Substituted cyclobutane, preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to substituted cyclobutane, a preparation method therefor and the pharmaceutical use thereof. Specifically, the present disclosure relates to substituted cyclobutane as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, particularly the use in the preparation of a drug for treating and / or preventing androgen receptor-mediated or -dependent diseases or conditions. Each group in general formula (I) is as defined in the description.

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 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group;

[0008] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0009] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

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

[0011] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0012] 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;

[0013] Each R a and R b The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 0 Replaced;

[0014] 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;

[0015] Each R 1 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;

[0016] 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, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0017] Or two Rs 3 Together with the atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 0 Replaced;

[0018] E is selected from

[0019] Q is CR 10 Or N;

[0020] 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;

[0021] Or two Rs8 Together with the carbon atom attached thereto, they form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is independently and optionally converted by one or more R groups. 0 Replaced;

[0022] 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;

[0023] Each R', 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;

[0024] R 15 and R 16The 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;

[0025] 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;

[0026] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0027] p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0028] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0029] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0030] Each v is the same or different, and each is independently 0, 1 or 2.

[0031] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0032] in:

[0033] Ring A is selected from 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group;

[0034] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0035] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0036] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0037] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0038] 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;

[0039] Each R a and R b The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R bTogether with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 0 Replaced;

[0040] 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;

[0041] Each R 1 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;

[0042] 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, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0043] Or two Rs 3 Together with the atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 0 Replaced;

[0044] E is selected from

[0045] Q is CR 10 Or N;

[0046] 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;

[0047] 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 NR13 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;

[0048] Each R', 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;

[0049] 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;

[0050] 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;

[0051] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0052] p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0053] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0054] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0055] Each v is the same or different, and each is independently 0, 1 or 2.

[0056] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0057] in:

[0058] Ring A is selected from 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group;

[0059] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0060] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0061] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0062] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0063] 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;

[0064] 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, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 0 Replaced;

[0065] 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;

[0066] Each R 1 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 14S(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;

[0067] 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 14 alkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0068] Or two Rs 3 Together with the atoms attached thereto, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally converted by one or more R groups. 0 Replaced;

[0069] E is selected from

[0070] Q is CR 10 Or N;

[0071] 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, NR11 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;

[0072] 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;

[0073] Each R', 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;

[0074] 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;

[0075] 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;

[0076] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0077] p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0078] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0079] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0080] Each v is the same or different, and each is independently 0, 1 or 2.

[0081] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0082] in:

[0083] Ring A is selected from 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group;

[0084] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0085] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0086] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0087] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0088] 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 NRc S(O) v The alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced;

[0089] 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, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 0 Replaced;

[0090] 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;

[0091] Each R 1 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;

[0092] 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 12C(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, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0093] E is selected from

[0094] Q is CR 10 Or N;

[0095] 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;

[0096] 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 OR14 =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;

[0097] Each R', 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;

[0098] 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;

[0099] 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;

[0100] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0101] p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0102] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0103] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0104] Each v is the same or different, and each is independently 0, 1 or 2.

[0105] 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 (IN) or a pharmaceutically acceptable salt thereof:

[0106] 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).

[0107] In some embodiments of this disclosure, ring A is a 6-membered heteroaryl group and is substituted with an oxo group; in some embodiments, ring A is selected from pyridinone, pyridazinone, pyrimidinone, and pyridoxide groups; in some embodiments, ring A is selected from... Key and L 1 Or C(O) connection; in some implementations, it is In some implementations, ring A is selected from... In some implementations, ring A is selected from... In some implementation schemes, The * bond is connected to C(O). Key and L 1 connect.

[0108] In some implementation schemes disclosed herein, Selected from X 4 For CR 3 Or N; X 1 X 2 X 3 and R 3 As defined in general formula (II); in some implementations, In some implementation schemes, Selected from In some implementation schemes, The * bond is connected to C(O). Key and L 1 connect.

[0109] In some embodiments disclosed herein, L 1 Selected from bond, O, NR c and (CR) a Rb ) 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.

[0110] 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 10-membered cycloalkyl or a 3- to 10-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... In some implementation schemes, ring B is In some implementation schemes, ring B is B 1 B 2 b1, b2, b3, b4 are as defined in general formula (II) or (III); in some embodiments, ring B is selected from... *Key and L 1 connect, Key and L 2 connect.

[0111] In some implementation schemes disclosed herein, Selected from

[0112] 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.

[0113] In some embodiments disclosed herein, L 4 Selected from bond, O, NRc 、(CR a R b ) x 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 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 bond, O, CH2, CH2CH2, NH, N(methyl), C(O), O-CH2, NHC(O), C(O)NH, C(O)-CH2 and NHC(O)-CH2.

[0114] In some embodiments of this disclosure, s3 is 0; in other embodiments, s3 is 1.

[0115] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0116] Among them, X 1 X 2 and X 3 Whether the same or different, and each independently constitutes a CR 3 Or N;

[0117] 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;

[0118] Rings C, E, L 2 L 3 s1, s2, q, r, x, R 1 To R 5 R' and m are as defined in general formula (I).

[0119] In some embodiments of this disclosure, R' is a hydrogen atom.

[0120] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0121] Where b3 is 0, 1, 2, 3 or 4; b4 is 0, 1, 2, 3 or 4;

[0122] q1 is 0, 1, 2, 3 or 4; q2 is 0, 1 or 2;

[0123] Rings C, E, L 2 L 3 s2, B 1 B 2 b1, b2, x, X 1 To X 3 R 1 m, R 2 R 4 R 5 And r is as defined in general formula (II).

[0124] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof, are compounds represented by general formula (IIIM) or pharmaceutically acceptable salts thereof:

[0125] Among them, R 1b For hydrogen atoms or R 1 ;

[0126] R 9a and R 9b The same or different, and each independently is R. 9 ;

[0127] R 0a and R 0b They may be the same or different, and each is independently a hydrogen atom or R. 0 ;

[0128] R 1 B 1 B 2 L 2 L 3 R 0 and R 9 As defined in general formula (III).

[0129] 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 (IV) or a pharmaceutically acceptable salt thereof:

[0130] Among them, R1a and R 1b They may be the same or different, and each is independently a hydrogen atom or R. 1 ;

[0131] R 1 To R 4 X 1 X 2 x, B 1 B 2 ,b1,b2,b3,b4,q1,q2,L 2 L 3 R 6 R 8 u, R 9 And y are as defined in general formula (III).

[0132] 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 (V) or a pharmaceutically acceptable salt thereof:

[0133] Among them, R 1a R 1b R 2 X 1 x, B 1 B 2 b1, b2, b3, b4, R 4 q1, q2, L 2 L 3 R 9 And y are as defined in general formula (IV).

[0134] In some embodiments disclosed herein, X 1 For CR 3 R 3 As defined in general formula (I); in some implementations, X 1 Selected from N, CH, and CF; in some implementations, X 1 For CH; in some implementations, X 1 For N or CH; in some implementations, X 1 Let N be the number of elements in the array.

[0135] In some embodiments disclosed herein, X 2 For CR 3 R 3 As defined in general formula (I); in some implementations, X 2 Selected from N, CH, and CF; in some implementations, X 2 For CH; in some implementations, X 2 For N or CH; in some implementations, X2 Let N be the number of elements in the array.

[0136] In some embodiments disclosed herein, X 3 For CR 3 R 3 As defined in general formula (I); in some implementations, X 3 Selected from N, CH, and CF; in some implementations, X 3 For CH; in some implementations, X 3 For N or CH; in some implementations, X 3 Let N be the number of elements in the array.

[0137] In some embodiments disclosed herein, X 1 Selected from N, CH and CF, and / or X 2 Selected from N, CH and CF, and / or X 3 Selected from N, CH, and CF; in some implementations, X 1 For CH, and / or X 2 For CH, and / or X 3 For CH; in some implementations, X 1 For N, and / or X 2 For CH, and / or X 3 For CH.

[0138] In some embodiments disclosed herein, X 4 For CR 3 R 3 As defined in general formula (I); in some implementations, X 4 Selected from N, CH, and CF; in some implementations, X 4 For CH.

[0139] 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.

[0140] In some embodiments of this disclosure, b1 is 0 or 1, and / or b2 is 0 or 1; in some embodiments, b1 is 1, and / or b2 is 1; in some embodiments, b1 is 0, and / or b2 is 0.

[0141] In some embodiments of this disclosure, b3 is 1 or 2, and / or b4 is 1 or 2; in some embodiments, b3 is 1, and / or b4 is 1.

[0142] 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.

[0143] In some embodiments disclosed herein, B 1 For CH or N, and / or B 2 For CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1, and / or b3 is 1 or 2, and / or b4 is 1 or 2; in some embodiments, B 1 For CH, and / or B 2 CH, and / or b1 is 1, and / or b2 is 1, and / or b3 is 1, and / or b4 is 1.

[0144] In some embodiments of this disclosure, s1 is 0; in other embodiments, s1 is 1.

[0145] 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 c x, 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 For key; in some implementations, L 2 For bonds or C(O);

[0146] In some implementations, L2 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 2 Selected from bond, O, S, 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 2 Selected from bonds, O, S, 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 bonds, O, CH2, O-CH2, C(O), C(O)NH, C(O)-CH2, C(O)-CH(CH3), and C(O)-C(CH3)2; in some embodiments, L 2 Selected from bond, O, (CR) a R b ) x and C(O)-(CR) a R b ) x2 In some implementation schemes, L 2 For C(O)-CD2; in some implementations, L 2 For key or O; in some implementations, L 2 It is O.

[0147] In some embodiments of this disclosure, ring C is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group; in some embodiments, ring C is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; in some embodiments, ring C is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; in some embodiments, ring C is a 3- to 6-membered cycloalkyl; in some embodiments, ring C is cyclobutyl; in some embodiments, ring C is selected from... In some implementations, ring C is In some implementations, it is cyclopropyl.

[0148] In some embodiments of this disclosure, s2 is 0; in other embodiments, s2 is 1.

[0149] 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.

[0150] In some embodiments disclosed herein, L 3 Selected from bond, O, NR c 、(CR a R b ) x O-(CR) a R b ) 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 In some implementation schemes, L 3 Selected from bond, O, NR c (CH2) x O-(CH2)x2 C 2-6 Alkyne group, C(O), NHC(O), C(O)NH, C(O)-(CH2) x2 and NR c C(O)-(CH2) x2 ;R a R b R c x, x1, x2 are as defined in general formula (I); in some implementations, L 3 Selected from bond, O, CH2, CH2CH2, propynyl, 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 C(O) or O; in some implementations, L 3 For O; in some implementations, L 3 Selected from bonds, C(O), O, CH2 and propyne groups; in some embodiments, L 3 Selected from bonds, C(O), O, CH2, CH2-O and propyne groups; in some embodiments, L 3 It is CH2-O;

[0151] 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)-(CRa 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, S, 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); in some embodiments, L 3 Selected from bonds, C(O), O, CH2, NH, propynyl, CH(CH3) and C(CH3)2.

[0152] 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 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; 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 the group consisting of bond, O, S, NH, CH2, CH(CH3), C(CH3)2 and propynyl group.

[0153] In some embodiments of this disclosure, x is 0 or 1, and / or L. 2Selected from bonds, O, C(O), (CR) a R b ) x C(O)-(CR) a R b ) x2 O-CR a R b And C(O)NH, and / or the ring C is a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocyclic group, and / or s2 is 0 or 1, and / or L 3 Selected from the following groups: bond, O, S, NH, CH2, CH(CH3), C(O), C(CH3)2, and propynyl group; 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; x2 is 0, 1, or 2; in some embodiments, x is 0 or 1, and / or 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 s2 is 0 or 1, and / or L 3 Selected from the groups O, S, NH, CH2, CH(CH3), C(O), C(CH3)2 and propyne; in some embodiments, x is 0, and / or L 2 The bond is O, and / or the ring C is a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group, and / or S2 is 0 or 1, and / or L. 3 Selected from bonds, CH2, C(O), and O; in some embodiments, x is 0, and / or L 2 The C1 bond is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, and / or the S2 group is 0 or 1, and / or L. 3 Selected from bonds, CH2, C(O) and O.

