosphine (730 mg, 2.78 mmol) were dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarboxylate (563 mg, 2.78 mmol, 0.55 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 8c (730 mg, yield: 71%).

[0543] MS m / z (ESI): 554.2 [M+1].

[0544] Step 3

[0545] 3-((6-bromo-2-fluoro-3-nitrophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 8d

[0546] Compound 8c (730 mg, 1.32 mmol) was dissolved in acetonitrile (20 mL) and water (2 mL), and cerium ammonium nitrate (4.2 g, 7.90 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (30 mL × 2), 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 silica gel column chromatography using elution system B to give the title compound 8d (520 mg, yield: 91%).

[0547] MS m / z (ESI): 434.1 [M+1].

[0548] Step 4

[0549] 7-Fluoro-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 8e

[0550] Compound 8d (520 mg, 1.20 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (780 mg, 2.40 mmol) and methanesulfonic acid [(R)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (114 mg, 0.12 mmol, adamas) were added. The mixture was purged with nitrogen three times and heated to 120 °C for 16 hours. The reaction solution was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (30 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 using system C as the elution medium to give the title compound 8e (250 mg, yield: 59%).

[0551] MS m / z (ESI): 354.2 [M+1].

[0552] Step 5

[0553] 7-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 8f

[0554] Compound 8e (250 mg, 0.70 mmol) and compound 2f (90 mg, 0.77 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (182 mg, 1.41 mmol, 0.25 mL) was added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using system C as the elution medium to give the title compound 8f (205 mg, yield: 65%).

[0555] MS m / z (ESI): 449.3 [M+1].

[0556] Step 6

[0557] 7-((((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 8g

[0558] Compound 8f (130 mg, 0.29 mmol), compound 2h (65 mg, 0.26 mmol), and triphenylphosphine (105 mg, 0.39 mmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (80 mg, 0.39 mmol, 80 μL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 8 g (130 mg, yield: 73%).

[0559] MS m / z (ESI): 678.4 [M+1].

[0560] Step 7

[0561] 8-Amino-7-((((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 8h

[0562] 8 g (130 mg, 0.19 mmol) of the compound was dissolved in ethyl acetate (5 mL), and palladium on carbon (30 mg, 0.03 mmol, 10% wt) was added. The mixture was purged with hydrogen three times, and stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 8h (116 mg). The product was used directly in the next reaction without purification.

[0563] MS m / z (ESI): 648.4 [M+1].

[0564] Step 8

[0565] 2-Amino-3-(((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3,5a,6,8,9-hexahydro-1H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-7(5H)-tert-butyl carboxylate 8i

[0566] Compound 8h (116 mg, 0.18 mmol) was dissolved in methanol (5 mL), and cyanogen bromide (29 mg, 0.27 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL × 2), 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 elution system A to give the title compound 8i (93 mg, yield: 77%).

[0567] MS m / z (ESI): 673.5 [M+1].

[0568] Step 9

[0569] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)cyclobutanecyclononafen-5 7 -tert-butyl carboxylate 8j

[0570] Compound 8i (93 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5 mL), and bis(trimethylsilylaminolithium) (0.4 mL, 1 M tetrahydrofuran solution) was added dropwise at 0 °C. The reaction mixture was heated to room temperature and stirred for 30 minutes. The reaction mixture was poured into 20 mL of ethyl acetate, washed successively with saturated ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 8j (70 mg, yield: 79%).

[0571] MS m / z (ESI): 641.3 [M+1].

[0572] Step 10

[0573] (7 1 s,7 3 s,E)-11 ,2 6 -Dimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5': 5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazino-2(2,4)-pyridazino-1(4,5)-pyrazola-7(1,3)-cyclobutazine-3-one 8k

[0574] Compound 8j (70 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane in 4 M hydrogen chloride (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (30 mL × 2), 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 to give crude title compound 8k (59 mg). The product was used directly in the next reaction without purification.

[0575] MS m / z (ESI): 541.4 [M+1].

[0576] Step 11

[0577] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)cyclobutanecyclononafen-5 7 -yl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0578] Compound 8k (59 mg, 0.11 mmol) and compound 2n were dissolved in 1,2-dichloroethane (5 mL), sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added, and the mixture was heated to 50 °C and reacted overnight. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give title compound 8 (25 mg, yield: 27%).

[0579] MS m / z (ESI): 847.5 [M+1].

[0580] 1 H NMR (500 MHz, CDCl3): δ 11.76-11.44 (m, 1H), 8.71 (s, 1H), 8.15 (s,1H), 8.08 (s, 1H), 7.57 (s, 1H), 6.90-6.71 (m, 2H), 6.50-6.37 (m, 2H), 5.41-5.30 (m, 2H), 5.07-3.62 (m, 14H), 3.42-2.46 (m, 16H), 2.44-1.89 (m, 6H), 1.36-1.24 (m, 1H).

[0581] Example 9

[0582] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrido[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridane-1(4,5)-pyrazola-7(1,3)-cyclobutane-cyclononafen-5 8 -yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 9

[0583]

[0584] Exact Mass: 860.39

[0585] Example 10

[0586] 3-(2,6-difluoro-4-(4-((7) 1 s,7 3 s,E)-1 1 ,2 6 5 4 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 5 5 5a 5 6 5 7 5 8 5 9 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4,5-f]pyrido[1,2-a]quinoxalo-2(2,4-pyrido-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen-5) 7 -yl)piperazine-1-yl)phenyl)piperidine-2,6-dione 10

[0587]

[0588] Exact Mass: 859.41

[0589] Example 11

[0590] (7 1 s,7 3 s,E)-5 7 -(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)-1 1 ,2 6 -Dimethyl-5 1 5 2 5 3 5 45 5 5 5a 5 6 5 7 5 8 5 9 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4,5-f]pyrido[1,2-a]quinoxalo-2(2,4-pyrido-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen-5) 5 3-Diketone 11

[0591]

[0592] Exact Mass: 859.37

[0593] Example 12

[0594] 3-(4-(4-((7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 4 5 4 -3-oxo-5-dioxide 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]thiazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclobutanezonaphthyl-5 7 -yl)piperazine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 12

[0595]

[0596] Exact Mass: 894.34

[0597] Example 13

[0598] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 13

[0599]

[0600]

[0601] first step

[0602] 4-((2-bromo-4-fluoro-5-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 13b

[0603] Compound 2a (571 mg, 5.00 mmol, BIDE), tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester 13a (900 mg, 4.17 mmol, BIDE), and triphenylphosphine (2.19 g, 8.34 mmol) were dissolved in tetrahydrofuran (8 mL), and diisopropyl azodicarboxylic acid (1.69 g, 8.34 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give title compound 13b (1.28 g, yield: 71%).

[0604] MS m / z (ESI): 431.3 [M+1].

[0605] Step 2

[0606] 5-Fluoro-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 13c

[0607] Compound 13b (432 mg, 1.0 mmol), palladium acetate (22.4 mg, 0.1 mmol), sodium acetate (164 mg, 2 mmol), and tetraethylammonium chloride (199 mg, 1.2 mmol) were dissolved in N,N-dimethylacetamide (5 mL), purged three times with nitrogen, and stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system C to give title compound 13c (193 mg, yield: 55%).

[0608] MS m / z (ESI): 351.3 [M+1]

[0609] Step 3

[0610] 5-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 13d

[0611] Compound 13c (193 mg, 0.55 mmol) and compound 2f (120 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (180 mg, 1.65 mmol) was added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (6 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 using system C as the elution medium to give the title compound 13d (245 mg, yield: 100%).

[0612] MS m / z (ESI): 446.52 [M+1].

[0613] Step 4

[0614] 5-((((1s,3s)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 13e

[0615] Compound 13d (245 mg, 0.55 mmol), compound 2h (109 mg, 0.5 mmol), and triphenylphosphine (289 mg, 1.1 mmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (223 mg, 1.1 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 13e (260 mg, yield: 70%).

[0616] MS m / z (ESI): 675.7 [M+1].

[0617] Step 5

[0618] 6-Amino-5-((((1s,3s)-3-(((4-(4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13f

[0619] Compound 13e (260 mg, 0.39 mmol) was dissolved in tetrahydrofuran (10 mL), and palladium hydroxide on carbon (130 mg, 10% wt, LEYEN) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 13f (274 mg). The product was used directly in the next reaction without purification.

[0620] MS m / z (ESI): 647.7 [M+1].

[0621] Step 6

[0622] 2-Amino-1-(((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3-dihydro-1H,6H-spiro[benzofurano[5,6-d]imidazol-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester 13g

[0623] Compound 13f (200 mg, 0.31 mmol) was dissolved in methanol (10 mL), and cyanogen bromide (94 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound 13 g (198 mg, yield: 95%).

[0624] MS m / z (ESI): 672.7 [M+1].

[0625] Step 7

[0626] (1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclobutanecyclononafen]-1-tert-butyl carboxylate 13h

[0627] 13 g (198 mg, 0.3 mmol) of compound was dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilylaminolithium) (3 mL, 1 M tetrahydrofuran solution) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 20 mL of ethyl acetate and washed successively with saturated ammonium chloride solution (10 mL × 2) and saturated sodium chloride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 13h (125 mg, yield: 65%).

[0628] MS m / z (ESI): 640.7 [M+1].

[0629] Step 8

[0630] (1's,3's,E)-1',6'-dimethylspiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclonona]-3'-one 13i

[0631] Compound 13h (125 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane in 4 M hydrogen chloride (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give crude title compound 13i (130 mg). The product was used directly in the next reaction without purification.

[0632] MS m / z (ESI): 540.6 [M+1].

[0633] Step 9

[0634] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 13

[0635] Compound 13i (130 mg, 0.2 mmol) and compound 2n (65 mg, 0.3 mmol) were dissolved in 1,2-dichloroethane (5 mL), and sodium triacetoxyborohydride (635 mg, 3 mmol) was added. The mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative high-performance liquid chromatography (HPLC) (Waters-2545 instrument, Welch Ultimate, Prep 30 × 250 mm; 5 μm; C18 column, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give title compound 13 (10 mg, yield: 5.9%).

[0636] MS m / z (ESI): 846.9 [M+1].

[0637] 1 H NMR (500 MHz, CDCl3): δ 11.6 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 6.98 (s, 1H), 6.80 (s, 1H), 6.48-6.42 (m, 2H),5.47-5.29 (m, 4H), 4.50-4.26 (m, 3H), 4.03-3.94 (m, 1H), 3.82-3.71 (m, 4H),3.08-2.62 (m, 8H), 2.56-1.86 (m, 12H), 1.75-1.58 (m, 8H).

[0638] Example 14

[0639] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-isobenzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 14

[0640]

[0641] Exact Mass: 845.38

[0642] Example 15

[0643] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,8'-9-oxa-4-aza-5(2,1)-isocyaneno[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 15

[0644]

[0645] Exact Mass: 859.40

[0646] Example 16

[0647] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',5',6'-trimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-imidazo[4,5-f]indolaza-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(1,3)-cyclobutacyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 16

[0648]

[0649] Exact Mass: 858.41

[0650] Example 17

[0651] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',6',6'-trimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-imidazo[4,5-f]isoindolaz-2(2,4)-pyridaz-1(4,5)-pyrazola-7(1,3)-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 17

[0652]

[0653] Exact Mass: 858.41

[0654] Example 18

[0655] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',6',6'-trimethyl-3'-oxospiro[piperidine-4,8'-9-oxa-4-aza-5(2,1)-imidazo[4,5-g]isoquinoline-2(2,4)-pyridazo-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 18

[0656]

[0657] Exact Mass: 872.43

[0658] Example 19

[0659] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 19

[0660]

[0661] first step

[0662] 4-((6-bromo-2-fluoro-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 19b

[0663] 6-Bromo-2-fluoro-3-nitrophenol 19a (1.60 g, 6.78 mmol, BIDE), 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 13a (1.50 g, 7.03 mmol, BIDE), and triphenylphosphine (4.45 g, 16.97 mmol) were dissolved in tetrahydrofuran (30 mL), and diisopropyl azodicarboxylic acid (3.43 g, 16.97 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give title compound 19b (1.6 g, yield: 55%).

[0664] MS m / z (ESI): 431.3 [M+1].

[0665] Step 2

[0666] tert-butyl 4-((6-bromo-2-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 19c

[0667] Compound 19b (1.30 g, 3.01 mmol) and compound 2f (458 mg, 3.02 mmol) were dissolved in acetonitrile (30 mL), and N,N-diisopropylethylamine (780 mg, 6.04 mmol) was added. The mixture was heated to 60 °C and reacted for 6 hours. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using system C as the elution medium to give title compound 19c (1.2 g, yield: 76%).

