Substituted cyclobutane, method for preparing same, and pharmaceutical use thereof

Abstract

Provided are a substituted cyclobutane, a method for preparing same, and pharmaceutical use thereof. Particularly, provided are a substituted cyclobutane of general formula (I), a method for preparing same, a pharmaceutical composition comprising the compound, and use thereof as a therapeutic agent, particularly in the preparation of a medicament for treating and / or preventing androgen receptor-mediated or -dependent diseases or disorders. The groups in the general formula (I) are as defined in the specification.

Description

Substituted cyclobutanes, their preparation methods and their pharmaceutical applications Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to substituted cyclobutanes, methods for their preparation, and their pharmaceutical applications. In particular, this disclosure relates to substituted cyclobutanes of general formula (I), methods for their preparation, and pharmaceutical compositions containing such compounds, as well as their use as RIPTAC AR and in the preparation of medicaments for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions. Background Technology

[0002] Cancer is a major public health problem worldwide and a leading contributor to the global disease burden. Prostate cancer is one of the most common and deadliest cancers in men, and its incidence is on the rise. Prostate cancer generally grows slowly, its onset is age-related, and it is more common in older men. Breast cancer has the highest incidence and mortality rate among women, seriously endangering their physical and mental health. Although treatments for prostate and breast cancer, including medications, are constantly evolving, some patients still experience recurrence or become unable to tolerate treatment. Therefore, there is an urgent need to develop anti-tumor drugs with higher efficacy and safety for clinical application.

[0003] Current anti-tumor drug treatments mainly include chemotherapy, targeted therapy including endocrine therapy, and immunotherapy. Building upon this foundation, developing drugs that utilize different mechanisms to exert anti-tumor activity may achieve better therapeutic effects and overcome recurrence caused by tumor drug resistance.

[0004] The publicly disclosed related patents include WO2024054603A1, CN118459483A and US2018099940A1, etc. 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] in:

[0007] Ring A is selected from

[0008] * The bond connects to C(O); Key and L 1 connect;

[0009] X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR 3X ;

[0010] Y is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0011] t1 and t2 are each independently 0, 1, 2 or 3;

[0012] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0013] a3 and a4 are each independently 0, 1, 2, 3, 4 or 5; and a3 and a4 are not both 0 at the same time;

[0014] A 1 For N or CR A1 A 2 For N or CR A2 ;

[0015] 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, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0016] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0017] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0018] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0019] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0020] L 1 L 2 L 3 and L 4 Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NRc -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced;

[0021] Each R a and R b The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 Replaced;

[0022] x, x1, x2, and x3 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0023] Each R 1 and R 3XThe same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, OR 14 NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0024] Each R 2 R 3 R 4 R 5 and R 5a Same or different, and each independently selected from hydrogen atom, deuterium atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0025] E is selected from

[0026] Q is CR 10 Or N;

[0027] Each R 6 R 7a R 8 R 9 and R 10The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 OR 14 NR 13 S(O) v R 14 NR 13 C(O)R 14 C(O)R 14 S(O) v R 14 C(O)OR 14 S(O) v OR 14 C(O)NR 11 R 12 S(O) v NR 11 R 12 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 Replaced;

[0028] R 7 and R 7b The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 alkylene-C(O)NR 11 R 12 alkylene-C(O)OR 14Cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 Replaced;

[0029] Each R', R m R c R 11 R 12 R 13 R 14 R d and R e They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclic alkyl, aryl and heteroaryl;

[0030] R 15 and R 16 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, arylalkyl groups, and heteroarylalkyl groups; the arylalkyl and heteroarylalkyl groups are each independently optionally selected by one or more R atoms. 0 Replaced;

[0031] Each R 0 They may be the same or different, and each is independently selected from deuterium, oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, S-alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0032] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0033] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5 or 6;

[0034] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0035] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0036] Each v is the same or different, and each is independently 0, 1 or 2.

[0037] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0038] in:

[0039] Ring A is selected from

[0040] * The bond connects to C(O); Key and L 1 connect;

[0041] X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR 3X ;

[0042] Y is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0043] t1 and t2 are each independently 0, 1, 2 or 3;

[0044] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0045] a3 and a4 are each independently 0, 1, 2, 3, 4 or 5; and a3 and a4 are not both 0 at the same time;

[0046] A 1 For N or CR A1 A 2 For N or CR A2 ;

[0047] 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, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0048] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0049] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0050] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0051] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0052] L 1 L 2 L 3 and L4 Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced;

[0053] Each R a and R bThe same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 Replaced;

[0054] x, x1, x2, and x3 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0055] Each R 1 and R 3X The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, OR 14 NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0056] Each R 2 R 3 R 4 R 5 and R 5a The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0057] E is selected from

[0058] Q is CR 10 Or N;

[0059] Each R 6 R 7a R 8 R 9 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 OR 14 NR 13 S(O) v R 14 NR 13 C(O)R 14 C(O)R 14 S(O) v R 14 C(O)OR 14 S(O) v OR 14 C(O)NR 11 R 12 S(O) v NR 11 R 12 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 Replaced;

[0060] R 7 and R 7b The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 alkylene-C(O)NR 11 R 12 alkylene-C(O)OR 14 Cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 Replaced;

[0061] Each R', R m R c R 11 R 12 R 13 R 14 R d and R e They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclic alkyl, aryl and heteroaryl;

[0062] R 15 and R 16 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, arylalkyl groups, and heteroarylalkyl groups; the arylalkyl and heteroarylalkyl groups are each independently optionally selected by one or more R atoms. 0 Replaced;

[0063] Each R 0 They may be the same or different, and each is independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, S-alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0064] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0065] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5 or 6;

[0066] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0067] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0068] Each v is the same or different, and each is independently 0, 1 or 2.

[0069] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0070] in:

[0071] Ring A is selected from

[0072] * The bond connects to C(O); Key and L 1 connect;

[0073] X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR 3X ;

[0074] Y is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O);

[0075] t1 and t2 are each independently 0, 1, 2 or 3;

[0076] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0077] a3 and a4 are each independently 0, 1, 2, 3, 4 or 5; and a3 and a4 are not both 0 at the same time;

[0078] A 1 For N or CR A1 A 2 For N or CR A2 ;

[0079] 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, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0080] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0081] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0082] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0083] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0084] L 1 L 2 L 3 and L 4 Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NRc C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced;

[0085] Each R a and R b The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 Replaced;

[0086] x, x1, x2, and x3 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0087] Each R 1 and R 3X The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, OR 14 NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0088] Each R 2 R 3 R 4 R 5 and R 5a The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0089] E is selected from

[0090] Q is CR 10 Or N;

[0091] Each R 6 R 7a R 8 R 9 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 Replaced;

[0092] R 7 and R 7b The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR11 R 12 OR 14 =CR 15 R 16 alkylene-C(O)NR 11 R 12 alkylene-C(O)OR 14 Cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 Replaced;

[0093] Each R', R m R c R 11 R 12 R 13 R 14 R d and R e They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclic alkyl, aryl and heteroaryl;

[0094] R 15 and R 16 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, arylalkyl groups, and heteroarylalkyl groups; the arylalkyl and heteroarylalkyl groups are each independently optionally selected by one or more R atoms. 0 Replaced;

[0095] Each R 0 They may be the same or different, and each is independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, S-alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0096] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0097] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5 or 6;

[0098] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0099] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0100] Each v is the same or different, and each is independently 0, 1 or 2.

[0101] 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 (IM) or a pharmaceutically acceptable salt thereof:

[0102] Among them, rings A, B, C, D, E, and L 1 To L 4 、R'、R 1 To R 5 R 5a , m, n, p, q, r, r2, s1, s2 and s3 are as defined in general formula (I).

[0103] In some embodiments disclosed herein, L 1 Selected from bond, O, NR c and (CR) a R b ) x ;R a R b R c And x is as defined in general formula (I); in some implementations, L 1 For bond or (CH2) x In some implementation schemes, L 1 (CH2) x x is as defined in general formula (I); in some implementations, L 1 (CH2) x x is 0, 1, 2, 3, or 4; in some implementations, L 1 Selected from bonds, CH2, CH2CH2, NH, N (methyl), C(O), O-CH2, CH2-O, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 1 It is a bond or CH2; in some implementations, it is a bond;

[0104] In some implementations, L 1 Selected from bonds, alkenyl groups, alkynyl groups, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O)x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced; in some implementations, L 1 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c , and NRc C(O)-(CR a R b ) x2 ;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 and C 1-6 Haloalkoxy; R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; x is 0, 1, 2, or 3; x1 is 0, 1, 2, or 3; x2 is 0, 1, 2, or 3; in some embodiments, L 1 Selected from bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH2 O, OCH2CH2, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O) and CH(CH3)-C(O).

[0105] In some embodiments of this disclosure, ring B is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, ring B is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; in some embodiments, ring B is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group; in some embodiments, ring B is... B 1 B 2 b1, b2 are as defined in general formula (II) or (III); in some embodiments, ring B is B 2 b1 and b2 are as defined in general formula (II) or (III).

[0106] In some embodiments of this disclosure, ring D is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, ring D is a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; in some embodiments, ring D is a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclic group.

[0107] In some embodiments disclosed herein, L 4 Selected from bond, O, NR c 、(CR a R b ) x C(O), C(O)-(CR) a R b ) x2 and NRc C(O)-(CR a R b ) x2 ;R a R b R c x, x2 are as defined in general formula (I); in some implementations, L 4 For bond or (CH2) x x is as defined in general formula (I); in some implementations, L 4 For key; in some implementations, L 4 Selected from bonds, O, CH2, CH2CH2, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2 and NHC(O)-CH2;

[0108] In some implementations, L 4 Selected from bonds, alkenyl groups, alkynyl groups, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced; in some implementations, L 4 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c , and NR c C(O)-(CR a R b ) x2 ;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 and C 1-6 Haloalkoxy; R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; x is 0, 1, 2, or 3; x1 is 0, 1, 2, or 3; x2 is 0, 1, 2, or 3; in some embodiments, L 4 Selected from the following groups: bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O), and CH(CH3)-C(O).

[0109] In some embodiments of this disclosure, s3 is 0; in other embodiments, s3 is 1.

[0110] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof:

[0111] in,

[0112] B 1 For N or CR 4 B 2 For N or CR 4 b1 and b2 are each independently 0, 1, 2, 3 or 4;

[0113] Rings C, E, L 2 L 3 s2, s1, X 1 To X 3 Y, A 1 A 2 R 1 To R 5 R', m, t1, t2, a1, a2, p, x, q and r are as defined in general formula (I).

[0114] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or pharmaceutically acceptable salts thereof are compounds represented by general formulas (IV) or (V) or pharmaceutically acceptable salts thereof:

[0115] Among them, R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0116] E, L 2 B 1 B 2 X 1 To X 3 A 1 A 2 R 2 R 3 R 4 , t1, t2, a1, a2, p, x, s1, b1, b2 and q are as defined in general formula (II) or (III).

[0117] 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 (VI) or (VII) or a pharmaceutically acceptable salt thereof:

[0118] in,

[0119] B 1 For N or CR 4 B 2 For N or CR 4 b1 and b2 are each independently 0, 1, 2, 3 or 4;

[0120] E, L 2 L 3 s1, X 1 To X 3 Y, A 1 A 2 R 1 To R 4 , q, R', m, t1, t2, a1, a2, a3, a4, p and x are as defined in general formula (I).

[0121] In some embodiments of this disclosure, ring A is selected from... X 1 To X 3 A 1 A 2 t1, t2, a1, a2, a3, and a4 are as defined in general formula (I); in some implementations, ring A is X 1 To X 3 Y, A 1 A 2 t1, t2, a1, and a2 are as defined in general formula (I); in some implementations, ring A is X 1 To X 3 Y, A 1 A 2 t1, t2, a1, a2, a3, and a4 are as defined in general formula (I);

[0122] In some implementations, ring A is selected from... A 1 A 2 t1 and t2 are as defined in general formula (I);

[0123] In some implementations, ring A is selected from...

[0124] In some implementations, ring A is

[0125] In some implementations, ring A is selected from... A 1 A 2 t1 and t2 are as defined in general formula (I);

[0126] In some implementations, ring A is selected from...

[0127] In some implementations, ring A is selected from...

[0128] In some implementations, ring A is selected from...

[0129] In some embodiments of this disclosure, R' is a hydrogen atom.

[0130] In some embodiments disclosed herein, X 1 Selected from N, CH, and CF; in some implementations, X 1 For N or CH; in some implementations, X 1 For N; in some implementations, X 1 For CH.

[0131] In some embodiments disclosed herein, X 2 For CR 3X R 3X As defined in general formula (I); in some implementations, X 2 Selected from N, CH, and CF; in some implementations, X 2 For N or CH; in some implementations, X 2 For N; in some implementations, X 2 For CH.

[0132] In some embodiments disclosed herein, X 3 For CR 3X R 3X As defined in general formula (I); in some implementations, X 3 Selected from N, CH, and CF; in some implementations, X 3 For N or CH; in some implementations, X3 For N; in some implementations, X 3 For CH.

[0133] In some embodiments disclosed herein, X 1 For N or CH, and / or X 2 For N or CH, and / or X 3 For N or CH; in some implementations, X 1 For N, and / or X 2 For CH, and / or X 3 For CH.

[0134] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III), (VI), (VII) or their pharmaceutically acceptable salts are used, wherein Y is O.

[0135] In some embodiments of this disclosure, 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; in some embodiments, t1 is 1, and / or t2 is 1.

[0136] In some embodiments of this disclosure, a1 is 0 or 1, and / or a2 is 0 or 1; in other embodiments, a1 is 1, and / or a2 is 1.

[0137] In some embodiments disclosed herein, A 1 For CH or N; in some implementations, A 1 Let N be the number of elements in the array.

[0138] In some embodiments disclosed herein, A 2 For CH or N; in some implementations, A 2 For N; in some implementations, A 2 For CH.

[0139] In some embodiments disclosed herein, X 1 For N, CF, or CH, and / or X 2 For N, CF, or CH, and / or X 3 For N, CF, or CH, and / or Y is O, and / or t1 is 0 or 1, and / or t2 is 0 or 1, and / or A 1 For CH or N, and / or A 2 For CH, CF, or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1; in some implementations, X 1 For N or CH, and / or X 2 For N or CH, and / or X 3For N or CH, and / or Y is O, and / or t1 is 0 or 1, and / or t2 is 0 or 1, 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; in some implementations, X 1 For N or CH, and / or X 2 For CH, and / or X 3 For CH, and / or t1 is 0, and / or t2 is 1, and / or A 1 For N, and / or A 2 Let N be a1 and / or a2 be 1.

[0140] In some embodiments of this disclosure, a3 is 1 or 2, and / or a4 is 1 or 2; in some embodiments, a3 is 1, and / or a4 is 1.

[0141] In some embodiments disclosed herein, B 1 For N or CH, and / or B 2 For N or CH; in some implementations, B 1 For CH, and / or B 2 For N or CH; in some implementations, B 1 For CH, and / or B 2 For CH.

[0142] In some embodiments of this disclosure, b1 is 0 or 1, and / or b2 is 0 or 1; in other embodiments, b1 is 0, and / or b2 is 0.

[0143] In some embodiments disclosed herein, 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.

[0144] In some embodiments disclosed herein, L 2 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 and NR c C(O)-(CR a R b ) x2 ;R a R b R cx, x2 are as defined in general formula (I); in some implementations, L 2 Selected from bond, O, (CH2) x C(O), ethynyl group, C(O)-(CH2) x2 and NR c C(O)-(CH2) x2 ;R c x, x2 are as defined in general formula (I); in some implementations, L 2 Selected from bond, O, CH2, CH2CH2, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 2 Selected from the group consisting of bond, O, CH2, C(O)-CH2, and acetylene; in some embodiments, L 2 Selected from bonds, O and CH2; in some implementations, L 2 Selected from bonds, O, and (CH2). x x is 0, 1, or 2; in some implementations, L 2 For O; in some implementations, L 2 For key;

[0145] In some implementations, L 2 Selected from bonds, alkenyl groups, alkynyl groups, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a Rb ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced; in some implementations, L 2 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 ;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 and C 1-6 Haloalkoxy; R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; x is 0, 1, 2, or 3; x1 is 0, 1, 2, or 3; x2 is 0, 1, 2, or 3; in some embodiments, L 2Selected from bonds, O, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O), and CH(CH3)-C(O); in some embodiments, L 2 Selected from the following groups: bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O), CH(CH3)-C(O), S(O)2, and C(O)-CD2; in some embodiments, L 2 S; in some implementations, L 2 It is S(O)2 or C(O)-CD2. In some implementations, L 2 Selected from bond, O, NR c 、(CR a R b ) x O(CR) a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 .

[0146] In some embodiments disclosed herein, L 2 x is 0, and / or x is 0 or 1.

[0147] In some embodiments of this disclosure, s1 is 0; in other embodiments, s1 is 1.

[0148] In some embodiments of this disclosure, the ring C is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl; in some embodiments, the ring C is 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl; in some embodiments, the ring C is 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclic; in some embodiments, the ring C is 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic; in some embodiments, the ring C is 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic. Heterocyclic group; in some embodiments, ring C is a 5- or 6-membered heterocyclic group; in some embodiments, ring C is a 3- to 6-membered cycloalkyl group; in some embodiments, ring C is selected from cyclopropyl, cyclobutyl, aziridine, phenyl, pyrrole, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and triazolyl; in some embodiments, ring C is selected from cyclopropyl, cyclobutyl, aziridine, and thiazolyl; in some embodiments, ring C is cyclopropyl; in some embodiments, ... In some implementations, it is cyclobutyl; in some implementations, it is...

[0149] In some embodiments of this disclosure, s2 is 0; in other embodiments, s2 is 1.

[0150] In some embodiments of this disclosure, ring B, ring C, or ring D is selected from... In some implementation schemes, ring B is selected from... Key and L 1 L 2 L 3 or L 4 Connection; in some implementations, the above ring connects from left to right with L in the general formula. 1 L 2 L 3 or L 4 Connection; in some implementations, the above ring connects to L from right to left. 1 L 2 L 3 or L 4 connect.

[0151] In some embodiments disclosed herein, L 3 Selected from bond, O, NR c 、(CR a R b ) x O-(CR) a Rb ) x2 C 2- 6-Alkyne group, C(O), C(O)-(CR) a R b ) x2 and NR c C(O)-(CR a R b ) x2 ;R a R b R c x, x2 are as defined in general formula (I); in some implementations, L 3 Selected from bonds, O, CH2, CH2CH2, NH, N (methyl), C(O), O-CH2, CH2-O, NHC(O), C(O)NH, C(O)-CH2, and NHC(O)-CH2; in some embodiments, L 3 For key or O; in some implementations, L 3 For key;

[0152] In some implementations, L 3 Selected from bonds, alkenyl groups, alkynyl groups, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1-C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced; in some implementations, L 3 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 ;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 and C 1-6 Haloalkoxy; R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; x is 0, 1, 2, or 3; x1 is 0, 1, 2, or 3; x2 is 0, 1, 2, or 3; in some embodiments, L 3Selected from bonds, O, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O), and CH(CH3)-C(O); in some embodiments, L 3 Selected from bonds, O and NH; in some implementations, L 3 Selected from bonds, O, S, and CH2; in some implementations, L 3 Selected from the groups O, S, CH2, CH2CH2, CH(CH3), C(CH3)2, CH2O, ethynyl, NH, and C(O)NH. In some embodiments, L 3 Selected from bond, O, S, S(O)2, NR c 、(CR a R b ) x 、(CR a R b ) x O, C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 .

[0153] In some embodiments disclosed herein, L 2 Selected from the following groups: bond, O, CH2, S, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, propynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O) and CH(CH3)-C(O), and / or L3 Selected from the group consisting of bond, O, S, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, propynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O), and CH(CH3)-C(O), and / or the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, and / or x is 0 or 1; in some embodiments, L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH 2、 C(O)NH, C(O)-C(CH3)2 and C(O)-CH(CH3), and / or the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, and / or L 3 Selected from bonds, O, S, NH, CH2, CH(CH3), C(CH3)2 and ethynyl groups;

[0154] In some implementations, L 2 Selected from bond, O, NR c 、(CR a R b ) x O(CR) a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 ; and / or the ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic, phenyl and 5 or 6-membered heteroaryl, and / or L 3 Selected from bond, O, NR c S, S(O)2, (CR) a R b ) x 、(CR a R b ) xO, C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 ;

[0155] In some implementations, L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH2, C(O)NH, C(O)(CD2), C(O)-C(CH3)2 and C(O)-CH(CH3), and / or the ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic, phenyl and 5 or 6-membered heteroaryl, and / or L 3 Selected from bond, O, S, S(O)2, CH2, CH2CH2, CH(CH3), C(CH3)2, CH2O, ethynyl group, NH and C(O)NH.

[0156] In some embodiments of this disclosure, s2 is 0, and / or L 3 For key.

[0157] In some implementation schemes disclosed herein, Selected from -O-、 -CH2-、 C(O)NH、 C(O)NHCH2、 CH2O, OCH2, (CH2)2O, O(CH2)2, O(CH2)2O, (CH2)2, O(CH2)3, (CH2)3O, (CH2)3, C(O), ethynyl, cyclopropyl, C(O)CH2CH2, C(O)CH2NH, C(O)CH2S, S, In some implementation schemes, it is selected from -O-、 -CH2-、 C(O)NH、 C(O)NHCH2、 CH2O, OCH2, (CH2)2O, O(CH2)2, O(CH2)2O, (CH2)2, O(CH2)3, (CH2)3O, (CH2)3, C(O), ethynyl and cyclopropyl;

[0158] In some implementations, the molecule is selected from C(O)CH2CH2, C(O)CH2NH, C(O)CH2S, S, In some implementation schemes, selected In some implementation schemes, O is selected. and CH2O.