[0154] 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)CH2CH2, C(O), ethynyl, cyclopropyl, C(O)CH2NH, C(O)CH2S, S, In some implementation schemes,

[0155] In some implementation schemes disclosed herein, Selected from In some implementation schemes, it is selected from In some implementation schemes, it is selected from

[0156] 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);

[0157] 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); in some implementations, E is selected from... 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 selected from...

[0158] In some implementations, E is selected from

[0159] In some implementations, E is selected from In some implementations, E is selected from In some implementations, E is selected from

[0160] 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 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 atom, Cl, methyl, methoxy, OCF3, and cyano; in some embodiments, R 1b For halogen; in some implementations, R 1b For Cl; in some implementations, R 1 C 1-6 Alkoxy; in some embodiments, R 1 It is methoxylated; in some embodiments, R 1 C 1- 6-Haloalkoxy; in some embodiments, R 1 It is OCF3 or OCHF2; in some implementations, R 1 For OCF3; in some implementations, R 1 It is OCHF2.

[0161] In some embodiments of this disclosure, m is 0, 1, 2 or 3; in some embodiments, m is 2.

[0162] 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.

[0163] In some implementation schemes disclosed herein, for R 1a and R 1b The same or different, and each 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; in some embodiments, for R 1a and R 1b They may be the same or different, and each is independently a hydrogen atom or R. 1 R 1 As defined in general formula (I).

[0164] 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 and C 1-6 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; in some embodiments, R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen, Cl, methyl, methoxy, OCF3 and cyano.

[0165] In some embodiments disclosed herein, R 1a It is a cyano group.

[0166] 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 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 1bSelected from hydrogen atom, Cl, methyl, methoxy, OCF3 and cyano; in some embodiments, R 1b C 1-6 Alkoxy; in some embodiments, R 1b It is methoxylated; in some embodiments, R 1b C 1-6 Haloalkoxy; in some embodiments, R 1b It is OCF3 or OCHF2; in some implementations, R 1b For OCF3; in some implementations, R 1b It is OCHF2.

[0167] 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.

[0168] In some embodiments disclosed herein, each R 3 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 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 Selected from hydrogen atoms, F and methyl; in some embodiments, R 3 It is a hydrogen atom.

[0169] In some embodiments of this disclosure, p is 0 or 1; in some embodiments, p is 0; and in some embodiments, p is 1.

[0170] In some embodiments disclosed herein, each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, and / or p is 0, 1 or 2.

[0171] 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.

[0172] 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.

[0173] 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 and C 1-6 Halogenated alkyl groups.

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

[0175] In some embodiments of this disclosure, q1 is 0, 1, or 2, and / or q2 is 0, 1, or 2; in other embodiments, q1 is 0, and / or q2 is 0.

[0176] 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.

[0177] 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 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 groups.

[0178] In some embodiments of this disclosure, r is 0, 1, 2 or 3; in other embodiments, r is 0.

[0179] 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 or 2.

[0180] 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.

[0181] In some embodiments of this disclosure, r2 is 0, 1, 2 or 3; in some embodiments, r2 is 0.

[0182] 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.

[0183] In some embodiments disclosed herein, R 7 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; 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 It is CH2-oxazolyl; in some embodiments, R 7 It is a 5-membered heteroaryl C 1-6 Alkyl; in some embodiments, R 7 (CH2) s-5-membered heteroaryl group, where s is 0, 1, 2, 3, or 4; in some embodiments, R 7 (CH2) s -5-membered heteroaryl, where s is 0, 1, or 2; in some embodiments, R 7 It is a CH2-5 heteroaryl group.

[0184] In some implementation schemes, 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 heteroaryl groups, each of which is independently bound by one or more R groups. 0 The y is replaced by 0, 1, 2, 3, or 4; in some implementations, R 7 The oxazolyl group is CH2-oxazolyl, and the oxazolyl group is optionally surrounded by one or more R groups. 0 Replaced; in some implementations, R 7 (CH2) s -5-membered heteroaryl, where s is 0, 1, 2, 3, or 4, wherein the 5-membered heteroaryl is optionally surrounded by one or more R 0 Replaced; in some implementations, R 7 (CH2) s -5-membered heteroaryl, where s is 0, 1, 2, 3, or 4, wherein the 5-membered heteroaryl is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituted alkoxy group and one or more of a 3- to 6-membered cycloalkyl group are used; in some embodiments, R 7 It is a CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituted alkoxy group and one or more of a 3- to 6-membered cycloalkyl group are used; in some embodiments, R 7 for In some implementation schemes, R 7 for

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

[0186] 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 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 7a The phenyl group is optionally substituted with one or more halogens; in some embodiments, R 7a for

[0187] 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 groups; 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.

[0188] In some embodiments of this disclosure, u is 2.

[0189] 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, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy C 1-6 Alkyl, cyano, C 2-6 alkenyl, C 2-6 acetylenic, NR 11 R 12 OR 14 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl C 1-6 Alkyl, 3 to 12-membered heterocyclic C 1-6 Alkyl, 6 to 10 aryl C 1-6 Alkyl and 5 to 10-membered heteroaryl C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 12-membered cycloalkyl C 1-6 Alkyl, 3 to 12-membered heterocyclic C 1-6 Alkyl, 6 to 10 aryl C 1-6 Alkyl and 5 to 10-membered heteroaryl C 1-6 Each alkyl group is independently and optionally converted by one or more R 0 Replaced;

[0190] In some implementation schemes, each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy 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 groups and 3 to 12-membered heterocyclic C groups 1-6 alkyl;

[0191] In some implementation schemes, each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, cyano groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 9 The same or different, and each independently selected from C 1-6Alkoxy, 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, cyclopropyl, and ethynyl; in some embodiments, R 9 C 1-6 Alkoxy; in some embodiments, R 9 It is methoxylated; in some embodiments, R 9 It is cyano; in some embodiments, R 9 C 1-6 Halogenated alkyl; in some embodiments, R 9 It is CHF2.

[0192] In some embodiments disclosed herein, R 9a and R 9b 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, cyano, C 2-6 alkenyl, C 2-6 Alkyne group, 3- to 6-membered cycloalkyl group and 3- to 6-membered heterocyclic group; in some embodiments, R 9a and R 9b Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 9a and R 9b They may be the same or different, and each is independently selected from hydrogen, methoxy, cyano, ethynyl, and cyclopropyl.

[0193] In some embodiments disclosed herein, R 9a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, C 2- 6-olefin, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group; in some embodiments, R 9a Selected from hydrogen atoms, C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 9a Selected from hydrogen atom, methoxy group, cyano group, and cyclopropyl group; in some embodiments, R9a For hydrogen atoms; in some implementations, R 9a It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 9a It is cyclopropyl.

[0194] In some embodiments disclosed herein, R 9b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 Alkoxy C 1-6 Alkyl, cyano, C 2- 6-olefin, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group; in some embodiments, R 9b Selected from hydrogen atoms, C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl; in some embodiments, R 9b Selected from hydrogen atom, methoxy group, cyano group, and cyclopropyl group; in some embodiments, R 9b For hydrogen atoms; in some implementations, R 9b It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 9b It is cyclopropyl; in some embodiments, R 9b C 1-6 Alkoxy; in some embodiments, R 9b It is methoxylated; in some embodiments, R 9b It is cyano; in some embodiments, R 9b C 1-6 Halogenated alkyl; in some embodiments, R 9b It is CHF2.

[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 and C 1-6 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 groups; in some embodiments, each R 9They 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 It is Cl.

[0196] In some embodiments of this disclosure, y is 0, 1, or 2; in other embodiments, y is 1.

[0197] 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.

[0198] 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).

[0199] 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 atoms 1-6 Alkyl and NR 11 R 12 R 11 and R 12 As defined in general formula (I).

[0200] In some embodiments of this disclosure, Q is selected from N, CH, and CF.

[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; and in some embodiments, x1 is 0.

[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.

[0205] 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, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 0 They may be the same or different, and each is independently selected from halogen, cyano, and C. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 0 It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 0 It is cyclopropyl.

[0206] In some embodiments disclosed herein, R 0a and R 0b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, R 0a and R 0b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 0a and R 0bThey may be the same or different, and each is independently a hydrogen atom or a 3- to 6-membered cycloalkyl group; in some embodiments, R 0a and R 0b They may be the same or different, and each is independently a hydrogen atom or a cyclopropyl group.

[0207] In some implementation schemes, R 0a Selected from hydrogen atom, halogen, cyano group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 0a It is a hydrogen atom or a cyclopropyl group; in some embodiments, R 0a It is a hydrogen atom.

[0208] In some implementation schemes, R 0b Selected from hydrogen atom, halogen, cyano group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 0b It is a hydrogen atom or a cyclopropyl group; in some embodiments, R 0b It is a hydrogen atom.

[0209] 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 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or an ethyl atom; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0210] 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.

[0211] In some embodiments disclosed herein, R 14 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, 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 It is tert-butyl.

[0212] 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.

[0213] In some embodiments of this disclosure, v is 2; in some embodiments, v is 1; and in some embodiments, v is 0.

[0214] In this disclosure, formulas (I) through (V) include formulas (I), (IM), (IN), (II), (III), (IIIM), (IV), and (V).

[0215] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt 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 and C 1-6 Haloalkoxy group; 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 Haloalkyl; R' is a hydrogen atom; X 1 For N or CR 3 X 2 For CR 3 X 3 For N or CR 3 Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; x is 0; 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; each R 4They 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 bonds; s2 is 0 or 1; ring C is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; r is 0, 1 or 2; 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; L 3 For C(O) 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.

[0216] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 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 group; R' is a hydrogen atom; X 1 For N or CH, X 2 For CH, X 3 For N or CH; x is 0; 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 S1 is a bond; S2 is 1; the ring C is a 3- to 6-membered cycloalkyl group; L 3 For C(O) 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. 1-6Alkyl and C 1-6 Haloalkyl; y is 0, 1 or 2.

[0217] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, 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 CH, X 3 For N or CH; x is 0; B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; b3 is 1 or 2, b4 is 1 or 2; q1 is 0; q2 is 0; L 2 s1 is the key; s2 is 0; L 3 For C(O) 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 groups; 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.

[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 The same or different, and each independently is C. 1-6 Alkyl group; R' is a hydrogen atom; ring A is selected from... Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For key; s1 is 1; ring B is B 1 For N or CH, B 2For N or CH; b1 is 0 or 1, b2 is 0 or 1; b3 is 1 or 2, b4 is 1 or 2; q is 0; L 2 S1 is a bond; S2 is 0 or 1; the ring C is a 3- to 6-membered cycloalkyl group; L 3 For C(O) or O; s3 is 0; L 4 For key; E is selected from

[0219] In some embodiments of this disclosure, the compounds represented by general formula (II) or (III) 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy group; 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 Haloalkyl; R' is a hydrogen atom; X 1 For N or CR 3 X 2 For N or CR 3 X 3 For N or CR 3 Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0220] 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; b3 is 1 or 2, b4 is 1 or 2; q is 0, 1 or 2; q1 is 0, 1 or 2; q2 is 0, 1 or 2; each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; 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, L 3 Selected from bonds, O, S, NH, CH2, CH(CH3), C(CH3)2 and propynyl groups; s2 is 0 or 1; r is 0; E is selected from R 6 C 1-6 Alkyl; R 7It 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.

[0221] In some embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, 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 Selected from N, CH and CF, X 2 Selected from N, CH and CF, X 3 Selected from N, CH, and CF; x is 0; s1 is 1; B 1 For N or CH, B 2 For N or CH; b1 is 1, b2 is 1; b3 is 1 or 2, b4 is 1; q is 0; q1 is 0; q2 is 0; L 2 Selected from bonds, O, C(O) and C(O)-CH(CH3), s2 is 0 or 1; ring C is a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocyclic group, L 3 Selected from O, C(O), CH2, and propynyl groups; r is 0; E is selected from... R 6 C 1-6 Alkyl; R 7 (CH2) s -5-membered heteroaryl group, s is 0, 1 or 2; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; each R 9 They may be the same or different, and each is independently a hydrogen atom or a halogen; y is 0, 1 or 2.