[0668] MS m / z (ESI): 526.2 [M+1].

[0669] Step 3

[0670] 2-(5-(((1s,3s)-3-(((3-bromo-2-((1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-nitrophenyl)amino)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester 19d

[0671] Compound 19c (680 mg, 1.29 mmol), compound 2h (385 mg, 1.56 mmol), and triphenylphosphine (678 mg, 2.59 mmol) were dissolved in tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (523 mg, 2.59 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 19d (510 mg, yield: 52%).

[0672] MS m / z (ESI): 755.4 [M+1].

[0673] Step 4

[0674] 7-((((1s,3s)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 19e

[0675] Compound 19d (670 mg, 0.89 mmol), palladium acetate (40 mg, 0.18 mmol), silver carbonate (489 mg, 1.77 mmol), and 1,3-bis(diphenylphosphine)propane (74 mg, 1.79 mmol) were dissolved in toluene (15 mL), purged three times with nitrogen, and stirred at 120 °C for 1 hour. The reaction mixture was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system C to give title compound 19e (451 mg, yield: 75%).

[0676] MS m / z (ESI): 675.4 [M+1].

[0677] Step 5

[0678] 6-Amino-7-((((1s,3s)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 19f

[0679] Compound 19e (480 mg, 0.71 mmol) and platinum dioxide (323 mg, 1.42 mmol) were dissolved in methanol (10 mL), purged three times with hydrogen, and stirred at room temperature for 3 hours. The reaction solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give crude title compound 19f (460 mg). The product was used directly in the next reaction without purification.

[0680] MS m / z (ESI): 647.5 [M+1].

[0681] Step 6

[0682] 2-Amino-1-(((1s,3s)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3-dihydro-1H,7H-spiro[benzofuran[6,7-d]imidazol-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 19g

[0683] Compound 19f (460 mg, 0.71 mmol) was dissolved in methanol (4 mL) and dichloromethane (10 mL), and cyanogen bromide (151 mg, 1.43 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound 19 g (360 mg, yield: 75%).

[0684] MS m / z (ESI): 672.5 [M+1].

[0685] Step 7

[0686] (1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofuran[6,7-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclobutanecyclononafen]-1-tert-butyl carboxylate 19h

[0687] 19 g (360 mg, 0.54 mmol) of compound was dissolved in tetrahydrofuran (15 mL), and bis(trimethylsilylaminolithium) (1 mL, 1 M tetrahydrofuran solution) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 20 mL of ethyl acetate and washed successively with saturated ammonium chloride solution (10 mL × 2) and saturated sodium chloride solution (10 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 19h (161 mg, yield: 47%).

[0688] MS m / z (ESI): 640.5 [M+1].

[0689] Step 8

[0690] (1's,3's,E)-1',6'-dimethylspiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofuran[6,7-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-3'-one19i

[0691] Compound 19h (160 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (3 mL). The pH of the reaction system was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the crude title compound 19i (140 mg). The product was used directly in the next reaction without purification.

[0692] MS m / z (ESI): 540.4 [M+1].

[0693] Step 9

[0694] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 19

[0695] Compound 19i (100 mg, 0.17 mmol) and compound 2n (84 mg, 0.26 mmol) were dissolved in 1,2-dichloroethane (5 mL), and N,N-diisopropylethylamine (225 mg, 1.74 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol) were added. The mixture was heated to 40 °C and stirred for 18 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545; column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give title compound 19 (15 mg, yield: 10%).

[0696] MS m / z (ESI): 846.6 [M+1].

[0697] 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.88 (s, 1H), 8.65 (s,1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.09 (q, 2H), 6.65 (d, 2H), 4.78 (s, 2H),4.57 (s, 2H), 4.11 (s, 3H), 4.09-4.02 (m, 2H), 3.85-3.80 (m, 2H), 3.72 (s,2H), 2.91 (s, 4H), 2.80-2.75 (m, 4H), 2.57 (s, 4H), 2.22 (s, 4H), 1.98 (s,4H), 1.85 (s, 3H), 1.71 (s, 2H), 1.50 (s, 2H).

[0698] Example 20

[0699] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-isobenzofurano[4,5-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 20

[0700]

[0701] Exact Mass: 845.38

[0702] Example 21

[0703] 3-(4-(4-((1's,3's,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-isocyaneno[7,8-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 21

[0704]

[0705] Exact Mass: 859.40

[0706] Example 22

[0707] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',6',8'-trimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-imidazo[4,5-g]indolaza-2(2,4)-pyridaza-1(4,5)-pyrazaza-7(1,3)-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 22

[0708]

[0709] Exact Mass: 858.41

[0710] Example 23

[0711] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',6',7'-trimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-imidazo[4,5-e]isoindolaz-2(2,4)-pyridaz-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 23

[0712]

[0713] Exact Mass: 858.41

[0714] Example 24

[0715] 3-(2,6-difluoro-4-(4-((1's,3's,E)-1',6',8'-trimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-imidazo[4,5-h]isoquinoline-2(2,4)-pyridazo-1(4,5-pyrazola-7(1,3-cyclobutanecyclononafen]-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione 24

[0716]

[0717] Exact Mass: 872.43

[0718] Examples 25-1 and 25-2

[0719] 3-(3-fluoro-6-methyl-5-(4-((5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6-trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)pyridin-2-yl)piperidin-2,6-dione 25-1 and

[0720] 3-(3-fluoro-6-methyl-5-(4-((5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)pyridin-2-yl)piperidin-2,6-dione 25-2

[0721]

[0722]

[0723]

[0724] first step

[0725] (S)-7-bromo-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 25b

[0726] 2-Bromo-3,4-difluoro-1-nitrobenzene 25a (10.0 g, 42.02 mmol, Bide) was dissolved in N,N-dimethylformamide (100 mL), and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (13.6 g, 62.88 mmol, Shaoyuan) and cesium carbonate (54.7 g, 168.07 mmol) were added. The mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into 500 mL of water, filtered, and the filter cake was stirred in a 3:1 mixture of petroleum ether and ethyl acetate (100 mL), filtered, and the filter cake was collected to give the title compound 25b (5.0 g, yield: 28%).

[0727] MS m / z (ESI): 412.1 [M-1].

[0728] Step 2

[0729] (S)-7-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 25d-1 and

[0730] (S)-7-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 25d-2

[0731] Compound 25b (500 mg, 1.21 mmol) was dissolved in dioxane (40 mL), and a mixture of ((1R,3S)-3-(aminomethyl)cyclopentyl)methanol 25c-2 and ((1S,3R)-3-(aminomethyl)cyclopentyl)methanol 25c-1 (200 mg, 1.21 mmol, prepared by the method of compound 136 in the example on page 96 of patent application WO2024246838A1), tris(dibenzylideneacetone)palladium (220 mg, 0.24 mmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (263 mg, 0.42 mmol) and cesium carbonate (1.18 g, 3.62 mmol) was added. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system B to give a mixture of title compounds 25d-1 and 25d-2 (350 mg, yield: 62%).

[0732] MS m / z (ESI): 463.4 [M+1].

[0733] Step 3

[0734] (S)-7-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 25e-1 and

[0735] (S)-7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 25e-2

[0736] A mixture of compounds 25d-1 and 25d-2 (250 mg, 0.54 mmol) was dissolved in tetrahydrofuran (50 mL), and the mixture was placed in an ice bath. Methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (140 mg, 0.54 mmol, prepared by the method of compound 247 in the example on page 123 of patent application WO2024246838A1), triphenylphosphine (283 mg, 1.08 mmol), and diisopropyl azodicarbonate (218 mg, 1.08 mmol) were added, and the mixture was heated to room temperature and stirred for 3 hours. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried with anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system C to give a mixture of title compounds 25e-1 and 25e-2 (500 mg, yield: 131%).

[0737] MS m / z (ESI): 706.6 [M+1].

[0738] Step 4

[0739] (S)-8-amino-7-((((1R,3S)-3-(((4-(4-((methyloxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 25f-1 and

[0740] (S)-8-amino-7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 25f-2

[0741] A mixture of compounds 25e-1 and 25e-2 (200 mg, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), Raney nickel (83 mg, 1.41 mmol) was added, and the mixture was purged with hydrogen three times and stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude mixture of the title compounds 25f-1 and 25f-2 (200 mg). The product was used directly in the next reaction without purification.

[0742] MS m / z (ESI): 676.6 [M+1].

[0743] Step 5

[0744] (S)-2-aminoimino-3-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5a,6,8,9-hexahydro-1H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-7(5H)-carboxylic acid tert-butyl ester 25g-1 and

[0745] (S)-2-aminoimino-3-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5a,6,8,9-hexahydro-1H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-7(5H)-carboxylic acid tert-butyl ester 25g-2

[0746] A mixture of compounds 25f-1 and 25f-2 (500 mg, 0.74 mmol) was dissolved in methanol (30 mL), and cyanogen bromide (235 mg, 2.21 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 25g-1 and 25g-2 (200 mg, yield: 38%).

[0747] MS m / z (ESI): 701.6 [M+1].

[0748] Step 6

[0749] (5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 59 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -tert-butyl carboxylate 25h-1 and

[0750] (5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -tert-butyl carboxylate 25h-2

[0751] A mixture of compounds 25 g-1 and 25 g-2 (200 mg, 0.28 mmol) was dissolved in tetrahydrofuran (20 mL). The mixture was placed in an ice bath, and a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (95 mg, 0.57 mmol, 0.57 mL, 1 M) was added. The mixture was heated to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 25 h-1 and 25 h-2 (130 mg, yield: 68%).

[0752] MS m / z (ESI): 669.5 [M+1].

[0753] Step 7

[0754] (5 5a S,7 1 R,73 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 25i-1

[0755] and

[0756] (5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 25i-2

[0757] A mixture of compounds 25h-1 and 25h-2 (130 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (3 mL). The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 25i-1 and 25i-2 (130 mg). The product was used directly in the next reaction without purification.

[0758] MS m / z (ESI): 569.7 [M+1].

[0759] Step 8

[0760] 8-(2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane 25k

[0761] 25 J of 6'-(benzyloxy)-3-fluoro-5-iodo-6-methyl-2'-phenoxy-2,3'-bipyridine (5.0 g, 9.49 mmol, Icon) was dissolved in 1,4-dioxane (50 mL), and 1,4-dioxane-8-azaspiro[4.5]decane (2.04 g, 14.25 mmol, Adamas), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (886 mg, 1.89 mmol), tris(dibenzylideneacetone)palladium (869 mg, 0.95 mmol), and cesium carbonate (9.28 g, 28.48 mmol) were added. Nitrogen gas was purged three times, and the mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature and poured into 50 mL of water. It was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 25k (4.2 g, yield: 81%).

[0762] MS m / z (ESI): 542.5 [M+1].

[0763] Step 9

[0764] 3-(3-fluoro-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-yl)piperidin-2,6-dione 25l

[0765] Compound 25k (2.0 g, 3.69 mmol) was dissolved in methanol (10 mL), and palladium on carbon (448 mg, 3.68 mmol, 10% wt) and palladium hydroxide (518 mg, 3.68 mmol, 10% wt) were added. Hydrogen was purged three times, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 25k (780 mg, yield: 58%).

[0766] MS m / z (ESI): 364.5 [M+1].

[0767] Step 10

[0768] 3-(3-fluoro-6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidin-2,6-dione 25m

[0769] Compound 25l (750 mg, 2.06 mmol) was dissolved in concentrated hydrochloric acid (4 mL) and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 25m (200 mg, yield: 30%).

[0770] MS m / z (ESI): 320.3 [M+1].

[0771] Step 11

[0772] 3-(3-fluoro-6-methyl-5-(4-((5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)pyridin-2-yl)piperidin-2,6-dione 25-1

[0773] and

[0774] 3-(3-fluoro-6-methyl-5-(4-((5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)pyridin-2-yl)piperidin-2,6-dione 25-2

[0775] Compound 25m (30 mg, 0.093 mmol), a mixture of compounds 25i-1 and 25i-2 (50 mg, 0.087 mmol), was dissolved in 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (65 mg, 0.30 mmol) was added, and the mixture was heated to 40 °C and reacted overnight. The reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with dichloromethane (15 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by preparative high performance liquid chromatography (instrument model: Waters-2545, column: XP tC18-AX, Prep 30 × 250 mm; 5 μm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-70%, flow rate: 30 mL / min) to give a mixture of title compounds 25-1 and 25-2 (10 mg, yield: 13%).