[0159] In some embodiments of this disclosure, E is selected from R 6 To R 10 R d R e Q, u, y, and w are as defined in general formula (I);

[0160] In some implementations, E is selected from R 6 To R 9 R d R e u and y are as defined in general formula (I);

[0161] In some implementations, E is selected from In some implementations, E is R 6 To R 9 u and y are as defined in general formula (I); in some implementations, E is selected from... In some implementations, E is R 7 R 9 And y is as defined in general formula (I); in some implementations, E is

[0162] In some implementations, E is selected from In some implementations, E is selected from

[0163] In some implementations, E is selected from

[0164] In some embodiments disclosed herein, each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; in some embodiments, each R 1 They may be the same or different, and each is independently selected from hydrogen, Cl, methyl, methoxy, OCF3 and cyano.

[0165] In some embodiments of this disclosure, m is 0, 1, 2 or 3; in some embodiments, m is 2.

[0166] In some embodiments disclosed herein, each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens and cyano groups, and / or m is 0, 1, 2 or 3.

[0167] In some implementation schemes disclosed herein, for R 1a and R 1b As defined in general formula (IV) or (V).

[0168] In some embodiments disclosed herein, R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C1-6 Haloalkoxy; in some embodiments, R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 alkyl.

[0169] In some embodiments disclosed herein, R 1a It is a cyano group.

[0170] In some embodiments disclosed herein, R 1b Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R 1b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1b For halogen; in some implementations, R 1b For Cl; in some implementations, R 1b C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R 1b Selected from Cl, methyl, methoxy and OCF3.

[0171] In some embodiments disclosed herein, each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 C 1-6 Alkyl; in some embodiments, R 2 It is a methyl group.

[0172] In some embodiments disclosed herein, each R 3X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 3X 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 3X For hydrogen atoms or F; in some implementations, R 3X It is a hydrogen atom.

[0173] In some embodiments disclosed herein, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1- 6-alkyl and C 1-6 Halogenated alkyl groups.

[0174] In some embodiments of this disclosure, p is 0, 1, 2 or 3; in other embodiments, p is 0.

[0175] In some embodiments disclosed herein, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl, and / or p is 0, 1, 2 or 3.

[0176] In some embodiments disclosed herein, each R a and R b They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R a R b Together with the carbon atom attached thereto, they form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, 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 and C 1-6 Halogenated alkyl; in some embodiments, R a and R b It is a hydrogen atom.

[0177] In some embodiments of this disclosure, x is 0, 1, 2, 3 or 4; in some embodiments, x is 0 or 1; in some embodiments, x is 0; and in some embodiments, x is 1.

[0178] In some embodiments disclosed herein, each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1- 6-alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl.

[0179] In some embodiments of this disclosure, q is 0, 1, 2 or 3; in other embodiments, q is 0.

[0180] In some embodiments disclosed herein, each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl group, and / or q is 0, 1, 2 or 3; in some embodiments, each R 4 Same or different, and each independently not C 1-6 Alkyl group, and / or q is 1.

[0181] In some embodiments disclosed herein, each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R5 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1- 6-alkyl and C 1-6 Halogenated alkyl groups.

[0182] In some embodiments of this disclosure, r is 0, 1, 2 or 3; in other embodiments, r is 0.

[0183] In some embodiments disclosed herein, each R 5 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl, and / or r is 0, 1, 2 or 3.

[0184] In some embodiments disclosed herein, each R 5a They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1- 6-hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 5a They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1- 6-alkyl and C 1-6 Halogenated alkyl groups.

[0185] In some embodiments of this disclosure, r2 is 0, 1, 2 or 3; in some embodiments, r2 is 0.

[0186] In some embodiments disclosed herein, each R 5a They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 The alkyl halogroup and / or r2 is 0, 1, 2 or 3.

[0187] In some embodiments disclosed herein, R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6 C 1-6 Alkyl; in some embodiments, R 6 It is a methyl group.

[0188] In some embodiments disclosed herein, R 7 Selected from hydrogen atom, halogen, cyano group, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1- 6-alkylene-C(O)NR 11 R 12 C 1-6 Alkylene-C(O)OR 14 , Phenyl C 1-6 Alkyl and 5 or 6-membered heteroaryl C 1- 6-alkyl; in some embodiments, R 7 Selected from C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl group, (CH2) y -C(O)NR 11 R 12 (CH2) y -C(O)OR 14 and (CH2) y -5 or 6-membered heteroaryl, y is 0, 1, 2, 3 or 4; R 11 R 12 and R 14 As defined in general formula (I); in some implementations, R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl;; in some embodiments, R 7 (CH2) y -5-membered heteroaryl, where y is 0, 1, or 2; in some embodiments, R 7 It is an oxazolylmethyl group.

[0189] In some embodiments disclosed herein, R 7a It is a phenyl or a 5- or 6-membered heteroaryl group, each of which is independently and optionally selected from one or more halogens, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more of the haloalkoxy groups are substituted; in some embodiments, R 7a The phenyl group is optionally oxidized by one or more radicals selected from halogens, cyano groups, C6 groups, and hydroxyl groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkyl and C 1-6 One or more of the haloalkoxy groups are substituted; in some embodiments, R 7aThe phenyl group is optionally substituted with one or more halogens; in some embodiments, R 7a for

[0190] In some embodiments disclosed herein, each R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 8 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, each R 8 The same or different, and each independently is C. 1-6 Alkyl; in some embodiments, R 8 It is a methyl group.

[0191] In some embodiments of this disclosure, u is 2.

[0192] In some embodiments disclosed herein, each R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 3- to 12-membered cycloalkyl C 1-6 Alkyl, 3 to 12-membered heterocyclic C 1-6 Alkyl, NR 11 R 12 OR 14 NR 13 C(O)R 14 and NR 13 S(O) v R 14 ;

[0193] In some implementation schemes, each R 9 They may be the same or different, and each is independently selected from halogens, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocyclic groups and NR 13 S(O) v R 14 ;

[0194] In some implementation schemes, each R 9 The same or different, and each independently selected from C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 9 It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 9 It is cyclopropyl; in some embodiments, R 9 Selected from methoxy, cyano, and cyclopropyl;

[0195] In some embodiments disclosed herein, each R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, NR 11 R 12 OR 14 NR 13 C(O)R 14 and NR 13 S(O) v R 14 ;

[0196] In some implementation schemes, each R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Hydroxyalkyl and NR 13 S(O)2R 14 ;R 13 and R 14 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1- 6-alkyl; in some embodiments, each R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, hydroxyl and C1-6 Alkoxy C 1-6 Alkyl; in some embodiments, each R 9 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, each R 9 They may be the same or different, and each is independently a halogen; in some implementations, R 9 For F or Cl; in some implementations, R 9 For Cl; in some implementations, R 9 For NR 13 S(O)2R 14 In some implementation schemes, R 9 Halogen or NHS(O)2C 1-6 Alkyl; in some embodiments, R 9 It is NHS(O)2ethyl.

[0197] In some embodiments of this disclosure, y is 0, 1, or 2; in other embodiments, y is 1.

[0198] In some embodiments disclosed herein, each R 9 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, and / or y is 0, 1 or 2.

[0199] In some embodiments disclosed herein, R 7b Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1- 6-alkylene-C(O)NR 11 R 12 C 1-6 Alkylene-C(O)OR 14 , Phenyl C 1-6 Alkyl and 5 or 6-membered heteroaryl C 1- 6-alkyl; R 11 R 12 and R 14 As defined in general formula (I).

[0200] In some embodiments disclosed herein, each R 10 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms1-6 Alkyl and NR 11 R 12 R 11 and R 12 As defined in general formula (I).

[0201] In some embodiments disclosed herein, R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R d C 1-6 Alkyl; in some embodiments, R d It is a methyl group.

[0202] In some embodiments disclosed herein, R e It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R e It is a hydrogen atom.

[0203] In some embodiments of this disclosure, x1 is 0, 1, or 2; in some embodiments, x1 is 2; in some embodiments, x1 is 0; and in some embodiments, x1 is 1.

[0204] In some embodiments of this disclosure, x2 is 0, 1, 2, 3 or 4; in some embodiments, x2 is 0, 1 or 2; in some embodiments, x2 is 1; and in some embodiments, x2 is 0.

[0205] In some embodiments of this disclosure, x3 is 0, 1, 2, 3 or 4; in some embodiments, x3 is 0, 1 or 2; in some embodiments, x3 is 1; and in some embodiments, x3 is 0.

[0206] In some embodiments disclosed herein, R m It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0207] In some embodiments disclosed herein, each R 0 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1- 6-alkoxy C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0208] In some embodiments disclosed herein, R 11 and R 12 Whether the atoms are the same or different, and each is independently a hydrogen atom, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or an ethyl atom; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0209] In some embodiments disclosed herein, R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 It is a hydrogen atom.

[0210] In some embodiments disclosed herein, R 14 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 14 C 1-6 Alkyl; in some embodiments, R 14 For tert-butyl; in some implementations, R 14 It is an ethyl group.

[0211] In some embodiments disclosed herein, R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 15 For hydrogen atoms, R 16 Selected from phenyl, 5- or 6-membered heteroaryl, phenyl C 1-6 Alkyl and 5 or 6-membered heteroaryl C 1-6 alkyl.

[0212] In some embodiments of this disclosure, v is 2; in some embodiments, v is 1; and in some embodiments, v is 0.

[0213] In this disclosure, formulas (I) through (VII) include formulas (I), (IM), (II), (III), (IV), (V), (VI), and (VII).

[0214] In some embodiments of this disclosure, the compounds represented by general formulas (IV) and (V), or their pharmaceutically acceptable salts, wherein R1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; X 1 For N or CR 3X X 2 For CR 3X X 3 For CR 3X Each R 3X 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; A 1 For N; A 2 For CH or N; t1 is 0 or 1, t2 is 0 or 1, a1 is 0 or 1, a2 is 0 or 1; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1- 6-alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; x is 0 or 1; s1 is 1; B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl, where q is 0, 1, 2 or 3; L 2 For O; for E R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 0, 1, or 2; each R 9 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; y is 0, 1 or 2.

[0215] In some embodiments of this disclosure, the compounds represented by general formulas (IV) and (V), or their pharmaceutically acceptable salts, wherein R 1a It is cyano; R1b Halogen; each R 2 The same or different, and each independently is C. 1-6 Alkyl; X 1 For N or CH, X 2 For N or CH, X 3 For N or CH; A 1 For CH or N; A 2 For CH or N; t1 is 0 or 1, t2 is 1, a1 is 0 or 1, a2 is 0 or 1; p is 0; x is 0 or 1; s1 is 1; B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; q is 0; L 2 For O; for E R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; y is 0.

[0216] In some embodiments of this disclosure, the compounds represented by general formulas (VI) and (VII) or their pharmaceutically acceptable salts, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl; m is 0, 1, 2 or 3; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; X 1 For N or CR 3X X 2 For CR 3X X 3 For CR 3X Each R 3X 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; A 1 For CH or N; A 2 For CH or N; t1 is 0 or 1, t2 is 0 or 1, a1 is 0 or 1, a2 is 0 or 1; a3 is 1 or 2, a4 is 1 or 2; Y is O; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; x is 0 or 1; s1 is 0; L 2Selected from bond, O, CH2, C(O)-CH2 and ethynyl group; L 3 For a bond or O; E is R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 0, 1, or 2; each R 9 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; y is 0, 1 or 2.

[0217] In some embodiments of this disclosure, the compounds represented by general formulas (VI) and (VII), or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1b Halogen; each R 2 The same or different, and each independently is C. 1-6 Alkyl; X 1 For N or CH, X 2 For N or CH, X 3 For N or CH; A 1 For CH or N; A 2 For CH or N; t1 is 0 or 1, t2 is 1, Y is 0; a1 is 0 or 1, a2 is 0 or 1; a3 is 1, a4 is 1; p is 0; x is 0 or 1; s1 is 0; L 2 Selected from bond, O, CH2, C(O)-CH2 and ethynyl group; L 3 For a bond or O; E is R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; y is 0.

[0218] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1b Halogen; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6Haloalkyl; R' is a hydrogen atom; ring A is selected from t1 is 0 or 1, t2 is 1; A 1 For CH or N; A 2 For CH or N; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For bonds or CH2; s1 is 0 or 1; ring B is B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; q is 0; L 2 Selected from bond, O, CH2, C(O)-CH2 and ethynyl group; s2 is 0; L 3 s3 is 0; L is 0. 4 For key; E is selected from

[0219] In some embodiments of this disclosure, the compounds represented by general formulas (II) and (III) or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1b Halogen; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; R' is a hydrogen atom; X 1 For N or CR 3X X 2 For CR 3X X 3 For CR 3X Each R 3X They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkyl halide; t1 is 0 or 1, t2 is 1; 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; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; x is 0 or 1; s1 is 0 or 1; B 1 For N or CH, B 2For N or CH; b1 is 0 or 1, b2 is 0 or 1; q is 0, 1 or 2; each R 4 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1- 6-Hydroalkyl and C 1-6 Hydroxyalkyl; L 2 Selected from bond, O, NR c 、(CR a R b ) x C(O), C 2-6 Alkyne group, C(O)-(CR) a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 C(O)NR c and NR c C(O)-(CR a R b ) x2 ;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 and C 1-6 Haloalkoxy; R c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; x is 0, 1, 2, or 3; x1 is 0, 1, 2, or 3; x2 is 0, 1, 2, or 3; the ring C is a 3- to 6-membered cycloalkyl; s2 is 0 or 1; r is 0, 1, or 2; each R 5 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; L 3 Selected from bonds, O and NH; E is R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 0, 1, or 2; each R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6Haloalkyl; y is 0, 1 or 2.

[0220] In some embodiments of this disclosure, the compounds represented by general formulas (II) and (III) or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1b Halogen; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; R' is a hydrogen atom; t1 is 0 or 1, t2 is 1; Y is O; A 1 For CH or N; A 2 For CH or N; a1 is 1, a2 is 1; p is 0; x is 0 or 1; s1 is 0 or 1; B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; q is 0; L 2 Selected from: bond, O, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O) and CH(CH3)-C(O); s2 is 0 or 1; ring C is 3 to 6 membered cycloalkyl; r is 0; L 3 Selected from bonds, O, CH2, NH, CH(CH3) and C(CH3)2; E is R 6 C 1-6 Alkyl; R 7 (CH2) y -5-membered heteroaryl group, y is 0, 1 or 2; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 0, 1, or 2; each R 9 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-Hydroalkyl; y is 0, 1 or 2.

[0221] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1bHalogen; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; R' is a hydrogen atom; ring A is selected from t1 is 0 or 1, t2 is 1; A 1 For CH or N; A 2 For CH or N; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For a bond or CH2; s1 is 0; q is 0;

[0222] L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH 2、 C(O)NH, C(O)-C(CH3)2, and C(O)-CH(CH3), where the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, r is 0; s2 is 0 or 1; L 3 Selected from bond, O, S, NH, CH2, CH(CH3), C(CH3)2 and ethynyl group; s3 is 0; L 4 r2 is the key; r2 is 0; E is selected from R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; R 9 Halogen or NHS(O)2C 1-6 Alkyl group; y is 0, 1 or 2.

[0223] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or their pharmaceutically acceptable salts, wherein for R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6Haloalkyl; R' is a hydrogen atom; ring A is selected from t1 is 0 or 1, t2 is 0 or 1; A 1 For CH or N; A 2 For CH or N; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For a bond or CH2; s1 is 0; q is 0;

[0224] L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH 2、 C(O)NH, C(O)-C(CH3)2, and C(O)-CH(CH3), where the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, r is 0; s2 is 0 or 1; L 3 Selected from bond, O, S, NH, CH2, O-CH2, CH2-O, CH(CH3), C(CH3)2 and ethynyl group; s3 is 0; L 4 r2 is the key; r2 is 0; E is selected from R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 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; u is 0, 1 or 2; R 9 Halogen or NHS(O)2C 1-6 Alkyl group; y is 0, 1 or 2.

[0225] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (IM), or their pharmaceutically acceptable salts, wherein for R 1a It is cyano; R 1b C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; R' is a hydrogen atom; ring A is selected from t1 is 0 or 1, t2 is 0 or 1; A 1 For CH or N; A 2 For CH or N; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, oxo groups, halogens, and C atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For a bond or CH2; s1 is 0; q is 0;

[0226] L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH 2、 C(O)NH, C(O)-C(CH3)2, and C(O)-CH(CH3), where the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, r is 0; s2 is 0 or 1; L 3 Selected from bond, O, S, NH, CH2, O-CH2, CH2-O, CH(CH3), C(CH3)2 and ethynyl group; s3 is 0; L 4 r2 is the key; r2 is 0; E is selected from R 6 C 1-6 Alkyl; R 7 It is a 5- or 6-membered heteroaryl C 1-6 Alkyl groups; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; R 9 Halogen or NHS(O)2C 1-6 Alkyl group; y is 0, 1 or 2.

[0227] In some embodiments of this disclosure, the compounds represented by general formulas (II), (III), (VI), and (VII), or pharmaceutically acceptable salts thereof, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; R 2 C 1-6 Alkyl group; R' is a hydrogen atom; X 1 For N, CF, or CH, X 2 For CH, X 3 For CH; A 1 For CH or N; A 2CH, CF, or N; t1 is 0 or 1, t2 is 1, Y is 0; a1 is 1, a2 is 1; a3 is 1, a4 is 1; p is 0; x is 0 or 1; s1 is 0; q is 0; L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH2, C(O)NH, C(O)-C(CH3)2, C(O)-CH(CH3), C(CH3)2, C(O)CD2, S, and S(O)2, where the ring C is a 3- to 6-membered cycloalkyl group, r is 0; s2 is 0 or 1; L 3 Selected from bond, O, S, NH, CH2, CH2CH2, O-CH2, CH2-O, CH(CH3), C(CH3)2, ethynyl group and C(O)NH; r is 0; E is selected from

[0228] Table A lists typical compounds disclosed herein, including but not limited to:

[0229] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IA) or (IMA).

[0230] Among them, R W It is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc or Cbz;

[0231] Rings A, R', R1 R 2 R 3 m, n and p are as defined in general formula (I).

[0232] Another aspect of this disclosure relates to compounds of general formulas (IIA), (IIIA), (IIa), (IIIa), (IIA-1), (IIIA-1) or salts thereof (in some embodiments, hydrochloride salts or trifluoroacetates),

[0233] Among them, R W It is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc or Cbz;

[0234] X 1 To X 3 Y, A 1 R 1 To R 3 ,m,R',t1,t2,a1,a2,p,B 1 b1, b2, R 4 And q as defined in general formula (II) or (III). Another aspect of this disclosure relates to compounds of general formula (IVA) or (VA) or salts thereof (in some embodiments, hydrochloride salts),

[0235] Among them, R W It is a hydrogen atom or an amino protecting group, and in some embodiments it is Boc or Cbz;

[0236] X 1 To X 3 A 1 R 1a R 1b R 2 R 3 t1, t2, a1, a2 and p are as defined in general formula (IV) or (V).

[0237] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IIB), (IIb), (IIC), and (IID).

[0238] Where x1 is 0, 1, 2, 3, 4 or 5; R P Selected from OH, alkoxy, and halogens;

[0239] R L For leaving groups; in some embodiments, R L For OMs;

[0240] Rings C, E, L2 L 3 s2, s1, x, B 1 B 2 b1, b2, R 4 R 5 , q and r are as defined in general formula (II).

[0241] Another aspect of this disclosure relates to compounds of general formula (IVB) or salts thereof.

[0242] Where x1 is 0, 1, 2, 3, 4 or 5;

[0243] E, L 2 B 2 b1, b2, R 4 And q are as defined in general formula (IV).

[0244] Another aspect of this disclosure relates to compounds of general formulas (IC) to (IC-6) or salts thereof.

[0245] Wherein, R is a hydrogen atom or an alkyl group, and in some embodiments, it is a hydrogen atom;

[0246] X is a halogen, which is Br in some implementations;

[0247] R W It can be a hydrogen atom or an amino protecting group; in some embodiments, the amino protecting group is Boc;

[0248] R Q Selected from hydrogen atom, OH, O-hydroxyl protecting group or amino protecting group; in some embodiments, the hydroxyl protecting group is benzyl; R P Selected from OH, alkoxy, and halogens;

[0249] X 1 X 2 X 3 Y, A 1 t1, t2, a1, a2, a3 and a4 are as defined in general formula (I).

[0250] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (VIB), (VIIB), (VIB-1), and (VIIB-1).

[0251] Among them, R P Selected from OH, halogens, and alkoxy groups; X is a halogen, and in some embodiments, it is Br;

[0252] X 1 X 2 X3 Y, A 1 A 2 ,t1,t2,a1,a2,a3,a4,R3,p,x,B 1 B 2 b1, b2, s1, R 4 , q, L 2 L 3 E is as defined in general formula (VI) or (VII).

[0253] In some implementation schemes, R P Selected from OH, methoxy, ethoxy, tert-butoxy, and Cl.

[0254] In some implementations, the hydroxyl protecting group is selected from benzyl, THP, and TBS.

[0255] Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:

[0256] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0257] A compound of general formula (IIA) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IIB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0258] A compound of general formula (IIIA) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IIB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0259] Among them, R W A is a hydrogen atom; 2Let N be x and x be 0, then B 1 CH is 1, and s1 is 1.

[0260] Rings C, E, L 2 L 3 s2, B 2 X 1 To X 3 Y, A 1 R 1 To R 5 , m, R', t1, t2, a1, a2, p, q, b1, b2 and r are as defined in general formula (II) or (III).