[0222] In some embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, 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 2For N or CH, X 3 For N or CH; x is 0; s1 is 1; B 1 For N or CH, B 2 For N or CH; b1 is 1, b2 is 1; b3 is 1 or 2, b4 is 1; q is 0; q1 is 0; q2 is 0; L 2 Selected from bonds, C(O) and C(O)-CH(CH3), s2 is 0 or 1; ring C is cyclopropyl or cyclobutyl, L 3 Selected from O, CH2, and propynyl groups; r is 0; E is selected from... R 6 C 1-6 Alkyl; R 7 It is a CH2-5 heteroaryl group; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; y is 0.

[0223] In some embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, 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; X 1 For N or CR 3 X 2 For N or CR 3 X 3 For N or CR 3 Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0224] 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; b3 is 1 or 2, b4 is 1 or 2; q is 0, 1 or 2; q1 is 0, 1 or 2; q2 is 0, 1 or 2; each R 4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; 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, L 3 Selected from bonds, O, S, NH, CH2, CH2O, CH(CH3), C(CH3)2, and propynyl groups; s2 is 0 or 1; r 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 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.

[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 Selected from halogens, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; each R 2 The same or different, and each independently is C. 1-6 Alkyl group; R' is a hydrogen atom; ring A is selected from... Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; p is 0, 1, 2 or 3; L 1 For key; s1 is 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; b3 is 1 or 2, b4 is 1 or 2; q is 0; L 2 For bond or C(O)-(CR) a R b ) x2 ;R a and R b Selected from hydrogen atoms, deuterium atoms, and C atoms 1-6 Alkyl; x2 is 0, 1, 2 or 3; s2 is 0; L 3 s3 is 0; L is 0. 4 For key; E is selected from

[0226] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for R 1a It is cyano; R 1b Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; each R 2 The same or different, and each independently is C. 1-6 Alkyl; X 1 For N or CH, X 2 For CH, X 3 For N or CH; x is 0; B 1 For N or CH, B 2 For N or CH; b1 is 0 or 1, b2 is 0 or 1; b3 is 1 or 2, b4 is 1 or 2; q1 is 0; q2 is 0; L 2 s1 is the key; s2 is 0; L 3 For C(O) or O; E is R 6 C 1-6 Alkyl; R 7 The oxazolyl group is CH2-oxazolyl, wherein the oxazolyl group is optionally selected from halogens, C 1-6 Alkyl groups and one or more of 3- to 6-membered cycloalkyl groups are substituted; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 0, 1, or 2; each R 9 The same or different, and each independently selected from C 1-6 Alkoxy, cyano, C 2-6 Alkyne group and 3 to 6-membered cycloalkyl group; y is 0 or 1.

[0227] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for R 1a It is cyano; R 1b Selected from halogens, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; each R 2 The same or different, and each independently is C. 1-6 Alkyl; X 1 Let N, X 2 For CH, X 3 CH; x is 0; B 1 For CH, B2 CH; b1 is 1, b2 is 1; b3 is 1, b4 is 1; q1 is 0; q2 is 0; L 2 s1 is the key; s2 is 0; L 3 For C(O) or O; E is R 6 C 1-6 Alkyl; R 7 It is CH2-oxazolyl; each R 8 The same or different, and each independently is C. 1-6 Alkyl; u is 2; each R 9 The same or different, and each independently selected from C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl; y is 1.

[0228] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for R 1a It is cyano; R 1b Selected from halogens, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; each R 2 The same or different, and each independently is C. 1-6 Alkyl; X 1 Let N, X 2 For CH, X 3 CH; x is 0; B 1 For CH, B 2 CH; b1 is 1, b2 is 1; b3 is 1, b4 is 1; q1 is 0; q2 is 0; L 2 s1 is the key; s2 is 0; L 3 For C(O) or O; E is selected from

[0229] Table A lists typical compounds disclosed herein, including but not limited to:

[0230] Another aspect of this disclosure relates to compounds of general formula (IA) or (IMA) or salts thereof (in some embodiments, hydrochloride salts).

[0231] Among them, R L The protecting group is selected from hydrogen atoms, leaving groups, OH, O-hydroxy protecting groups, and amino protecting groups; in some embodiments, the hydroxy protecting group is Ms or TBDPS; in some embodiments, the amino protecting group is Boc;

[0232] Ring A, Ring B, L 1 、R'、R 1 To R 4 m, n, p and q are as defined in general formula (I).

[0233] Another aspect of this disclosure relates to compounds of general formulas (IIA), (IIIA), (IIA-2), (IIIA-2) or salts thereof (in some embodiments, hydrochloride salts),

[0234] Among them, R L Selected from hydrogen atoms, leaving groups, OH, O-hydroxy protecting groups, and amino protecting groups; in some embodiments, the hydroxy protecting group is Ms or TBDPS; in some embodiments, the amino protecting group is Boc; R P Selected from OH, halogens, and alkoxy groups;

[0235] R 1 m, R 2 、R'、X 1 To X 3 x, B 1 B 2 R 4 q, b1, b2, q1, q2, b3 and b4 are as defined in general formula (II) or (III).

[0236] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IB), (IB-2), (IE), (IF), (IF-1), or (IF-2).

[0237] Among them, R P Selected from hydrogen atoms, OH, halogens, and alkoxy groups; in some embodiments, R P Selected from OH, halogens, and alkoxy groups; R P In some implementation schemes, R P It is OH or ethoxy;

[0238] RE The group is selected from hydrogen atom, hydroxyl group, O-hydroxy protecting group and oxo group; in some embodiments, the hydroxy protecting group is TBS; a1 is 0, 1, 2, 3 or 4; a2 is 1, 2, 3 or 4;

[0239] R 6 To R 9 u and y are as defined in general formula (I).

[0240] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IC), (ID), (IG), and (IH).

[0241] Among them, R P Selected from OH, halogens, and alkoxy groups; in some embodiments, OH, methoxy, or ethoxy.

[0242] B 2 When R is N, W It is an amino protecting group; B 2 When it is CH, R W It is an O-hydroxyl protecting group;

[0243] In some embodiments, the amino protecting group is Boc; in some embodiments, the hydroxy protecting group is TBDPS.

[0244] X 1 To X 3 B 1 B 2 b1, b2, b3, b4, R 4 q, q1 and q2 are as defined in general formula (II) or (III).

[0245] In some implementation schemes, R P It is OH or ethoxy.

[0246] Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:

[0247] 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:

[0248] A compound of general formula (IIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIB) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (II) of C(O) or their pharmaceutically usable salts, or

[0249] The compound of general formula (IIA-2) or a salt thereof may optionally undergo a nucleophilic substitution reaction with the compound of general formula (IIb) or a salt thereof to give B. 2 For CH and L 2 Compounds of general formula (II) of type O or their pharmaceutically usable salts, or

[0250] The compound of general formula (IIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (IIb-2) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (II) or their pharmaceutically acceptable salts, or

[0251] A compound of general formula (IIA-2) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIb-3) or a salt thereof to yield a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0252] Among them, R L It is an OH group or a leaving group; in some embodiments, the leaving group is OMs;

[0253] R P Selected from OH, halogens, and alkoxy groups, with OH being the preferred form in some embodiments;

[0254] E, L 3 , ring C, s2, B 1 b1, b2, R 4 , q, R 5 r, x, X 1 To X 3 R 1 m, R 2 R' is as defined in general formula (II).

[0255] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0256] A compound of general formula (IIIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIB) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (III) of C(O) or their pharmaceutically usable salts, or

[0257] The compound of general formula (IIIA-2) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIb) or its salt to give B. 2 For CH and L 2 Compounds of general formula (III) of type O or their pharmaceutically usable salts, or

[0258] The compound of general formula (IIIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (IIb-2) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (III) or their pharmaceutically acceptable salts, or

[0259] A compound of general formula (IIIA-2) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIIB) or a salt thereof to yield a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0260] Among them, R L It is an OH group or a leaving group; in some embodiments, the leaving group is OMs;

[0261] R P Selected from OH, halogens, and alkoxy groups, with OH being the preferred form in some embodiments;

[0262] E, L 3 , ring C, s2, B 1 b1, b2, b3, b4, R 4 q1, q2, R 5 r, x, X 1 To X 3 R 1 m and R 2 As defined in general formula (III).

[0263] In some embodiments of this disclosure, the R L It is a leaving group; in some embodiments, it is OH.

[0264] In some implementations, when R LWhen OH is present, the Mitsunobu reaction occurs; in some embodiments, the reagent for this reaction is a combination of triphenylphosphine (PPh3) and diethyl azodicarbonate (DEAD) / or diisopropyl azodicarbonate (DIAD) or bis(4-chlorobenzyl)azodicarbonate (DCAD), or cyanomethylene tri-n-butylphosphine (CMBP) or (1,2-bis(ethoxycarbonyl)hydrazino)triphenylphosphine trifluoromethanesulfonate (BEHT Triflate); in some embodiments, the reagent is cyanomethylene tri-n-butylphosphine.

[0265] In some embodiments of this disclosure, the nucleophilic substitution reaction optionally occurs under basic conditions. When R L When R is a leaving group, the nucleophilic substitution reaction occurs under basic conditions; wherein, the reagent providing the basic conditions is cesium carbonate; when R L When the OH group is present, no base is required to participate in the reaction.

[0266] In some embodiments of this disclosure, the reductive amination reaction occurs in the presence of a reducing agent; in other embodiments, the reductive amination reaction occurs in the presence of a reducing agent and under acidic conditions.

[0267] Reagents providing acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, acetic acid, glacial acetic acid, Ti(i-PrO)3 ​​and BF3·Et2O, TiCl4, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, titanium tetrachloride, Me3SiCl, and TMSOTf. In some embodiments, the reagent providing acidic conditions is an added acidic reagent, and / or an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the acidic salt of the reactants; in some embodiments, the reagent providing acidic conditions is an acid introduced from the hydrochloride salt of the reactants.

[0268] 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.

[0269] In the above synthesis scheme, the condensation reaction occurs under alkaline conditions; the reagent providing the alkaline conditions is N,N-diisopropylethylamine.

[0270] 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 or cesium carbonate.

[0271] 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.

[0272] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (V) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0273] This disclosure further relates to the use of compounds of general formulas (I) to (V) or any of those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, in the preparation of medicaments for regulating or inhibiting the function of effector proteins essential for cell survival.

[0274] This disclosure further relates to the use of compounds of general formulas (I) to (V) or any of those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, in the preparation of medicaments for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions.

[0275] This disclosure further relates to the use of compounds of any of the above general formulas (I) to (V) 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.

[0276] 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 (V) or any of those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0277] 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 (V) or any of those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0278] 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 (V) or any of those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0279] This disclosure further relates to a compound of general formula (I) to (V) or any of those shown in 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.

[0280] This disclosure further relates to a compound of general formula (I) to (V) or any of the compounds shown in 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.

[0281] This disclosure further relates to a compound of general formula (I) to (V) or any of those shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for regulating or inhibiting the function of effector proteins essential for cell survival.

[0282] This disclosure further relates to a compound of general formula (I) to (V) or any of the compounds shown in 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.

[0283] This disclosure further relates to a compound of general formula (I) to (V) or any of those shown in 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.

[0284] In some embodiments, the cell-sustaining effector protein is BET, and in other embodiments, the cell-sustaining effector protein is BRD4.

[0285] 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. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0286] 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.

[0287] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0288] 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.

[0289] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] Terminology Explanation

[0302] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0303] 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 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0304] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0310] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0311] 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:

[0312] Its connection point can be anywhere;

[0313] wait.

[0314] 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:

[0315] Its connection point can be anywhere; wait.

[0316] 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:

[0317] Its connection point can be anywhere.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0323] "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.