[0776] MS m / z (ESI): 872.5 [M+1].

[0777] 1 H NMR (500 MHz, CDCl3): δ 11.89-11.61 (m, 1H), 8.61 (s, 1H), 8.10 (s,1H), 7.57 (s, 1H), 7.08-7.00 (m, 1H), 6.89-6.70 (m, 2H), 4.66-3.85 (m, 7H), 3.74 (s, 3H), 3.36-2.79 (m, 7H), 2.75-2.33 (m, 13H), 2.33-1.51 (m, 14H), 1.45-1.14 (m, 3H).

[0778] Examples 26-1 and 26-2

[0779] 3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 2,6-dione carboxylate 26-1 and yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carboxylate

[0780] 3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 85 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 26-2-yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carbamate

[0781]

[0782] first step

[0783] 4-Fluoro-3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane] 26b

[0784] 1,2,3-trifluoro-4-nitrobenzene 26a (500 mg, 2.82 mmol, Biotin) was dissolved in N,N-dimethylformamide (10 mL), and (1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol hydrochloride (590 mg, 2.82 mmol, prepared by the method of compound 120 in the example on page 106 of patent application WO2019183367A1), cesium carbonate (1.6 g, 4.84 mmol), and stirred at room temperature for 72 hours. The solution was concentrated under reduced pressure, diluted with 100 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 26b (90 mg, yield: 24%).

[0785] MS m / z (ESI): 311.0 [M+1].

[0786] Step 2

[0787] ((1S,3R)-3-(((3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyridino[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methanol 26c-1 and

[0788] ((1R,3S)-3-(((3-nitro-6a,7,9,10-tetrahydro-6H--spiro[benzo[b]pyridino[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methanol26c-2

[0789] Compound 26b (100 mg, 0.35 mmol) was dissolved in dimethyl sulfoxide (2 mL), and a mixture of compounds 25c-1 and 25c-2 (180 mg, 0.71 mmol) and N,N-diisopropylethylamine (230 mg, 1.78 mmol) were added. The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give a mixture of title compounds 26c-1 and 26c-2 (80 mg, yield: 53%).

[0790] MS m / z (ESI): 420.1 [M+1].

[0791] Step 3

[0792] 2-(1,3-Dimethyl-5-(((1S,3R)-3-(((3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methoxy)-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester 26d-1 and

[0793] 2-(1,3-Dimethyl-5-(((1R,3S)-3-(((3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methoxy)-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester 26d-2

[0794] A mixture of compounds 26c-1 and 26c-2 (700 mg, 166.88 mmol) was dissolved in tetrahydrofuran (10 mL). The mixture was placed in an ice bath, and methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (390 mg, 150.20 mmol), triphenylphosphine (660 mg, 2.50 mmol), and diisopropyl azodicarbonate (510 mg, 2.50 mmol) were added. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give a mixture of title compounds 26d-1 and 26d-2 (800 mg, yield: 72%).

[0795] MS m / z (ESI): 663.4 [M+1].

[0796] Step 4

[0797] 2-(5-(((1S,3R)-3-(((3-amino-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 26e-1 and

[0798] 2-(5-(((1R,3S)-3-(((3-amino-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-4-yl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 26e-2

[0799] A mixture of compounds 26d-1 and 26d-2 (1.0 g, 1.55 mmol) was dissolved in tetrahydrofuran (20 mL), and Raney nickel (177 mg, 3.02 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 6 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 26e-1 and 26e-2 (600 mg). The product was used directly in the next reaction without purification.

[0800] MS m / z (ESI): 633.5 [M+1].

[0801] Step 5

[0802] 2-(5-(((1S,3R)-3-((2-amino-1,2,5a,6,8,9-hexahydro-3H,5H-spiro[imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazine-7,2'-[1,3]dioxapentane]-3-yl)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 26f-1 and

[0803] 2-(5-(((1R,3S)-3-((2-amino-1,2,5a,6,8,9-hexahydro-3H,5H-spiro[imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazine-7,2'-[1,3]dioxapentane]-3-yl)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester 26f-2

[0804] A mixture of compounds 26e-1 and 26e-2 (140 mg, 0.22 mmol) was dissolved in methanol (5 mL), and cyanogen bromide (35 mg, 0.33 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 26f-1 and 26f-2 (100 mg, yield: 69%).

[0805] MS m / z (ESI): 658.4 [M+1].

[0806] Step 6

[0807] (1R,3S,E)-1,3,6-trimethylspiro[9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-7,2'-[1,3]dioxapentane-3-one 26g-1 and

[0808] (1S,3R,E)-1,3,6-trimethylspiro[9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-7,2'-[1,3]dioxapentane-3-one 26g-2

[0809] A mixture of compounds 26f-1 and 26f-2 (400 mg, 0.61 mmol) was dissolved in tetrahydrofuran (20 mL), placed in an ice bath, and a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (204 mg, 1.22 mmol, 1.2 mL, 1 M) was added. The mixture was heated to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 26g-1 and 26g-2 (200 mg, yield: 53%).

[0810] MS m / z (ESI): 626.6 [M+1].

[0811] Step 7

[0812] (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 ,3-dione 26h-1 and

[0813] (7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-52 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 ,3-Diketone 26h-2

[0814] A mixture of compounds 26g-1 and 26g-2 (100 mg, 0.16 mmol) was dissolved in water (2 mL), and concentrated hydrochloric acid (4 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water (3 mL). The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 26h-1 and 26h-2 (50 mg). The product was used directly in the next reaction without purification.

[0815] MS m / z (ESI): 582.4 [M+1].

[0816] Step 8

[0817] 3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-57 2,6-dione carboxylate 26-1 and yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carboxylate

[0818] 3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5 ª,5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 26-2-yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carbamate

[0819] A mixture of compounds 26h-1 and 26h-2 (45 mg, 0.077 mmol) was dissolved in 1,2-dichloroethane (5 mL), and compound 26i (24 mg, 0.077 mmol, prepared by the method of compound Step 6 in the example on page 160 of patent application WO2021255212A1), N,N-diisopropylethylamine (50 mg, 0.39 mmol), and sodium triacetoxyborohydride (65 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545; column: Welch Xtimate Perp C18 5um 30×150mm; mobile phase: water (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15%-50%, flow rate: 30 mL / min) to give a mixture of title compounds 26-1 and 26-2 (19 mg, yield: 20%).

[0820] MS m / z (ESI): 875.5 [M+1].

[0821] 1H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.88 (d, 1H), 8.54 (s,1H), 8.25 (s, 1H), 7.46 (s, 1H), 6.99 (dd, 1H), 6.89 (d, 1H), 6.65 (d, 2H),4.38 (d, 2H), 4.17 (s, 1H), 4.06 (dt, 2H), 3.97 (d, 1H), 3.67 (s, 3H), 3.23-3.17 (m, 3H), 3.06 (d, 1H), 2.79 (dd, 2H), 2.63 (d, 4H), 2.60 (s, 2H), 2.55(d, 3H), 2.48 (s, 3H), 2.42 (d, 2H), 2.15-2.06 (m, 2H), 1.99 (ddt, 4H), 1.83(s, 3H), 1.64 (s, 1H), 1.54-1.39 (m, 3H), 1.35-1.26(m, 2H).

[0822] Examples 27-1 and 27-2

[0823] 3-(3-fluoro-6-methyl-5-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione 27-1 and

[0824] 3-(3-fluoro-6-methyl-5-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione 27-2

[0825]

[0826]

[0827]

[0828] A mixture of compounds 26h-1 and 26h-2 (45 mg, 0.077 mmol) was dissolved in 1,2-dichloroethane (5 mL), and 3-(3-fluoro-6-methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione 27a (24 mg, 0.077 mmol, prepared by the method of intermediate 12 on page 108 of the specification in patent application WO2024246838A1), N,N-diisopropylethylamine (50 mg, 0.39 mmol), and sodium triacetoxyborohydride (65 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 1 hour. The residue was filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (instrument: Waters-2545; column: Welch Xtimate Perp C18 5um 30×150 mm; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 30 mL / min) to give a mixture of title compounds 27-1 and 27-2 (12 mg, yield: 18%).

[0829] MS m / z (ESI): 872.5 [M+1].

[0830] 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.88 (s, 1H), 8.54 (s,1H), 7.46 (s, 1H), 7.22-7.17 (m, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 4.41 (s,1H), 4.16 (dd, 3H), 3.98 (s, 1H), 3.67 (s, 3H), 3.07 (s, 1H), 2.92 (s, 2H),2.78-2.68 (m, 4H), 2.65(s, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.39 (s, 3H),2.37-2.36 (m, 1H), 2.31-2.21 (m, 3H), 2.08-2.03 (m, 2H), 2.02 (s, 1H), 1.99(dd, 3H), 1.95 (s, 1H), 1.84 (s, 4H), 1.75-1.70 (m, 1H), 1.65 (s, 1H), 1.55 (s, 1H), 1.46 (t, 2H), 1.31 (d, 2H).

[0831] Examples 28-1 and 28-2

[0832] 3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 28-1 and

[0833] 3-(2,6-difluoro-4-(4-((7)1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 28-2

[0834]

[0835]

[0836]

[0837] first step

[0838] 8-Fluoro-9-nitro-7-oxo-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28c

[0839] Methyl 2,6-difluoro-3-nitrobenzoate 28a (5.0 g, 23.02 mmol, Biotin) was dissolved in dimethyl sulfoxide (50 mL), and tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylic acid 28b (6.0 g, 27.74 mmol) and N,N-diisopropylethylamine (6.0 g, 46.42 mmol) were added. The mixture was stirred at 120 °C for 18 hours. The reaction solution was cooled to room temperature, poured into 200 mL of water, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system B to give the title compound 28c (5.0 g, yield: 57%).

[0840] MS m / z (ESI): 382.3 [M+1].

[0841] Step 2

[0842] 4-(3-fluoro-2-(hydroxymethyl)-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 28d

[0843] Compound 28c (2.0 g, 5.24 mmol) was dissolved in tetrahydrofuran (50 mL), cooled with ice water, and diisobutylaluminum hydride (10.5 mL, 10.54 mmol) was added dropwise. The mixture was allowed to rise naturally to room temperature and stirred for 3 hours. The reaction solution was poured into 200 mL of water and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 28d (1.1 g, yield: 54%).

[0844] Step 3

[0845] 8-Fluoro-9-nitro-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazineheptane28e

[0846] Compound 28d (1.0 g, 2.60 mmol) was dissolved in toluene (20 mL), and (±)-camphor-10-sulfonic acid (1.2 g, 5.16 mmol) was added. The mixture was stirred at 100 °C for 18 hours. The reaction solution was cooled to room temperature and poured into 100 mL of water. The solution was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography using elution system B to give the title compound 28e (480 mg, yield: 69%).

[0847] MS m / z (ESI): 268.2 [M+1].

[0848] Step 4

[0849] 8-Fluoro-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 28f

[0850] Compound 28e (480 mg, 1.80 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (700 mg, 5.39 mmol), 4-dimethylaminopyridine (45 mg, 0.36 mmol), and di-tert-butyl dicarbonate (600 mg, 2.70 mmol) were added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of water was added. The solution was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 28f (500 mg, yield: 76%).

[0851] MS m / z (ESI): 368.2 [M+1].

[0852] Step 5

[0853] 8-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28g-1 and

[0854] 8-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28g-2

[0855] Compound 28f (400 mg, 1.10 mmol) was dissolved in acetonitrile (20 mL), and a mixture of compounds 25c-1 and 25c-2 (220 mg, 1.32 mmol) and N,N-diisopropylethylamine (423 mg, 3.27 mmol) were added. The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give a mixture of title compounds 28g-1 and 28g-2 (400 mg, yield: 77%).

[0856] MS m / z (ESI): 477.6 [M+1].

[0857] Step 6

[0858] 8-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28h-1 and

[0859] 8-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28h-2

[0860] A mixture of compounds 28 g-1 and 28 g-2 (400 mg, 0.84 mmol) was dissolved in tetrahydrofuran (20 mL). The mixture was placed in an ice bath, and methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (265 mg, 1.01 mmol), triphenylphosphine (330 mg, 1.26 mmol), and diisopropyl azodicarbonate (255 mg, 1.26 mmol) were added. The mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give a mixture of title compounds 28 h-1 and 28 h-2 (260 mg, yield: 43%).