[0261] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (II) and (III) or pharmaceutically acceptable salts thereof, the method comprising:

[0262] A compound of general formula (IIA-2) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIC) or a salt thereof under basic conditions to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0263] A compound of general formula (IIIA-2) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIC) or a salt thereof under basic conditions to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0264] Among them, A 2 N is a integer, x is 0; L 2 For C(O), s1 is 0;

[0265] Rings C, E, L 3 s2, X 1 To X 3 Y, A 1 t1, t2, a1, a2, R 1 m, R 2 、R'、R 3 p, R 5 And r as defined in general formula (II) or (III).

[0266] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (II) and (III) or pharmaceutically acceptable salts thereof, the method comprising:

[0267] A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIB-2) or a salt thereof under basic conditions to yield a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0268] A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIIB-2) or a salt thereof under basic conditions to yield a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0269] Where R' is a hydrogen atom; R P Selected from OH, halogens, and alkoxy groups;

[0270] Rings C, E, L 3 s2, L 2 s1, B 1 B 2 b1, b2, x, X 1 To X 3 Y, A 1 A 2 t1, t2, a1, a2, R 3 p, R 1 m, R 2 R 4 , q, R 5 And r as defined in general formula (II) or (III).

[0271] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV) and (V) or pharmaceutically acceptable salts thereof, the method comprising:

[0272] A compound of general formula (IVA) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IVB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (IV) or a pharmaceutically acceptable salt thereof.

[0273] A compound of general formula (VA) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IVB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (V) or a pharmaceutically acceptable salt thereof.

[0274] Among them, R W A is a hydrogen atom; 2 Let N be x and x be 0, then B 1 CH is 1, and s1 is 1.

[0275] E, L 2 B 2 X1 To X 3 A 1 R 1a R 1b R 2 To R 4 t1, t2, a1, a2, p, q, b1, and b2 are as defined in general formula (IV) or (V).

[0276] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (VI) and (VII) or pharmaceutically acceptable salts thereof, the method comprising:

[0277] A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (VIB) or a salt thereof under basic conditions to yield a compound of general formula (VI) or a pharmaceutically usable salt thereof.

[0278] A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (VIIB) or a salt thereof under basic conditions to yield a compound of general formula (VII) or a pharmaceutically usable salt thereof.

[0279] Where R' is a hydrogen atom; R P Selected from OH, halogens, and alkoxy groups;

[0280] E, L 2 L 3 s1, B 1 B 2 b1, b2, x, X 1 To X 3 Y, t1, t2, A 1 A 2 a1, a2, a3, a4, R 1 To R 4 , q, p and m are as defined in general formula (VI) or (VII).

[0281] Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, 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.

[0282] In the above synthesis scheme, 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.

[0283] 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.

[0284] 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.

[0285] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (VII) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0286] This disclosure further relates to the use of compounds of general formulas (I) to (VII) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for regulating or inhibiting the function of effector proteins essential for cell survival.

[0287] This disclosure further relates to the use of compounds of general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions.

[0288] This disclosure further relates to the use of compounds of the above general formulas (I) to (VII) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of tumors, male sexual dysfunction, and Kennedy's disease; in some embodiments, the use in the preparation of medicaments for the treatment and / or prevention of prostate cancer, benign prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; in some embodiments, the use in the preparation of medicaments for the treatment and / or prevention of prostate cancer; and in some embodiments, the use in the preparation of medicaments for the treatment and / or prevention of hormone-sensitive or hormone-refractory prostate cancer.

[0289] This disclosure further relates to a method of regulating or inhibiting the function of effector proteins essential for cell survival, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0290] This disclosure further relates to a method of treating and / or preventing androgen receptor-mediated or dependent diseases or conditions, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0291] This disclosure further relates to a method of treating and / or preventing tumors, male sexual dysfunction, and Kennedy's disease, comprising administering to a desired patient a compound of formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0292] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a drug; in some embodiments, it is used as a drug for regulating or inhibiting the function of an effector protein essential for cell survival; in some embodiments, it is used as a drug for regulating or inhibiting the function of BRD4.

[0293] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for treating and / or preventing androgen receptor-mediated or dependent diseases or conditions.

[0294] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for regulating or inhibiting the function of effector proteins essential for cell survival.

[0295] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on androgen receptors.

[0296] This disclosure further relates to a compound of general formula (I) to (VII) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of tumors, male sexual dysfunction, and Kennedy's disease.

[0297] In some embodiments, the cell-sustaining effector protein is BET, and in other embodiments, the cell-sustaining effector protein is BRD4.

[0298] In some embodiments, the androgen receptor-mediated or dependent diseases or conditions described in this disclosure are selected from tumors, male sexual dysfunction, and Kennedy's disease; in some embodiments, they are selected from prostate cancer, benign prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; in some embodiments, prostate cancer; and in some embodiments, hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

[0299] 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.

[0300] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0301] 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.

[0302] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0311] 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.

[0312] 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.

[0313] 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.

[0314] Terminology Explanation

[0315] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0316] 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, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0317] 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.

[0318] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0319] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0320] 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.

[0321] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 5 or 6 ring atoms.

[0322] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0323] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0324] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0325] Its connection point can be anywhere;

[0326] wait.

[0327] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0328] Its connection point can be anywhere; wait.

[0329] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0330] Its connection point can be anywhere.

[0331] 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.

[0332] 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.

[0333] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group has heterocyclic groups with 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic groups), heterocyclic groups with 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic groups), and heterocyclic groups with 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic groups), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 5 or 6 ring atoms.

[0334] 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.

[0335] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0336] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms within its ring, as defined above. In some embodiments, it is a 3- to 12-membered nitrogen-containing heterocyclic group or a 3- to 10-membered nitrogen-containing heterocyclic group; in some embodiments, it is a 4- to 7-membered nitrogen-containing heterocyclic group; and in some embodiments, it is a 5- or 6-membered nitrogen-containing heterocyclic group.

[0337] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments, it is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered mono-spiroheterocyclic group. Non-limiting examples include:

[0338] wait.

[0339] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, it is a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0340] wait.

[0341] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0342] wait.

[0343] 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:

[0344] wait.

[0345] 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.

[0346] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl). In some embodiments, the aryl group has 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, it has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Monocyclic aryl groups include, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthracene, phenanthrene, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including: wait.

[0347] 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.

[0348] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0349] 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.

[0350] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.

[0351] 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.

[0352] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0353] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0354] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0355] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0366] The term "hydroxyl group" refers to -OH.

[0367] The term "amino" refers to -NH2.

[0368] The term "cyano" refers to -CN.

[0369] The term "nitro" refers to -NO2.

[0370] The term "oxo" or "oxo group" refers to "=O".

[0371] The term "carbonyl" refers to C=O.

[0372] TBS refers to tert-butyldimethylsilyl.

[0373] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect a hydroxyl group from reacting on other functional groups of a compound. Examples of hydroxyl protecting groups include, but are not limited to: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl; in some embodiments, the hydroxyl protecting group is benzoyl.

[0374] 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.

[0375] A "leaving group," or simply leaving group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa of the conjugate acid means that the corresponding leaving group does not need to combine with other atoms, and its tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include, but are not limited to, halogens (Br, I, Cl), OTs (p-toluenesulfonate groups), OMs (methanesulfonate groups), OTf (trifluoromethanesulfonate groups), and OH.

[0376] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0377] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0378] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. They also include transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. For example, some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0379] 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:

[0380] 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:

[0381] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0382] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0383] 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.

[0384] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0385] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1- "6-alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0386] "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).

[0387] "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.

[0388] "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.

[0389] 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.

[0390] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0391] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations. Detailed Implementation

[0392] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0393] Example

[0394] 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).

[0395] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0396] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0397] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0398] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0399] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0400] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0401] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0402] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0403] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0404] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0405] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0406] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0407] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0408] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0409] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0410] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0411] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0412] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0413] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0414] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0415] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0416] Example 1

[0417] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1(R)-N -((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1-p1

[0418] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1-p2

[0419] first step

[0420] (R)-8-(tert-butoxycarbonyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-3-carboxylic acid 1b

[0421] (R)-3-bromo-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridino[3,2-b][1,4]oxazine-8(6H)-carboxylic acid tert-butyl ester 1a (1.0 g, 2.70 mmol, prepared by the method disclosed in Example 11 on page 59 of patent application “CN118459483A”) was dissolved in tetrahydrofuran (10 mL), and a 2.5 M n-butyllithium solution in n-hexane (1.5 mL) was added at -78 °C. The reaction mixture was stirred at a constant temperature for 20 minutes, then carbon dioxide was introduced into the reaction solution. The mixture was stirred at -78°C for 30 minutes, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (15 mL). The aqueous phase was collected, and the pH was adjusted to >7 with saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 1b (700 mg), which was used directly in the next reaction without purification.

[0422] MS m / z(ESI): 336.4 [M+1].

[0423] Step 2

[0424] (R)-3-(((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-tert-butyl carboxylate 1d

[0425] Crude compound 1b (300 mg, 894 μmol), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride 1c (282 mg, 894 μmol, prepared by the method of compound 609 disclosed on page 244 of patent application “US2018099940”) were dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (578 mg, 4.47 mmol) and n-butylphosphine anhydride (966 mg, 1.34 mmol, 50% ethyl acetate solution) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain title compound 1d (350 mg, yield: 65.6%).

[0426] MS m / z(ESI): 596.7 [M+1].

[0427] Step 3

[0428] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-3-carboxamide hydrochloride 1e

[0429] Compound 1d (350 mg, 587 μmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2 mL) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 1e (312 mg). The product was used directly in the next step of the reaction without purification.

[0430] MS m / z(ESI): 496.5 [M+1].

[0431] Step 4

[0432] 2-(((S)-4-(4-((1r,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)phenyl)-2,3,9-trimethyl-6H-thiopheno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazole1h

[0433] (S)-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptidyl-4-yl)phenol 1f (388 mg, 957 μmol, prepared by the method disclosed in Example 13 on page 367 of patent application "WO2024054603") and trans-3-((tert-butyldimethyl) 1 g (194 mg, 959 μmol, Shanghai Bide) of silyl)oxy)cyclobutanol was dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (502 mg, 1.91 mmol) and diisopropyl azodicarbonate (387 mg, 1.91 mmol) were added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1 h (350 mg, yield: 62%).

[0434] MS m / z(ESI): 590.6 [M+1].

[0435] Step 5

[0436] (1S,3r)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobut-1-ol 1i

[0437] Compound 1h (350 mg, 593.3 μmol) was dissolved in dichloromethane (3 mL), and a 4M hydrogen chloride solution of 1,4-dioxane (3 mL) was added. The mixture was stirred for 1 hour, extracted with ethyl acetate (15 mL × 1), and the aqueous phase was collected. The pH was adjusted to >7 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 1i (260 mg), which was used directly in the next reaction without purification.

[0438] MS m / z(ESI): 476.5 [M+1].

[0439] Step 6

[0440] (S)-3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobut-1-one1j

[0441] The crude compound 1i (260 mg, 547 μmol) was dissolved in dichloromethane (5 mL), and Dys-Martin oxidant (380 mg, 896 μmol, Shanghai Shaoyuan) was added. The mixture was stirred for 2 hours, and saturated sodium bicarbonate solution was added to the reaction solution. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1j (239 mg, yield: 92.3%).

[0442] MS m / z(ESI):474.5[M+1].

[0443] Step 7

[0444] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1(R)-N -((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1-p1

[0445] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 1-p2

[0446] Crude compound 1j (35.5 mg, 70 μmol) and crude compound 1e (40 mg, 75 μmol) were dissolved in tetrahydrofuran (1 mL), and sodium triacetoxyborohydride (31.8 mg, 150 μmol) were added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 1 (110 mg). The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to obtain title compound (15 mg, yield: 19.5%) and (3 mg, yield: 4.2%).

[0447] Single configuration compound (shorter retention time): (15 mg, yield: 19.5%).

[0448] MS m / z(ESI): 953.9 [M+1].

[0449] HPLC analysis: retention time 1.61 min, purity: 90% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD3OD): δ8.26(d,1H),7.92(s,1H),7.74(d,1H),7.41(d,1H),7.34(d,2H),7.15(d,2H),7.00(dd,1H),6.87(d,2H),4.35(dd,1H),4. 30(s,1H),4.15(s,1H),3.98(tdd,3H),3.53(dt,1H),3.09–2.91(m,3H), 2.86–2.77(m,2H),2.72(s,3H),2.66–2.59(m,1H),2.48(s,3H),2.21(t,J 3H),1.79(t,1H),1.72(s,3H),1.68–1.57(m,3H),1.29(s,6H),1.23(s,6H).

[0450] Longer retention time for single-configuration compounds: (3 mg, yield: 4.2%).

[0451] MS m / z(ESI): 953.9 [M+1].

[0452] HPLC analysis: retention time 1.62 min, purity: 85% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0453] 1H NMR (500MHz, CD3OD): δ8.26(d,1H),7.92(s,1H),7.74(dd,1H),7.42(d,1H),7.34(d,2H),7.16–7.14 (m,2H),7.00(dd,1H),6.84(d,2H),4.75(d,1H),4.58(s,1H),4.37(d,1H),4.30(s,1H),4.15(s,1H) ,3.98(ddd,3H),3.54(d,1H),3.11(d,2H),3.05(d,1H),2.96(d,1H),2.80(t,1H),2.72(s,3H),2.51 (d,1H),2.48(s,3H),2.34(d,1H),2.09(s,1H),1.72(s,3H),1.61(s,3H),1.29(s,6H),1.23(s,6H).

[0454] Example 2

[0455] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2 or

[0456] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2-p1 or

[0457] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2-p2

[0458] first step

[0459] 1-Benzyl-4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 2b

[0460] 2-(4-bromo-2-fluorophenyl)acetic acid methyl ester 2a (3 g, 12.14 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (418 mg, 10.91 mmol, 60% purity) was added at 0 °C, and the mixture was stirred for 30 minutes. Then, sodium iodide (183 mg, 1.22 mmol) and N-benzyl-N,N-bis(2-chloroethyl)amine (3.39 g, 14.60 mmol, Shanghai Shaoyuan) were added, and the mixture was stirred for 1 hour. The reaction mixture was added dropwise to 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 2b (1.3 g, yield: 26.4%).

[0461] MS m / z(ESI): 407.3 [M+1].

[0462] Step 2

[0463] 4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 2c

[0464] Compound 2b (1.2 g, 2.95 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 1-chloroethyl chloroformate (4.23 g, 29.59 mmol) was added. The reaction mixture was reacted at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (20 mL). The reaction mixture was reacted at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 2c (380 mg, yield: 40.7%).

[0465] MS m / z(ESI): 317.2 [M+1].

[0466] Step 3

[0467] 1-(tert-butyl)4-methyl4-(4-bromo-2-fluorophenyl)piperidine-1,4-dicarboxylic acid ester 2d

[0468] Compound 2c (380 mg, 1.20 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (365 mg, 3.61 mmol) and di-tert-butyl dicarbonate (315 mg, 1.44 mmol) were added. The mixture was stirred for 2 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2d (300 mg, yield: 60.0%).

[0469] MS m / z(ESI):417.2[M+1].

[0470] Step 4

[0471] 4-(4-bromo-2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 2e

[0472] Compound 2d (300 mg, 0.72 mmol) was dissolved in tetrahydrofuran (4 mL), and a 1 M lithium aluminum hydride tetrahydrofuran solution (0.74 mL) was added at 0 °C. After stirring at 0 °C for 0.5 hours, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain crude title compound 2e (279 mg). The product was directly used for the next reaction without purification.

[0473] MS m / z(ESI): 389.3 [M+1].

[0474] Step 5

[0475] 6-Bromo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 2f

[0476] The crude compound 2e (279 mg, 0.72 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (186 mg, 1.65 mmol) was added. The tube was sealed and reacted at 100 °C for 30 min. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2f (200 mg, yield: 75.6%). MS m / z (ESI): 369.9 [M+1].

[0477] Step 6

[0478] 2g of 1'-(tert-butyl)6-methyl 2H-spiro[benzofuran-3,4'-piperidine]-1',6-dicarboxylic acid ester

[0479] Compound 2f (720 mg, 1.95 mmol) was dissolved in N,N-dimethylformamide (6 mL) and methanol (4 mL), and palladium acetate (61 mg, 273 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (161 mg, 391 μmol), and triethylamine (890 mg, 8.80 mmol) were added. The mixture was replaced with carbon monoxide and reacted at 90 °C for 16 hours. After cooling the reaction solution to room temperature, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2 g (529 mg, yield: 77.8%).

[0480] MS m / z(ESI):248.3[M-99].

[0481] Step 7

[0482] 1'-(tert-butoxycarbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid 2h

[0483] 2 g (320 mg, 921 μmol) of the compound was dissolved in tetrahydrofuran (6 mL) and water (4 mL), and lithium hydroxide monohydrate (116 mg, 2.76 mmol) was added. The mixture was stirred for 6 hours. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2h (307 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 234.4 [M-99].

[0484] Step 8

[0485] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2

[0486] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2-p1 or

[0487] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2-p2

[0488] Using the synthetic route of Example 1, the starting material 1b in the second step was replaced with compound 2h to obtain crude title compound 2 (120 mg). It was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min). The fractions with shorter retention times were collected to obtain title compound 2-p1 or 2-p2 (19 mg, yield: 15.7%).

[0489] MS m / z(ESI): 951.8 [M+1].

[0490] 1 H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.38(dd,1H),7.34(d,2H),7.30(d,1H),7.19(d,1H ),7.16–7.12(m,2H),7.00(dd,1H),6.88(d,2H),4.75(dd,2H),4.56(t,1H),4.48(s,2H),4.30(s,1H ),4.15(s,1H),3.98(qd,2H),2.96(d,2H),2.81(dt,2H),2.72(s,3H),2.65–2.56(m,1H),2.48(s,3H ),2.21(t,2H),1.98(d,1H),1.80(d,2H),1.72(s,3H),1.65–1.57(m,2H),1.29(s,6H),1.24(s,6H).

[0491] Example 3

[0492] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazheptan]-3'-formamide 3

[0493] first step

[0494] 2-(benzyloxy)-6-formyl-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 3b

[0495] 2-(benzyloxy)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 3a (11.48 g, 34.64 mmol, prepared by the method disclosed in Example 1 on page 69 of patent application "WO2024051741") and tetramethylethylenediamine (4.20 g, 36.14 mmol) were dissolved in diethyl ether (150 mL), and a 1.3 M sec-butyllithium solution in n-hexane (35 mL) was added dropwise at -78 °C while maintaining the temperature and stirring. After stirring for 2 hours, an ether solution (15 mL) of N,N-dimethylformamide (3.80 g, 51.99 mmol) was added, and the reaction was stirred for 0.5 hours while maintaining the temperature. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (80 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 3b (12.4 g). The product was directly used for the next reaction without purification.

[0496] Step 2

[0497] 2-(benzyloxy)-6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 3c

[0498] The crude title compound 3b (12.4 g, 34.50 mmol) was dissolved in methanol (120 mL), and sodium borohydride (2.52 g, 66.61 mmol) was added at 0 °C. The mixture was stirred at this temperature for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 3c (1.1 g, yield: 8.8%).

[0499] MS m / z(ESI):262.0[M-99].

[0500] Step 3

[0501] 2-(benzyloxy)-6-(((2,5-dibromopyridin-3-yl)methoxy)methyl)-7-azaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester 3e

[0502] Compound 3c (1.1 g, 3.04 mmol) was dissolved in dichloromethane (15 mL), and 2,5-dibromo-3-(bromomethyl)pyridine 3d (1.75 g, 5.31 mmol, Shanghai Bide), silver oxide (1.25 g, 5.25 mmol), and tetrabutylammonium iodide (450 mg, 1.22 mmol) were added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 3e (900 mg, yield: 48.4%).

[0503] MS m / z(ESI): 508.8 [M-99].

[0504] Step 4

[0505] 2-(benzyloxy)-6-(((2,5-dibromopyridin-3-yl)methoxy)methyl)-7-azaspiro[3,5]nonane 2,2,2-trifluoroacetate 3f

[0506] Compound 3e (900 mg, 1.47 mmol) was dissolved in dichloromethane (13 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 3f (920 mg). The product was used directly in the next reaction without purification.

[0507] MS m / z(ESI): 508.8 [M+1].

[0508] Step 5

[0509] 3-(benzyloxy)-3'-bromo-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyrido[2,1-c:2',3'-e][1,4]oxazheptan]3g

[0510] The crude compound 3f (920 mg, 1.48 mmol) was dissolved in dimethyl sulfoxide (20 mL), and cesium carbonate (5.48 g, 16.82 mmol) was added. The mixture was purged with nitrogen and stirred at 110 °C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3 g (100 mg, yield: 13.8%).

[0511] MS m / z(ESI):428.9[M+1].

[0512] Step 6

[0513] 3-(benzyloxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyrido[2,1-c:2',3'-e][1,4]oxazheptan]-3'-carboxylic acid methyl ester 3h

[0514] 3 g (100 mg, 233 μmol) of the compound was dissolved in N,N-dimethylformamide (1.5 mL) and methanol (1.5 mL), and palladium acetate (8 mg, 35 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (20 mg, 48 μmol), and triethylamine (107 mg, 1.05 mmol) were added. The mixture was replaced with carbon monoxide and reacted at 90 °C for 16 h. After cooling the reaction solution to room temperature, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3h (90 mg, yield: 94.6%).

[0515] MS m / z(ESI):409.0[M+1].

[0516] Step 7

[0517] 3-Hydroxy-7a',8',10',11'-Tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyrido[2,1-c:2',3'-e][1,4]oxazheptan]-3'-carboxylic acid methyl ester 3i

[0518] Compound 3h (90 mg, 220 μmol) was dissolved in ethyl acetate (5 mL), and 10% palladium on carbon hydrogenation catalyst (90 mg) was added. The mixture was purged with hydrogen, stirred at 50 °C for 16 hours, and then quenched with sodium sulfate decahydrate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3i (60 mg, yield: 85.5%).