[0324] 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:

[0325] wait.

[0326] 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:

[0327] wait.

[0328] 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:

[0329] wait.

[0330] 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:

[0331] wait.

[0332] 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.

[0333] 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:

[0334] wait.

[0335] 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.

[0336] 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).

[0337] 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.

[0338] 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:

[0339] wait.

[0340] 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.

[0341] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0342] The term "heterocyclic oxy group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0343] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0344] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0351] 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.

[0352] 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.

[0353] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; in some embodiments, they are -alkyl-alkoxy groups; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.

[0354] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0355] The term "hydroxyl group" refers to -OH.

[0356] The term "amino" refers to -NH2.

[0357] The term "cyano" refers to -CN.

[0358] The term "nitro" refers to -NO2.

[0359] The term "oxo" or "oxo group" refers to "=O".

[0360] The term "carbonyl" refers to C=O.

[0361] TBS refers to tert-butyldimethylsilyl.

[0362] 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.

[0363] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group in a reaction 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), methanesulfonyl (Ms), p-toluenesulfonyl (Ts), formyl, acetyl, benzoyl, and p-nitrobenzoyl.

[0364] 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.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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:

[0369] 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:

[0370] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0371] 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.

[0372] 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.

[0373] 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.

[0374] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation will occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0375] "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).

[0376] "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.

[0377] "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.

[0378] 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.

[0379] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0380] 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

[0381] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0382] Implementation Scheme 1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0383] in:

[0384] Ring A is selected from 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group;

[0385] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0386] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0387] Ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0388] s1 is 0 or 1; s2 is 0 or 1; s3 is 0 or 1;

[0389] 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) vThe alkenyl, ynyl, and heterocyclic groups are each independently and optionally converted by one or more R groups. 0 Replaced;

[0390] Each R a and R b The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 0 Replaced;

[0391] 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;

[0392] Each R 1 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;

[0393] 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 14C(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, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 Replaced;

[0394] E is selected from

[0395] Q is CR 10 Or N;

[0396] 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;

[0397] Or two Rs 8 Together with the carbon atom attached thereto, they form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is independently and optionally converted by one or more R groups. 0 Replaced;

[0398] 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)OR14 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;

[0399] Each R', 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;

[0400] 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;

[0401] 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;

[0402] m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4, 5 or 6;

[0403] p is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, 5 or 6;

[0404] r is 0, 1, 2, 3, 4, 5 or 6; r2 is 0, 1, 2, 3, 4, 5 or 6;

[0405] u is 0, 1, or 2; y is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; and

[0406] Each v is the same or different, and each is independently 0, 1 or 2.

[0407] Implementation Scheme 2. The compound or its pharmaceutically acceptable salt according to Implementation Scheme 1, wherein 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 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 R 14 R 0 R 7 R 7b u, y, w, R d and R e As defined in Implementation Scheme 1; in some implementation schemes, E is selected from... R 6 To R 9 R d R e u and y are as defined in implementation scheme 1; in some implementation schemes, E is selected from...

[0408] Implementation Scheme 3. The compound according to Implementation Scheme 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridinone, pyridazinone, pyrimidinone, and pyridoxide groups; in some embodiments, ring A is selected from... Or for

[0409] Implementation Scheme 4. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1 or 2, wherein the compound is represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0410] Among them, X 1 X 2 and X 3 Whether the same or different, and each independently constitutes a CR 3 Or N;

[0411] 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;

[0412] Rings C, E, L 2 L 3 s1, s2, q, r, x, R 1 To R 5 R' and m are as defined in Implementation Scheme 1.

[0413] Implementation Scheme 5. The compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1 or 2, wherein the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0414] Where b3 is 0, 1, 2, 3 or 4; b4 is 0, 1, 2, 3 or 4;

[0415] q1 is 0, 1, 2, 3 or 4; q2 is 0, 1 or 2;

[0416] Rings C, E, L 2 L 3 s2, B 1 B 2 b1, b2, x, X 1 To X 3 R 1 m, R 2 R 4 R 5 And r as defined in implementation scheme 4.

[0417] Implementation Scheme 6. A compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, 2 or 5, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (IV):

[0418] Among them, R 1a and R 1b They may be the same or different, and each is independently a hydrogen atom or R. 1 ;

[0419] R 1 To R 4 X 1 X 2 x, B 1 B 2 ,b1,b2,b3,b4,q1,q2,L 2 L 3 R 6 R 8 u, R 9 And y are as defined in Implementation Scheme 5.

[0420] Implementation Scheme 7. A compound or a pharmaceutically acceptable salt thereof according to Implementation Scheme 1, 2, 5 or 6, wherein the compound or a pharmaceutically acceptable salt thereof is represented by general formula (V):

[0421] Among them, R 1a R 1b R 2 X 1 x, B 1 B 2 b1, b2, b3, b4, R 4 q1, q2, L 2 and L 3 As defined in Implementation Scheme 5, R 9 And y are as defined in Implementation Scheme 1.

[0422] Implementation Scheme 8. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 4 to 7, wherein B 1 For CH or N, and / or B 2 For CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1; in some implementations, B 1 For CH, and / or B 2 For CH, and / or b1 is 1, and / or b2 is 1; in some implementations, B 1 For CH, and / or B 2 CH, and / or b1 is 1, and / or b2 is 1, and / or b3 is 1, and / or b4 is 1.

[0423] Implementation Scheme 9. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 8, wherein x is 0 or 1, and / or L 2 Selected from bonds, O, C(O), (CR) a R b ) x C(O)-(CR) a R b ) x2 O-CR a Rb And C(O)NH, and / or the ring C is a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocyclic group, and / or s2 is 0 or 1, and / or L 3 Selected from the following groups: bond, O, S, NH, CH2, CH(CH3), C(O), C(CH3)2, and propynyl group; 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; x2 is 0, 1, or 2; in some embodiments, x is 0 or 1, and / or 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 s2 is 0 or 1, and / or L 3 Selected from the groups O, S, NH, CH2, CH(CH3), C(O), C(CH3)2 and propyne; in some embodiments, x is 0, and / or L 2 The C1 bond is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, and / or the S2 group is 0 or 1, and / or L. 3 Selected from bonds, CH2, C(O), and O; in some embodiments, x is 0, and / or L 2 For key, and / or L 3 It is O.

[0424] Implementation Scheme 10. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 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 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, halogen and cyano groups, and / or m is 0, 1 or 2.

[0425] Implementation Scheme 11. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 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 Halogenated alkyl; in some embodiments, R 2 C 1-6 Alkyl; in some embodiments, R 2 It is a methyl group.

[0426] Implementation Scheme 12. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 11, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 Selected from hydrogen atoms, F and methyl; in some embodiments, R 3 It is a hydrogen atom.

[0427] Implementation Scheme 13. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 6, 8 to 10, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or 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, R 6 C 1-6 Alkyl groups; and / or each of the R groups 8 The same or different, and each independently is C. 1-6 Alkyl; in some embodiments, R 6 Methyl; and / or R 8 It is a methyl group.

[0428] Implementation Scheme 14. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 13, wherein each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, hydroxyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; preferably, each R 9 The same or different, and each independently selected from C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl groups.

[0429] Implementation Scheme 15. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 14, wherein L 3 It is O.

[0430] Implementation Scheme 16. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 15, wherein R 9 It is a 3- to 6-membered cycloalkyl group; in some embodiments, R 9 It is cyclopropyl.

[0431] Implementation Scheme 17. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 15, wherein R 9 C 1-6 Halogenated alkyl; in some embodiments, R 9 It is CHF2.

[0432] Implementation Scheme 18. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 15, wherein R 9 It is a cyano group.

[0433] Implementation Scheme 19. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 18, wherein y is 0.

[0434] Implementation Scheme 20. The compound or its pharmaceutically usable salt according to any one of Implementation Schemes 1 to 18, wherein y is 1.

[0435] Implementation Scheme 21. The compound or its pharmaceutically acceptable salt according to any one of 6 to 20, wherein R 1a It is a cyano group.

[0436] Implementation Scheme 22. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 6 to 21, wherein R 1b For halogen; in some implementations, R 1b It is Cl.

[0437] Implementation Scheme 23. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 6 to 21, wherein R 1b It is an alkoxy group; in some embodiments, R 1b It is a methoxy group.

[0438] Implementation Scheme 24. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 6 to 21, wherein R 1b C 1-6 Haloalkoxy; in some embodiments, R 1b It is either OCF3 or OCHF2.

[0439] Implementation Scheme 25. The compound or its pharmaceutically acceptable salt according to any one of Implementation Schemes 1 to 24, selected from the compounds in Table A.

[0440] Implementation Scheme 26. A compound of general formula (IIA), (IIA-2), (IIIA) or (IIIA-2), or a salt thereof:

[0441] Among them, R L Selected from hydrogen atoms, leaving groups, OH, O-hydroxy protecting groups, and amino protecting groups; in some embodiments, the hydroxy protecting group is Ms or TBDPS; in some embodiments, the amino protecting group is Boc; R P Selected from OH, halogens, and alkoxy groups;

[0442] R 1 m, R 2 、R'、X 1 To X 3 x, B 1 B 2 R 4 b1, b2, q1, q2, b3, and b4 are as defined in implementation scheme 4 or 5.

[0443] Implementation Scheme 27. A compound or a salt thereof, selected from the compounds in Table B.

[0444] Implementation Scheme 28. A method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0445] A compound of general formula (IIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIB) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (II) of C(O) or their pharmaceutically usable salts, or

[0446] The compound of general formula (IIA-2) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIb) or its salt to give B. 2 For CH and L 2 Compounds of general formula (II) of type O or their pharmaceutically usable salts, or

[0447] The compound of general formula (IIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (IIb-2) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (II) or their pharmaceutically acceptable salts, or

[0448] A compound of general formula (IIA-2) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIb-3) or a salt thereof to yield a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0449] Among them, R L It is an OH or leaving group; in some embodiments, R L For OMs; R P Selected from OH, halogens, and alkoxy groups, in some embodiments, R P It is OH;

[0450] E, L 3 , ring C, s2, R 5 ,r,B 1 b1, b2, R 4 q, x, X 1 To X 3 R 1 m, R 2 R' is as defined in implementation scheme 4.

[0451] Implementation Scheme 29. A method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0452] A compound of general formula (IIIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a condensation reaction with a compound of general formula (IIB) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (III) of C(O) or their pharmaceutically usable salts, or

[0453] The compound of general formula (IIIA-2) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIb) or its salt to give B. 2 For CH and L 2 Compounds of general formula (III) of type O or their pharmaceutically usable salts, or

[0454] The compound of general formula (IIIA-1) or a salt thereof (in some embodiments, a hydrochloride salt) undergoes a reductive amination reaction with the compound of general formula (IIb-2) or a salt thereof to give B. 2 For N and L 2 Compounds of general formula (III) or their pharmaceutically acceptable salts, or

[0455] A compound of general formula (IIIA-2) or a salt thereof undergoes a condensation reaction with a compound of general formula (IIIB) or a salt thereof to yield a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0456] Among them, R LIt is an OH group or a leaving group; in some embodiments, the leaving group is OMs;

[0457] R P Selected from OH, halogens, and alkoxy groups, in some embodiments, R P It is OH;

[0458] E, L 3 , ring C, s2, B 1 b1, b2, b3, b4, R 4 q1, q2, R 5 r, x, X 1 To X 3 R 1 m and R 2 As defined in Implementation Scheme 5.

[0459] Implementation Scheme 30. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 25, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0460] Implementation Scheme 31. Use of the compound of any one of Implementation Schemes 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of Implementation Scheme 30 in the preparation of a medicament for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions.

[0461] Implementation Scheme 32. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Implementation Schemes 1 to 25, or the pharmaceutical composition according to Implementation Scheme 30, in the preparation of a medicament for the treatment and / or prevention of tumors, male sexual dysfunction, and Kennedy's disease; in some embodiments, use in the preparation of a medicament 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, use in the preparation of a medicament for the treatment and / or prevention of prostate cancer; in some embodiments, said prostate cancer is hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

[0462] Example

[0463] 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).