[0861] MS m / z (ESI): 720.7 [M+1].

[0862] Step 7

[0863] 9-Amino-8-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28i-1 and

[0864] 9-Amino-8-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazheptan-3(4H)-carboxylic acid tert-butyl ester 28i-2 A mixture of compounds 28h-1 and 28h-2 (260 mg, 0.36 mmol) was dissolved in methanol (20 mL), 50% palladium on carbon (100 mg, 0.47 mmol) was added, and the mixture was purged with hydrogen three times and stirred at room temperature for 6 hours. Insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give a mixture of title compounds 28i-1 and 28i-2 (150 mg, yield: 60%).

[0865] MS m / z (ESI): 690.6 [M+1].

[0866] Step 8

[0867] 2-Amino-3-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-1,2,3,4,6a,7,9,10-octahydroimidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxazheptan-8(6H)-carboxylic acid tert-butyl ester 28j-1 and

[0868] 2-Amino-3-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-1,2,3,4,6a,7,9,10-octahydroimidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxazheptan-8(6H)-carboxylic acid tert-butyl ester 28j-2

[0869] A mixture of compounds 28i-1 and 28i-2 (150 mg, 0.22 mmol) was dissolved in methanol (5 mL), and cyanogen bromide (45 mg, 0.44 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 28j-1 and 28j-2 (56 mg, yield: 36%).

[0870] MS m / z (ESI): 715.7 [M+1].

[0871] Step 9

[0872] (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 - tert-butyl carboxylate 28kJ and

[0873] (7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 - tert-butyl carboxylate 28k-2

[0874] A mixture of compounds 28j-1 and 28j-2 (56 mg, 0.08 mmol) was dissolved in tetrahydrofuran (5 mL), and the mixture was placed in an ice bath. A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (27 mg, 0.16 mmol, 0.2 mL, 1 M) was added, and the mixture was heated to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 28k-1 and 28k-2 (30 mg, yield: 56%).

[0875] MS m / z (ESI): 683.5 [M+1].

[0876] Step 10

[0877] (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononadenosine-3-one 28l-1 and

[0878] (7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-5 1 52 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 28l-2

[0879] A mixture of compounds 28k-1 and 28k-2 (30 mg, 0.04 mmol) was dissolved in dichloromethane (4 mL), and dioxane hydrochloride solution (4 mL, 1 M) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (3 mL). The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 28l-1 and 28l-2 (30 mg). The product was used directly in the next reaction without purification.

[0880] MS m / z (ESI): 583.5 [M+1].

[0881] Step 11

[0882] 3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 28-1 and

[0883] 3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 6 5 6a 5 7 5 8 5 9 5 10 -Decahydrogen-1 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':3,4]benzo[1,2-e]pyrazino[2,1-c][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 28-2

[0884] A mixture of compounds 28l-1 and 28l-2 (30 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (5 mL), and compound 2n (24 mg, 0.077 mmol), N,N-diisopropylethylamine (50 mg, 0.39 mmol), and sodium triacetoxyborohydride (36 mg, 0.17 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument: SHIMADZU LC; column: Boston Phlex Perp C18 5µm 30×150 mm; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 30 mL / min) to give a mixture of title compounds 28-1 and 28-2 (10 mg, yield: 23%).

[0885] MS m / z (ESI): 889.7 [M+1].

[0886] 1 H NMR (500 MHz, DMSO-d6): δ 12.93-12.47 (m, 1H), 10.90 (s, 1H), 8.70-8.33 (m, 1H), 7.70-7.30 (m, 2H), 7.08-6.81 (m, 1H), 6.80-6.49 (m, 2H), 5.49-4.48 (m, 4H), 4.46-3.46(m, 9H), 3.33-3.03 (m, 4H), 3.01-2.16 (m, 12H), 2.16-1.38 (m, 10H), 1.39-1.13 (m, 4H), 1.14-0.98 (m, 1H), 0.92-0.80 (m, 1H), 0.80-0.62 (m, 1H).

[0887] Examples 29-1 and 29-2

[0888] 3-((1'-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-5-yl)amino)piperidine-2,6-dione carbamate 29-1 and

[0889] 3-((1'-((7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 57 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-5-yl)amino)piperidine-2,6-dione carbamate 29-2

[0890]

[0891]

[0892] A mixture of compounds 26h-1 and 26h-2 (30 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (5 mL), and 3-((1,3-dihydrospiro[indene-2,4'-piperidin]-5-yl)amino)piperidin-2,6-dione 29a (16 mg, 0.05 mmol, prepared by the method of compound Step 7 in Example 5 on page 71 of patent application CN117384165), N,N-diisopropylethylamine (66 mg, 0.51 mmol), and sodium triacetoxyborohydride (43 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545; column: Welch Xtimate Perp C18 5um 30×150 mm; mobile phase: water (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-50%, flow rate: 30 mL / min) to give a mixture of title compounds 29-1 and 29-2 (8 mg, yield: 18%).

[0893] MS m / z (ESI): 879.6 [M+1].

[0894] 1H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.77 (d, 1H), 8.54 (s,1H), 8.25 (s, 1H), 7.46 (s, 1H), 6.99 (d, 1H), 6.89 (d, 1H), 6.57-6.52 (m,1H), 6.45 (dt, 1H), 5.56 (t, 1H),5.37-5.27 (m, 1H), 4.38 (s, 2H), 4.25 (dt,2H), 4.17 (s, 2H), 3.98 (d, 2H), 3.67 (s, 3H), 3.45-3.35 (m, 3H), 3.06 (s,1H),2.92-2.84 (m, 1H), 2.74 (td, 2H), 2.67-2.63 (m, 3H), 2.56 (s, 3H), 2.49(s, 6H), 2.11 (dq, 2H), 2.00 (dt, 4H), 1.85 (dd, 3H), 1.62-1.55 (m, 4H), 1.48-1.42 (m, 1H), 1.26 (d, 4H).

[0895] Examples 30-1 and 30-2

[0896] 3-(2,6-Difluoro-4-(2-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)-2,7-diazaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-dione carbamate 30-1 and

[0897] 3-(2,6-Difluoro-4-(2-((7) 1S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 7 -yl)-2,7-diazaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-dione carbamate 30-2

[0898]

[0899]

[0900] A mixture of compounds 26h-1 and 26h-2 (30 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (5 mL), and 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione 30a (24 mg, 0.06 mmol, prepared by the method of compound Step 2 in Example 18 on page 80 of patent application WO2023138607), N,N-diisopropylethylamine (66 mg, 0.51 mmol), and sodium triacetoxyborohydride (43 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545; column: Welch Xtimate Perp C18 5um 30×150 mm; mobile phase: water (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 50%-85%, flow rate: 30 mL / min) to give a mixture of title compounds 30-1 and 30-2 (12 mg, yield: 25%).

[0901] MS m / z (ESI): 915.5 [M+1].

[0902] 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.87 (s, 1H), 8.54 (s,1H), 8.25 (s, 1H), 7.46 (s, 1H), 6.98 (d, 1H), 6.85 (dd, 1H), 6.69-6.60 (m,2H), 5.33 (t, 1H), 4.45-4.24 (m, 3H), 4.17 (s, 2H), 4.10-3.93 (m, 3H), 3.67(s, 3H), 3.51 (d, 1H), 3.20 (t, 3H), 3.01-2.92 (m, 3H), 2.89-2.71 (m, 3H),2.68-2.62 (m, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.38-2.34 (m, 1H), 2.13-1.94(m, 4H), 1.94-1.78 (m, 3H), 1.77-1.60 (m, 6H), 1.47 (q, 1H), 1.33-1.25 (m, 4H).

[0903] Examples 31-1-1 and 31-1-2 or 31-2-1 and 31-2-2

[0904] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-1

[0905] and

[0906] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-2

[0907] or

[0908] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-1

[0909] and

[0910] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 S,73 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-2

[0911] and

[0912] or

[0913] and

[0914]

[0915] first step

[0916] (S)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione 31a-1

[0917] and

[0918] (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione 31a-2

[0919] 3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)piperidin-2,6-dione 31a (26 g, 71.0 mmol, prepared by the method of compound 0284 (step 5) in the example on page 44 of patent application CN 119060067 A) was resolved by chiral preparative column (instrument model: Waters SFC 150, column: DAICELCHIRALCEL® OJ, 250*50mm 10 μm; mobile phase: supercritical CO2 and methanol, flow rate: 145 mL / min) to give the title compound (11.9 g, yield 45.8%) and (11.5 g, yield 44.2%).

[0920] Title compound: Single configuration compound (short retention time, 11.9 g, yield 45.8%);

[0921] MS m / z (ESI): 367.1 [M+1].

[0922] Chiral HPLC analysis: retention time 2.259 min, purity (ee): 98% (column: DAICELCHIRALCEL® OJ, 100*3mm 3 um; mobile phase: supercritical CO2 and methanol, flow rate: 1.5 mL / min), gradient ratio: supercritical CO2 and methanol (+0.1% diethanolamine) = 85%: 15%).

[0923] Title compound: Single configuration compound (longer retention time, 11.5 g, yield 44.2%).

[0924] MS m / z (ESI): 367.1 [M+1].

[0925] Chiral HPLC analysis: retention time 2.989 min, purity (ee): 98% (column: DAICELCHIRALCEL® OJ, 100*3mm 3u m; mobile phase: supercritical CO2 and methanol, flow rate: 0.5 mL / min), gradient ratio: supercritical CO2 and methanol (+0.1% diethanolamine) = 85%: 15%).

[0926] Step 2

[0927] (S)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidin-2,6-dione 31b-1

[0928] or

[0929] (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidin-2,6-dione 31b-2

[0930] The compounds with a retention time of 2.259 minutes from 31a-1 and 31a-2 (11.9 g, 32.5 mmol) were dissolved in water (500 mL), and concentrated hydrochloric acid (12 M, 1.30 mol, 108.3 mL) was added. The mixture was heated to 50 °C and reacted for 5 hours. The reaction solution was cooled to 0 °C, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. Dichloromethane (500 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound (9.5 g). The product was used directly in the next reaction without purification.

[0931] MS m / z (ESI): 323.1 [M+1].

[0932] Step 3

[0933] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-1

[0934] and

[0935] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-52 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-2

[0936] or

[0937] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-1

[0938] and

[0939] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-2

[0940] Compound 31b-1 or 31b-2 (29 mg, 0.089 mmol, prepared in one step from the shorter retention time (2.259 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 25i-1 and 25i-2 (50 mg, 0.087 mmol) was added, sodium triacetoxyborohydride (61 mg, 0.28 mmol) and N,N-diisopropylethylamine (106 mg, 0.82 mmol) were added, and the mixture was heated to 40 °C and reacted overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) using Waters-2545, column: XPtC18-AX, Prep 30×250 mm; 5 μm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 30 mL / min) to obtain a mixture of compounds 31-1-1 and 31-1-2 or a mixture of compounds 31-2-1 and 31-2-2 (5.0 mg, yield: 7%).

[0941] MS m / z (ESI): 875.7 [M+1].

[0942] 1 H NMR (500 MHz, CDCl3): δ 12.02-11.52 (m, 1H), 8.62 (s, 1H), 8.19 (s,1H), 7.58 (s, 1H), 7.02-6.64 (m, 2H), 6.61-6.28 (m, 2H), 5.55-5.28 (m, 1H), 4.68-3.55 (m, 14H), 3.42-2.45 (m, 14H), 2.40-1.56 (m, 12H), 1.42-1.20 (m, 3H).

[0943] Examples 31-1-1 and 31-1-2 or 31-2-1 and 31-2-2

[0944] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-1

[0945] and

[0946] (S)-3-(2,6-difluoro-4-(4-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-1-2

[0947] or

[0948] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-1

[0949] and

[0950] (R)-3-(2,6-difluoro-4-(4-((5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 31-2-2

[0951] and

[0952] or

[0953] and

[0954]

[0955] first step

[0956] (S)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidin-2,6-dione 31b-1

[0957] or

[0958] (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidin-2,6-dione 31b-2

[0959] The compounds with a retention time of 2.989 minutes in 31a-1 and 31a-2 (11.5 g, 87.67 mmol) were dissolved in water (500 mL), concentrated hydrochloric acid (12 M, 1.30 mol, 108.3 mL) was added, and the mixture was heated to 50 °C and reacted for 5 hours. The reaction solution was cooled to 0 °C, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. Dichloromethane (500 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound (9.0 g). The product was used directly in the next reaction without purification.