[0519] MS m / z(ESI): 319.3 [M+1].

[0520] Step 8

[0521] 3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyrido[2,1-c:2',3'-e][1,4]oxazheptan]-3'-carboxylic acid methyl ester 3j

[0522] Compound 1f (77 mg, 190 μmol) and compound 3i (60 mg, 188 μmol) were dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (75 mg, 286 μmol) and diisopropyl azodicarbonate (58 mg, 286 μmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 3j (100 mg, yield: 74.7%).

[0523] MS m / z(ESI): 705.9 [M+1].

[0524] Step 9

[0525] 3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyrido[2,1-c:2',3'-e][1,4]oxazheptan]-3'-carboxylic acid 3h

[0526] Compound 3j (100 mg, 142 μmol) was dissolved in tetrahydrofuran (2.5 mL) and methanol (5 mL), and lithium hydroxide monohydrate (60 mg, 1.43 mmol) was added. The mixture was stirred at 35 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The pH was adjusted to approximately 5 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3h (98 mg), which was used directly in the next reaction without purification.

[0527] MS m / z(ESI): 692.3 [M+1].

[0528] Step 10

[0529] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazheptan]-3'-formamide 3

[0530] The crude compound 3h (98 mg, 142 μmol) and compound 1c (67 mg, 212 μmol) were dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (92 mg, 712 μmol) and n-butylphosphine anhydride (153 mg, 212 μmol, 50% ethyl acetate solution) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 3 (70 mg, yield: 51.8%).

[0531] MS m / z(ESI): 952.7 [M+1].

[0532] 1 H NMR (500MHz, CD3OD): δ8.62-8.60(m,1H),7.89-7.87(m,2H),7.72(d,1H),7.32(d,2H),7.13-7.12(m,2H),6.98(dd,1 H),6.83(s,1H),6.82(s,1H),4.83-4.71(m,3H),4.67-4.63(m,1H),4.35-4.30(m,1H),4.28(s,1H),4.15(s,1H),4.0 1-3.86(m,3H),3.79-3.71(m,1H),3.50-3.40(m,1H),3.16-3.02(m,1H),2.70(s,3H),2.69-2.63(m,1H),2.45(s,3H) ,2.40-2.34(m,1H),2.01-1.93(m,2H),1.85-1.76(m,2H),1.76-1.66(m,2H),1.70(s,3H),1.28(d,6H),1.22(s,6H).

[0533] Examples 3-p1, 3-p2, 3-p3, 3-p4

[0534] (1R,3S,7a'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazaheptan]-3'-formamide 3-p1

[0535] (1S,3R,7a'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazaheptan]-3'-formamide 3-p2

[0536] (1R,3R,7a'S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazaheptan]-3'-formamide 3-p3

[0537] (1S,3S,7a'S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)-7a',8',10',11'-tetrahydro-5'H,7'H-spiro[cyclobutane-1,9'-dipyridino[2,1-c:2',3'-e][1,4]oxazaheptan]-3'-formamide 3-p4

[0538] Compound 3 (180 mg) was resolved by a chiral column (Shimadzu LC-20AD, column: ChiralPak OZ, 10 μm, 25 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 30:70, flow rate: 40 mL / min) to give the title compound (50 mg, yield: 27.7%), (50 mg, yield: 27.7%) and component A (50 mg, yield: 27.7%).

[0539] Single configuration compound (shorter retention time): (50 mg, yield: 27.7%).

[0540] MS m / z(ESI): 952.7 [M+1].

[0541] Chiral HPLC analysis: retention time 15.281 min, purity: 99.8% (column: ChiralPak OZ, 5 μm, 4.6 mm * 150 mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 30:70, flow rate: 1.0 mL / min).

[0542] 1H NMR (500MHz, CD3OD): δ8.62(d,1H),7.89(s,1H),7.88(d,1H),7.72(d,1H),7.32(s,1H),7.31(s,1H),7.13(d,1H),7.12 (s,1H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.86-4.79(m,2H),4.77-4.71(m,2H),4.64(d,1H),4.35-4.31(m,1H), 4.28(s,1H),4.15(s,1H),4.01-3.87(m,3H),3.73(dd,1H),3.45-3.41(m,1H),2.70(s,3H),2.69-2.65(m,1H),2.46(s, 3H),2.41-2.36(m,1H),2.00-1.91(m,2H),1.83-1.80(m,2H),1.75-1.67(m,2H),1.70(s,3H),1.28(d,6H),1.22(s,6H).

[0543] Single-configuration compound (longer retention time): (50 mg, yield: 27.7%).

[0544] MS m / z(ESI): 952.7 [M+1].

[0545] Chiral HPLC analysis: retention time 18.513 min, purity: 99.1% (column: ChiralPak OZ, 5μm, 4.6mm*150mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 30:70, flow rate: 1.0mL / min).

[0546] 1H NMR (500MHz, CD3OD): δ8.62(d,1H),7.89(s,1H),7.88(d,1H),7.72(d,1H),7.32(s,1H),7.31(s,1H),7.13(d,1H),7.12 (s,1H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.86-4.79(m,2H),4.77-4.71(m,2H),4.64(d,1H),4.35-4.31(m,1H), 4.28(s,1H),4.15(s,1H),4.01-3.87(m,3H),3.73(dd,1H),3.45-3.41(m,1H),2.70(s,3H),2.69-2.65(m,1H),2.46(s, 3H),2.41-2.36(m,1H),2.00-1.91(m,2H),1.83-1.80(m,2H),1.75-1.67(m,2H),1.70(s,3H),1.28(d,6H),1.22(s,6H).

[0547] Component A (50 mg) was resolved by a chiral column (Shimadzu LC-20AD, column: ChiralPak IG, 10 μm, 5 mm * 250 mm; mobile phase A: dichloromethane, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 95:5, flow rate: 30 mL / min) to give the title compound (10 mg, yield: 20%).

[0548] Single configuration compound (shorter retention time): (10 mg, yield: 20%).

[0549] MS m / z(ESI): 952.7 [M+1].

[0550] Chiral HPLC analysis: retention time 4.343 min, purity: 99.9% (column: ChiralPak IG, 5 μm, 4.6 mm * 250 mm; mobile phase A: dichloromethane, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 95:5, flow rate: 1.0 mL / min).

[0551] 1H NMR (500MHz, CD3OD): δ8.61(d,1H),7.89-7.88(m,2H),7.72(d,1H),7.32(s,1H),7.31(s,1H),7.13(d,1H),7.12(s,1 H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.86-4.79(m,2H),4.77-4.71(m,2H),4.67(d,1H),4.32-4.29(m,1H),4.2 8(s,1H),4.15(s,1H),4.01-3.90(m,3H),3.77(dd,1H),3.51-3.47(m,1H),2.70(s,3H),2.69-2.64(m,1H),2.46(s,3H ),2.40-2.34(m,1H),2.01-1.94(m,2H),1.86-1.78(m,2H),1.73-1.67(m,2H),1.70(s,3H),1.28(d,6H),1.22(s,6H).

[0552] Single configuration compound (longer retention time): (10 mg, yield: 20%).

[0553] MS m / z(ESI): 952.7 [M+1].

[0554] Chiral HPLC analysis: retention time 5.107 min, purity: 99.9% (column: ChiralPak IE, 5 μm, 4.6 mm * 150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0555] 1H NMR (500MHz, CD3OD): δ8.61(d,1H),7.89-7.88(m,2H),7.72(d,1H),7.32(s,1H),7.31(s,1H),7.13(d,1H),7.12(s,1 H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.86-4.79(m,2H),4.77-4.71(m,2H),4.67(d,1H),4.32-4.29(m,1H),4.2 8(s,1H),4.15(s,1H),4.01-3.90(m,3H),3.77(dd,1H),3.51-3.47(m,1H),2.70(s,3H),2.69-2.64(m,1H),2.46(s,3H ),2.40-2.34(m,1H),2.01-1.94(m,2H),1.86-1.78(m,2H),1.73-1.67(m,2H),1.70(s,3H),1.28(d,6H),1.22(s,6H).

[0556] Example 4

[0557] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-6a',7',9',10'-tetrahydro-6'H-spiro[cyclobutane-1,8'-dipyrido[3,2-b:1',2'-d][1,4]oxazine]-3'-formamide 4

[0558] first step

[0559] 6-(hydroxymethyl)-7-azaspiro[3.5]non-2-ol 2,2,2-trifluoroacetate 4b

[0560] 2-((tert-butyldimethylsilyl)oxy)-6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 4a (700 mg, 1.81 mmol, prepared by the method disclosed in intermediate 8 on page 42 of patent application "CN114057740A") was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 4b (517 mg). The product was used directly in the next reaction without purification.

[0561] Step 2

[0562] 7-(5-bromo-3-fluoropyridin-2-yl)-6-(hydroxymethyl)-7-azaspiro[3.5]non-2-ol 4c

[0563] The crude compound 4b (517 mg, 1.81 mmol) was dissolved in dimethyl sulfoxide (10 mL), and 5-bromo-2,3-difluoropyridine (345 mg, 1.78 mmol, Shanghai Shaoyuan) and N,N-diisopropylethylamine (2.35 g, 18.18 mmol) were added. The mixture was stirred at 120 °C for 30 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 4c (30 mg, yield: 4.8%).

[0564] MS m / z(ESI): 344.9 [M+1].

[0565] Step 3

[0566] 3'-Bromo-6a',7',9',10'-Tetrahydro-6'H-spiro[cyclobutane-1,8'-dipyrido[3,2-b:1',2'-d][1,4]oxazine]-3-ol 4d

[0567] Compound 4c (30 mg, 87 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), and cesium carbonate (57 mg, 175 μmol) was added. The mixture was stirred at 100 °C for 16 hours, then cooled to room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4d (15 mg, yield: 53.1%).

[0568] MS m / z(ESI): 324.9 [M+1].

[0569] Step 4

[0570] 3'-Bromo-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-6a',7',9',10'-tetrahydro-6'H-spiro[cyclobutane-1,8'-dipyrido[3,2-b:1',2'-d][1,4]oxazine]4e

[0571] Compound 1f (20 mg, 49 μmol) and compound 4d (15 mg, 46 μmol) were dissolved in tetrahydrofuran (1 mL), and triphenylphosphine (19 mg, 72 μmol) and diisopropyl azodicarbonate (14 mg, 69 μmol) were added. The mixture was stirred at 70 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 4e (25 mg, yield: 76.1%).

[0572] MS m / z(ESI):711.9[M+1].

[0573] Step 5

[0574] 3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-6a',7',9',10'-tetrahydro-6'H-spiro[cyclobutane-1,8'-dipyrido[3,2-b:1',2'-d][1,4]oxazine]-3'-carboxylic acid ethyl ester 4f

[0575] Compound 4e (25 mg, 35 μmol) was dissolved in dimethyl sulfoxide (1 mL) and ethanol (1.5 mL), and palladium acetate (2 mg, 9 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (5 mg, 11 μmol), and potassium carbonate (10 mg, 72 μmol) were added. The mixture was then replaced with carbon monoxide and reacted at 90 °C for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4f (24 mg). The product was used directly in the next reaction without purification.

[0576] MS m / z(ESI): 705.9 [M+1].

[0577] Step 6

[0578] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-6a',7',9',10'-tetrahydro-6'H-spiro[cyclobutane-1,8'-dipyrido[3,2-b:1',2'-d][1,4]oxazine]-3'-formamide 4

[0579] Using the synthetic route in Example 3, the starting material compound 3j in step 9 was replaced with compound 4f to obtain title compound 4 (2 mg, yield: 36.8%).

[0580] MS m / z(ESI): 937.9 [M+1].

[0581] 1 H NMR (500MHz, CD3OD): δ8.23-8.21(m,1H),7.89(s,2H),7.72(d,1H),7.37-7.35(m,1H),7.32(d,2H),7.13-7.11(m,2H),6 .98(dd,1H),6.84(s,1H),6.82(s,1H),4.83-4.79(m,1H),4.74-4.71(m,1H),4.66-4.58(m,1H),4.31-4.23(m,1H),4.27 (s,1H),4.13(s,1H),4.01-3.89(m,3H),3..47-3.35(m,1H),2.86-2.75(m,1H),2.70(s,3H),2.70-2.65(m,1H),2.45(s, 3H),2.43-2.37(m,1H),2.05-1.97(m,2H),1.93-1.85(m,1H),1.78-1.60(m,3H),1.70(s,3H),1.27(s,6H),1.21(s,6H).

[0582] Example 5

[0583] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 5

[0584] first step

[0585] (S)-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)methanol5b

[0586] (S)-2-((4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazole 5a (300 mg, 708 μmol), was prepared using the example on page 367 of the specification in patent application "WO2024054603". 23. Potassium trifluoroborate (255 mg, 1.41 mmol, Shanghai Titan) was prepared by the method disclosed in this paper. It was dissolved in 1,4-dioxane (12 mL) and water (1.5 mL), and palladium acetate (80 mg, 356 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (295 mg, 719 μmol), and potassium phosphate (755 mg, 3.56 mmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 5b (110 mg, yield: 37%).

[0587] MS m / z(ESI): 420.3 [M+1].

[0588] Step 2

[0589] (S)-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzaldehyde 5c

[0590] Compound 5b (35 mg, 83 μmol) was dissolved in dichloromethane (2 mL), and Dys-Martin oxidant (75 mg, 177 μmol) was added. The mixture was stirred for 1 hour, and saturated sodium bicarbonate solution was added to the reaction solution. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (35 mg). The product was used directly in the next reaction without purification.

[0591] MS m / z(ESI):418.3[M+1].

[0592] Step 3

[0593] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide hydrochloride 5d

[0594] Using the synthetic route of Example 1 in steps two and three, the starting material compound 1b in step two was replaced with compound 2h to obtain the crude title compound 5d (50mg).

[0595] MS m / z(ESI):494.3[M+1].

[0596] Step 4

[0597] 3-(6-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)azacyclobutane-1-carboxylic acid tert-butyl ester 5e

[0598] The crude compound 5d (50 mg, 94 μmol) and 1-(tert-butoxycarbonyl)-3-azacyclobutanone (29 mg, 169 μmol, Shanghai Bide) were dissolved in tetrahydrofuran (1.5 mL), and sodium triacetoxyborohydride (50 mg, 169 μmol) were added. The reaction mixture was reacted at 50 °C for 16 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added. The mixture was then coated with ethyl acetate (5 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 5e (60 mg, yield: 98%).

[0599] MS m / z(ESI): 649.6 [M+1].

[0600] Step 5

[0601] 1'-(azacyclobutane-3-yl)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 2,2,2-trifluoroacetate 5f

[0602] Compound 5e (26 mg, 40 μmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 0.5 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 5f (27 mg). The product was used directly in the next reaction without purification.

[0603] MS m / z(ESI): 549.5 [M+1].

[0604] Step 6

[0605] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 5

[0606] Crude compound 5c (20 mg, 48 μmol) and crude compound 5f (27 mg, 41 μmol) were dissolved in tetrahydrofuran (2 mL), and sodium triacetoxyborohydride (26 mg, 123 μmol) was added. The mixture was reacted at 50 °C for 1.5 h. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added. The mixture was then coated with ethyl acetate (5 mL × 3), and the organic phases were combined. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 5 (19 mg, yield: 49%).

[0607] MS m / z(ESI): 950.8 [M+1].

[0608] 1 H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.40-7.34(m,5H),7.30-7.26(m,1H),7.20-7.18(m, 1H),7.16-7.14(m,2H),7.00(d,1H),4.81-4.78(m,1H),4.46(s,1H),4.30(s,1H),4.15(s,1H),4.07-3 .94(m,2H),3.75(s,2H),3.57-3.52(m,2H),3.12-3.04(m,3H),2.85-2.76(m,2H),2.73(s,3H),2.47(s ,3H),2.10-1.96(m,4H),1.80-1.74(m,2H),1.68(s,3H),1.66-1.59(m,2H),1.29(s,6H),1.24(s,6H).

[0609] Example 6

[0610] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6

[0611] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6-p1

[0612] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6-p2

[0613] first step

[0614] 2-((4-(4-(3-((tert-butyldimethylsilyl)oxy)azacyclobut-1-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazol6b

[0615] 3-((tert-butyldimethylsilyl)oxy)azacyclobutane 6a (266 mg, 1.42 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 5a (300 mg, 708 μmol), cesium carbonate (577 mg, 1.77 mmol), tris(dibenzylacetone)dipalladium (130 mg, 142 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (164 mg, 283 μmol) were added. The mixture was purged with nitrogen and stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 6b (155 mg, 38.1% yield).

[0616] MS m / z(ESI): 575.2 [M+1].

[0617] Step 2

[0618] 1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-ol 6c

[0619] Compound 6b (155 mg, 270 μmol) was dissolved in tetrahydrofuran (6 mL), and 808 μL of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 6c (92 mg, 74.1% yield).

[0620] MS m / z(ESI):461.4[M+1].

[0621] Step 3

[0622] 1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobut-3-one

[0623] Compound 6c (92 mg, 200 μmol) was dissolved in dichloromethane (3 mL), and Dys-Martin oxidant (170 mg, 401 μmol) was added. The mixture was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was dried over dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 6d (90 mg, yield: 98.2%).

[0624] MS m / z(ESI):459.4[M+1].

[0625] Step 4

[0626] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6

[0627] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6-p1

[0628] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 6-p2

[0629] Compound 6d (70 mg, 453 μmol) and crude compound 5d (81 mg, 153 μmol) were dissolved in tetrahydrofuran (5 mL), and sodium triacetoxyborohydride (100 mg, 472 μmol) was added. The mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 6 (10 mg, yield: 7%).

[0630] Compound 6 (27 mg) was resolved by a chiral column (Gilson-281, column: ChiralPak IE, 5 μm, 20 mm * 250 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B = 40:60, flow rate: 20 mL / min) to give the title compound (12 mg, yield: 44.4%) and (10 mg, yield: 37%).

[0631] Single configuration compound (shorter retention time): (12 mg, yield: 44.4%).

[0632] MS m / z(ESI): 936.6 [M+1].

[0633] Chiral HPLC analysis: retention time 8.279 min, purity: 99.9% (column: ChiralPak IE, 5 μm, 4.6 mm * 150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0634] 1 H NMR (500MHz, CD3OD): δ7.91(s,1H),7.74(d,1H),7.40-7.36(m,1H),7.32-7.24(m,3H),7.21-7.18(m, 1H),7.16-7.12(m,2H),7.03-6.98(m,1H),6.50-6.45(m,2H),4.76-4.69(m,1H),4.50(s,2H),4.30(s, 1H),4.17-4.07(m,3H),4.03-3.92(m,2H),3.83-3.76(m,2H),2.99-2.92(m,2H),2.72(s,3H),2.48(s ,3H),2.16-1.97(m,5H),1.85-1.77(m,2H),1.75(s,3H),1.65-1.58(m,1H),1.29(s,6H),1.24(s,6H).

[0635] Single configuration compound (longer retention time): (10 mg, yield: 37%).

[0636] MS m / z(ESI): 936.6 [M+1].

[0637] Chiral HPLC analysis: retention time 11.597 min, purity: 99.9% (column: ChiralPak IE, 5 μm, 4.6 mm * 150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0638] 1H NMR (500MHz, CD3OD): δ7.91(s,1H),7.74(d,1H),7.40-7.36(m,1H),7.32-7.24(m,3H),7.21-7.18(m, 1H),7.16-7.12(m,2H),7.03-6.98(m,1H),6.50-6.45(m,2H),4.76-4.69(m,1H),4.50(s,2H),4.30(s, 1H),4.17-4.07(m,3H),4.03-3.92(m,2H),3.83-3.76(m,2H),2.99-2.92(m,2H),2.72(s,3H),2.48(s ,3H),2.16-1.97(m,5H),1.85-1.77(m,2H),1.75(s,3H),1.65-1.58(m,1H),1.29(s,6H),1.24(s,6H).

[0639] Example 7

[0640] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 7

[0641] first step

[0642] (1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)methanol7b)

[0643] Using the synthetic route in Example 6, step one and two were performed, replacing the starting compound 6a in the first step with 3-(((tert-butyldimethylsilyl)oxy)methyl)azacyclobutane 7a (prepared using the method disclosed in Intermediate F on page 412 of patent application "WO2023278759") to obtain title compound 7b (90 mg, yield: 98%).

[0644] MS m / z(ESI): 475.3 [M+1].

[0645] Step 2

[0646] 1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carboxaldehyde 7c

[0647] Oxaloyl chloride (13 mg, 105 μmol) was dissolved in dichloromethane (0.5 mL), and dimethyl sulfoxide (16 mg, 210 μmol) was added at -78 °C. After stirring for 30 minutes, a dichloromethane solution of compound 7b (25 mg, 52 μmol) was added (0.5 mL). After stirring for 1 hour, triethylamine (32 mg, 316 μmol) was added and stirred for 30 minutes. Water was added, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7c (25 mg), which was used directly in the next reaction without purification.

[0648] MS m / z(ESI):473.3[M+1].

[0649] Step 3

[0650] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 7

[0651] Crude compound 7c (18 mg, 38 μmol) and crude compound 5d (10 mg, 19 μmol) were dissolved in tetrahydrofuran (0.5 mL), and sodium triacetoxyborohydride (6 mg, 28 μmol) was added. The mixture was stirred for 0.5 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to obtain title compound 7 (10 mg, yield: 55.8%, isomer S:R = 4:1).

[0652] MS m / z(ESI): 950.5 [M+1].