[0464] 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);

[0465] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector);

[0466] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

[0467] 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.

[0468] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0469] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0470] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0471] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0472] 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.

[0473] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0474] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0475] 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.

[0476] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0477] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0478] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0479] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0480] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0481] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0482] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0483] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0484] 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.

[0485] Example 1

[0486] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-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)benzoyl)-2-azaspiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 1

[0487] first step

[0488] 7-(4-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 1c

[0489] Methyl 2-oxo-1,2-dihydropyridine-4-carboxylate 1a (649 mg, 4.24 mmol, Shanghai Shaoyuan), and tert-butyl 7-((methanesulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid on page 281 of patent application "WO2022032026" were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (2.76 g, 10.91 mmol) was added. The mixture was stirred in a microwave at 100 °C for 45 minutes. After cooling the reaction solution to room temperature, it 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*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30mL / min) to obtain title compound 1c (10mg, yield: 0.6%).

[0490] MS m / z(ESI): 377.5 [M+1].

[0491] Step 2

[0492] 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]non-7-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 1d

[0493] Compound 1c (24 mg, 64 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (8 mg, 191 μmol) 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 (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 1d (23 mg), which was used directly in the next reaction without purification.

[0494] MS m / z(ESI): 361.4 [M-1].

[0495] Step 3

[0496] 7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-2-oxopyridin-1(2H)-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 1f

[0497] Crude compound 1d (23 mg, 63 μmol) and 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride 1e (20 mg, 63 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 (41 mg, 317 μmol) and n-butylphosphine anhydride (69 mg, 95 μmol, 50% ethyl acetate solution) were added. The mixture was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was eluted 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. The residue was purified by silica gel column chromatography using eluent system B to give title compound 1f (21 mg, yield: 53%).

[0498] MS m / z(ESI): 623.5 [M+1].

[0499] Step 4

[0500] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(2-azaspiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide hydrochloride 1g

[0501] Compound 1f (21 mg, 34 μmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (1 mL) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 1 g (19 mg). The product was used directly in the next reaction without purification.

[0502] MS m / z(ESI): 523.6 [M+1].

[0503] Step 5

[0504] (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)ethyl benzoate 1i

[0505] (S)-2-((4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptidyl-6-yl)methyl)oxazole 1h (800 mg, 1.89 mmol, prepared by the method disclosed in Example 23 on page 367 of patent application "WO2024054603") was dissolved in ethanol (15 mL) and dimethyl sulfoxide (30 mL), and palladium acetate (85 mg, 379 μmol), 1,3-bis(diphenylphosphine)propane (DPPP) (161 mg, 391 μmol), potassium carbonate (521 mg, 3.77 mmol), and carbon monoxide was added. The reaction was carried out at 90 °C for 7 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1i (870 mg). The product was used directly in the next reaction without purification.

[0506] MS m / z(ESI):462.4[M+1].

[0507] Step 6

[0508] (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)benzoic acid 1j

[0509] The crude compound 1i (870 mg, 1.88 mmol) was dissolved in methanol (20 mL) and water (10 mL), and lithium hydroxide monohydrate (396 mg, 9.43 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 (20 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 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 obtain the title compound 1j (600 mg, yield: 73.4%).

[0510] MS m / z(ESI): 434.5 [M+1].

[0511] Step 7

[0512] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-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)benzoyl)-2-azaspiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 1

[0513] Compound 1j (15 mg, 34 μmol) and compound 1g (19 mg, 34 μmol) were dissolved in N,N-dimethylformamide (2 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (19 mg, 51 μmol) and N,N-diisopropylethylamine (17 mg, 136 μmol) were added at 0 °C. The mixture was stirred at room temperature for 2 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 30-55%, flow rate: 30 mL / min) to give title compound 1 (14 mg, yield: 9.4%).

[0514] MS m / z(ESI): 938.9 [M+1].

[0515] 1 H NMR (500MHz, CD3OD): δ: 7.93 (s, 1H), 7.86 (d, 1H), 7.78-7.68 (m, 3H), 7.54-7.50 (m, 2H), 7.17-7.13 (m, 2H) ,7.02-6.97(m,1H),6.88-6.84(m,1H),6.70-6.62(m,1H),4.60(s,1H),4.30-4.28(m,1H),4.23-4.18(m,1H ),4.15-4.12(m,1H),4.09-3.95(m,4H),3.89(s,1H),2.74(s,3H),2.49-2.47(m,2H),2.24-2.19(m,4H),1. 88-1.78(m,4H),1.72-1.68(m,3H),1.33-1.30(m,3H),1.29(s,3H),1.28(s,3H),1.24(s,3H),1.23(s,3H).

[0516] Example 2

[0517] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2

[0518] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(2-(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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p1

[0519] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p2

[0520] first step

[0521] 2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-one 2b

[0522] 2-Hydroxyspiro[3.5]non-7-one 2a (2.93 g, 19.0 mmol, prepared by the method disclosed in Example 35 on page 68 of patent application “CN118772110A”) was dissolved in dichloromethane (35 mL), and imidazole (5.17 g, 75.94 mmol) and tert-butyldiphenylchlorosilane (13 g, 47.44 mmol) were added. The mixture was stirred for 16 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain title compound 2b (10 g, yield: 134%).

[0523] Step 2

[0524] 2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-ol 2c

[0525] The crude compound 2b (5 g, 12.73 mmol) was dissolved in methanol (40 mL), sodium borohydride (960 mg, 25.3 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with water, concentrated under reduced pressure, and water was added to the residue. The organic phases were combined with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2c (2.5 g, yield: 49.7%).

[0526] Step 3

[0527] 2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-ylmethanesulfonate 2d

[0528] Compound 2c (1.23 g, 3.11 mmol) and triethylamine (946 mg, 9.35 mmol) were dissolved in dichloromethane (15 mL). Methanesulfonyl chloride (715 mg, 6.24 mmol) was added under ice bath conditions, and the reaction mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 2d (1.47 g), which was used directly in the next reaction without purification.

[0529] Step 4

[0530] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester 2e

[0531] Compound 2d (1.47 g, 3.11 mmol) and compound 1a (476 mg, 3.11 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (2.0 g, 6.14 mmol) was added. The mixture was stirred in a microwave at 85 °C for 30 minutes. 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, 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 2e (42 mg, yield: 2.5%).

[0532] MS m / z(ESI): 530.5 [M+1].

[0533] Step 5

[0534] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 2f

[0535] Compound 2e (42 mg, 79 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (15 mg, 357 μmol) was added. The mixture was stirred for 16 hours. The pH of the reaction solution was adjusted to about 5 with 1 M hydrochloric acid solution. The solution 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 2f (41 mg), which was used directly in the next step of the reaction without purification.

[0536] MS m / z(ESI): 516.5 [M+1].

[0537] Step 6

[0538] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1,2-dihydropyridine-4-carboxamide 2g

[0539] The crude compounds 2f (41 mg, 79 μmol) and 1e (23 mg, 73 μmol) were dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (31 mg, 240 μmol) and n-butylphosphine anhydride (43 mg, 119 μmol, 50% ethyl acetate solution) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. Water was added, and the mixture was eluted 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2 g (52 mg, yield: 84.2%).

[0540] MS m / z(ESI): 776.7 [M+1].

[0541] Step 7

[0542] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-hydroxyspiro[3.5]non-7-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide 2h

[0543] 2 g (52 mg, 67 μmol) of the compound was dissolved in tetrahydrofuran (2 mL), and 204 μL of a 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The mixture was stirred for 2 hours, and 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 2h (36 mg, yield: 99%).

[0544] MS m / z(ESI): 538.4 [M+1].

[0545] Step 8

[0546] 7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-2-oxopyridine-1(2H)-yl)spiro[3.5]non-2-ylmethanesulfonate 2i

[0547] Compound 2h (36 mg, 67 μmol) and triethylamine (21 mg, 207 μmol) were dissolved in dichloromethane (1 mL). Methanesulfonyl chloride (16 mg, 140 μmol) was added under ice bath conditions, and the reaction was stirred for 0.5 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (5 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 2i (42 mg), which was used directly in the next reaction without purification.

[0548] MS m / z(ESI): 616.4 [M+1].

[0549] Step 9

[0550] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2

[0551] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(2-(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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p1

[0552] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p2

[0553] Compound 2i (42 mg, 68 μmol), (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 2j (30 mg, 74 μmol, prepared by the method disclosed in Example 13 on page 367 of patent application "WO2024054603") were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (75 mg, 230 μmol) was added. The mixture was stirred at 90 °C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep). C18, C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30mL / min) to obtain title compound 2 (10mg, yield: 15.8%).

[0554] MS m / z(ESI): 925.5 [M+1].

[0555] 1 H NMR (500MHz, CD3OD): δ: 7.91 (s, 1H), 7.84-7.80 (m, 1H), 7.74 (d, 1H), 7.34 (d, 2H), 7.16-7.12 (m, 2H),7.01-6.98(m,1H),6.87-6.83(m,3H),6.68-6.65(m,1H),4.81-4.71(m,3H),4.29(s,1H),4.1 4(s,1H),4.04-3.93(m,2H),2.72(s,3H),2.67-2.61(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.07 -2.00(m,1H),1.99-1.87(m,4H),1.85-1.80(m,2H),1.76-1.59(m,7H),1.29(s,6H),1.23(s,6H).

[0556] Compound 2 (24 mg) was resolved by a chiral column (Gilson-281, column: (S,S)-Whelk-O1, 10 μm, 20 mm * 250 mm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B = 10:90, flow rate: 20 mL / min) to give title compounds 2-p1 (3 mg, yield: 12.5%) and 2-p2 (17.5 mg, yield: 73%).

[0557] Single configuration compound (shorter retention time): 2-p1 (3 mg, yield: 12.5%).

[0558] MS m / z(ESI): 925.5 [M+1].

[0559] Chiral HPLC analysis: retention time 4.267 min, purity: 99.9% (column: (S,S)-Whelk-O1, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.5 mL / min).

[0560] 1 H NMR (500MHz, CD3OD): δ: 7.91 (s, 1H), 7.84-7.80 (m, 1H), 7.74 (d, 1H), 7.34 (d, 2H), 7.16-7.12 (m, 2H),7.01-6.98(m,1H),6.87-6.83(m,3H),6.68-6.65(m,1H),4.81-4.71(m,3H),4.29(s,1H),4.1 4(s,1H),4.04-3.93(m,2H),2.72(s,3H),2.67-2.61(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.07 -2.00(m,1H),1.99-1.87(m,4H),1.85-1.80(m,2H),1.76-1.59(m,7H),1.29(s,6H),1.23(s,6H).

[0561] Single configuration compound (longer retention time): 2-p2 (17.5 mg, yield: 73%).

[0562] MS m / z(ESI): 925.5 [M+1].

[0563] Chiral HPLC analysis: retention time 6.359 min, purity: 99.9% (column: (S,S)-Whelk-O1, 3*100mm, 3μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.5 mL / min).

[0564] 1H NMR (500MHz, CD3OD): δ: 7.91 (s, 1H), 7.84-7.80 (m, 1H), 7.74 (d, 1H), 7.34 (d, 2H), 7.16-7.12 (m, 2H),7.01-6.98(m,1H),6.87-6.83(m,3H),6.68-6.65(m,1H),4.81-4.71(m,3H),4.29(s,1H),4.1 4(s,1H),4.04-3.93(m,2H),2.72(s,3H),2.67-2.61(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.07 -2.00(m,1H),1.99-1.87(m,4H),1.85-1.80(m,2H),1.76-1.59(m,7H),1.29(s,6H),1.23(s,6H).

[0565] Examples 2-p2-1, 2-p2-2

[0566] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p2-1

[0567] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,2-dihydropyridine-4-carboxamide 2-p2-2

[0568] Compound 2-p2 (38 mg) was resolved by a chiral column (Gilson-281, column: ChiralPak IC, 20*250 mm, 5 μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 20:80, flow rate: 20 mL / min) to give the title compound (8 mg, yield: 21.1%) and (8 mg, yield: 21.1%).