[0960] MS m / z (ESI): 323.1 [M+1].

[0961] Step 2

[0962] Compound 31b-1 or 31b-2 (31 mg, 0.096 mmol, prepared in one step from the compound with the longer retention time (2.989 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 25i-1 and 25i-2 (50 mg, 0.087 mmol) was added, sodium triacetoxyborohydride (65 mg, 0.30 mmol) and N,N-diisopropylethylamine (113 mg, 0.88 mmol) were added, and the mixture was heated to 40 °C and reacted overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545, column: XP tC18-AX, Prep 30×250 mm; 5um, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 30 mL / min) to obtain a mixture of compounds 31-1-1 and 31-1-2 or a mixture of compounds 31-2-1 and 31-2-2 (5.0 mg, yield: 6%).

[0963] MS m / z (ESI): 875.7 [M+1].

[0964] 1 H NMR (500 MHz, CDCl3): δ 12.02-11.52 (m, 1H), 8.62 (s, 1H), 8.02 (s,1H), 7.59 (s, 1H), 6.95-6.64 (m, 2H), 6.55-6.25 (m, 2H), 5.55-5.28 (m, 1H), 4.66-3.54 (m, 12H), 3.42-2.45 (m, 14H), 2.40-1.83 (m, 10H), 1.42-1.20 (m, 7H).

[0965] Examples 32-1-1 and 32-1-2 or 32-2-1 and 32-2-2

[0966] (R)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-1

[0967] and

[0968] (R)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-2

[0969] or

[0970] (S)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-1

[0971] and

[0972] (S)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-2

[0973] or

[0974]

[0975]

[0976]

[0977] first step

[0978] 6-Bromo-2-fluoro-3-nitrophenol 32b

[0979] 2-Fluoro-3-nitrophenol 32a (10.0 g, 63.65 mmol) was dissolved in chloroform (100 mL), and N-bromosuccinimide (12.0 g, 67.42 mmol) was added. The mixture was reacted at room temperature for 4 hours, and the solution was poured into 100 mL of water. The layers were separated, and the organic phase was washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and purified by silica gel column chromatography using elution system A to give the title compound 32b (6.2 g, 41.3% yield).

[0980] MS m / z (ESI): 236.0 [M+1]

[0981] Step 2

[0982] 4-((6-bromo-2-fluoro-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 32c

[0983] Compound 32b (0.60 g, 2.54 mmol), 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.54 g, 2.53 mmol, Biotin), and triphenylphosphine (0.81 g, 3.05 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarbonate (0.617 g, 3.05 mmol) was added under ice bath conditions, and the mixture was heated to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give title compound 32c (1.01 g, yield: 92.1%).

[0984] MS m / z (ESI): 431.1 [M+1].

[0985] Step 3

[0986] 4-((6-bromo-2-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 32d-1 and

[0987] 4-((6-bromo-2-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 32d-2

[0988] A mixture of compounds 25c-2 and 25c-1 (1.0 g, 6.03 mmol) and compound 32c (1.01 g, 2.34 mmol) was dissolved in N,N-dimethylformamide (6 mL), and anhydrous potassium carbonate (971 mg, 7.03 mmol) was added. Under nitrogen protection, the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into 30 mL of water, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 32d-1 and 32d-2 (600 mg, yield: 47.4%).

[0989] MS m / z (ESI): 540.4 [M+1].

[0990] Step 4

[0991] 2-(5-(((1S,3R)-3-(((3-bromo-2-((1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-nitrophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester 32e-1 and

[0992] 2-(5-(((1R,3S)-3-(((3-bromo-2-((1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-nitrophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinic acid methyl ester 32e-2

[0993] A mixture of compounds 32d-1 and 32d-2 (2.0 g, 4.32 mmol) was dissolved in tetrahydrofuran (100 mL). Methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (1.12 g, 4.28 mmol), triphenylphosphine (1.7 g, 6.48 mmol), and diisopropyl azodicarbonate (1.3 g, 6.42 mmol) were added under ice bath conditions. The mixture was heated to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 32e-1 and 32e-2 (560 mg, yield: 64.4%).

[0994] MS m / z (ESI): 783.5 [M+1].

[0995] Step 5

[0996] 7-((((1R,3S)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 32f-1 and

[0997] 7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 32f-2

[0998] A mixture of compounds 32e-1 and 32e-2 (560 mg, 0.714 mmol) was dissolved in toluene (25 mL), palladium acetate (32 mg, 0.143 mmol), 1,3-bis(diphenylphosphine)propane (59 mg, 0.143 mmol), and silver carbonate (395 mg, 0.143 mmol). The mixture was purged three times with nitrogen, heated to 115 °C, and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 32f-1 and 32f-2 (300 mg, yield: 59.7%).

[0999] MS m / z (ESI): 703.6 [M+1].

[1000] Step 6

[1001] 6-Amino-7-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 32g-1 and

[1002] 6-Amino-7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 32g-2

[1003] A mixture of compounds 32f-1 and 32f-2 (300 mg, 0.427 mmol) was dissolved in methanol (20 mL), Raney nickel (194 mg, 0.854 mmol) was added, and the mixture was purged three times with hydrogen and stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude mixture of the title compounds 32g-1 and 32g-2 (285 mg). The product was used directly in the next reaction without purification.

[1004] MS m / z (ESI): 675.1 [M+1].

[1005] Step 7

[1006] 2-Amino-1-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3-dihydro-1H,7H-spiro[benzofurano[6,7-d]imidazol-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 32h-1 and

[1007] 2-Amino-1-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3-dihydro-1H,7H-spiro[benzofurano[6,7-d]imidazol-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 32h-2

[1008] A mixture of compounds 32g-1 and 32g-2 (285 mg, 0.422 mmol) was dissolved in methanol (20 mL), and cyanogen bromide (50 mg, 0.472 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography using elution system B to give a mixture of title compounds 32h-1 and 32h-2 (268 mg, yield: 90.6%).

[1009] MS m / z (ESI): 700.5 [M+1].

[1010] Step 8

[1011] (1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-carboxylic acid tert-butyl ester 32i-1 and

[1012] (1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-carboxylic acid tert-butyl ester 32i-2

[1013] A mixture of compounds 32h-1 and 32h-2 (268 mg, 0.383 mmol) was dissolved in tetrahydrofuran (15 mL). A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (129 mg, 0.771 mmol, 0.771 mL, 1 M) was added under ice bath conditions. The mixture was heated to room temperature and stirred for 1 hour. The reaction solution was poured into 30 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system B to give a mixture of title compounds 32i-1 and 32i-2 (130 mg, yield: 50.8%).

[1014] MS m / z (ESI): 668.5 [M+1].

[1015] Step 9

[1016] (1'R,3'S,E)-1',3',6'-trimethylspiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclopentacyclonona]-3'-one 32j-1 and

[1017] (1'S,3'R,E)-1',3',6'-trimethylspiro[piperidine-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclopentacyclonona]-3'-one 32j-2

[1018] A mixture of compounds 32i-1 and 32i-2 (130 mg, 0.194 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (3 mL). The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered to remove the drying agent, yielding a crude mixture of title compounds 32j-1 and 32j-2 (80 mg). The product was used directly in the next reaction without purification.

[1019] MS m / z (ESI): 568.6 [M+1].

[1020] Step 10

[1021] (R)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-1

[1022] and

[1023] (R)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-2

[1024] or

[1025] (S)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-1

[1026] and

[1027] (S)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-2

[1028] Compound 31b-1 or 31b-2 (51 mg, 0.158 mmol, prepared in one step from the compound with the longer retention time (2.989 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 32j-1 and 32j-2 (65 mg, 0.095 mmol) was added, sodium triacetoxyborohydride (61 mg, 0.28 mmol) and N,N-diisopropylethylamine (106 mg, 0.82 mmol) were added, the mixture was heated to 50 °C, and the reaction was stirred for 36 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (instrument model: Waters-2545, column: Ultimate Phenyl-Hexyl 5um 30 × 250 mm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-95%, flow rate: 30 mL / min) to obtain a mixture of compounds 32-1-1 and 32-1-2 or a mixture of compounds 32-2-1 and 32-2-2 (12.5 mg, yield: 15%).

[1029] MS m / z (ESI): 874.6 [M+1].

[1030] 1H NMR (500 MHz, CDCl3) δ 11.78 (brs, 1H), 8.61 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6.46 (d, 2H), 4.58 (s, 2H), 4.47-4.45 (m, 1H), 4.25-4.18 (m, 2H), 4.00-3.97 (m, 2H), 3.79-3.75 (m, 4H), 3.05-3.03 (m, 2H), 2.87-2.81 (m, 3H), 2.74-2.64 (m, 5H), 2.56-2.51 (m, 2H), 2.43-2.23 (m, 3H), 2.18-2.15 (m, 1H), 2.08-2.03 (m, 3H), 1.99-1.87 (m, 5H), 1.74-1.67 (m, 6H), 1.37-1.32 (m, 4H).

[1031] Examples 32-1-1 and 32-1-2 or 32-2-1 and 32-2-2

[1032] (R)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-1

[1033] and

[1034] (R)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-1-2

[1035] or

[1036] (S)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-1

[1037] and

[1038] (S)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,6'-9-oxa-4-aza-5(2,1)-benzofurano[6,7-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 32-2-2

[1039] or

[1040]

[1041]

[1042] Compound 31b-1 or 31b-2 (51 mg, 0.158 mmol, prepared in one step from the shorter retention time (2.259 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 32j-1 and 32j-2 (65 mg, 0.095 mmol) was added, sodium triacetoxyborohydride (61 mg, 0.28 mmol) and N,N-diisopropylethylamine (106 mg, 0.82 mmol) were added, the mixture was heated to 50 °C, and the reaction was stirred for 36 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (instrument model: Waters-2545, column: Ultimate Phenyl-Hexyl 5um 30 × 250 mm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-95%, flow rate: 30 mL / min) to obtain a mixture of compounds 32-1-1 and 32-1-2 or a mixture of compounds 32-2-1 and 32-2-2 (11.8 mg, yield: 14.2%).

[1043] MS m / z (ESI): 874.6 [M+1].

[1044] 1 H NMR (500 MHz, CDCl3) δ 11.78 (brs, 1H), 8.61 (s, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6.46 (d, 2H), 4.58 (s, 2H), 4.50-4.45 (m, 1H), 4.25-4.18 (m, 2H), 4.00-3.97 (m, 2H), 3.79-3.75 (m, 4H), 3.05-3.03 (m, 2H), 2.87-2.81 (m, 3H), 2.74-2.68 (m, 2H), 2.67-2.64 (m, 4H), 2.55-2.51 (m, 2H), 2.43-2.24 (m, 4H), 2.19-2.15 (m, 1H), 2.08-2.03 (m, 3H), 1.99-1.84 (m, 6H), 1.75-1.70 (m, 3H), 1.36-1.33 (m, 4H).

[1045] Examples 33-1-1 and 33-1-2 or 33-2-1 and 33-2-2

[1046] (3S)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6 ª,5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-1

[1047] (3S)-3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-2 or

[1048] (3R)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-1

[1049] (3R)-3-(2,6-difluoro-4-(4-((7) 1 S,73 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-2

[1050] or

[1051]

[1052]

[1053] first step

[1054] 8-Bromo-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine-3-carboxylic acid ester 33b

[1055] 2-Bromo-3,4-difluoro-1-nitrobenzene 33a (5.4 g, 22.7 mmol, Biotin) was dissolved in N,N-dimethylformamide (80 mL), and tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (5.2 g, 22.7 mmol, Shaoyuan) and cesium carbonate (44.4 g, 136.1 mmol) were added. The mixture was stirred at room temperature for 72 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 33b (3.9 g, yield: 40.1%).

[1056] MS m / z (ESI): 372.1 [M-55].

[1057] Step 2

[1058] 8-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine-3-carboxylic acid tert-butyl ester 33c-1 and

[1059] 8-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine-3-carboxylic acid tert-butyl ester 33c-2

[1060] Compound 33b (500 mg, 1.17 mmol) was dissolved in dioxane (40 mL), and a mixture of compounds 25c-2 and 25c-1 (213 mg, 1.29 mmol), tris(dibenzylacetone)palladium (214 mg, 0.23 mmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (291 mg, 0.47 mmol) and cesium carbonate (1.14 g, 3.50 mmol) were added. The mixture was purged with nitrogen three times, heated to 103 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system B to obtain a mixture of title compounds 33c-1 and 33c-2 (300 mg, yield: 53.9%).