[0653] Chiral HPLC analysis: retention times 9.093 min (77.3%), 12.807 min (20.6%) (Column: ChiralPak IK, 5 μm, 4.6 mm * 150 mm; Mobile phase A: n-hexane, Mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0654] 1 H NMR (500MHz, CD3OD): δ7.91(s,1H),7.74(d,1H),7.39(dd,1H),7.30(d,1H),7.24(d,2H),7.20(d,1H), 7.15(d,1H),7.13(s,1H),7.00(dd,1H),6.44–6.38(m,2H),4.71(dd,1H),4.49(s,2H),4.31(s,1H),4.1 5(s,1H),4.10(t,2H),4.03–3.89(m,2H),3.64(dd,2H),3.08(p,1H),2.99–2.94(m,2H),2.78(d,2H),2. 72(s,3H),2.48(s,3H),2.25(d,1H),2.04(td,3H),1.79(d,2H),1.75(s,3H),1.29(s,6H),1.24(s,6H).

[0655] Example 8

[0656] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8

[0657] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8-p1

[0658] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8-p2

[0659] first step

[0660] 1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carboxylic acid tert-butyl ester 8b

[0661] Azacyclobutane-3-carboxylic acid tert-butyl hydrochloride 8a (183 mg, 944 μmol) was dissolved in 1,4-dioxane (2.5 mL), compound 5a (200 mg, 472 μmol), cesium carbonate (615 mg, 1.89 mmol), tris(dibenzylacetone)dipalladium (88 mg, 96 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (109 mg, 189 μmol) were added. The mixture was purged with nitrogen and stirred at 110 °C for 24 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 8b (200 mg, 77.8% yield).

[0662] MS m / z(ESI): 545.3 [M+1].

[0663] Step 2

[0664] 1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carboxylic acid 8c

[0665] Compound 8b (200 mg, 367 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 8c (170 mg, 94.7% yield).

[0666] MS m / z(ESI):489.1[M+1].

[0667] Step 3

[0668] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8

[0669] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8-p1

[0670] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)azacyclobutane-3-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 8-p2

[0671] Compound 8c (60 mg, 123 μmol) and crude compound 5d (60 mg, 113 μmol) were dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (64 mg, 169 μmol) and N,N-diisopropylethylamine (73 mg, 565 μmol) were added. The mixture was stirred for 1 hour, and the reaction solution was filtered. The filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 8 (48 mg, yield: 49.7%).

[0672] Compound 8 (45 mg) was resolved by a chiral column (Gilson-281, column: ChiralPak IK, 10 μm, 20 mm * 250 mm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B = 40:60, flow rate: 20 mL / min) to give the title compound (3.5 mg, yield: 7.8%) and (33 mg, yield: 73.3%).

[0673] Single-configuration compound (shorter retention time): (3.5 mg, yield: 7.8%).

[0674] MS m / z(ESI): 964.8 [M+1].

[0675] Chiral HPLC analysis: retention time 5.842 min, purity: 99.9% (column: ChiralPak IK, 5 μm, 4.6 mm * 150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0676] 1 H NMR (500MHz, CD3OD): δ7.91(s,1H),7.74(dd,1H),7.42–7.37(m,1H),7.33(dd,1H),7.26(d,2H),7.22(d, 1H),7.15(d,1H),7.13(s,1H),7.00(dt,1H),6.50–6.43(m,2H),4.72(ddd,1H),4.51(d,1H),4.31(s,1H) ,4.18(dt,4H),4.07(t,1H),4.03–3.92(m,3H),3.80(d,1H),3.28(s,1H),2.97(t,1H),2.72(d,3H),2.48 (s,3H),2.09(s,1H),1.98–1.89(m,2H),1.85(d,2H),1.75(s,3H),1.64(s,1H),1.29(s,6H),1.25(s,6H).

[0677] Single-configuration compound (longer retention time): (33 mg, yield: 73.3%).

[0678] MS m / z(ESI): 964.8 [M+1].

[0679] Chiral HPLC analysis: retention time 9.180 min, purity: 99.9% (column: ChiralPak IK, 5 μm, 4.6 mm * 150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0680] 1 H NMR (500MHz, CD3OD): δ7.91(s,1H),7.74(d,1H),7.39(dt,1H),7.33(dd,1H),7.26(d,2H),7.22(d,1H),7. 15(d,1H),7.13(s,1H),7.00(dd,1H),6.49–6.43(m,2H),4.72(dd,1H),4.51(dd,1H),4.31(s,1H),4.23–4. 11(m,4H),4.07(t,1H),4.02–3.92(m,3H),3.79(d,1H),3.29(d,1H),3.00–2.92(m,1H),2.72(s,3H),2.48( s,3H),2.05(dd,1H),1.98–1.89(m,2H),1.83(dd,2H),1.75(s,3H),1.62(t,1H),1.29(s,6H),1.25(s,6H).

[0681] Example 9

[0682] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-6-carboxamide 9-p1

[0683] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-6-carboxamide 9-p2

[0684] first step

[0685] 4-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 9b

[0686] 5-Bromo-2-iodopyridine-3-phenol 9a (1.75 g, 5.73 mmol, Shanghai Bide) was dissolved in tetrahydrofuran (50 mL), and tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid (1.5 g, 7.03 mmol, Shanghai Bide), triphenylphosphine (3.83 g, 14.60 mmol), and di-tert-butyl azodicarbonate (2.95 g, 14.59 mmol) were added. The mixture was stirred for 0.5 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 9b (2.34 g, yield: 81%).

[0687] MS m / z(ESI):439.0[M-55].

[0688] Step 2

[0689] 6-Bromo-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 9c

[0690] Compound 9b (2.2 g, 4.44 mmol) was dissolved in toluene (25 mL), and tri-n-butyltin hydride (3.9 g, 13.40 mmol) and azobisisobutyronitrile (2.2 g, 13.40 mmol) were added. The mixture was reacted at 115 °C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, and 20% potassium fluoride solution was added and stirred for 3 hours. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 9c (1.16 g, yield: 70.9%).

[0691] MS m / z(ESI): 369.1 [M+1].

[0692] Step 3

[0693] 1'-(tert-butoxycarbonyl)-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-6-carboxylic acid 9d

[0694] Compound 9c (200 mg, 541 μmol) was dissolved in tetrahydrofuran (2 mL), and a 2.5 M n-butyllithium solution in n-hexane (240 μL) was added at -78 °C. After maintaining the temperature for 0.5 hours, carbon dioxide was introduced and the reaction was continued for 1 hour. Saturated ammonium chloride was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 9d (110 mg). The product was directly used for the next reaction without purification.

[0695] MS m / z(ESI): 335.1 [M+1].

[0696] Step 4

[0697] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-6-carboxamide 9-p1

[0698] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[furano[3,2-b]pyridine-3,4'-piperidine]-6-carboxamide 9-p2

[0699] Using the synthetic route of Example 1, the starting compound 1b in the second step was replaced with compound 9d to obtain the title compound 9-p1 or 9-p2 (9 mg, yield: 9.3%).

[0700] MS m / z(ESI): 952.7 [M+1].

[0701] 1H NMR (500MHz, CD3OD): δ8.47(d,1H),7.92(s,1H),7.74(d,1H),7.48(d,1H),7.34(d,2 H),7.19–7.11(m,2H),7.00(dd,1H),6.88(d,2H),4.75(dd,1H),4.55(t,1H),4.30(s ,1H),4.17(s,1H),3.98(qd,2H),3.02(s,2H),2.84–2.76(m,2H),2.72(s,3H),2.48( s,3H),2.15(d,3H),2.05(d,6H),1.80(d,2H),1.72(s,3H),1.30(s,6H),1.24(s,6H).

[0702] Example 10

[0703] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-fluoro-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 10-p1

[0704] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-fluoro-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 10-p2

[0705] Using the synthetic route of Example 9, the starting material 9a in the first step was replaced with compound 2-bromo-5-chloro-3-fluorophenol (Shanghai Bide) to obtain the title compound (20 mg, yield: 22.6%) and (2 mg, yield: 2.2%).

[0706] Single configuration compound (shorter retention time): (20 mg, yield: 22.6%).

[0707] MS m / z(ESI): 969.5 [M+1].

[0708] HPLC analysis: retention time 1.97 min, purity: 90% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0709] 1 H NMR(500MHz,CD3OD):H NMR(500MHz,CD3OD)δ7.91(s,1H),7.74(d,1H),7.34(d,2H),7.16-7.13(m,2H),7.10-7.07(m,1H),7.06-7.04 (m,1H),7.02-6.97(m,1H),6.89-6.85(m,2H),4.78-4.73(m,1H),4.57-4.51(m,3H),4.30(s,1H),4.14(s,1H) ,4.04-3.93(m,2H),3.02-2.95(m,2H),2.82-2.75(m,2H),2.72(s,3H),2.63-2.57(m,1H),2.48(s,3H),2.40- 2.32(m,2H),2.07-1.95(m,4H),1.88-1.82(m,1H),1.72(s,3H),1.66-1.57(m,2H),1.28(s,6H),1.24(s,6H).

[0710] Single-configuration compound (longer retention time): (2 mg, yield: 2.2%).

[0711] MS m / z(ESI): 969.5 [M+1].

[0712] HPLC analysis: retention time 1.99 min, purity: 85% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0713] 1H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.34(d,2H),7.16-7.13(m,2H),7.10-7.07(m,1H),7.0 6-7.04(m,1H),7.02-6.97(m,1H),6.85-6.81(m,2H),4.78-4.73(m,1H),4.55(s,2H),4.30(s,1H),4.15 (s,1H),4.05-3.92(m,2H),3.05-2.98(m,2H),2.82-2.76(m,2H),2.72(s,3H),2.48(s,3H),2.40-2.29( m,2H),2.09-2.00(m,5H),1.98-1.82(m,2H),1.72(s,3H),1.66-1.59(m,2H),1.28(s,6H),1.24(s,6H).

[0714] Example 11

[0715] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,4r)-4-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclohexyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 11-p1

[0716] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,4s)-4-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclohexyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 11-p2

[0717] first step

[0718] 4'-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptidyl-4-yl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-ol 11b

[0719] 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)cyclohexyl-3-enol 11a (100 mg, 446 μmol, Nanjing Pharmaceutical), compound 5a (150 mg, 354 μmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium(II) chloride (23 mg, 35 μmol), and cesium carbonate (230 mg, 707 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). The mixture was purged with nitrogen and reacted at 105 °C for 4 hours. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 11b (140 mg, yield: 81.4%).

[0720] MS m / z(ESI): 486.5 [M+1].

[0721] Step 2

[0722] (S)-4-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclohexyl-1-ol 11c

[0723] Compound 11b (140 mg, 288 μmol) was dissolved in methanol (5 mL), and 200 mg of 10% palladium on carbon hydrogenation catalyst (wet) was added. The mixture was purged with hydrogen and stirred at 45 °C for 3 days. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11c (140 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 488.4 [M+1].

[0724] Step 3

[0725] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,4r)-4-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclohexyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 11-p1

[0726] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,4s)-4-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclohexyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 11-p2

[0727] Using the synthetic route of Example 1, steps six and seven were performed, with the starting compound 1i in step six replaced by compound 11c and the starting compound 1e in step seven replaced by compound 5d, to obtain the title compound (2 mg, yield: 3.4%).

[0728] Single configuration compound (shorter retention time): (2 mg, yield: 3.4%).

[0729] MS m / z(ESI): 963.5 [M+1].

[0730] HPLC analysis: retention time 2.15 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0731] 1 H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.39(dd,1H),7.33(d,2H),7.31(d,1H) ,7.28(d,2H),7.20(d,1H),7.15(d,2H),7.00(dd,1H),4.78(d,1H),4.51(s,2H),4.31(s ,1H),4.16(s,1H),4.00(qd,2H),3.11(s,2H),2.73(s,3H),2.60(s,1H),2.47(s,3H),2. 15(s,2H),2.06(s,8H),1.85(d,2H),1.68(s,3H),1.58(s,3H),1.29(s,6H),1.25(s,6H).

[0732] Longer retention time for single-configuration compounds: (2 mg, yield: 3.4%).

[0733] MS m / z(ESI): 963.5 [M+1].

[0734] HPLC analysis: retention time 2.33 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0735] 1 H NMR (500MHz, CD3OD): δ7.93(s,1H),7.74(d,1H),7.40–7.34(m,5H),7.30(d,1H),7.19(d ,1H),7.15(d,2H),7.00(dd,1H),4.79(d,1H),4.47(s,2H),4.31(s,1H),4.15(s,1H),4.0 6–3.94(m,2H),3.12(d,2H),2.88(s,1H),2.74(s,3H),2.48(s,4H),2.15(t,3H),2.06–2. 03(m,5H),1.91(d,2H),1.79(d,2H),1.73(d,2H),1.70(s,3H),1.29(s,6H),1.25(s,6H).

[0736] Example 12

[0737] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 12

[0738] Crude compounds 5c (26 mg, 62 μmol) and 5d (33 mg, 62 μmol) were dissolved in tetrahydrofuran (2 mL), and sodium triacetoxyborohydride (50 mg, 236 μmol) was added. The mixture was reacted at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution was added. The mixture was then coated with ethyl acetate (5 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. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 12 (23 mg, yield: 41.2%).

[0739] MS m / z(ESI): 895.8 [M+1].

[0740] 1 H NMR (500MHz, CD3OD): δ7.93(s,1H),7.74(d,1H),7.45-7.35(m,5H),7.29-7.26(m,1H),7.19-7 .17(m,1H),7.16-7.13(m,2H),7.01-6.97(m,1H),4.83-4.77(m,1H),4.46(s,2H),4.30(s,1H) ,4.15(s,1H),4.07-3.94(m,2H),3.67(s,2H),2.97-2.90(m,2H),2.74(s,3H),2.48(s,3H),2. 25-2.17(m,2H),2.07-1.98(m,3H),1.79-1.72(m,2H),1.70(s,3H),1.29(s,6H),1.24(s,6H).

[0741] Example 13

[0742] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(2-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)acetyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 13

[0743] first step

[0744] (S)-2-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)tert-butyl acetate 13a

[0745] Compound 1f (110 mg, 271 μmol) and tert-butyl bromoacetate (56 mg, 285 μmol, Shanghai Titan) were dissolved in acetonitrile (1 mL) and N,N-dimethylformamide (0.5 mL). Potassium carbonate (75 mg, 542 μmol) was added and the mixture was stirred for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 13a (140 mg, yield: 99%).

[0746] MS m / z(ESI): 520.5 [M+1].

[0747] Step 2

[0748] (S)-2-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)acetic acid 13b

[0749] Compound 13a (48 mg, 92 μmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 13b (42 mg, 98% yield).

[0750] MS m / z(ESI):464.4[M+1].

[0751] Step 3

[0752] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(2-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)acetyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 13

[0753] Compound 13b (43 mg, 93 μmol) and crude compound 5d (50 mg, 94 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (54 mg, 141 μmol) and N,N-diisopropylethylamine (49 mg, 377 μmol) were added. The mixture was stirred for 0.5 h, filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-60%, flow rate: 30 mL / min) to give title compound 13 (50 mg, yield: 56.4%).

[0754] MS m / z(ESI): 939.5 [M+1].

[0755] 1H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.38(t,3H),7.24(d,1H),7.22(s,1H ),7.15(d,2H),7.01(t,3H),5.01–4.90(m,2H),4.77(dd,1H),4.58(s,2H),4.47(d,1H ),4.31(s,1H),4.16(s,1H),3.99(dq,3H),3.36(d,1H),2.97(t,1H),2.73(s,3H),2.4 8(s,3H),2.03–1.93(m,1H),1.90–1.79(m,3H),1.74(s,3H),1.30(s,6H),1.25(s,6H).

[0756] Example 14

[0757] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclopropane-1-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 14

[0758] first step

[0759] 4-Bromo-2-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-4-yl)phenoxy)methyl butyrate 14a

[0760] Compound 1f (110 mg, 271 μmol) and methyl 2,4-dibromobutyrate (154 mg, 592 μmol, Shanghai Bide) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (136 mg, 986 μmol) was added. The mixture was stirred for 2 hours, the reaction solution was filtered, and the filtrate was used directly for the next reaction.

[0761] MS m / z(ESI): 584.3 [M+1].

[0762] Step 2

[0763] (S)-1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclopropane-1-carboxylic acid methyl ester 14b

[0764] The solution obtained in the first step was cooled to -40°C, and 0.5 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added. The temperature was maintained and the mixture was stirred for 10 minutes. The pH of the reaction solution was adjusted to neutral with 1 M hydrochloric acid and then used directly in the next step of the reaction.

[0765] MS m / z(ESI): 504.4 [M+1].

[0766] Step 3

[0767] (S)-1-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclopropane-1-carboxylic acid 14c

[0768] The solution obtained in the second step was diluted with tetrahydrofuran (3 mL) and water (2 mL), and lithium hydroxide monohydrate (208 mg, 4.96 mmol) was added. The mixture was stirred for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The aqueous phase was separated, and the pH was adjusted to <7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14c (150 mg). The product was used directly in the next step without purification.

[0769] MS m / z(ESI):490.4[M+1].

[0770] Step 4

[0771] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(1-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclopropane-1-carbonyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 14

[0772] Compound 14c (46 mg, 94 μmol) and compound 5d (50 mg, 94 μmol) were dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (54 mg, 141 μmol) and N,N-diisopropylethylamine (61 mg, 471 μmol) were added. The mixture was stirred for 0.5 h, filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-60%, flow rate: 30 mL / min) to give title compound 14 (16 mg, yield: 17.5%).

[0773] MS m / z(ESI): 965.5 [M+1].

[0774] 1 H NMR (500MHz, CD3OD): δ7.93(s,1H),7.74(d,1H),7.41(d,2H),7.33–7.22(m,1H),7.18(d,1H), 7.17–7.13(m,2H),7.11(d,2H),7.00(dd,1H),6.86(s,1H),4.79(dd,1H),4.62(s,1H),4.51(s ,2H),4.31(s,2H),4.15(s,1H),4.02(qd,2H),2.89(s,1H),2.73(s,3H),2.48(s,3H),2.05(d, 1H),1.76(s,6H),1.66–1.49(m,3H),1.44–1.38(m,1H),1.30(s,6H),1.24(s,6H),1.17(s,1H).

[0775] Example 15

[0776] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)prop-2-yn-1-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 15

[0777] first step

[0778] 2-((2,3,9-trimethyl-4-(4-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazol15a

[0779] Compound 5a (150 mg, 354 μmol) was dissolved in acetonitrile (2 mL), and 2-(2-propynyl-1-yloxy)tetrahydro-2H-pyran (149 mg, 1.06 mmol, Shanghai Titan) was added, cesium carbonate (346 mg, 1.06 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (28 mg, 35 μmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (20 mg, 35 μmol). The mixture was purged with nitrogen and stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 15a (150 mg, 80.3% yield).

[0780] MS m / z(ESI): 528.3 [M+1].

[0781] Step 2

[0782] 3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)prop-2-yn-1-ol 15b

[0783] Compound 15a (180 mg, 341 μmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL), and p-toluenesulfonic acid monohydrate (324 mg, 1.71 mmol) was added. The mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give title compound 15b (50 mg, yield: 33%).

[0784] MS m / z(ESI): 444.5 [M+1].

[0785] Step 3

[0786] 3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)prop-2-yn-1-ylmethanesulfonate 15c

[0787] Compound 15b (25 mg, 56 μmol) was dissolved in dichloromethane (0.5 mL), and N,N-diisopropylethylamine (29 mg, 225 μmol) and methanesulfonyl chloride (13 mg, 116 μmol) were added. The mixture was stirred for 15 minutes, water was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 15c (29 mg), which was used directly in the next reaction without purification.

[0788] MS m / z(ESI): 522.4 [M+1].

[0789] Step 4

[0790] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-(3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)prop-2-yn-1-yl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 15

[0791] Crude compound 15c (29 mg, 55 μmol) and compound 5d (29 mg, 55 μmol) were dissolved in acetonitrile (0.5 mL), and potassium carbonate (23 mg, 167 μmol) was added. The mixture was stirred at 40 °C for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-50%, flow rate: 30 mL / min) to obtain title compound 15 (12 mg, yield: 23.5%, isomer S:R = 1:1).

[0792] MS m / z(ESI): 919.5 [M+1].

[0793] Chiral HPLC analysis: retention times 6.3263 min (50%), 9.884 min (50%) (Column: ChiralPak IK, 5 μm, 4.6 mm * 150 mm; Mobile phase A: n-hexane, Mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[0794] 1 H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.48(d,2H),7.41(d,2H),7.37( d,1H),7.33(d,1H),7.20(s,1H),7.15(s,2H),7.00(dd,1H),4.81(dd,1H),4.50(s ,2H),4.30(s,1H),4.15(s,1H),4.01(qd,2H),3.63(s,2H),3.08(d,2H),2.73(s,3 H),2.46(d,5H),2.05(d,2H),1.84(d,2H),1.72(s,3H),1.29(s,6H),1.24(s,6H).

[0795] Example 16

[0796] N 6 -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-N 1 '-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)-2H-spiro[benzofuran-3,4'-piperidine]-1',6-dicarboxamide16

[0797] first step

[0798] (4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)tert-butyl carbamate 16a

[0799] Tert-butyl carbamate (221 mg, 1.89 mmol) was dissolved in 1,4-dioxane (15 mL), and compound 5a (400 mg, 943 μmol), cesium carbonate (768 mg, 2.36 mmol), tris(dibenzylacetone)dipalladium (173 mg, 189 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (218 mg, 377 μmol) were added. The mixture was purged with nitrogen and stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 16a (450 mg, yield: 94.5%).

[0800] MS m / z(ESI): 505.4 [M+1].