[0569] Single configuration compound (shorter retention time): (8 mg, yield: 21.1%).

[0570] MS m / z(ESI): 925.5 [M+1].

[0571] Chiral HPLC analysis: retention time 8.091 min, purity: 99.9% (column: ChiralPak IC, 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).

[0572] 1 H NMR (500MHz, CD3OD): δ: 7.91 (s, 1H), 7.84-7.80 (m, 1H), 7.74 (d, 1H), 7.34 (d, 2H), 7.16-7.12 (m, 2H),7.01-6.98(m,1H),6.87-6.83(m,3H),6.68-6.65(m,1H),4.81-4.71(m,3H),4.29(s,1H),4.1 4(s,1H),4.04-3.93(m,2H),2.72(s,3H),2.67-2.61(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.07 -2.00(m,1H),1.99-1.87(m,4H),1.85-1.80(m,2H),1.76-1.59(m,7H),1.29(s,6H),1.23(s,6H).

[0573] Single-configuration compound (longer retention time): (8 mg, yield: 21.1%).

[0574] MS m / z(ESI): 925.5 [M+1].

[0575] Chiral HPLC analysis: retention time 9.538 min, purity: 95.3% (column: ChiralPak IC, 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).

[0576] 1H NMR (500MHz, CD3OD): δ: 7.91 (s, 1H), 7.84-7.80 (m, 1H), 7.74 (d, 1H), 7.34 (d, 2H), 7.16-7.12 (m, 2H),7.01-6.98(m,1H),6.87-6.83(m,3H),6.68-6.65(m,1H),4.81-4.71(m,3H),4.29(s,1H),4.1 4(s,1H),4.04-3.93(m,2H),2.72(s,3H),2.67-2.61(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.07 -2.00(m,1H),1.99-1.87(m,4H),1.85-1.80(m,2H),1.76-1.59(m,7H),1.29(s,6H),1.23(s,6H).

[0577] Example 3

[0578] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide 3-p1 or

[0579] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide 3-p2

[0580] first step

[0581] 2-(((S)-4-(4-((1s,3R)-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)oxazol3b

[0582] Compound 2j (388 mg, 957 μmol) and trans-3-((tert-butyldimethylsilyl)oxy)cyclobutanol 3a (194 mg, 959 μmol, Shanghai Bide) were 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 title compound 3b (350 mg, yield: 62%).

[0583] MS m / z(ESI): 590.6 [M+1].

[0584] Step 2

[0585] (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)cyclobut-1-ol 3c

[0586] Compound 3b (350 mg, 593.3 μmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (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 3c (260 mg), which was used directly in the next reaction without purification.

[0587] MS m / z(ESI): 476.5 [M+1].

[0588] Step 3

[0589] (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])

[0590] diazaheptan-4-yl)phenoxy)cyclobut-1-one 3d

[0591] The crude compound 3c (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 3d (239 mg, yield: 92.3%).

[0592] MS m / z(ESI):474.5[M+1].

[0593] Step 4

[0594] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide hydrochloride 3f

[0595] Using the synthetic route of Example 1, steps three and four were performed, replacing the starting compound 1d in step three with compound 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 3e (prepared by the method disclosed in Compound 7 on page 86 of the specification of patent application "WO2024073475"), to obtain crude title compound 3f (26 mg).

[0596] MS m / z(ESI):483.4[M+1].

[0597] Step 5

[0598] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide3

[0599] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide 3-p1 or

[0600] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-oxo-1-(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)piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide 3-p2

[0601] Crude compound 3f (26 mg, 50 μmol) and compound 3d (26 mg, 55 μmol) were dissolved in tetrahydrofuran (2 mL). After stirring for 1 hour, sodium triacetoxyborohydride (35 mg, 165 μmol) was added, and the reaction was continued for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude title compound 3 (50 mg). It 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 3-p1 or 3-p2 (9 mg, yield: 18%).

[0602] MS m / z(ESI): 940.8 [M+1].

[0603] 1 H NMR (500MHz, CD3OD): δ: 7.92(s,1H),7.80(d,1H),7.74(d,1H),7.36-7.31(m,2H),7.16-7.13(m,2H),7.00(dd,1 H),6.89-6.85(m,3H),6.69(dd,1H),4.78-4.73(m,1H),4.61-4.52(m,1H),4.29(s,1H),4.14(s,1H),4.04-3.92( m,2H),3.16-3.09(m,2H),2.86-2.78(m,2H),2.72(s,3H),2.69-2.62(m,1H),2.48(s,3H),2.23-2.19(m,2H),2. 16-2.09(m,2H),2.08-2.02(m,2H),1.94-1.91(m,2H),1.72(s,3H),1.66-1.58(m,2H),1.29(s,6H),1.23(s,6H).

[0604] Example 4

[0605] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4

[0606] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4-p1

[0607] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4-p2

[0608] first step

[0609] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester 4b

[0610] Methyl 6-oxo-1,6-dihydropyridazine-4-carboxylic acid ester 4a (3.75 g, 24.33 mmol, Shanghai Titan) and compound 2c (10.0 g, 25.34 mmol) were dissolved in tetrahydrofuran (130 mL). Triphenylphosphine (12.76 g, 48.65 mmol) and diisopropyl azodicarbonate (9.85 g, 48.71 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 4b (10 g, yield: 77.4%).

[0611] MS m / z(ESI): 531.3 [M+1].

[0612] Step 2

[0613] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid 4c

[0614] Compound 4b (10.0 g, 18.84 mmol) was dissolved in tetrahydrofuran (30 mL), and an aqueous solution of lithium hydroxide monohydrate (3.96 g, 94.37 mmol) (30 mL) was added under ice bath conditions. The mixture was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 4c (10 g, yield: 102.7%), which was used directly in the next reaction without purification.

[0615] MS m / z(ESI): 517.4 [M+1].

[0616] Step 3

[0617] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 4d

[0618] Crude compounds 4c (7.0 g, 13.55 mmol) and 1e (3.85 g, 12.21 mmol) were dissolved in dichloromethane (125 mL). N,N-diisopropylethylamine (8.76 g, 67.78 mmol) and n-butylphosphine (14.64 g, 20.33 mmol, 50% ethyl acetate solution) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 4d (9.4 g, yield: 89.2%).

[0619] MS m / z(ESI): 778.5 [M+1].

[0620] Step 4

[0621] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 4e

[0622] Compound 4d (43 mg, 55 μmol) was dissolved in tetrahydrofuran (1 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (142 μL) was added. The mixture was stirred at 40 °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 using eluent system B to give the title compound 4e (25 mg, yield: 83.9%).

[0623] MS m / z(ESI): 539.1 [M+1].

[0624] Step 5

[0625] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4

[0626] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4-p1

[0627] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 4-p2

[0628] Compound 4e (1.15 g, 2.13 mmol) and compound 2j (909 mg, 2.24 mmol) were dissolved in toluene (60 mL), and cyanomethylenetri-n-butylphosphine (2.3 g, 9.53 mmol) was added. The mixture was stirred at 125 °C for 2 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: 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 4 (1.5 g, yield: 75.9%).

[0629] MS m / z(ESI): 926.5 [M+1].

[0630] 1 H NMR (500MHz, CD3OD): δ:8.22-8.19(m,1H),7.92(s,1H),7.74(d,1H),7.34(d,2H),7.26-7.23(m,1H),7.16-7.13(m,2H),7.02-6.98(m,1H),6.8 4(d,2H),4.80-4.72(m,2H),4.29(s,1H),4.15(s,1H),4.04-3.93(m,2H ),2.72(s,3H),2.62-2.57(m,1H),2.48(s,3H),2.41-2.35(m,1H),2.24 -1.78(m,9H),1.73(s,3H),1.67-1.59(m,2H),1.30(s,6H),1.23(s,6H).

[0631] Compound 4 (1.5 g) was resolved by a chiral column (column: CHIRALCEL OX, 10 μm, 50 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: methanol (0.1% diethylamine), gradient ratio: A:B = 30:70, flow rate: 60 mL / min) to give the title compounds 4-p2 (664 mg, yield: 44.3%) and 4-p1 (703 mg, yield: 46.9%).

[0632] Single configuration compound (shorter retention time): 4-p2 (664 mg, yield: 44.3%).

[0633] MS m / z(ESI): 926.5 [M+1].

[0634] Chiral HPLC analysis: retention time 4.611 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).

[0635] 1 H NMR(500MHz,CD3OD)δ:8.22-8.19(m,1H),7.92(s,1H),7.74(d,1H),7.34(d,2H),7.26-7.23(m,1H),7.16-7.13(m,2H),7.02-6.98(m,1H),6.8 4(d,2H),4.80-4.72(m,2H),4.29(s,1H),4.15(s,1H),4.04-3.93(m,2H ),2.72(s,3H),2.62-2.57(m,1H),2.48(s,3H),2.41-2.35(m,1H),2.24 -1.78(m,9H),1.73(s,3H),1.67-1.59(m,2H),1.30(s,6H),1.23(s,6H).

[0636] Single configuration compound (longer retention time): 4-p1 (703 mg, yield: 46.9%).

[0637] MS m / z(ESI): 926.5 [M+1].

[0638] Chiral HPLC analysis: retention time 4.950 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).

[0639] 1H NMR(500MHz,CD3OD)δ:8.22-8.19(m,1H),7.92(s,1H),7.74(d,1H),7.34(d,2H),7.26-7.23(m,1H),7.16-7.13(m,2H),7.02-6.98(m,1H),6.8 4(d,2H),4.80-4.72(m,2H),4.29(s,1H),4.15(s,1H),4.04-3.93(m,2H ),2.72(s,3H),2.62-2.57(m,1H),2.48(s,3H),2.41-2.35(m,1H),2.24 -1.78(m,9H),1.73(s,3H),1.67-1.59(m,2H),1.30(s,6H),1.23(s,6H).

[0640] Example 5

[0641] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyrimidine-4-carboxamide 5

[0642] first step

[0643] (2-Hydroxyspiro[3.5]non-7-yl)tert-butyl carbamate 5b

[0644] Compound (2-oxospiro[3.5]non-7-yl)carbamate tert-butyl 5a (250 mg, 987 μmol, Shanghai Biotech) was dissolved in methanol (2 mL), and sodium borohydride (75 mg, 1.98 mmol) was added under ice bath. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, 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 the title compound 5b (260 mg), which was used directly in the next reaction without purification.

[0645] MS m / z(ESI):256.4[M+1].

[0646] Step 2

[0647] (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)spiro[3.5]non-7-yl)tert-butyl carbamate 5c

[0648] Crude compound 5b (150 mg, 587 μmol), compound 2j (238 mg, 587 μmol), and triphenylphosphine (308 mg, 1.17 mmol, Shanghai Titan) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (238 mg, 1.17 mmol) was added under ice bath conditions, and the mixture was stirred at 70 °C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain crude title compound 5c (377 mg), which was used directly in the next reaction without purification.

[0649] MS m / z(ESI): 643.5 [M+1].

[0650] Step 3

[0651] (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)spiro[3.5]non-7-amine 5d

[0652] The crude compound 5c (377 mg, 587 μmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (1 mL) was added. The mixture was stirred for 1 hour. Water was added to the reaction solution, and the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (5 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 5d (150 mg, yield: 47.1%).

[0653] MS m / z(ESI): 543.3 [M+1].

[0654] Step 4

[0655] (S)-6-oxo-1-(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)spiro[3.5]non-7-yl)-1,6-dihydropyrimidine-4-carboxylic acid methyl ester 5e

[0656] Methyl 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid ester (10 mg, 65 μmol) was dissolved in N,N'-dimethylacetamide (1 mL), and then added... Molecular sieve (28 mg, 65 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (31 mg, 82 μmol), and 1,8-diazabicycloundec-7-ene (15 mg, 97 μmol) were stirred for 5 minutes. Then, compound 5d (38 mg, 72 μmol) was added, and the reaction was stirred for another 2 hours. Water was added to the reaction mixture, 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 purified by silica gel column chromatography using eluent system A to give the title compound 5e (25 mg, yield: 56.7%).