[1061] MS m / z (ESI): 477.6 [M+1].

[1062] Step 3

[1063] 8-((((1R,3S)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine-3-carboxylic acid tert-butyl ester 33d-1 and

[1064] 8-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazheptan-3-carboxylic acid tert-butyl ester 33d-2

[1065] A mixture of compounds 33c-1 and 33c-2 (400 mg, 0.84 mmol) was dissolved in tetrahydrofuran (10 mL), and the mixture was placed in an ice bath. Methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (263 mg, 1.00 mmol, prepared by the method of compound 247 in the example on page 123 of patent application WO2024246838), triphenylphosphine (330 mg, 1.26 mmol), and diisopropyl azodicarbonate (255 mg, 1.26 mmol) were added, and the mixture was heated to room temperature and stirred for 2 hours. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried with anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to obtain a mixture (800 mg) of crude title compounds 33d-1 and 33d-2. The product was used directly in the next reaction without purification.

[1066] MS m / z (ESI): 720.7 [M+1].

[1067] Step 4

[1068] 9-Amino-8-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine-3-carboxylic acid tert-butyl ester 33e-1 and

[1069] 9-Amino-8-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazheptan-3-carboxylic acid tert-butyl ester 33e-2

[1070] A mixture of compounds 33d-1 and 33d-2 (800 mg, 1.11 mmol) was dissolved in tetrahydrofuran (5 mL), and Raney nickel (326 mg, 5.55 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 33e-1 and 33e-2 (700 mg). The product was used directly in the next reaction without purification.

[1071] MS m / z (ESI): 690.8 [M+1].

[1072] Step 5

[1073] 2-Amino-3-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5,6,6a,7,9,10-octahydro-1H,8H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazopentane-8-carboxylic acid tert-butyl ester 33f-1 and

[1074] 2-Amino-3-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5,6,6a,7,9,10-octahydro-1H,8H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazopentane-8-carboxylic acid tert-butyl ester 33f-2

[1075] A mixture of compounds 33e-1 and 33e-2 (700 mg, 1.01 mmol) was dissolved in methanol (4 mL) and dichloromethane (10 mL), and cyanogen bromide (223 mg, 2.03 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to give a mixture of title compounds 33f-1 and 33f-2 (260 mg, yield: 35.8%).

[1076] MS m / z (ESI): 715.9 [M+1].

[1077] Step 6

[1078] (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 - tert-butyl carboxylate 33g-1

[1079] and

[1080] (7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 - tert-butyl carboxylate 33g-2

[1081] A mixture of compounds 33f-1 and 33f-2 (260 mg, 0.36 mmol) was dissolved in tetrahydrofuran (20 mL). The mixture was placed in an ice bath, and a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (122 mg, 0.73 mmol, 0.73 mL, 1 M) was added. The mixture was heated to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to give a mixture of title compounds 33g-1 and 33g-2 (200 mg, yield: 80.5%).

[1082] MS m / z (ESI): 683.7 [M+1].

[1083] Step 7

[1084] (7 1 R,7 3 S,E)-1 1,1 3 ,2 6 -trimethyl-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 33h-1 and

[1085] (7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 33h-2

[1086] A mixture of compounds 33g-1 and 33g-2 (200 mg, 0.29 mmol) was dissolved in a 4 M solution of dioxane (2 mL) of hydrogen chloride and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to alkaline with saturated sodium bicarbonate solution. The residue was extracted with dichloromethane (30 mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude mixture of the title compounds 33h-1 and 33h-2 (150 mg). The product was used directly in the next reaction without purification.

[1087] MS m / z (ESI): 583.5 [M+1].

[1088] Step 8

[1089] (3S)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6 ª,5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-1

[1090] (3S)-3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-2 or

[1091] (3R)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-11 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-1

[1092] (3R)-3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-2

[1093] A mixture of compounds 33h-1 and 33h-2 (120 mg, 0.19 mmol) was dissolved in 1,2-dichloroethane (4 mL), and compounds 31b-1 or 31b-2 (63 mg, 0.19 mmol, prepared in one step from the shorter retention time (2.259 min) of 31a-1 and 31a-2) were added, along with N,N-diisopropylethylamine (251 mg, 1.94 mmol) and sodium triacetoxyborohydride (123 mg, 0.58 mmol). The mixture was heated to 40 °C and reacted for 3 hours. The reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with dichloromethane (15 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give a mixture of title compounds 33-1-1 and 33-1-2 or a mixture of 33-2-1 and 33-2-2 (20 mg, yield: 11.6%).

[1094] MS m / z (ESI): 889.7 [M+1].

[1095] 1 H NMR (500 MHz, CDCl3): δ 11.8 (s, 1H), 8.58 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 6.94-6.84 (m, 2H), 6.49-6.41 (m, 2H), 5.45-5.32 (m, 1H), 4.75-4.67 (m, 1H), 4.61-4.51 (m, 1H), 4.36-4.11 (m, 3H), 4.01-3.90 (m, 2H), 3.80-3.77 (m, 1H), 3.74 (s, 3H), 3.30-3.20 (m, 3H), 3.00-2.48 (m, 13H), 2.41-2.13(m, 3H), 2.06-1.85 (m, 5H), 1.76-1.63 (m, 5H), 1.37-1.26 (m, 4H), 0.95-0.85(m, 1H).

[1096] Examples 33-1-1 and 33-1-2 or 33-2-1 and 33-2-2

[1097] (3S)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6 ª,5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-1

[1098] (3S)-3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-1-2 or

[1099] (3R)-3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6-trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-1

[1100] (3R)-3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 6 5 6a 5 7 5 8 5 9 5 10 -octahydro-1 1 H,5 1 H,5 5 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxa-aza-heptane-2(2,4)-pyridazane-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 8 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 33-2-2

[1101] or

[1102]

[1103]

[1104] A mixture of compounds 33h-1 and 33h-2 (160 mg, 0.26 mmol) was dissolved in 1,2-dichloroethane (6 mL), and compounds 31b-1 or 31b-2 (92 mg, 0.29 mmol, prepared in one step from the compound with the longer retention time (2.989 min) of 31a-1 and 31a-2) were added, along with N,N-diisopropylethylamine (334 mg, 2.58 mmol) and sodium triacetoxyborohydride (165 mg, 0.78 mmol). The mixture was heated to 40 °C and reacted for 16 hours. The reaction was cooled to room temperature, quenched with water (5 mL), extracted with dichloromethane (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give a mixture of title compounds 33-1-1 and 33-1-2 or a mixture of 33-2-1 and 33-2-2 (8 mg, yield: 3.5%).

[1105] MS m / z (ESI): 889.7 [M+1].

[1106] 1 H NMR (500 MHz, CDCl3): δ 11.7 (s, 1H), 8.58 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 6.94-6.84 (m, 2H), 6.49-6.41 (m, 2H), 5.45-5.32 (m, 1H), 4.75-4.67 (m, 1H), 4.61-4.51 (m, 1H), 4.36-4.11 (m, 3H), 4.01-3.90 (m, 2H), 3.80-3.77 (m, 1H), 3.74 (s, 3H), 3.30-3.20 (m, 3H), 3.00-2.48 (m, 13H), 2.41-2.13(m, 3H), 2.06-1.85 (m, 5H), 1.76-1.63 (m, 5H), 1.37-1.26 (m, 4H), 0.95-0.85(m, 1H).

[1107] Examples 34-1-1 and 34-1-2 or 34-2-1 and 34-2-2

[1108] (R)-3-(2,6-difluoro-4-(4-(3-(5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-1-1

[1109] and

[1110] (R)-3-(2,6-difluoro-4-(4-(3-(5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-1-2

[1111] or

[1112] (S)-3-(2,6-difluoro-4-(4-(3-((55a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-2-1

[1113] and

[1114] (S)-3-(2,6-difluoro-4-(4-(3-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-2-2

[1115]

[1116] or

[1117]

[1118]

[1119] first step

[1120] 3-((5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 34a-1 tert-butyl 1-(azirocyclobutane-1-carboxylic acid)

[1121] and

[1122] 3-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 34a-2-( ...

[1123] 3-oxozycyclobutane-1-carboxylic acid tert-butyl ester (30 mg, 0.175 mmol) was dissolved in 1,2-dichloroethane (5 mL), and a mixture of compounds 25i-1 and 25i-2 (50 mg, 0.087 mmol) was added, along with sodium triacetoxyborohydride (61 mg, 0.28 mmol) and acetic acid (1 mg, 0.016 mmol). The reaction mixture was reacted overnight at room temperature. The reaction solution was quenched with water (15 mL), extracted with dichloromethane (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 34a-1 and 34a-2 (30 mg, yield: 47%).

[1124] MS m / z (ESI): 724.6 [M+1].

[1125] Step 2

[1126] (5 5a S,7 1 R,7 3 S,E)-5 7 -(azacyclobut-3-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-3-one 34b-1

[1127] and

[1128] (5 5a S,7 1 S,7 3 R,E)-5 7 -(azacyclobut-3-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 55a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononadenosine-3-one 34b-2

[1129] A mixture of compounds 34a-1 and 34a-2 (30 mg, 0.041 mmol) was dissolved in dichloromethane (1 mL), and 4 M dioxane hydrochloride solution (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate solution (15 mL), extracted with dichloromethane (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude mixture of 34b-1 and 34b-2 (25 mg). The product was used directly in the next reaction without purification.

[1130] MS m / z (ESI): 624.5 [M+1].

[1131] Step 3

[1132] (R)-3-(2,6-difluoro-4-(4-(3-(5) 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-1-1

[1133] and

[1134] (R)-3-(2,6-difluoro-4-(4-(3-(5) 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-1-2

[1135] or

[1136] (S)-3-(2,6-difluoro-4-(4-(3-((5 5a S,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-2-1

[1137] and

[1138] (S)-3-(2,6-difluoro-4-(4-(3-((5 5a S,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)azacyclobut-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 34-2-2

[1139] Compound 31b-1 or 31b-2 (25 mg, 0.077 mmol, prepared in one step from the compound with the longer retention time (2.989 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (3 mL), a mixture of 34b-1 and 34b-2 (25 mg, 0.040 mmol) was added, sodium triacetoxyborohydride (25 mg, 0.117 mmol) and N,N-diisopropylethylamine (51 mg, 0.394 mmol) were added, and the mixture was heated to 40 °C and reacted overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (instrument model: Waters-2545, column: XP tC18-AX, Prep 30×250 mm; 5 μm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 75%-95%, flow rate: 30 mL / min) to give a mixture of title compounds 34-1-1 and 34-1-2 or a mixture of compounds 34-2-1 and 34-2-2 (10 mg, yield: 26%).

[1140] MS m / z (ESI): 930.9 [M+1].

[1141] 1H NMR (500 MHz, CDCl3): δ 11.87-11.54 (m, 1H), 8.62 (s, 1H), 8.05 (s,1H), 7.52 (s, 1H), 6.88-6.69 (m, 2H), 6.47-6.36 (m, 2H), 5.43-5.29 (m, 1H), 4.61-3.53 (m, 15H), 3.31-2.49 (m, 15H), 2.39-1.78 (m, 12H), 1.51-1.32 (m,5H), 0.94-0.86 (m, 1H).

[1142] Examples 35-1-1 and 35-1-2 or 35-2-1 and 35-2-2

[1143] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-1

[1144] and

[1145] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 57 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-2

[1146] or

[1147] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-1

[1148] and

[1149] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-2

[1150]

[1151]

[1152] first step

[1153] (R)-7-bromo-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 35a

[1154] Compound 25a (10.0 g, 42.02 mmol, Biotin) was dissolved in N,N-dimethylformamide (100 mL), and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (13.6 g, 62.88 mmol, Shaoyuan) and cesium carbonate (54.7 g, 168.07 mmol) were added. The mixture was stirred at room temperature for 72 hours. The reaction solution was poured into 500 mL of water, filtered, and the filter cake was stirred in a mixture of petroleum ether and ethyl acetate (V / V==3:1) (100 mL), filtered, and the filter cake was collected to give the title compound 35a (3.5 g, yield: 20%).

[1155] MS m / z (ESI): 412.1 [M-1].

[1156] Step 2

[1157] (R)-7-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 35b-1 and

[1158] (R)-7-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 35b-2

[1159] Compound 35a (600 mg, 1.44 mmol) was dissolved in dioxane (40 mL), and a mixture of compounds 25c-2 and 25c-1 (200 mg, 1.21 mmol), tris(dibenzylacetone)palladium (265 mg, 0.29 mmol), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (315 mg, 0.51 mmol) and cesium carbonate (1.41 g, 4.32 mmol) were added. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system B to give a mixture of title compounds 35b-1 and 35b-2 (350 mg, yield: 52%).