[0801] Step 2

[0802] 4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)aniline

[0803] 4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)aniline 16b

[0804] Compound 16a (500 mg, 991 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 16b (60 mg, yield: 15%).

[0805] MS m / z(ESI): 405.3 [M+1].

[0806] Step 3

[0807] N 6 -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-N 1 '-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)-2H-spiro[benzofuran-3,4'-piperidine]-1',6-dicarboxamide16

[0808] Compound 5d (40 mg, 81 μmol) was dissolved in toluene (3 mL), and N,N-diisopropylethylamine (63 mg, 487 μmol) and triphosgene (26 mg, 89 μmol) were added. After stirring for 0.5 hours, the mixture was cooled to 0 °C, and a toluene solution of compound 16b (33 mg, 81 μmol) (1 mL) was added. The mixture was allowed to return to room temperature for 1 hour. The reaction solution was quenched with a small amount of water and filtered. The filtrate was purified by preparative high-performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-50%, flow rate: 30 mL / min) to give title compound 16 (5 mg, yield: 6.6%). MS m / z (ESI): 924.6 [M+1].

[0809] 1 H NMR (500MHz, CDCl3): δ7.90(s,1H),7.72(d,1H),7.45(d,,2H),7.37(dd,1H),7.31( dd,3.9Hz,3H),7.20(d,1H),7.13(d,2H),6.98(dd,1H),4.57(s,2H),4.29(s,1H),4. 22–4.09(m,3H),3.98(qd,3H),3.11(d,2H),2.71(s,3H),2.47(s,3H),2.19(t,1H), 2.10–1.90(m,4H),1.81(d,2H),1.73(s,3H),1.61(s,2H),1.27(s,4H),1.23(s,5H).

[0810] Example 17

[0811] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzyl)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 17

[0812] first step

[0813] tert-Butyldimethyl(3-((4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)methylene)cyclobutoxy)silane 17b

[0814] 2,2,6,6-Tetramethylpiperidine (728 mg, 5.15 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (10 mL). Under a nitrogen atmosphere, a 2.5 M n-butyllithium solution in n-hexane (2 mL) was added at -30 °C. After stirring for 0.5 hours, the temperature was lowered to -78 °C, and a tetrahydrofuran solution of bis[(pinacol)boryl]methane (1.15 g, 4.29 mmol, Shanghai Bide) (3 mL) was added dropwise. After stirring for 0.5 hours, 3-((tert-butyldi) A tetrahydrofuran solution (3 mL) of methylsilyl)oxy)cyclobutanone 17a (860 mg, 4.29 mmol, Shanghai Bide) was stirred at room temperature for 16 hours under natural conditions. The reaction mixture was quenched with saturated ammonium chloride in an ice bath and extracted with ethyl acetate (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 silica gel column chromatography with eluent system B to give title compound 17b (950 mg, yield: 68.2%).

[0815] MS m / z(ESI): 325.4 [M+1].

[0816] Step 2

[0817] 2-(((6S)-4-(4-((3-((tert-butyldimethylsilyl)oxy)cyclobutylidene)methyl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepoxide-6-yl)methyl)oxazolium17c

[0818] Compound 5a (500 mg, 1.18 mmol) was dissolved in 1,4-dioxane (7 mL) and water (1 mL), and compound 17b (500 mg, 1.54 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium (77 mg, 118 μmol), and cesium carbonate (768 mg, 2.35 mmol) were added. The mixture was purged with nitrogen and reacted at 105 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 17c (600 mg, yield: 86.8%).

[0819] MS m / z(ESI): 586.4 [M+1].

[0820] Step 3

[0821] (S)-2-((4-(4-((3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methyl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptide-6-yl)methyl)oxazol 17d

[0822] Compound 17c (300 mg, 512 μmol) was dissolved in methanol (10 mL), and 10% palladium on carbon hydrogenation catalyst (wet) (300 mg) was added. The mixture was purged with hydrogen and stirred at 40 °C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 17d (300 mg). The product was used directly in the next reaction without purification.

[0823] MS m / z(ESI): 588.5 [M+1].

[0824] Step 4

[0825] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)benzyl)cyclobutyl)-6,6a,7,8,9,10-hexahydropyrazin[1,2-d]pyrido[3,2-b][1,4]oxazin-3-carboxamide 17

[0826] Using steps five to seven of the synthetic route in Example 1, the starting compound 1h in step five was replaced with compound 17d to obtain title compound 17 (70 mg, yield: 50.5%, cis-trans isomer ratio 2:1).

[0827] MS m / z(ESI): 951.7 [M+1].

[0828] 1H NMR (500MHz, CDCl3): δ8.25(d,1H),7.92(s,1H),7.74(d,1H),7.41(d,1H),7.32(dd,2H),7.23(d d,2H),7.15(d,2H),7.00(dd,1H),4.78(dd,1H),4.57(d,1H),4.33(dd,1H),4.30(s,1H),4.15(s ,1H),4.06–3.92(m,3H),3.50(s,1H),3.06–2.85(m,4H),2.78(d,2H),2.73(s,3H),2.47(s,3H), 2.29–2.24(m,1H),2.08(dd,3H),2.00–1.90(m,2H),1.67–1.59(m,4H),1.29(s,6H),1.23(s,6H).

[0829] Example 18

[0830] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-8-carboxamide 18-p1

[0831] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-8-carboxamide 18-p2

[0832] first step

[0833] (R)-3-((5-bromo-2-iodophenoxy)methyl)-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester 18c

[0834] (R)-3-hydroxymethyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester 18a (8.34 g, 26.69 mmol, prepared by the method disclosed in Synthesias of 2 on page 291 of patent application "WO2021173923") and 5-bromo-2-iodophenol 18b (6.65 g, 22.24 mmol, Shanghai Bide) were dissolved in tetrahydrofuran (80 mL), and triphenylphosphine (8.75 g, 33.37 mmol) and diisopropyl azodicarbonate (6.75 g, 33.37 mmol) were added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 18c (13.1 g, yield: 99.2%).

[0835] MS m / z(ESI): 592.9 [M+1].

[0836] Step 2

[0837] (R)-3-((5-bromo-2-iodophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 18d

[0838] Compound 18c (13.1 g, 22.08 mmol) was dissolved in methanol (80 mL) and water (20 mL), and potassium carbonate (9.15 g, 66.24 mmol) was added. The mixture was stirred for 2 hours, and water was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 18d (8.78 g, yield: 80%).

[0839] MS m / z(ESI):496.9[M+1].

[0840] Step 3

[0841] (R)-8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl formate 18e

[0842] Compound 18d (2 g, 4.02 mmol) was dissolved in toluene (80 mL), and palladium acetate (46 mg, 205 μmol), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (376 mg, 604 μmol), and cesium carbonate (3.94 g, 12.09 mmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 3 h. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 18e (1.2 g, yield: 81%).

[0843] MS m / z(ESI): 368.9 [M+1].

[0844] Step 4

[0845] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-8-carboxamide 18-p1

[0846] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-8-carboxamide 18-p2

[0847] Using the synthetic route in Example 1, the starting compound 1a in the first step was replaced with compound 18e to obtain the title compound 18-p1 or 18-p2 (11 mg, yield: 9.5%).

[0848] MS m / z(ESI): 952.5 [M+1].

[0849] 1H NMR (500MHz, CDCl3): δ7.91(s,1H),7.74(d,1H),7.38(dd,1H),7.34(d,2H),7.25(d,1H),7.17–7.13(m,2H), 7.00(dd,1H),6.93(d,1H),6.90–6.85(m,2H),4.75(dd,1H),4.56(q,1H),4.30(d,2H),4.14(s,1H),4.05–3.9 2(m,3H),3.88(dt,1H),3.24(ddt,1H),3.06(d,1H),2.97(dt,1H),2.89–2.76(m,3H),2.72(s,3H),2.62(p,1 H),2.48(s,3H),2.15(td,1H),2.09(s,1H),1.77(t,1H),1.72(s,3H),1.62(t,1H),1.29(d,6H),1.23(s,6H).

[0850] Example 19

[0851] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 19-p1

[0852] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 19-p2

[0853] first step

[0854] 9-Benzyl-3-methyl(R)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazheptan-3,9(7H)-dicarboxylic acid ester 19b

[0855] Using steps three to six of the synthetic route in Example 3, the starting compound 3c in step three was replaced with 4-benzyl-1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester 19a (Shanghai Shaoyuan) to prepare title compound 19b (385 mg, yield: 81%).

[0856] MS m / z(ESI): 398.5 [M+1].

[0857] Step 2

[0858] (R)-9-((benzyloxy)carbonyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazine-3-carboxylic acid 19c

[0859] Compound 19b (385 mg, 969 μmol) was dissolved in tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (165 mg, 3.93 mmol) was added. The mixture was stirred for 16 hours. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 19c (346 mg), which was used directly in the next reaction without purification.

[0860] MS m / z(ESI): 384.3 [M+1].

[0861] Step 3

[0862] (R)-3-(((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazineheptane-9(7H)-carboxylic acid benzyl ester 19d

[0863] Crude compound 19c (346 mg, 902 μmol) and compound 1c (270 mg, 856 μmol) were dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (584 mg, 4.52 mmol) and n-butylphosphine anhydride (488 mg, 1.35 mmol, 50% ethyl acetate solution) were added under ice bath conditions. The mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed successively with water and saturated sodium chloride solution. The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 19d (364 mg, yield: 62.6%).

[0864] MS m / z(ESI): 644.4 [M+1].

[0865] Step 4

[0866] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridino[2,3-e][1,4]oxazineheptane-3-carboxamide 19e

[0867] Compound 19d (364 mg, 565 μmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL), and 10% palladium on carbon hydrogenation catalyst (350 mg) was added. The mixture was purged with hydrogen, stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give title compound 19e (40 mg, yield: 13.9%).

[0868] MS m / z(ESI): 510.4 [M+1].

[0869] Step 5

[0870] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 19-p1

[0871] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 19-p2

[0872] Compound 19e (40 mg, 78 μmol) was dissolved in tetrahydrofuran (2 mL), 1 drop of acetic acid was added, and crude compound 1j (40 mg, 84 μmol) and sodium triacetoxyborohydride (40 mg, 189 μmol) were added under ice bath conditions. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give the title compound 19-p1 or 19-p2 (13 mg, yield: 17%).

[0873] MS m / z(ESI): 967.7 [M+1].

[0874] 1H NMR (500MHz, CDCl3): δ8.64(d,1H),7.93-7.90(m,2H),7.74(d,1H),7.34(d,2H),7.17-7.12(m,2H),7.00(d d,1H),6.87(d,1H),4.77-4.68(m,2H),4.60-4.52(m,1H),4.30(s,1H),4.26-4.21(m,1H),4.17(s,1H),4.0 4-3.83(m,4H),3.67-3.61(m,1H),3.41-3.34(m,2H),2.92-2.87(m,1H),2.85-2.76(m,3H),2.72(s,3H),2. 64-2.57(m,1H),2.47(s,3H),2.28-2.18(m,2H),2.12-2.02(m,4H),1.72(s,3H),1.30(s,6H),1.24(s,6H).

[0875] Example 20

[0876] (S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1R,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 20-p1

[0877] (S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-((1S,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]oxazheptan-3-carboxamide 20-p2

[0878] Using the synthetic route in Example 19, the first-step starting compound 19a was replaced with 4-benzyl-1-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester (Shanghai Haohong) to prepare the title compound 20-p1 or 20-p2 (3 mg, yield: 7.8%).

[0879] MS m / z(ESI): 967.7 [M+1].

[0880] 1 H NMR (500MHz, CDCl3): δ8.64(d,1H),7.91(d,2H),7.74(d,1H),7.34(d,2H),7.17–7.11(m,2H),7.00(dd, 1H),6.87(d,2H),4.73(d,2H),4.56(d,1H),4.30(s,1H),4.27–4.21(m,1H),4.17(s,1H),4.04–3.91(m, 3H),3.87(dd,1H),3.68–3.61(m,1H),3.38(s,1H),2.90(d,1H),2.80(dt,3H),2.72(s,3H),2.61(t,1H) ,2.48(s,3H),2.28–2.24(m,1H),2.11(d,1H),1.72(s,3H),1.65–1.60(m,3H),1.30(s,6H),1.24(s,6H).

[0881] Example 21

[0882] (7aR,9S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazol-3-carboxamide 21-p1

[0883] (7aR,9R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazol-3-carboxamide 21-p2

[0884] first step

[0885] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-7a,8,10,11-tetrahydro-5H,7H-spiro[bispyrido[2,1-c:2',3'-e][1,4]oxazepane-9,2'-[1,3]dioxapentane]-3-carboxamide 21b

[0886] Using the synthetic route in Example 19, steps one to three were performed, replacing the starting compound 19a in the first step with (R)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester 21a (prepared by the method disclosed in Intermediate 12 on page 32 of the specification in patent application "WO2022238335") to obtain title compound 21b (40 mg, yield: 20.5%).

[0887] MS m / z(ESI): 567.5 [M+1].

[0888] Step 2

[0889] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-oxo-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazepane-3-carboxamide 21c

[0890] Compound 21b (40 mg, 70 μmol) was dissolved in tetrahydrofuran (5 mL), and 2M sulfuric acid solution (0.4 mL) was added. The mixture was stirred at 70 °C for 2 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (5 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 21c (36 mg). The product was used directly in the next reaction without purification.

[0891] MS m / z(ESI): 523.3 [M+1].

[0892] Step 3

[0893] (S)-3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester 21d

[0894] Compound 1f (150 mg, 370 μmol) and tert-butyl 3-hydroxyazacyclobutane-1-carboxylic acid (366 mg, 2.11 mmol, Shanghai Shaoyuan) were dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (438 mg, 1.67 mmol) and diisopropyl azodicarbonate (336 mg, 1.66 mmol) were added. The mixture was stirred at 70 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound 21d (90 mg, yield: 43.4%).

[0895] MS m / z(ESI): 561.5 [M+1].

[0896] Step 4

[0897] (S)-2-((4-(4-(azacyclobut-3-yloxy)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazol hydrochloride 21e

[0898] Compound 21d (90 mg, 160 μmol) was dissolved in dichloromethane (2 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 21e (79 mg). The product was used directly in the next reaction without purification.

[0899] MS m / z(ESI):461.1[M+1].

[0900] Step 5

[0901] (7aR,9S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazol-3-carboxamide 21-p1

[0902] (7aR,9R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazol-3-carboxamide 21-p2

[0903] Crude compound 21e (36 mg, 69 μmol) and crude compound 1e (34 mg, 68 μmol) were dissolved in dichloromethane (5 mL), and one drop of acetic acid, sodium acetate (28 mg, 341 μmol), and sodium triacetoxyborohydride (44 mg, 208 μmol) were added. The mixture was stirred for 16 hours, methanol was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give the title compound (25 mg, yield: 37.5%) and (9.6 mg, yield: 14.4%).

[0904] Single configuration compound (shorter retention time): (25 mg, yield: 37.5%).

[0905] MS m / z(ESI): 967.7 [M+1].

[0906] HPLC analysis: retention time 1.54 min, purity: 90% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0907] 1H NMR (500MHz, CDCl3): δ8.57(d,1H),7.97(s,1H),7.78(d,1H),7.63(s,1H),7.56(d,1H),7.34(d,2H),7.04( s,1H),6.96(d,1H),6.81-6.79(m,1H),6.72(d,2H),6.05(d,1H),4.83-4.81(m,1H),4.76-4.69(m,2H),4.5 8(d,1H),4.53-4.49(m,1H),4.15-4.01(m,4H),3.94-3.91(m,1H),3.83-3.75(m,3H),3.52(d,1H),3.18-3. 16(m,2H),3.00(t,1H),2.66(s,3H),2.53-2.52(m,1H),2.40(s,3H),1.85-1.62(m,6H),1.26-1.22(m,12H).

[0908] (Longer retention time for single-configuration compounds): (9.6 mg, yield: 14.4%).

[0909] MS m / z(ESI): 967.7 [M+1].

[0910] HPLC analysis: retention time 1.60 min, purity: 85% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0911] 1 H NMR (500MHz, CDCl3): δ8.56(d,1H),7.97(s,1H),7.76(d,1H),7.63(s,1H),7.5 6(d,1H),7.35(d,2H),7.04(s,1H),6.96(d,1H),6.81-6.79(m,1H),6.73(d,2H ),6.07(d,1H),4.90-4.61(m,4H),4.15-4.01(m,5H),4.00-3.42(m,6H),3.16- 3.05(m,3H),2.70(s,3H),2.40(s,3H),1.86-1.52(m,6H),1.26-1.21(m,12H).

[0912] Example 22

[0913] (6aR,8S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxamide 22-p1

[0914] (6aR,8R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxamide 22-p2

[0915] first step

[0916] (R)-(1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol hydrochloride 22a

[0917] Compound 21a (1 g, 3.66 mmol) was dissolved in dichloromethane (10 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (10 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 22a (827 mg). The product was used directly in the next reaction without purification.

[0918] MS m / z(ESI):174.1[M+1].

[0919] Step 2

[0920] (R)-3-bromo-6a,7,9,10-tetrahydro-6H-spiro[bispyrido[3,2-b:1',2'-d][1,4]oxazine-8,2'-[1,3]dioxapentane]22b

[0921] Using the synthetic route in Example 4, steps two and three were performed, replacing the starting compound 4b in step two with compound 22a to obtain the title compound 22b (196 mg, yield: 73.2%).

[0922] MS m / z(ESI): 326.9 [M+1].

[0923] Step 3

[0924] (R)-6a,7,9,10-tetrahydro-6H-spiro[bispyrido[3,2-b:1',2'-d][1,4]oxazine-8,2'-[1,3]dioxapentane]-3-carboxylic acid methyl ester 22c

[0925] Compound 22b (196 mg, 599 μmol) was dissolved in N,N-dimethylformamide (4 mL) and methanol (4 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (44 mg, 60 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (20 mg, 48 μmol), and triethylamine (122 mg, 1.20 mmol) were added. The mixture was replaced with carbon monoxide and reacted at 90 °C for 16 hours. After cooling the reaction solution to room temperature, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 22c (175 mg, yield: 95.3%).

[0926] MS m / z(ESI): 307.4 [M+1].

[0927] Step 4

[0928] (R)-8-oxo-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxylic acid methyl ester 22d

[0929] Compound 22c (175 mg, 571 μmol) was dissolved in methanol (5 mL) and water (5 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 65 °C for 4 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 22d (112 mg, yield: 74.7%).

[0930] MS m / z(ESI):263.1[M+1].

[0931] Step 5

[0932] (R)-8-oxo-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxylic acid 22e

[0933] Compound 22d (112 mg, 427 μmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide monohydrate (72 mg, 1.71 mmol) was added. The mixture was stirred for 16 hours. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 22e (108 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 249.1 [M+1].

[0934] Step 6

[0935] (R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-oxo-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxamide 22f

[0936] The crude compound 22e (107 mg, 431 μmol) and compound 1c (136 mg, 431 μmol) were dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (279 mg, 2.16 mmol) and n-butylphosphine (466 mg, 647 μmol, 50% ethyl acetate solution) were added under ice bath conditions. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 22f (129 mg, yield: 58.8%).

[0937] MS m / z(ESI): 509.4 [M+1].

[0938] Step 7

[0939] (6aR,8S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxamide 22-p1

[0940] (6aR,8R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-8-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-6,6a,7,8,9,10-hexahydrodipyrido[3,2-b:1',2'-d][1,4]oxazine-3-carboxamide 22-p2

[0941] Crude compound 22f (64 mg, 126 μmol) and crude compound 21e (63 mg, 127 μmol) were dissolved in dichloromethane (5 mL) and tetrahydrofuran (2 mL). One drop of acetic acid and sodium acetate (52 mg, 634 μmol) were added. After stirring for 5 minutes, sodium triacetoxyborohydride (80 mg, 377 μmol) was added, and the mixture was stirred for 5 hours. Methanol was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give the title compound (19.8 mg, yield: 16.5%) and (14.2 mg, yield: 11.8%).

[0942] Single configuration compound (shorter retention time): (19.8 mg, yield: 16.5%).

[0943] MS m / z(ESI): 953.6 [M+1].

[0944] HPLC analysis: retention time 1.79 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0945] 1H NMR (500MHz, DMSO-d6): δ8.27(s,1H),8.05(s,1H),7.92-7.90(m,1H),7.62-7.60(m,1H),7.42(s,1H),7. 31-7.30(m,2H),7.21(s,1H),7.14-7.09(m,1H),7.01-6.97(m,1H),6.88-6.86(m,2H),4.83-4.80(m,1H) ,4.69-4.62(m,2H),4.31-4.29(m,2H),4.06-4.04(m,1H),3.96-3.72(m,6H),3.04-3.00(m,2H),2.71-2. 61(m,5H),2.43-2.32(m,5H),1.86-1.82(m,2H),1.65-1.60(m,3H),1.24-1.21(m,6H),1.12-1.07(m,6H).

[0946] (Longer retention time for single-configuration compounds): (14.2 mg, yield: 11.8%).

[0947] MS m / z(ESI): 953.6 [M+1].

[0948] HPLC analysis: retention time 1.91 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0949] 1H NMR (500MHz, DMSO-d6): δ8.27(s,1H),8.05(s,1H),7.92-7.90(m,1H),7.62-7.60(m,1H),7.40(s,1H),7.31-7.30( m,2H),7.24-7.21(m,1H),7.13(s,1H),7.02-7.00(m,1H),6.89-6.87(m,2H),4.87-4.83(m,1H),4.65-4.62(m,1H) ,4.38-4.23(m,3H),4.06-4.04(m,1H),3.91-3.77(m,5H),3.63-3.59(m,1H),3.02-2.92(m,3H),2.63-2.61(m,4H) ,2.43-2.37(m,4H),1.69-1.65(m,4H),1.55-1.49(m,1H),1.35-1.30(m,1H),1.24-1.22(m,6H),1.12-1.05(m,6H).