[0657] MS m / z(ESI): 680.2 [M+1].

[0658] Step 5

[0659] (S)-6-oxo-1-(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)spiro[3.5]non-7-yl)-1,6-dihydropyrimidine-4-carboxylic acid 5f

[0660] Compound 5e (25 mg, 37 μmol) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and lithium hydroxide monohydrate (10 mg, 238 μmol) was added. The mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution 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 the crude title compound 5f (25 mg), which was used directly in the next reaction without purification.

[0661] MS m / z(ESI): 666.4 [M+1].

[0662] Step 6

[0663] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyrimidine-4-carboxamide 5

[0664] The crude compound 5f (25 mg, 38 μmol) and compound 1e (12 mg, 38 μmol) were dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (15 mg, 113 μmol) and n-butylphosphine (41 mg, 56 μmol, 50% ethyl acetate solution) were added. The mixture was stirred for 2 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 title compound 5 (10 mg, yield: 28.7%).

[0665] MS m / z(ESI): 926.5 [M+1].

[0666] 1 H NMR(500MHz,CD3OD)δ:8.56(d,1H),7.92(s,1H),7.74(dd,1H),7.34(d,2H),7.16(t,1H) ,7.14(s,1H),7.06(s,1H),7.01(dt,1H),6.88-6.81(m,2H),4.81-4.71(m,2H),4.60(s,1 H),4.34(d,1H),4.04(s,1H),4.03-3.92(m,2H),2.72(s,3H),2.65(s,1H),2.48(s,3H),2 .40(d,1H),2.04-1.83(m,8H),1.73(s,3H),1.72-1.63(m,2H),1.29(t,6H),1.22(s,6H).

[0667] Example 6

[0668] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(1-((R)-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)propionyl)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide 6

[0669] first step

[0670] (R)-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)methyl propionate 6b

[0671] Compound 2j (500 mg, 1.23 mmol), L-methyl lactate 6a (130 mg, 1.25 mmol, Shanghai Titan), and triphenylphosphine (500 mg, 1.91 mmol) were dissolved in tetrahydrofuran (20 mL). Diethyl azodicarbonate (330 mg, 1.89 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 3 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 6b (510 mg, yield: 84.1%).

[0672] MS m / z(ESI):492.9[M+1].

[0673] Step 2

[0674] (R)-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)propionic acid 6c

[0675] Compound 6b (500 mg, 1.02 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (200 mg, 4.77 mmol) was added. The mixture was stirred for 30 minutes. The pH of the reaction solution was adjusted to approximately 4 with 1 M hydrochloric acid solution. The solution was extracted 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 to obtain crude compound 6c (400 mg), which was used directly in the next reaction without purification.

[0676] MS m / z(ESI):478.4[M+1].

[0677] Step 3

[0678] 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester 6d

[0679] Compound 4a (300 mg, 1.95 mmol) and 1-tert-butoxycarbonyl-4-hydroxypiperidine (400 mg, 1.99 mmol, Shanghai Titan) were dissolved in tetrahydrofuran (10 mL). Triphenylphosphine (1.02 g, 3.89 mmol) and diisopropyl azodicarbonate (787 mg, 3.89 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6d (528 mg, yield: 80.4%).

[0680] MS m / z(ESI): 338.3 [M+1].

[0681] Step 4

[0682] 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid 6e

[0683] Compound 6d (528 mg, 1.57 mmol) was dissolved in tetrahydrofuran (6 mL) and water (3 mL), and lithium hydroxide monohydrate (350 mg, 8.34 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 (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 the crude title compound 6e (506 mg), which was used directly in the next reaction without purification.

[0684] MS m / z(ESI): 324.2 [M+1].

[0685] Step 5

[0686] 4-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-6-oxopyridazine-1(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester 6f

[0687] Crude compound 6e (500 mg, 1.55 mmol) and compound 1e (430 mg, 1.36 mmol) were dissolved in dichloromethane (20 mL). N,N-diisopropylethylamine (900 mg, 6.96 mmol) and n-butylphosphine anhydride (1.67 g, 2.32 mmol, 50% ethyl acetate solution) were added under ice bath conditions. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6f (620 mg, yield: 68.6%).

[0688] MS m / z(ESI): 584.4 [M+1].

[0689] Step 6

[0690] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide hydrochloride 6g

[0691] Compound 6f (60 mg, 103 μmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (1 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 6 g (59 mg). The product was used directly in the next step of the reaction without purification.

[0692] MS m / z(ESI):484.4[M+1].

[0693] Step 7

[0694] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(1-((R)-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)propionyl)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide 6

[0695] Crude compound 6 g (59 mg, 113 μmol) and crude compound 6c (55 mg, 115 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), and N,N-diisopropylethylamine (59 mg, 457 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (65 mg, 171 μmol) were added. The mixture was stirred for 20 min. The reaction solution 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 6 (54 mg, yield: 50.5%).

[0696] MS m / z(ESI): 943.7 [M+1].

[0697] 1 H NMR (500MHz, CD3OD): δ8.19(d,1H),7.92(s,1H),7.74(d,1H),7.40-7.34(m,2H),7.27(d,1H),7.1 7-7.13(m,2H),7.02-6.98(m,1H),6.95-6.88(m,2H),4.79-4.73(m,1H),4.68-4.60(m,1H),4.46-4 .28(m,2H),4.18-4.14(m,1H),4.05-3.93(m,2H),3.43-3.36(m,1H),2.93-2.84(m,1H),2.72(s,3H ),2.48(s,3H),2.12-1.73(m,8H),1.66-1.56(m,3H),1.38-1.34(m,1H),1.30(d,6H),1.23(d,6H).

[0698] Example 7

[0699] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide7

[0700] first step

[0701] 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 7b

[0702] Compound 2j (2 g, 4.93 mmol) and methyl 2,4-dibromobutyrate 7a (1.55 g, 5.96 mmol, Shanghai Bio-Tech) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.37 g, 9.91 mmol) was added. The mixture was stirred for 7 hours. The reaction solution was diluted with saturated sodium chloride solution, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 7b (3 g), which was used directly in the next reaction without purification.

[0703] MS m / z(ESI): 584.2 [M+1].

[0704] Step 2

[0705] (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 7c

[0706] The crude compound 7b (3 g, 5.13 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -40 °C, and a 1 M potassium tert-butoxide solution in tetrahydrofuran (4.6 mL) was added. The mixture was stirred steadily for 20 minutes. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (30 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 7c (911 mg, yield: 35.2%).

[0707] MS m / z(ESI): 504.5 [M+1].

[0708] Step 3

[0709] (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 7d

[0710] Compound 7c (911 mg, 1.81 mmol) was dissolved in tetrahydrofuran (15 mL) and water (7.5 mL), and lithium hydroxide monohydrate (759 mg, 18.1 mmol) was added. The mixture was stirred for 8 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), 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 7d (900 mg), which was used directly in the next reaction without purification.

[0711] MS m / z(ESI): 490.3 [M+1].

[0712] Step 4

[0713] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide7

[0714] 6 g (58 mg, 111 μmol) of crude compound 7d (55 mg, 112 μmol) was dissolved in N,N'-dimethylformamide (1.5 mL), and N,N-diisopropylethylamine (58 mg, 449 μmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (64 mg, 168 μmol) were added. The mixture was stirred for 20 min. The reaction solution 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 7 (38 mg, yield: 35.7%).

[0715] MS m / z(ESI): 955.6 [M+1].

[0716] 1H NMR(500MHz,CD3OD)δ:8.08(d,1H),7.92(s,1H),7.74(d,1H),7.40-7.34(m,2H),7.23(d,1H),7 .17-7.13(m,2H),7.11-7.06(m,2H),7.00(dd,1H),4.81-4.71(m,1H),4.55-4.43(m,1H),4.32-4 .25(m,1H),4.18-4.09(m,1H),4.07-3.92(m,2H),2.91-2.79(m,1H),2.73(s,3H),2.48(s,3H), 2.06-1.76(m,4H),1.72(s,3H),1.68-1.31(m,6H),1.29(s,6H),1.22(s,6H),1.19-1.10(m,1H).

[0717] Example 8

[0718] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(4-((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)oxy)cyclohexyl)-1,6-dihydropyridazine-4-carboxamide8

[0719] first step

[0720] tert-Butyldimethyl((4-(prop-2-yn-1-yloxy)cyclohexyl)oxy)silane 8b

[0721] 4-((tert-butyldimethylsilyl)oxy)cyclohexanol 8a (230 mg, 998 μmol, Shanghai Bide) was dissolved in tetrahydrofuran (4 mL). Sodium hydride (60 mg, 1.5 mmol, 60% purity) was added in an ice bath, and the reaction was stirred for 20 minutes. Then, 3-bromopropyne (237.5 mg, 2.0 mmol, Shanghai Titan) was added, and the reaction was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution, 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 8b (214 mg, yield: 79.9%).

[0722] Step 2

[0723] 4-(prop-2-yn-1-yloxy)cyclohexyl-1-ol 8c

[0724] Compound 8b (214 mg, 797 μmol) was dissolved in methanol (0.5 mL), and 1,4-dioxane solution (3 mL) of 4M hydrogen chloride was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The pH of the residue was adjusted to approximately 7-8 with saturated sodium bicarbonate solution, and the residue 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 8c (123 mg). The product was used directly in the next reaction without purification.

[0725] Step 3

[0726] 6-Oxo-1-(4-(prop-2-yn-1-yloxy)cyclohexyl)-1,6-dihydropyridazine-4-carboxylic acid methyl ester 8d

[0727] Crude compound 8c (123 mg, 798 μmol), compound 4a (123 mg, 798 μmol, Shanghai Adamas), and triphenylphosphine (418 mg, 1.60 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (323 mg, 1.60 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8d (200 mg, yield: 86.3%).

[0728] MS m / z(ESI):291.0[M+1].

[0729] Step 4

[0730] 6-Oxo-1-(4-((3-(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)phenyl)prop-2-yn-1-yl)oxy)cyclohexyl)-1,6-dihydropyridazine-4-carboxylic acid 8e

[0731] Compound 8d (200 mg, 689 μmol) and compound 1h (150 mg, 354 μmol) were dissolved in acetonitrile (8 mL). Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2) (56 mg, 71 μmol), 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene) (41 mg, 71 μmol), and cesium carbonate (345 mg, 1.06 mmol) were added, and the mixture was stirred at 100 °C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 8e (160 mg, yield: 68.1%).

[0732] MS m / z(ESI): 664.9 [M+1].

[0733] Step 5

[0734] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(4-((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)oxy)cyclohexyl)-1,6-dihydropyridazine-4-carboxamide8

[0735] Compound 8e (160 mg, 241 μmol) and compound 1e (76 mg, 241 μmol) were dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (156 mg, 1.21 mmol) and n-butylphosphine anhydride (260 mg, 362 μmol, 50% ethyl acetate solution) were added under ice bath conditions. The mixture was stirred at room temperature for 1 hour. 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, 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 (20 mg, yield: 9.0%).

[0736] MS m / z(ESI): 924.7 [M+1].

[0737] 1H NMR(500MHz, CDCl3)δ:8.16(dd,1H),7.64(s,1H),7.58(d,1H),7.43-7.40(m,2H),7.36( d,2H),7.08(s,1H),7.05(s,1H),6.95(s,1H),6.79(dd,1H),6.19(t,1H),4.99-4.92(m,1 H),4.74(t,1H),4.43(d,2H),4.13-4.03(m,4H),3.92(s,1H),2.68(s,3H),2.40(s,3H), 2.21-2.12(m,3H),2.02-1.86(m,2H),1.69-1.61(m,4H),1.34-1.25(m,8H),1.21(s,6H).