[1160] MS m / z (ESI): 463.4 [M+1].

[1161] Step 3

[1162] (R)-7-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 35c-1 and

[1163] (R)-7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 35c-2

[1164] A mixture of compounds 35b-1 and 35b-2 (350 mg, 0.75 mmol) was dissolved in tetrahydrofuran (50 mL), and the mixture was placed in an ice bath. Methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (199 mg, 0.76 mmol, prepared by the method of compound 247 in the example on page 123 of patent application WO2024246838A1), triphenylphosphine (238 mg, 0.90 mmol), and diisopropyl azodicarbonate (183 mg, 0.90 mmol) were added, and the mixture was heated to room temperature and stirred for 3 hours. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give a mixture of title compounds 35c-1 and 35c-2 (400 mg, yield: 75%).

[1165] MS m / z (ESI): 706.6 [M+1].

[1166] Step 4

[1167] (R)-8-amino-7-((((1R,3S)-3-(((4-(4-((methyloxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 35d-1 and

[1168] (R)-8-amino-7-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl carboxylate 35d-2

[1169] A mixture of compounds 35c-1 and 35c-2 (400 mg, 0.56 mmol) was dissolved in tetrahydrofuran (10 mL), and Raney nickel (115 mg, 1.98 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 35d-1 and 35d-2 (400 mg). The product was used directly in the next reaction without purification.

[1170] MS m / z (ESI): 676.6 [M+1].

[1171] Step 5

[1172] (R)-2-aminoimino-3-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5a,6,8,9-hexahydro-1H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-7(5H)-tert-butyl carboxylate 35e-1 and

[1173] (R)-2-aminoimino-3-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3,5a,6,8,9-hexahydro-1H-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-7(5H)-tert-butyl carboxylate 35e-2

[1174] A mixture of compounds 35d-1 and 35d-2 (400 mg, 0.59 mmol) was dissolved in methanol (30 mL), and cyanogen bromide (71 mg, 0.71 mmol) was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was poured into 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 35e-1 and 35e-2 (350 mg, yield: 84%).

[1175] MS m / z (ESI): 701.6 [M+1].

[1176] Step 6

[1177] (5 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -tert-butyl carboxylate 35f-1 and

[1178] (5 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 - tert-butyl carboxylate 35f-2

[1179] A mixture of compounds 35e-1 and 35e-2 (350 mg, 0.49 mmol) was dissolved in tetrahydrofuran (20 mL), placed in an ice bath, and a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (250 mg, 1.49 mmol, 1.49 mL, 1 M) was added. The mixture was heated to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, and purified the residue by silica gel column chromatography with elution system A to give a mixture of title compounds 35f-1 and 35f-2 (230 mg, yield: 68%).

[1180] MS m / z (ESI): 669.5 [M+1].

[1181] Step 7

[1182] (5 5a R,7 1 R,7 3 S,E)-1 1 ,13 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-3-one 35g-1

[1183] and

[1184] (5 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-3-one 35g-2

[1185] A mixture of compounds 35f-1 and 35f-2 (230 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (3 mL). The pH of the reaction system was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with a dichloromethane / methanol mixture (V / V = 10 / 1, 10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 35g-1 and 35g-2 (200 mg). The product was used directly in the next reaction without purification.

[1186] MS m / z (ESI): 569.7 [M+1].

[1187] Step 8

[1188] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-1

[1189] and

[1190] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-2

[1191] or

[1192] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-1

[1193] and

[1194] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-2

[1195] Compound 31b-1 or 31b-2 (29 mg, 0.089 mmol, prepared in one step from the shorter retention time (2.259 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 35 g-1 and 35 g-2 (50 mg, 0.087 mmol) was added, sodium triacetoxyborohydride (61 mg, 0.28 mmol) and N,N-diisopropylethylamine (106 mg, 0.82 mmol) were added, and the mixture was heated to 50 °C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) (instrument model: Waters-2545, column: XP tC18-AX, Prep 30×250 mm; 5 μm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 30 mL / min) to obtain a mixture of compounds 35-1-1 and 35-1-2 or a mixture of compounds 35-2-1 and 35-2-2 (10 mg, yield: 14%).

[1196] MS m / z (ESI): 875.7 [M+1].

[1197] 1 H NMR (500 MHz, CDCl3): δ 12.01-11.51 (m, 1H), 8.63 (s, 1H), 8.19 (s,1H), 7.58 (s, 1H), 7.02-6.65 (m, 2H), 6.62-6.26 (m, 2H), 5.55-5.28 (m, 1H), 4.68-3.55 (m, 14H), 3.42-2.46 (m, 14H), 2.41-1.56 (m, 12H), 1.42-1.19 (m, 3H).

[1198] Examples 35-1-1 and 35-1-2 or 35-2-1 and 35-2-2

[1199] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 58 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-1

[1200] and

[1201] (S)-3-(2,6-difluoro-4-(4-((5 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-1-2

[1202] or

[1203] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,51 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-1

[1204] and

[1205] (R)-3-(2,6-difluoro-4-(4-((5) 5a R,7 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 5 3 5 5 5 5a 5 6 5 7 5 8 5 9 -octahydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,3)-imidazo[4',5':5,6]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-2(2,4)-pyridazin-1(4,5)-pyrazola-7(1,3)-cyclopentazocine-5 7 -yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 35-2-2

[1206]

[1207]

[1208] Compound 31b-1 or 31b-2 (30 mg, 0.092 mmol, prepared in one step from the compound with the longer retention time (2.989 min) of 31a-1 and 31a-2) was dissolved in 1,2-dichloroethane (10 mL), a mixture of 35 g-1 and 35 g-2 (48 mg, 0.15 mmol) was added, sodium triacetoxyborohydride (106 mg, 0.50 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were added, and the mixture was heated to 50 °C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) (instrument model: Waters-2545, column: XP tC18-AX, Prep 30×250 mm; 5 μm, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-80%, flow rate: 30 mL / min) to obtain a mixture of compounds 35-1-1 and 35-1-2 or a mixture of compounds 35-2-1 and 35-2-2 (6 mg, yield: 13.8%).

[1209] MS m / z (ESI): 875.7 [M+1].

[1210] 1 H NMR (500 MHz, CDCl3): δ 12.01-11.51 (m, 1H), 8.63 (s, 1H), 8.19 (s,1H), 7.58 (s, 1H), 7.02-6.65 (m, 2H), 6.62-6.26 (m, 2H), 5.55-5.28 (m, 1H), 4.68-3.55 (m, 14H), 3.42-2.46 (m, 14H), 2.41-1.56 (m, 12H), 1.42-1.19 (m, 3H).

[1211] Examples 36-1 and 36-2

[1212] 3-(2,6-difluoro-4-(4-((7) 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-11 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 3 1-yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carbamate 36-1

[1213] and

[1214] 3-(2,6-difluoro-4-(4-((7) 1 S,7 3 R,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 1 5 2 5 3 5 4 5 4a 5 5 5 9 5 10 -octahydro-1 1 H,5 8 H-9-oxa-4-aza-5(9,10)-imidazo[4',5':4,5]benzo[1,2-b]pyrido[1,2-d][1,4]oxazinza-2(2,4)-pyridazinza-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen-5 3 1-yl)piperazine-1-yl)phenyl)piperidine-2,6-dione carbamate 36-2

[1215]

[1216] Using the preparation method of Example 26, the starting material 26a in the first step was replaced with 2,4,5-trifluoronitrobenzene. The final product was purified by high performance liquid chromatography (instrument model: Waters-2545; column: Welch Xtimate PerpC18 5um 30×150 mm; mobile phase: water (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15%-50%, flow rate: 30 mL / min) to obtain a mixture of title compounds 36-1 and 36-2 (4 mg, yield: 17%).

[1217] MS m / z (ESI): 875.8 [M+1].

[1218] 1H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), δ 10.88 (d, 1H), 8.53 (s,1H), 8.25 (s, 1H), 7.44 (s, 1H), 7.06 (d, 1H), 6.90 (d, 1H), 6.71-6.60 (m,2H), 4.25 (d, 2H), 4.16 (d, 2H), 4.06 (dd, 2H), 3.92 (t, 1H), 3.67 (s, 3H),3.54 (d, 1H), 3.44 (s, 2H), 3.21 (s, 4H), 3.01 (s, 1H), 2.89 (s, 2H), 2.79(ddd, 2H), 2.64 (s, 3H), 2.55 (s, 3H), 2.48 (s, 2H), 2.42-2.34 (m, 2H), 2.10(dd, 2H), 2.02 (d, 2H), 1.97-1.88 (m, 2H), 1.88-1.81 (m, 2H), 1.81-1.69 (m, 2H), 1.69-1.55 (m, 2H).

[1219] Examples 37-1 and 37-2

[1220] 3-(4-((1'R,3'S,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridazo-1(4,5)-pyrazola-7(1,3)-cyclopentacyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 37-1 and

[1221] 3-(4-((1'S,3'R,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazaza-7(1,3-cyclopentacyclonona]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 37-2

[1222]

[1223]

[1224] first step

[1225] 5-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 37a-1 and

[1226] 5-((((1S,3R)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 37a-2

[1227] A mixture of compound 13c (600 mg, 1.71 mmol), compound 25c-2, and compound 25c-1 (445 mg, 3.44 mmol) was dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (1017 mg, 8.57 mmol) was added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (6 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give a mixture of title compounds 37a-1 and 37a-2 (500 mg, yield: 63.5%).

[1228] MS m / z (ESI): 460.5 [M+1].

[1229] Step 2

[1230] 5-((((1R,3S)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 37b-1 and

[1231] 5-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 37b-1

[1232] A mixture of compounds 37a-1 and 37a-2 (500 mg, 1.09 mmol), compound 2h (323 mg, 1.31 mmol), and triphenylphosphine (514 mg, 1.96 mmol) were dissolved in tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (396 mg, 1.96 mmol) was added. The mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give a crude mixture of title compounds 37b-1 and 37b-2 (1500 mg). The product was used directly in the next reaction without purification.

[1233] MS m / z (ESI): 689.6 [M+1].

[1234] Step 3

[1235] 6-Amino-5-((((1R,3S)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 37c-1 and

[1236] 6-Amino-5-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 37c-2

[1237] A mixture of compounds 37b-1 and 37b-2 (600 mg, 0.87 mmol) was dissolved in methanol (15 mL), and platinum dioxide (396 mg, 1.74 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude mixture of the title compounds 37c-1 and 37c-2 (600 mg). The product was used directly in the next reaction without purification.

[1238] MS m / z (ESI): 661.6 [M+1].

[1239] Step 4

[1240] 2-Amino-1-(((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3-dihydro-1H,6H-spiro[benzofurano[5,6-d]imidazol-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester 37d-1 and

[1241] 2-Amino-1-(((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)-2,3-dihydro-1H,6H-spiro[benzofurano[5,6-d]imidazol-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester 37d-2

[1242] A mixture of compounds 37c-1 and 37c-2 (572 mg, 0.87 mmol) was dissolved in methanol (4 mL) and dichloromethane (10 mL), and cyanogen bromide (200 mg, 1.82 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 37d-1 and 37d-2 (230 mg, yield: 38.7%).

[1243] MS m / z (ESI): 686.7 [M+1].

[1244] Step 5

[1245] (1'R,3'S,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-carboxylic acid tert-butyl ester 37e-1 and

[1246] (1'S,3'R,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-carboxylic acid tert-butyl ester 37e-2

[1247] A mixture of compounds 37d-1 and 37d-2 (230 mg, 0.34 mmol) was dissolved in tetrahydrofuran (6 mL), and bis(trimethylsilylaminolithium) (0.67 mL, 1 M tetrahydrofuran solution) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was poured into 20 mL of ethyl acetate and washed successively with saturated ammonium chloride solution (10 mL × 2) and saturated sodium chloride solution (10 mL × 2). 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 elution system A to give a mixture of title compounds 37e-1 and 37e-2 (160 mg, yield: 73%).

[1248] MS m / z (ESI): 654.7 [M+1].