[0950] Example 23

[0951] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23

[0952] (3R,3”R,4'S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23-p1

[0953] (3S,3”S,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23-p2

[0954] first step

[0955] 2-(benzyloxy)spiro[3.5]non-6-ene-7-carboxylic acid methyl ester 23b

[0956] 2-(benzyloxy)spiro[3.5]non-6-en-7-yl trifluoromethanesulfonate 23a (2 g, 5.31 mmol, prepared by the method disclosed in Example 7 on page 58 of patent application "WO2021216661") was dissolved in N,N-dimethylformamide (15 mL) and methanol (15 mL), and palladium acetate (61 mg, 272 μmol), triphenylphosphine (142 mg, 541 μmol), triethylamine (1.08 g, 10.67 mmol) were added, and the mixture was substituted with carbon monoxide. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 23b (1.4 g, yield: 92%).

[0957] MS m / z(ESI):287.0[M+1].

[0958] Step 2

[0959] (2-(benzyloxy)spiro[3.5]non-6-en-7-yl)methanol 23c

[0960] Compound 23b (1.4 g, 4.89 mmol) was dissolved in tetrahydrofuran (30 mL), and a 1 M diisobutylaluminum hydride solution in n-hexane (10.8 mL) was added at -78 °C. The mixture was allowed to return to room temperature and stirred for 1 hour. The reaction mixture was then quenched with methanol at -78 °C, followed by the addition of sodium sulfate decahydrate. After stirring for 1 hour, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 23c (1 g, yield: 79.2%).

[0961] Step 3

[0962] 3-((2-(benzyloxy)spiro[3.5]non-6-en-7-yl)methoxy)-4-bromobenzoic acid ethyl ester 23e

[0963] Ethyl 4-bromo-3-hydroxybenzoate 23d (1.05 g, 4.28 mmol, Shanghai Leyan) was dissolved in tetrahydrofuran (50 mL), and compound 23c (1 g, 3.87 mmol), triphenylphosphine (1.53 g, 5.83 mmol), and di-tert-butyl azodicarbonate (1.18 g, 5.83 mmol) were added. The mixture was allowed to return to room temperature and stirred for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 23e (1.87 g, yield: 99.5%).

[0964] Step 4

[0965] 3”-(benzyloxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxylic acid ethyl ester 23f

[0966] Compound 23e (1.22 g, 2.51 mmol) was dissolved in toluene (20 mL), and tri-n-butyltin hydride (2.62 g, 9.03 mmol) and azobisisobutyronitrile (1.25 g, 7.61 mmol) were added. The reaction mixture was reacted at 115 °C for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, and 20% potassium fluoride solution was added and stirred for 3 hours. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 23f (1.1 g, yield: 70.5%).

[0967] MS m / z(ESI):407.0[M+1].

[0968] Step 5

[0969] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23

[0970] (3R,3”R,4'S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23-p1

[0971] (3S,3”S,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 23-p2

[0972] Using the synthetic route of Example 3, the starting compound 3h in step 7 was replaced with compound 23f to obtain title compound 23 (73 mg). This was then resolved by a chiral column (Gilson-281, column: ChiralPak ID, 5 μm, 20 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B = 5:95, flow rate: 15 mL / min) to obtain title compound (20 mg, yield: 27.2%) and (20 mg, yield: 27.2%).

[0973] Single configuration compound (shorter retention time): (20 mg, yield: 27.2%).

[0974] MS m / z(ESI): 936.7 [M+1].

[0975] Chiral HPLC analysis: retention time 4.478 min, purity: 99.9% (column: ChiralPak ID, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[0976] 1H NMR (500MHz, CD3OD): δ7.92(d,1H),7.74(d,1H),7.40–7.31(m,3H),7.27(d,1H),7.20–7.13(m, 3H),7.00(dd,1H),6.88–6.83(m,2H),4.81–4.72(m,2H),4.49–4.42(m,2H),4.30(s,1H),4.15( s,1H),3.99(qd,2H),2.73(s,3H),2.67(td,1H),2.48(s,3H),2.43–2.35(m,1H),1.99–1.92(m, 3H),1.89–1.82(m,2H),1.78(dd,2H),1.73(s,3H),1.66–1.58(m,3H),1.29(s,6H),1.24(s,6H).

[0977] Single-configuration compound (longer retention time): (20 mg, yield: 27.2%).

[0978] MS m / z(ESI): 936.7 [M+1].

[0979] Chiral HPLC analysis: retention time 4.935 min, purity: 99.9% (column: ChiralPak ID, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[0980] 1 H NMR (500MHz, CD3OD): δ7.92(s,1H),7.74(d,1H),7.39–7.30(m,3H),7.25(d,1H),7.19–7.12 (m,3H),7.03–6.97(m,1H),6.85(d,2H),4.81–4.70(m,2H),4.50–4.41(m,2H),4.30(s,1H),4 .15(s,1H),3.99(qd,2H),2.73(s,3H),2.66(td,1H),2.48(s,3H),2.40(dd,1H),1.95(q,3H ),1.86(d,2H),1.80–1.75(m,2H),1.73(s,3H),1.67–1.58(m,3H),1.29(s,6H),1.24(s,6H).

[0981] Example 24

[0982] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24

[0983] (1S,3R,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24-p1

[0984] (1R,3S,4'S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24-p2

[0985] first step

[0986] 3-(benzyloxy)-6”-bromo-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]24b

[0987] Using steps three and four of the synthetic route in Example 23, the starting compound 23d in step three was replaced with 5-bromo-2-iodopyridine-3-phenol 24a (prepared using the method disclosed in the literature "Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, #24, p. 6784-6788") to obtain title compound 24b (850 mg, yield: 46.1%).

[0988] MS m / z(ESI):413.9[M+1].

[0989] Step 2

[0990] 3-(benzyloxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-methyl carboxylate 24c

[0991] Compound 24b (850 mg, 2.05 mmol) was dissolved in N,N-dimethylformamide (15 mL) and methanol (15 mL), and palladium acetate (70 mg, 312 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (170 mg, 412 μmol), and triethylamine (935 mg, 9.24 mmol) were added. The mixture was replaced with carbon monoxide and reacted at 90 °C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 24c (580 mg, yield: 71.8%).

[0992] MS m / z(ESI):394.0[M+1].

[0993] Step 3

[0994] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24

[0995] (1S,3R,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24-p1

[0996] (1R,3S,4'S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2”H-dispiro[cyclobutane-1,1'-cyclohexane-4',3”-furano[3,2-b]pyridine]-6”-formamide 24-p2

[0997] Using steps seven through ten of the synthetic route of Example 3, the starting compound 3h in step seven was replaced with compound 24c to obtain title compound 24 (290 mg). This was then resolved by a chiral column (Gilson-281, column: Lux Amylose-2, 5 μm, 21.2 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% 7M ammonia methanol solution), gradient ratio: A:B = 15:85, flow rate: 15 mL / min) to obtain title compound (100 mg, yield: 34.5%) and (100 mg, yield: 34.5%).

[0998] Single configuration compound (shorter retention time): (100 mg, yield: 34.5%).

[0999] MS m / z(ESI): 936.9 [M+1].

[1000] Chiral HPLC analysis: retention time 5.381 min, purity: 99.6% (column: ChiralPak AY, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[1001] 1H NMR (500MHz, CD3OD): δ8.42(d,1H),7.89(s,1H),7.72(d,1H),7.46(d,1H),7.32(d,2H),7.13-7. 11(m,2H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.80-4.72(m,2H),4.58(s,2H),4.28(s,1H), 4.15(s,1H),4.02-3.91(m,2H),2.70(s,3H),2.66-2.62(m,1H),2.46(s,3H),2.40-2.34(m,1H), 2.02-1.89(m,5H),1.85-1.80(m,1H),1.71(s,3H),1.69-1.54(m,4H),1.28(s,6H),1.22(s,6H).

[1002] Single-configuration compound (longer retention time): (100 mg, yield: 34.5%).

[1003] MS m / z(ESI): 936.9 [M+1].

[1004] Chiral HPLC analysis: retention time 7.114 min, purity: 99.9% (column: ChiralPak ID, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[1005] 1H NMR (500MHz, CD3OD): δ8.41(d,1H),7.90(s,1H),7.72(d,1H),7.46(d,1H),7.32(d,2H),7.13-7. 11(m,2H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.80-4.72(m,2H),4.58(s,2H),4.28(s,1H), 4.15(s,1H),4.02-3.91(m,2H),2.71(s,3H),2.66-2.62(m,1H),2.46(s,3H),2.40-2.34(m,1H), 2.01-1.88(m,5H),1.85-1.80(m,1H),1.71(s,3H),1.69-1.54(m,4H),1.28(s,6H),1.22(s,6H).

[1006] Example 25

[1007] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1s,3S)-3-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1

[1008] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1r,3R)-3-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2

[1009] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1-p1

[1010] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3S)-3-(3-fluoro-4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1-p2

[1011] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2-p1

[1012] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3R)-3-(3-fluoro-4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2-p2

[1013] first step

[1014] (3-(4-bromo-3-fluorophenoxy)cyclobutoxy)(tert-butyl)dimethylsilane 25b

[1015] 4-Bromo-3-fluorophenol 25a (500 mg, 2.62 mmol, Shanghai Titan) and 3-((tert-butyldimethylsilyl)oxy)cyclobutanol (530 mg, 2.62 mmol, Shanghai Titan) were dissolved in tetrahydrofuran (15 mL), and triphenylphosphine (1 g, 3.81 mmol) and diisopropyl azodicarbonate (800 mg, 3.96 mmol) were added. The mixture was stirred at 70 °C for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 25b (900 mg, yield: 91.6%).

[1016] Step 2

[1017] tert-butyl(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenoxy)cyclobutoxy)dimethylsilane 25c

[1018] Compound 25b (900 mg, 3.40 mmol), pinacol diboronate (800 mg, 3.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (300 mg, 410 μmol), and potassium acetate (710 mg, 7.23 mmol) were dissolved in 1,4-dioxane (20 mL), purged with nitrogen, and reacted at 90 °C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 25c (610 mg, yield: 60.2%).

[1019] MS m / z(ESI):423.2[M+1].

[1020] Step 3

[1021] 2-((4-(4-(3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)-2-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazol25e

[1022] Compound 25c (310 mg, 734 μmol), 2-((4-chloro-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptidyl-6-yl)methyl)oxazole 25d (200 mg, 575 μmol, as described in Example on page 460 of patent application "WO2024054603") The compound was prepared by the method disclosed in 37. Tris(dibenzylacetone)palladium (100 mg, 109 μmol), tricyclohexylphosphine (50 mg, 178 μmol), and potassium phosphate (400 mg, 1.88 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), purged with nitrogen, and reacted at 90 °C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 25e (160 mg, yield: 45.7%).

[1023] MS m / z(ESI): 608.4 [M+1].

[1024] Step 4

[1025] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1s,3S)-3-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1

[1026] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1r,3R)-3-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2

[1027] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1-p1

[1028] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3S)-3-(3-fluoro-4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-1-p2

[1029] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2-p1

[1030] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3R)-3-(3-fluoro-4-((R)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 25-2-p2

[1031] Using steps five through seven of the synthetic route in Example 1, the starting compound 1h in step five was replaced with compound 25e, and the starting compound 1e in step seven was replaced with compound 5d, to obtain title compound 25-1 or 25-2 (30 mg, yield: 43.4%).

[1032] Compounds 25-1 or 25-2 (30 mg) were resolved by a chiral column (Gilson-281, column: ChiralPak IE, 5 μm, 20 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: ethanol, gradient ratio: A:B = 40:60, flow rate: 20 mL / min) to give the title compound (15 mg, yield: 50%) and (12 mg, yield: 40%).

[1033] Single configuration compound (shorter retention time): (15 mg, yield: 50%).

[1034] MS m / z(ESI): 968.9 [M+1].

[1035] Chiral HPLC analysis: retention time 6.598 min, purity: 99% (column: ChiralPak IE, 5 μm, 4.6 mm * 150 mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 40:60, flow rate: 1.0 mL / min).

[1036] 1 H NMR (500MHz, CD3OD): δ7.90(s,1H),7.73-7.63(m,2H),7.40-7.34(m,1H),7.33-7.25(m,2H),7.18(dd,1H),7.1 6-7.08(m,2H),7.01-6.95(m,1H),6.75-6.70(m,1H),6.63-6.56(m,1H),4.78-4.75(m,1H),4.58-4.55(m,1H),4 .47(s,2H),4.28(s,1H),4.14-4.12(m,1H),4.01-3.91(m,2H),3.10-2.96(m,2H),2.88-2.76(m,2H),2.78-2.72 (m,1H),2.70(s,3H),2.43(s,3H),2.26-1.96(m,6H),1.88-1.76(m,2H),1.71(s,3H),1.27(s,6H),1.22(s,6H).

[1037] Single configuration compound (longer retention time): (12 mg, yield: 40%).

[1038] MS m / z(ESI): 968.9 [M+1].

[1039] Chiral HPLC analysis: retention time 8.987 min, purity: 99% (column: ChiralPak OZ, 5 μm, 4.6 mm * 150 mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 30:70, flow rate: 1.0 mL / min).

[1040] 1 H NMR (500MHz, CD3OD): δ7.90(s,1H),7.73-7.63(m,2H),7.40-7.34(m,1H),7.33-7.25(m,2H),7.18(dd,1H),7.1 6-7.08(m,2H),7.01-6.95(m,1H),6.75-6.70(m,1H),6.63-6.56(m,1H),4.78-4.74(m,1H),4.57-4.54(m,1H),4 .47(s,2H),4.28(s,1H),4.14-4.12(m,1H),4.01-3.91(m,2H),3.03-2.96(m,2H),2.86-2.76(m,2H),2.70(s,3H ),2.68-2.62(m,1H),2.43(s,3H),2.16-1.96(m,6H),1.84-1.76(m,2H),1.71(s,3H),1.27(s,6H),1.22(s,6H).

[1041] Example 26

[1042] (3R,3”R,4'r)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 26-1

[1043] (3S,3”S,4’S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 26-2

[1044] first step

[1045] N-(4-(benzyloxy)-3-bromophenyl)-N-(ethylsulfonyl)ethanesulfonamide 26b

[1046] 4-(benzyloxy)-3-bromoaniline 26a (1 g, 13.59 mmol, prepared by the method disclosed in the literature "[Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, #17, p. 4686-4691]") was dissolved in dichloromethane (10 mL), and ethylsulfonyl chloride (1.16 g, 9.02 mmol, Shanghai Shaoyuan) and N,N-diisopropylethylamine (1.16 g, 8.97 mmol) were added under ice bath. The reaction was stirred at the temperature for hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 26b (1.6 g, yield: 96.2%).

[1047] Step 2

[1048] N-(4-(benzyloxy)-3-bromophenyl)ethanesulfonamide 26c

[1049] Compound 26b (2.9 g, 6.27 mmol) was dissolved in tetrahydrofuran (100 mL), and 1 M sodium hydroxide aqueous solution (31.5 mL) was added. The reaction mixture was reacted at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 26c (1.8 g, yield: 77.5%).

[1050] MS m / z(ESI): 367.8 [M-1].

[1051] Step 3

[1052] N-(4-(benzyloxy)-3-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide 26d

[1053] Compound 26c (1.8 g, 4.86 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2.08 g, 4.86 mmol, prepared by the method disclosed in the literature "Journal of Medicinal Chemistry, 2017, vol.60, #20, p.8369-8384") was dissolved in 1,4-dioxane (80 mL) and water (20 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (711 mg, 972 μmol) and potassium carbonate (1.67 g, 12.08 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 26d (2 g, yield: 69.5%).

[1054] MS m / z(ESI): 592.4 [M+1].

[1055] Step 4

[1056] N-(4-hydroxy-3-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide 26e

[1057] Compound 26d (2 g, 3.38 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (20 mL), and palladium hydroxide on carbon hydrogenation catalyst (475 mg) was added. The mixture was purged with hydrogen and stirred at 50 °C for 48 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 26e (650 mg, yield: 38.3%).

[1058] MS m / z(ESI): 502.3 [M+1].

[1059] Step 5

[1060] 3”-Hydroxy-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxylic acid ethyl ester 26f

[1061] Compound 24f (1.56 g, 3.84 mmol) was dissolved in ethyl acetate (35 mL), and 10% palladium on carbon hydrogenation catalyst (1.56 g) was added. The mixture was purged with hydrogen and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 26f (770 mg, yield: 63.4%).

[1062] MS m / z(ESI): 317.0 [M+1].

[1063] Step 6

[1064] (3R,3”R,4'r)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxylic acid ethyl ester 26g-1

[1065] (3S,3”S,4's)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxylic acid ethyl ester 26g-2

[1066] Compound 26e (238 mg, 474 μmol) and compound 26f (150 mg, 474 μmol) were dissolved in tetrahydrofuran (3 mL) and toluene (15 mL), and cyanomethylenetri-n-butylphosphine (343 mg, 1.42 mmol) was added. The mixture was stirred at 110 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound (46 mg, yield: 12.1%) and (80 mg, yield: 21.1%).

[1067] Single configuration compound (shorter retention time): (46 mg, yield: 12.1%).

[1068] MS m / z(ESI):800.4[M+1].

[1069] HPLC analysis: retention time 3.43 min, purity: 90% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1070] Longer retention time for single-configuration compounds: (80 mg, yield: 21.1%).

[1071] MS m / z(ESI):800.4[M+1].

[1072] HPLC analysis: retention time 3.57 min, purity: 90% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1073] Step 7

[1074] (3R,3”R,4'r)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 26h-1

[1075] Using steps nine and ten of the synthetic route in Example 3, the starting compound 3j in step nine was replaced with the compound 26g-1 or 26g-2 with a longer retention time to obtain the title compound 26h-1 or 26h-2 (60 mg, yield: 64%).

[1076] MS m / z(ESI):1032.5[M+1].

[1077] Step 8

[1078] (3R,3”R,4'r)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 26-1

[1079] (3S,3”S,4’S)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3”-(4-(ethylsulfonamido)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 26-2

[1080] Compound 26h⁻¹ or 26h⁻² (40 mg, 39 μmol) was dissolved in methanol (5 mL), and sodium hydroxide (15 mg, 375 μmol) was added. The reaction mixture was reacted at 30 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound (10 mg, yield: 29.4%).

[1081] MS m / z(ESI): 878.6 [M+1].

[1082] 1 H NMR (500MHz, CD3OD): δ7.72(d,1H),7.32(dd,3H),7.26–7.19(m,3H),7.13(d d,2H),6.98(dd,1H),6.92(d,1H),6.30(d,1H),4.73(t,1H),4.40(m,2H),4.2 8(s,1H),4.13(s,1H),3.70(s,3H),3.08(m,2H),2.55(m,1H),2.29(m,1H),1 .80(m,4H),1.67(m,3H),1.52(m,3H),1.34(t,3H),1.27(s,6H),1.22(s,6H).

[1083] Example 27

[1084] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 27-p1

[1085] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 27-p2

[1086] first step

[1087] (S)-2-((4-(4-(5,8-dioxaspiro[3.4]oct-2-yl)phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepoxide-6-yl)methyl)oxazol27a

[1088] Compound 5a (500 mg, 1.18 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II) (101 mg, 117 μmol), zinc powder (231 mg, 3.54 mmol), sodium chloride (207 mg, 3.54 mmol), sodium octanoate (196 mg, 1.18 mmol) were mixed in water (10 mL), 2-bromo-5,8-dioxaspiro[3,4]octane (455 mg, 2.35 mmol, Shanghai Bide), tetramethylethylenediamine (411 mg, 3.54 mmol), octanol (307 mg, 2.36 mmol), nitrogen was purged, and the reaction was carried out at 50 °C for 4 days. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-65%, flow rate: 30 mL / min) to give the title compound 27a (45 mg, yield: 7.6%).

[1089] MS m / z(ESI): 502.2 [M+1].

[1090] Step 2

[1091] (S)-3-(4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptan-4-yl)phenyl)cyclobut-1-one 27b

[1092] Compound 27a (45 mg, 90 μmol) was dissolved in tetrahydrofuran (0.5 mL), and 2 M hydrochloric acid solution (0.25 mL) was added. The mixture was stirred at 50 °C for 10 minutes. After the reaction solution was cooled to room temperature, the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 27b (41 mg), which was used directly in the next reaction without purification.

[1093] MS m / z(ESI): 458.5 [M+1].

[1094] Step 3

[1095] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 27c

[1096] Compound 5d (100 mg, 189 μmol) was dissolved in dichloromethane, the pH was adjusted to >7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 27c (70 mg, yield: 75.1%).

[1097] MS m / z(ESI):494.2[M+1].

[1098] Step 4

[1099] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1S,3R)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 27-p1

[1100] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1R,3S)-3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenyl)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 27-p2

[1101] Compound 27c (41 mg, 90 μmol) and crude compound 27e (45 mg, 91 μmol) were dissolved in tetrahydrofuran (1 mL). After stirring for 2 hours, sodium triacetoxyborohydride (30 mg, 141 μmol) was added and the mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give the title compound (3 mg, yield: 3.6%) and (12 mg, yield: 14.3%).

[1102] Single configuration compound (shorter retention time): (3 mg, yield: 3.6%).

[1103] MS m / z(ESI): 935.5 [M+1].

[1104] HPLC analysis: retention time 1.90 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1105] 1 H NMR (500MHz, CD3OD): δ7.93(s,1H),7.74(d,1H),7.41–7.37(m,5H),7.31(d,1H),7.20(d,1H) ,7.15(d,2H),7.00(dd,1H),4.79(dd,1H),4.48(s,2H),4.31(s,1H),4.16(s,1H),4.01(qd,2 H),3.63–3.53(m,1H),3.12(s,1H),3.04(s,2H),2.74(s,3H),2.56(q,2H),2.48(s,3H),2.39 –2.30(m,2H),2.06(s,3H),1.83(d,2H),1.70(s,3H),1.64(s,1H),1.29(s,6H),1.25(s,6H).

[1106] Longer retention time for single-configuration compounds: (12 mg, yield: 14.3%).

[1107] MS m / z(ESI): 935.5 [M+1].

[1108] HPLC analysis: retention time 1.97 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1109] 1 H NMR (500MHz, CD3OD): δ7.93(s,1H),7.74(d,1H),7.41–7.28(m,6H),7.20(d,1H),7.15(t ,2H),7.00(dd,1H),4.79(dd,1H),4.49(s,2H),4.30(s,1H),4.15(s,1H),4.08–3.95(m,2 H),3.30–3.23(m,1H),2.98(d,2H),2.87(d,1H),2.74(s,3H),2.70–2.56(m,2H),2.48(s, 3H),2.06–2.01(m,5H),1.81(d,2H),1.69(s,3H),1.62(t,1H),1.29(s,6H),1.24(s,6H).

[1110] Example 28

[1111] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-fluoro-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 28

[1112] (3R,3”R,4'S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-fluoro-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 28-p1

[1113] (3S,3”S,4'R)-N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-fluoro-3”-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)-2H-dispiro[benzofuran-3,1'-cyclohexane-4',1”-cyclobutane]-6-carboxamide 28-p2

[1114] Using the synthetic route of Example 23, the starting compound 23d in the third step was replaced with methyl 4-bromo-3-fluoro-5-hydroxybenzoate (prepared using the method disclosed in Example 7 on page 58 of the specification in patent application "") to obtain title compound 28 (60 mg). This was then resolved by a chiral column (Gilson-281, column: Lux Amylose-2, 5 μm, 21.2 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.5% 7M ammonia methanol solution), gradient ratio: A:B = 5:95, flow rate: 15 mL / min) to obtain title compound (30 mg, yield: 31.4%) and (30 mg, yield: 31.4%).

[1115] Single configuration compound (shorter retention time): (30 mg, yield: 31.4%).

[1116] MS m / z(ESI): 954.6 [M+1].

[1117] Chiral HPLC analysis: retention time 5.108 min, purity: 99.9% (column: ChiralPak AY, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[1118] 1H NMR (500MHz, CD3OD): δ7.90(s,1H),7.72(d,1H),7.32(d,2H),7.13-7.11(m,2H),7.05(d,1H),7.03-7.01(m, 1H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.79-4.71(m,2H),4.52-4.48(m,2H),4.28(s,1H),4.12(s,1H), 4.02-3.91(m,2H),2.71(s,3H),2.66-2.60(m,1H),2.46(s,3H),2.37-2.32(m,1H),2.21-2.05(m,2H),1.94- 1.90(m,2H),1.86-1.80(m,1H),1.77-1.65(m,3H),1.71(s,3H),1.60-1.50(m,2H),1.27(s,6H),1.22(s,6H).

[1119] Single-configuration compound (longer retention time): (30 mg, yield: 31.4%).

[1120] MS m / z(ESI): 954.6 [M+1].

[1121] Chiral HPLC analysis: retention time 6.280 min, purity: 97.5% (column: ChiralPak AY, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 1.0 mL / min).

[1122] 1H NMR (500MHz, CD3OD): δ7.90(s,1H),7.72(d,1H),7.32(d,2H),7.13-7.11(m,2H),7.05(d,1H),7.03-7.01(m, 1H),6.98(dd,1H),6.84(s,1H),6.82(s,1H),4.79-4.71(m,2H),4.52-4.48(m,2H),4.28(s,1H),4.12(s,1H), 4.02-3.91(m,2H),2.71(s,3H),2.66-2.60(m,1H),2.46(s,3H),2.37-2.32(m,1H),2.21-2.05(m,2H),1.94- 1.90(m,2H),1.86-1.80(m,1H),1.77-1.65(m,3H),1.71(s,3H),1.60-1.50(m,2H),1.27(s,6H),1.22(s,6H).

[1123] Example 29

[1124] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1s,3S)-3-(2-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptide-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 29-1 or

[1125] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1'-((1r,3R)-3-(2-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptide-4-yl)phenoxy)cyclobutyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxamide 29-2

[1126] Using the synthetic route of Example 25, the starting compound 25a in the first step was replaced with 4-bromo-2-fluorophenol (Shanghai Titan) to obtain the title compound 29-1 or 29-2 (12 mg, yield: 9.3%).

[1127] MS m / z(ESI): 968.9 [M+1].

[1128] 1H NMR(500MHz,CD3OD):7.90(s,1H),7.76-7.63(m,2H),7.40-7.33(m,1H),7.31-7.26(m,1H),7.23-7.16 (m,2H),7.14-7.08(m,2H),7.01-6.94(m,2H),4.75-4.72(m,1H),4.565-4.55(m,1H),4.46(s,2H),4.28 (s,1H),4.14-4.12(m,1H),4.02-3.91(m,2H),3.02-2.92(m,2H),2.85-2.77(m,2H),2.70(s,3H),2.68 -2.62(m,1H),2.47(s,3H),2.16-1.95(m,6H),1.84-1.76(m,2H),1.73(s,3H),1.27(s,6H),1.22(s,6H)

[1129] Example 30

[1130] (3R,4'S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-2H-spiro[benzofuran-3,1'-cyclohexane]-6-carboxamide 30-p1

[1131] (3S,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-2H-spiro[benzofuran-3,1'-cyclohexane]-6-carboxamide 30-p2

[1132] first step

[1133] 3-((1,4-dioxaspiro[4.5]dec-7-en-8-yl)methoxy)-4-bromobenzoate ethyl 30b

[1134] Compound 23d (5.79 g, 23.62 mmol) and (1,4-dioxolane[4.5]dec-7-en-8-yl)methanol (4.06 g, 23.86 mmol, prepared by the method disclosed in the literature "Synthetic Communications, 1994, vol. 24, #2, p. 197-203") were dissolved in tetrahydrofuran (120 mL). Triphenylphosphine (9.4 g, 35.83 mmol) and diisopropyl azodicarbonate (7.24 g, 35.80 mmol) were added under ice bath. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 30b (9.16 g, yield: 96.6%).

[1135] MS m / z(ESI): 397.2 [M+1].

[1136] Step 2

[1137] 2H-Dispiro[benzofuran-3,1'-cyclohexane-4',2”-[1,3]dioxane-2'-ene-6-carboxylic acid ethyl ester 30c

[1138] Compound 30b (7.1 g, 17.87 mmol) was dissolved in toluene (120 mL), and palladium acetate (802 mg, 3.57 mmol), 1,3-bis(diphenylphosphine propane) (1.47 g, 3.57 mmol), and silver carbonate (9.86 g, 35.75 mmol) were added. The mixture was purged with nitrogen and reacted at 115 °C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and 20% potassium fluoride solution was added and stirred for 3 hours. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-60%, flow rate: 30mL / min) to give the title compound 30c (1.4g, yield: 24.7%).

[1139] MS m / z(ESI): 317.0 [M+1].

[1140] Step 3

[1141] 2H-dispiro[benzofuran-3,1'-cyclohexane-4',2”-[1,3]dioxapentane]-6-carboxylic acid ethyl ester 30d

[1142] Compound 30c (1.4 g, 4.42 mmol) was dissolved in ethyl acetate (15 mL) and ethanol (30 mL), and 10% palladium on carbon hydrogenation catalyst (336 mg) was added. The mixture was purged with hydrogen, stirred for 16 hours, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 30d (967 mg, yield: 68.6%).

[1143] MS m / z(ESI): 319.0 [M+1].

[1144] Step 4

[1145] (3R,4'S)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-2H-spiro[benzofuran-3,1'-cyclohexane]-6-carboxamide 30-p1

[1146] (3S,4'R)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4'-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)azacyclobutyl-1-yl)-2H-spiro[benzofuran-3,1'-cyclohexane]-6-carboxamide 30-p2

[1147] Using steps five through seven of the synthetic route of Example 22, the starting compound 22d in step five was replaced with compound 30d, and the starting compound 1e in step seven was replaced with compound 5d, to obtain the title compound (18 mg, yield: 9%) and (30 mg, yield: 15.1%).

[1148] Single configuration compound (shorter retention time): (18 mg, yield: 9%).

[1149] MS m / z(ESI): 951.6 [M+1].

[1150] HPLC analysis: retention time 1.86 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1151] 1H NMR (500MHz, DMSO-d6): δ8.05(s,1H),7.91(d,1H),7.72(d,1H),7.36(dd,1H),7.31(d,2H),7.27(d,1H), 7.21-7.20(m,2H),7.14(d,1H),7.01(dd,1H),6.87(d,2H),4.81(brs,1H),4.64(t,1H),4.39(s,2H),4.3 2(s,1H),4.04(d,1H),3.89(dd,1H),3.81(dd,1H),3.72(brs,2H),2.98(brs,2H),2.61(s,3H),2.43(s,3 H),2.18-2.12(m,1H),1.80-1.73(m,2H),1.70-1.65(m,7H),1.22(s,6H),1.13(s,6H),1.08-1.01(m,2H).

[1152] Longer retention time for single-configuration compounds: (30 mg, yield: 15.1%).

[1153] MS m / z(ESI): 951.6 [M+1].

[1154] HPLC analysis: retention time 1.93 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1155] 1 H NMR (500MHz, DMSO-d6): δ8.05(s,1H),7.91(d,1H),7.74(d,1H),7.37(dd,1H),7.31(d,2H),7.26(d ,1H),7.21(s,2H),7.14(s,1H),7.01(dd,2H),6.89(d,2H),4.87(quat,1H),4.64(t,1H),4.38(s,2H ),4.32(s,1H),4.05(d,1H),3.89(dd,1H),3.83-3.75(m,3H),2.95(brs,2H),2.61(s,3H),2.43(s,3 H),1.93-1.88(m,3H),1.66(s,3H),1.63-1.46(m,3H),1.42-1.40(m,2H),1.22(s,6H),1.14(s,6H).

[1156] Example 31

[1157] (7aR)-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-9-(3-(4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptan-4-yl)phenoxy)cyclobutyl)-7,7a,8,9,10,11-hexahydro-5H-dipyrido[2,1-c:2',3'-e][1,4]oxazaheptan-3-carboxamide 31

[1158] first step

[1159] 1-(tert-butyl)-2-methyl(2R)-4-hydroxypiperidine-1,2-dicarboxylic acid ester 31b

[1160] 1-(tert-butyl)-2-methyl(R)-4-oxoperidin-1,2-dicarboxylic acid ester 31a (3 g, 11.66 mmol, Jiangsu Aikang) was dissolved in methanol (10 mL) and tetrahydrofuran (20 mL). Sodium borohydride (441 mg, 11.66 mmol) was added at 0 °C, and the reaction was stirred for 0.5 h while maintaining the temperature. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (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 to obtain crude title compound 31b (3.2 g). The product was directly used in the next reaction without purification.

[1161] MS m / z(ESI):160.0[M-99].

[1162] Step 2

[1163] 1-(tert-butyl)-2-methyl(2R)-4-bromopiperidine-1,2-dicarboxylic acid ester 31c

[1164] Compound 31b (3.2 g, 12.34 mmol) was dissolved in dichloromethane (40 mL), and triphenylphosphine (4.86 g, 18.53 mol) and carbon tetrabromide (6.14 g, 18.51 mmol) were added. The mixture was purged with nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 31c (2 g, yield: 50.2%).

[1165] MS m / z(ESI):221.8[M-99].

[1166] Step 3

[1167] 1-(tert-butyl)-2-methyl(2R)-4-(3-(benzyloxy)cyclobutyl)piperidine-1,2-dicarboxylic acid ester 31d

[1168] The crude compound 31c (1.8 g, 5.59 mmol) and ((3-bromocyclobutoxy)methyl)benzene (2.02 g, 8.38 mmol, Shanghai Bide) were dissolved in acetonitrile (50 mL). Sodium carbonate (1.18 g, 11.13 mmol), tetrabutylammonium bromide (3.99 g, 13.95 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (63 mg, 56 μmol, Shanghai Leyan), and 4,4'-bis(1,1-dimethyl) [Ethyl)-2,2'-bipyridine]nickel(II) chloride (63 mg, 56 μmol, Shanghai Leyan), tris(trimethylsilyl)silanol (2.22 g, 8.39 mmol, Shanghai Titan), nitrogen purging, stirred under blue light for 16 hours, diluted with water, extracted with ethyl acetate (30 mL × 3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give title compound 31d (770 mg, yield: 34.1%).

[1169] MS m / z(ESI): 304.38 [M-99].

[1170] Step 4

[1171] (2R)-4-(3-benzyloxy)cyclobutyl)-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 31e

[1172] Compound 31d (770 mg, 1.91 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium bo...

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from * The bond connects to C(O); Key and L 1 connect; X 1 X 2 and X 3 Whether they are the same or different, and each is independently N or CR 3X ; Y is selected from bond, O, S(O). v C(O), C(O)O, OC(O), NR m C(O)NR m and NR m C(O); t1 and t2 are each independently 0, 1, 2 or 3; a1 and a2 are each independently 0, 1, 2, 3, 4 or 5; a3 and a4 are each independently 0, 1, 2, 3, 4 or 5; and a3 and a4 are not both 0 at the same time; A 1 For N or CR A1 A 2 For N or CR A2 ; 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, alkoxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1; L 1 L 2 L 3 and L 4 Same or different, and each independently selected from bonds, alkenyl, alkynyl, (CR) a R b ) x O, S(O) v C(O), NR c 、((CR a R b ) x1 -O) x3 -(CR a R b ) x2 、(CR a R b ) x1 -NR c -(CR a R b ) x2 、(CR a R b ) x1 -C(O)NR c -(CR a R b ) x2 、(CR a R b ) x1 -NR c C(O)-(CR a R b ) x2 、(CR a R b ) x1 -C(O)-(CR a R b ) x2 、(CR a R b ) x1 -heterocyclic-(CR) a R b ) x2 C(O)NR c NR c C(O), S(O) v NR c and NR c S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced; Each R a and R b The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... 0 Replaced; x, x1, x2, and x3 may be the same or different, and each is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; Each R 1 and R 3X The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, OR 14 NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced; Each R 2 R 3 R 4 R 5 and R 5a Same or different, and each independently selected from hydrogen atom, deuterium atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced; E is selected from Q is CR 10 Or N; Each R 6 R 7a R 8 R 9 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 OR 14 NR 13 S(O) v R 14 NR 13 C(O)R 14 C(O)R 14 S(O) v R 14 C(O)OR 14 S(O) v OR 14 C(O)NR 11 R 12 S(O) v NR 11 R 12 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 Replaced; R 7 and R 7b The same or different, and each independently selected from hydrogen atom, oxo group, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 =CR 15 R 16 alkylene-C(O)NR 11 R 12 alkylene-C(O)OR 14 Cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 Replaced; Each R', R m R c R 11 R 12 R 13 R 14 R d and R e They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocyclic alkyl, aryl and heteroaryl; R 15 and R 16 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, arylalkyl groups, and heteroarylalkyl groups; the arylalkyl and heteroarylalkyl groups are each independently optionally selected by one or more R atoms. 0 Replaced; Each R 0 They may be the same or different, and each is independently selected from deuterium, oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, S-alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3, 4, 5 or 6; r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6; u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and Each v is the same or different, and each is independently 0, 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 6 R 7a R 8 R 9 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, nitro, NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein each of the alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 Replaced; R 11 R 12 and R 14 As defined in claim 1.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (II) or (III): in, B 1 For N or CR 4 B 2 For N or CR 4 b1 and b2 are each independently 0, 1, 2, 3 or 4; Rings C, E, L 2 L 3 s2, s1, X 1 To X 3 Y, A 1 A 2 R 1 To R 5 R', m, t1, t2, a1, a2, p, x, q, and r are as defined in claim 1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... A 1 A 2 t1 and t2 are as defined in claim 1; preferably, ring A is selected from... More preferably, ring A is selected from 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (VI) or (VII): in, B 1 For N or CR 4 B 2 For N or CR 4 b1 and b2 are each independently 0, 1, 2, 3 or 4; E, L 2 L 3 s1, X 1 To X 3 Y, A 1 A 2 R 1 To R 4 , q, R', m, t1, t2, a1, a2, a3, a4, p and x as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein E is selected from... E is selected from R 6 To R 9 R d R e u and y are as defined in claim 1; preferably, E is selected from...

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, 2, 3, 5 or 6, wherein X 1 For N, CF, or CH, and / or X 2 For N, CF, or CH, and / or X 3 For N, CF, or CH, and / or Y is O, and / or t1 is 0 or 1, and / or t2 is 0 or 1, and / or A 1 For CH or N, and / or A 2 For CH, CF, or N, and / or a1 is 0 or 1, and / or a2 is 0 or 1; preferably, X 1 For N or CH, and / or X 2 For N or CH, and / or X 3 For N or CH, and / or Y is O, and / or t1 is 0 or 1, and / or t2 is 0 or 1, 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; more preferably, X 1 For N or CH, and / or X 2 For CH, and / or X 3 For CH, and / or t1 is 0, and / or t2 is 1, and / or A 1 For N, and / or A 2 Let N be a1 and / or a2 be 1.

8. The compound 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 according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from the following groups: bond, O, CH2, S, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, propynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O) and CH(CH3)-C(O), and / or L 3 Selected from the group consisting of bond, O, S, CH2, CH2CH2, CH(CH3), C(CH3)2, (CH2)2O, O(CH2)2, (CH2)3O, O(CH2)3, (CH2)3, vinyl, ethynyl, propynyl, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2, NHC(O)-CH2, C(O)-C(CH3)2, C(O)-CH(CH3), CH2-C(O), C(CH3)2-C(O) and CH(CH3)-C(O), and / or the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, and / or x is 0 or 1; preferably, L 2 Selected from bonds, O, C(O), CH2, C(O)-CH2, O-CH2, C(O)NH, C(O)-C(CH3)2 and C(O)-CH(CH3), and / or the ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, and / or L 3 Selected from bonds, O, S, NH, CH2, CH(CH3), C(CH3)2 and ethynyl groups; more preferably, L 2 x is 0, and / or x is 0 or 1.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; preferably, each R 1 They may be the same or different, and each is independently selected from hydrogen, halogen and cyano groups, and / or m is 0, 1 or 2.

11. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, and / or n is 2, 3 or 4; preferably, R 2 C 1-6 alkyl.

12. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein... Selected from -O-、 -CH2-、 C(O)NH、 C(O)NHCH2、 CH2O, OCH2, (CH2)2O, O(CH2)2, O(CH2)2O, (CH2)2, O(CH2)3, (CH2)3O, (CH2)3, C(O), ethynyl and cyclopropyl, or selected from C(O)CH2CH2, C(O)CH2NH, C(O)CH2S, S, Or selected from 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

14. A compound of general formula (IIA) or (IIIA) or a salt thereof: in, R W It is a hydrogen atom or an amino protecting group, preferably Boc; X 1 To X 3 Y, A 1 R 1 To R 3 m, R', t1, t2, a1, a2 and p are as defined in claim 3.

15. A compound or a salt thereof represented by general formula (VIB), (VIIB), (VIB-1), (VIIB-1): in, R P Selected from OH, halogens, and alkoxy groups; X is a halogen, and in some embodiments, it is Br; X 1 X 2 X 3 Y, A 1 A 2 ,t1,t2,a1,a2,a3,a4,R3,p,x,B 1 B 2 b1, b2, s1, R 4 , q, L 2 L 3 And E as defined in claim 5.

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

17. A method for preparing compounds of general formulas (II) and (III) or pharmaceutically acceptable salts thereof, the method comprising: A compound of general formula (IIA) or a salt thereof (preferably a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IIB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (II) or a pharmaceutically usable salt thereof. A compound of general formula (IIIA) or a salt thereof (preferably a hydrochloride salt) undergoes a reductive amination reaction with a compound of general formula (IIB) or a salt thereof in the presence of a reducing agent to yield a compound of general formula (III) or a pharmaceutically acceptable salt thereof. Among them, R W A is a hydrogen atom; 2 Let N be x and x be 0, then B 1 CH is 1, and s1 is 1. Rings C, E, L 2 L 3 s2, B 2 X 1 To X 3 Y, A 1 R 1 To R 5 m, R', t1, t2, a1, a2, p, q, b1, b2, and r are as defined in claim 3.

18. A method for preparing compounds of general formulas (VI) and (VII) or pharmaceutically acceptable salts thereof, the method comprising: A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (VIB) or a salt thereof under basic conditions to yield a compound of general formula (VI) or a pharmaceutically usable salt thereof. A compound of general formula (VIA) or a salt thereof undergoes a condensation reaction with a compound of general formula (VIIB) or a salt thereof under basic conditions to yield a compound of general formula (VII) or a pharmaceutically usable salt thereof. Where R' is a hydrogen atom; R P Selected from OH, halogens, and alkoxy groups; E, L 2 L 3 s1, B 1 B 2 b1, b2, x, X 1 To X 3 Y, t1, t2, A 1 A 2 a1, a2, a3, a4, R 1 To R 4 , q, p and m as defined in claim 5.

19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19 in the preparation of a medicament for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions.

21. Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19 in the preparation of medicaments for the treatment and / or prevention of tumors, male sexual dysfunction, and Kennedy's disease; preferably in the preparation of medicaments for the treatment and / or prevention of prostate cancer, benign prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; more preferably in the preparation of medicaments for the treatment and / or prevention of prostate cancer; further preferably in hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

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