[1249] Step 6

[1250] (1'R,3'S,E)-1',6'-dimethylspiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclopentacyclonona]-3'-one 37f-1 and

[1251] (1'S,3'R,E)-1',6'-dimethylspiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4-pyridaza-1(4,5-pyrazola-7(1,3-cyclopentacyclonona]-3'-one 37f-2

[1252] A mixture of compounds 37e-1 and 37e-2 (160 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane in 4 M hydrogen chloride (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to 7-8 with saturated sodium bicarbonate solution. The residue was extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude mixture of the title compounds 37f-1 and 37f-2 (130 mg). The product was used directly in the next reaction without purification.

[1253] MS m / z (ESI): 554.4 [M+1].

[1254] Step 7

[1255] 3-(4-(4-((1'R,3'S,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazola-7(1,3)-cyclopentacyclononafen]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 37-1 and

[1256] 3-(4-(4-((1'S,3'R,E)-1',6'-dimethyl-3'-oxospiro[piperidine-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridaza-1(4,5-pyrazaza-7(1,3-cyclopentacyclonona]-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione 37-2

[1257] A mixture of compounds 37f-1 and 37f-2 (60 mg, 0.11 mmol) and compound 2n (37 mg, 0.11 mmol) were dissolved in 1,2-dichloroethane (5 mL), N,N-diisopropylethylamine (132 mg, 1.02 mmol) was added, and sodium triacetoxyborohydride (65 mg, 0.31 mmol) was added. The mixture was heated to 40 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by preparative high performance liquid chromatography (instrument model: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give a mixture of title compounds 37-1 and 37-2 (27 mg, yield: 30.9%).

[1258] MS m / z (ESI): 860.6 [M+1].

[1259] 1 H NMR (500 MHz, CDCl3): δ 11.8 (s, 1H), 8.56 (s, 1H), 8.20-8.14 (m,2H), 7.55 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.46-6.42 (m, 2H), 5.37-5.29(m, 1H), 4.55-4.43 (m, 3H), 4.29-4.21 (m, 1H), 4.09-3.94 (m, 2H), 3.87-3.74(m, 5H), 3.07-3.01 (m, 2H), 2.99-2.80 (m, 4H), 2.73-2.52 (m, 6H), 2.41-1.62 (m, 18H).

[1260] Examples 38-1-1 and 38-2-1 or 38-1-2 and 38-2-2

[1261] (S)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 38-1-1 and

[1262] (S)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 38-2-1 or

[1263] (R)-3-(2,6-difluoro-4-(4-((1'R,3'S,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 38-1-2 and

[1264] (R)-3-(2,6-difluoro-4-(4-((1'S,3'R,E)-1',3',6'-trimethyl-3'-oxospiro[piperidin-4,7'-9-oxa-4-aza-5(2,1)-benzofurano[5,6-d]imidazo-2(2,4)-pyridazo-1(4,5-pyrazo-7(1,3-cyclopentacyclonona]-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione 38-2-2

[1265]

[1266] or

[1267]

[1268]

[1269] first step

[1270] 5-((((1R,3S)-3-(((4-(4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 38a-1 and

[1271] 5-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 38a-2

[1272] A mixture of compounds 37a-1 and 37a-2 (230 mg, 0.50 mmol), methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (157 mg, 0.60 mmol), and triphenylphosphine (236 mg, 0.90 mmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (182 mg, 0.90 mmol) was added. The mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give a mixture of title compounds 38a-1 and 38a-2 (650 mg, yield: 185%).

[1273] MS m / z (ESI): 703.7 [M+1].

[1274] Step 2

[1275] 6-Amino-5-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxytert-butyrate 38b-1 and

[1276] 6-Amino-5-((((1S,3R)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridin-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 38b-2

[1277] A mixture of compounds 38a-1 and 38a-2 (650 mg, 0.92 mmol) wa...

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof: in: The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Ring D is selected from polycyclic cycloalkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; W is selected from bond, O, and S(O). v 、(CR a R b ) x C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); V is N or CR 0 ; R 0 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; X 4 X 5 and X 6 Whether they are the same or different, and each is independently N or CR 3 ; R 2 R 3 and R 5 The same or different, and each independently selected from hydrogen atom, oxo group, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl, alkenyl, alkynyl, cyano, NR 11 R 12 C(O)NR 11 R 12 alkylene NR 11 R 12 alkylene C(O)NR 11 R 12 OR 14 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v OR 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced; Or two Rs 3 Together with the carbon atom attached to it, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or two R groups. 5 Together with the ring atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or R 5 R 7 Together with the ring atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, and heteroaryl groups; each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R groups. 01 Replaced; J 1 Selected from bond, O, S(O) v NR J C(O), C(O)NR J NR J C(O), (CR) c R d ) y cycloalkyl and heterocyclic groups; each of the cycloalkyl and heterocyclic groups is independently and optionally composed of one or more R groups. 02 Replaced; J 2 J 3 J 4 J 5 and J 6 Same or different, and each is independently selected from the key, (CR c R d ) y O, S(O) v NR J C(O), C(O)NR J NR J C(O), cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently optionally coupled with one or more R 6 Replaced; L 1 L 2 L 3 L 4 L 5 and L 6 They may be the same or different, and each is independently selected from the bond, O, and S(O). v O(CR) e R f ) u 、(CR e R f ) u O、C(O)(CR e R f ) u 、(CR e R f ) u C(O), C(O)N(R) L ), N(R L )C(O), (CR e R f ) u 、N(R L (CR) e R f ) u 、(CR e R f ) u N(R L ), alkenyl, alkyneyl, cycloalkyl, heterocyclic, (CR) e R f ) u -Heterocyclic group, heterocyclic group-(CR) e R f ) u 、(CR e R f ) u -heterocyclic-(CR) e R f ) u aryl and heteroaryl; each of the alkenyl, alkyneyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally composed of one or more R 7 Replaced; Each R a R b R c R d R e and R f The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is optionally independently bound by one or more R... 03 Replaced; R 4 R m R 11 R 12 R 13 R 14 R J and R L The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected by one or more R atoms. 03 Replaced; Each R 6 R 7 R 8 R 01 R 02 and R 03 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 21 R 22 C(O)NR 21 R 22 alkylene NR 21 R 22 alkylene C(O)NR 21 R 22 NR 23 C(O)R 24 C(O)R 24 C(O)OR 24 S(O) v R 24 S(O) v OR 24 OR 24 S(O) v NR 21 R 22 =CR 15 R 16 =NR 23 , cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclicalkyl, aryl and heteroaryl; R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, cyano groups, cycloalkyl groups, and heterocyclic groups; Each R 21 R 22 R 23 and R 24 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups; x is 0, 1, 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4, 5 or 6; u can be 0, 1, 2, 3, 4, 5, or 6; a is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3, 4, 5, 6, 7 or 8; r is 0, 1, 2, 3, 4, 5, or 6; 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 ring C is a 5- to 10-membered heteroaryl group, and / or J 4 It is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; preferably, the ring C is a 5- or 6-membered heteroaryl group, and / or J 4 Selected from cyclopropyl, cyclobutyl, and cyclopentyl; more preferably, ring C is pyrazolyl, and / or J 4 It is cyclobutyl.

3. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a pharmaceutically acceptable salt thereof is: in, Ring B is a cycloalkyl or heterocyclic group; B 1 B 2 and B 3 Whether they are the same or different, and each is independently N or CR 7a ;R 7a For hydrogen atoms or R 7 ; R 1 Selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkylalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; s is 0, 1, 2 or 3; s1 is 0 or 1; s2 is 0 or 1; b1 and b2 may be the same or different, and each can be 0, 1, 2, 3 or 4 independently; m, p, q, y1 and y2 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6; y3 and y4 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5 or 6; Ring A, L 3 L 5 ,u,t,ring D,J 1 R 2 To R 8 and r as defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring D is selected from... , , and Preferably, ring D is or * Fusing to the imidazole ring at the * end, Key and L 1 Connection; X 1 and X 2 Whether they are the same or different, and each is independently N or CR 5 ; Y is selected from bond, O, S(O). v C(O), (CR) a R b ) x C(O)O, OC(O), NR m C(O)NR m NR m C(O) and NR m C(O)NR m ; t1 and t2 are each independently 0, 1, 2, 3, 4 or 5; a1 and a2 are each independently 0, 1, 2, 3, 4 or 5; A 1 For N or CR A1 A 2 For N or CR A2 ; R A1 and R A2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, hydroxyalkyl, haloalkyl, hydroxyl, cyano, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic and cycloalkylalkyl; R a R b x, R m R 5 and v as defined in claim 1; More preferably, ring D is selected from , , and .

5. The compound of general formula (I) according to claim 1, 3 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof: in, t is 0, 1, 2, 3, 4, 5, or 6; r is 0, 1, 2, 3, or 4; R 1 To R 8 B 1 B 2 B 3 Ring B, L 5 , b1, b2, s1, s2, p, q, u, Y, t1, t2, a1, a2, A 1 A 2 J 1 , s, y1 to y4 and m as defined in claim 3 or 4.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IIIM), (IVM), (VM), (VIM) or (VII), or a pharmaceutically acceptable salt thereof: in, Q is CR 8a Or N; R 8a For hydrogen atoms or R 8 ; X is selected from bonds, O, S, and (CH2). z E 1 For CR 8b Or N; R 8b For hydrogen atoms or R 8 ; z is 0, 1, 2, or 3; r is 0, 1, 2, or 3; e1, e2, and e3 are each independently 0, 1, 2, or 3; B 1 B 2 Ring B, B 3 L 5 ,W,s2,s1,b1,b2,u,p,q,Y,t1,t2,a1,a2,A 1 A 2 ,t,J 1 R 1 To R 8 , s, y1 to y4 and m as defined in claim 5.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, Y is selected from O, NH, N(CH3), and S(O). v C(O)NH and NHC(O), and / or A 1 For CH or N, and / or A 2 For CH or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1, and / or t1 is 0 or 1, and / or t2 is 0 or 1; preferably, A 1 For N, and / or A 2 Let N be the number of elements in the array.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, B 1 For CH or N, and / or B 2 It is CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1.

9. The compound of general formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein, u is 0 or 1, and / or L 5 For bond or (CH2) u2 u2 is 0, 1, or 2, and / or ring B is a 5- or 6-membered heterocyclic group; preferably, u is 0, and / or L 5 s1 is the key, and / or s2 is 0.

10. The compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein, J 1 y1 is 0, and / or y2 is 0, 1 or 2, and / or y3 is 0, 1 or 2, and / or y4 is 1 or 2.

11. The compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein, Each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; and / or R 1 C 1-6 Alkyl, and / or R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl, and / or R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms, and / or R 5 It is a hydrogen atom; preferably, R 8 It is a halogen.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

13. A compound of the general formula (IIIA-2), (IVA-2), (VA-2), (VA-4) or (VIA-2), or a salt thereof: in, R W The protecting group can be a hydrogen atom or an amino group; the amino protecting group is preferably Boc. Y, t1, t2, a1, a2, A 1 A 2 J 1 R 1 To R 7 、u、B 1 B 2 b1, b2, p, s, t, y1 to y4 and m as defined in claim 5.

14. A compound or a salt thereof, selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

15. A method for preparing compounds of the above general formulas (IIIM), (IVM), (VM) and (VIM) or pharmaceutically acceptable salts thereof, the method comprising: The compound of general formula (IIIA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (IIIM) CH or their pharmaceutically acceptable salts. The compound of general formula (IVA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (IVM) CH or their pharmaceutically acceptable salts, The compound of general formula (VA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (VM) CH or pharmaceutically acceptable salts thereof, or The compound of general formula (VA-4) or its salt reacts with the compound of general formula (VB-2) or its salt in a reductive amination reaction to give A. 2 For CH and B 1 Compounds of the general formula (VM) for N or their pharmaceutically acceptable salts, The compound of general formula (VIA-3) or its salt reacts with the compound of general formula (VB) or its salt in a reductive amination reaction to give A. 2 For N and B 1 Compounds of the general formula (VIM) CH or their pharmaceutically usable salts. Where u is 0 and s1 is 1; B 2 Ring B, B 3 L 5 ,Q,W,s2,b1,b2,p,q,r,Y,t1,t2,a1,a2,A 1 ,t,J 1 R 1 To R 8 , s, y1 to y4 and m as defined in claim 6.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for regulating EGFR ubiquitination and degradation.

18. Use of the compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for the treatment and / or prevention of EGFR-mediated or dependent diseases or conditions.

19. Use of the compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing cancer; preferably, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, salivary gland cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer, thyroid cancer, glioblastoma, brain metastases, solid tumors, oropharyngeal cancer, bronchial tumors, and skin cancer; more preferably lung cancer; more preferably non-small cell lung cancer.

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