[0738] Example 9

[0739] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)benzyl)-2-azaspiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 9

[0740] first step

[0741] 7-(4-(methoxycarbonyl)-6-oxopyridazine-1(6H)-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 9b

[0742] Compound 4a (1 g, 6.49 mmol), compound 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 9a (1.65 g, 6.84 mmol, Shanghai Leyan), and triphenylphosphine (3.41 g, 13.0 mmol) were dissolved in tetrahydrofuran (32 mL). Diisopropyl azodicarbonate (2.63 g, 13.0 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. 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 9b (1.34 g, yield: 54.7%).

[0743] MS m / z(ESI): 378.3 [M+1].

[0744] Step 2

[0745] 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid 9c

[0746] Compound 9b (340 mg, 901 μmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (114 mg, 2.7 mmol) was added. The mixture was stirred for 2 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 (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 9c (328 mg), which was used directly in the next reaction without purification.

[0747] MS m / z(ESI): 364.3 [M+1].

[0748] Step 3

[0749] 7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)aminocarbonyl)-6-oxopyridazine-1(6H)-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 9d

[0750] Crude compound 9c (327 mg, 900 μmol) and compound 1e (284 mg, 901 μmol) were dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (582 mg, 4.5 mmol) and n-butylphosphine anhydride (972 mg, 1.35 mmol, 50% ethyl acetate solution) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The residue was extracted with ethyl acetate (10 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 B to give the title compound 9d (540 mg, yield: 96.1%).

[0751] MS m / z(ESI): 624.0 [M+1].

[0752] Step 4

[0753] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(2-azaspiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide hydrochloride 9e

[0754] Compound 9d (100 mg, 160 μmol) was dissolved in methanol (0.5 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (4 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 9e (90 mg). The product was used directly in the next reaction without purification.

[0755] MS m / z(ESI): 524.5 [M+1].

[0756] Step 5

[0757] 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)benzaldehyde 9g

[0758] 2-((4-chloro-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaheptane-6-yl)methyl)oxazole 9f (200 mg, 575 μmol, prepared by the method disclosed in Example 37 on page 461 of patent application "WO2024054603"), 4-formylphenylboronic acid (112 mg, 748 μmol, Shanghai Titan) were dissolved in dioxane (10 mL) and water (1 mL), and tris(dibenzylideneacetone)dipalladium(II) (105 mg, 115 μmol), tricyclohexylphosphine (48 mg, 173 μmol) and potassium phosphate (427 mg, 2.01 mmol) were added, and the mixture was stirred at 90 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give 9 g (180 mg, yield: 75.0%) of the title compound.

[0759] MS m / z(ESI):418.4[M+1].

[0760] Step 6

[0761] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)benzyl)-2-azaspiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 9

[0762] Crude compound 9e (90 mg, 161 μmol) and compound 9g (67 mg, 161 μmol) were dissolved in tetrahydrofuran (3 mL), and sodium acetate (66 mg, 804 μmol) and sodium triacetoxyborohydride (341 mg, 1.61 mmol) were added. The mixture was stirred for 1 hour, then heated to 50 °C and stirred for another hour. After the reaction mixture cooled to room temperature, saturated sodium chloride solution was added, 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. 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 9 (10 mg, yield: 6.7%).

[0763] MS m / z(ESI): 925.7 [M+1].

[0764] 1 H NMR (500MHz, CDCl3): δ8.12(d,1H),7.63(s,1H),7.57(d,1H),7.35(d,2H),7.27(s,1H),7 .05(d,2H),6.95(d,1H),6.79(dd,1H),6.14(d,1H),4.89-4.83(m,2H),4.74(t,1H),4.14- 4.03(m,4H),3.67(s,2H),3.09(s,2H),3.00(s,2H),2.68(s,3H),2.40(s,3H),2.22(t,1H) ,2.09-2.01(m,3H),1.76-1.72(m,4H),1.70-1.61(m,3H),1.31-1.24(m,9H),1.21(s,3H).

[0765] Examples 9-p1, 9-p2

[0766] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)benzyl)-2-azaspiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 9-p1

[0767] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(2-(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)benzyl)-2-azaspiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 9-p2

[0768] Compound 9 (118 mg) was resolved by a chiral column (column: ChiralPak IG, 5 μm, 20 mm ID*250 mm L (Daicel); mobile phase A: acetonitrile, mobile phase B: ethanol, gradient ratio: A:B = 20:80, flow rate: 20 mL / min) to give the title compound (44 mg, yield: 37.3%) and (44 mg, yield: 37.3%).

[0769] Single configuration compound (shorter retention time): (44 mg, yield: 37.3%).

[0770] MS m / z(ESI): 924.9 [M+1].

[0771] Chiral HPLC analysis: retention time 4.900 min, purity: 100.0% (column: ChiralPak IG, 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).

[0772] 1 H NMR(500MHz, CDCl3)δ:8.11(d,1H),7.64(s,1H),7.58(d,1H),7.41(d,2H),7.3 4(d,2H),7.05(d,2H),6.95(d,1H),6.80(d,1H),6.15(d,1H),4.86(t,1H),4.75 (dd,1H),4.10-4.05(m,4H),3.90(s,2H),3.30(s,4H),2.68(s,3H),2.41(s,3H ),2.25-2.19(m,4H),1.78-1.66(m,4H),1.59(s,3H),1.24(s,9H),1.21(s,3H).

[0773] Single-configuration compound (longer retention time): (44 mg, yield: 37.3%).

[0774] MS m / z(ESI): 924.9 [M+1].

[0775] Chiral HPLC analysis: retention time 7.732 min, purity: 99.4% (column: ChiralPak IG, 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).

[0776] 1 H NMR(500MHz, CDCl3)δ:8.11(d,1H),7.64(s,1H),7.58(d,1H),7.45(d,2H),7. 38(d,2H),7.05(d,2H),6.95(d,1H),6.80(d,1H),6.15(d,1H),4.86(t,1H),4 .75(dd,1H),4.13-4.05(m,6H),3.70-3.25(m,4H),2.69(s,3H),2.41(s,3H), 2.26-2.20(m,2H),1.81-1.65(m,6H),1.60(s,3H),1.24(s,9H),1.21(s,3H).

[0777] Example 10

[0778] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)methyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide 10

[0779] first step

[0780] (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)methyl)cyclopropane-1-carboxylic acid ethyl ester 10b

[0781] Compound 2j (75 mg, 0.19 mmol), ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate 10a (43 mg, 0.30 mmol, Shanghai Titan), and triphenylphosphine (97 mg, 0.37 mmol) were dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarbonate (75 mg, 0.37 mmol) 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 using eluent system A to give title compound 10b (88 mg, yield: 89.5%).

[0782] MS m / z(ESI): 531.9 [M+1].

[0783] Step 2

[0784] (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)methyl)cyclopropane-1-carboxylic acid 10c

[0785] Compound 10b (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (70 mg, 1.66 mmol) was added, and the mixture was stirred at 40 °C for 1 hour. The pH of the reaction solution was adjusted to approximately 4 with 1 M hydrochloric acid solution. The mixture was extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 10c (84 mg), which was used directly in the next reaction without purification.

[0786] MS m / z(ESI): 503.9 [M+1].

[0787] Step 3

[0788] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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)methyl)cyclopropane-1-carbonyl)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide 10

[0789] Crude compound 10c (84 mg, 0.17 mmol), compound 6 g (88 mg, 0.17 mmol), and N,N-diisopropylethylamine (110 mg, 0.85 mmol) were dissolved in dichloromethane (3 mL). 1-Butylphosphine anhydride (183 mg, 0.25 mmol, 50% ethyl acetate solution) was added at 0 °C, and the mixture was stirred for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (Waters-2545-2489-2767, column: Welch Xtimate C18, prep 30*150 mm; 5 μm; C18, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40-70%, flow rate: 30 mL / min) to give title compound 10 (85 mg, yield: 52.0%).

[0790] MS m / z(ESI): 968.9 [M+1].

[0791] 1 H NMR(500MHz, CDCl3)δ:8.12(d,1H),7.63(s,1H),7.59(d,1H),7.35(d,2H),7.1 0(d,1H),7.04(s,1H),6.97(d,1H),6.80(dd,3H),6.21(d,1H),5.13(t,1H),4.7 5(s,2H),4.70(t,1H),4.12-4.01(m,6H),2.67(s,3H),2.41(s,3H),1.92(s,4H) ,1.69(s,3H),1.46(s,3H),1.26(d,6H),1.22(s,5H),1.10(s,2H),0.98(t,2H).

[0792] Example 11

[0793] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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-d2)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide11

[0794] first step

[0795] (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]diazepeptidyl-4-yl)phenoxy)methyl acetate-d2 11b

[0796] Compound 2j (75 mg, 0.19 mmol) and methyl 2-bromoacetate-d2 11a (46 mg, 0.30 mmol, Alfaesa) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (77 mg, 0.56 mmol) was added. The mixture was stirred for 3 hours. The reaction solution was diluted with saturated sodium chloride solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 11b (88 mg), which was used directly in the next reaction without purification.

[0797] MS m / z(ESI):479.9[M+1].

[0798] Step 2

[0799] (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]diazepeptidyl-4-yl)phenoxy)acetic acid-2,2-d2 11c

[0800] The crude compound 11b (88 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1.5 mL) and water (0.5 mL), and lithium hydroxide monohydrate (39 mg, 0.93 mmol) was added. The mixture was stirred for 3 hours. The pH of the reaction solution was adjusted to about 4 with 1 M hydrochloric acid solution. The solution was extracted with dichloromethane (10 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 to obtain the crude title compound 11c (85 mg), which was used directly in the next step of the reaction without purification.

[0801] MS m / z(ESI):466.5[M+1].

[0802] Step 3

[0803] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-(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-d2)piperidin-4-yl)-1,6-dihydropyridazine-4-carboxamide11

[0804] Crude compound 11c (78 mg, 0.17 mmol), compound 6 g (88 mg, 0.17 mmol), and N,N-diisopropylethylamine (109 mg, 0.85 mmol) were dissolved in dichloromethane (3 mL). 1-Butylphosphine anhydride (181 mg, 0.25 mmol, 50% ethyl acetate solution) was added at 0 °C, and the mixture was stirred for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (Waters-2545-2489-2767, column: Welch Xtimate C18, prep 30*150 mm; 5 μm; C18, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40-70%, flow rate: 30 mL / min) to give title compound 11 (90 mg, yield: 57.7%).

[0805] MS m / z(ESI): 930.9 [M+1].

[0806] 1 H NMR(500MHz, CDCl3)δ:8.13(d,1H),7.63(s,1H),7.58(d,1H),7.35(d,2H),7.09 (d,1H),7.04(s,1H),6.96(s,1H),6.92(dd,2H),6.80(dd,1H),6.21(dd,1H),5. 13(d,1H),4.71(t,2H),4.17-4.05(m,5H),3.25-3.20(m,1H),2.78(t,1H),2.67 (s,3H),2.40(s,3H),1.93-1.88(m,4H),1.69(s,3H),1.25(s,6H),1.21(s,6H).

[0807] Example 12

[0808] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-methyl-6-oxo-5-(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]diazepeptide-4-yl)phenoxy)-7-azaspiro[3.5]non-7-yl)-1,6-dihydropyridine-2-carboxamide 12

[0809] first step

[0810] 2-((tert-butyldiphenylsilyl)oxy)-7-azaspiro[3.5]nonane 12b

[0811] 7-azaspiro[3.5]nonane-2-ol hydrochloride 12a (1.1 g, 6.19 mmol, prepared by the method disclosed in Example 59 on page 77 of patent application "WO2017001660") and imidazole (1.69 g, 24.82 mmol) were dissolved in dichloromethane (35 mL), and tert-butyldiphenylchlorosilane (4.26 g, 15.50 mmol) was added under ice bath. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 12b (1.7 g, yield: 66.0%).

[0812] MS m / z(ESI): 380.2 [M+1].

[0813] Step 2

[0814] 5-(2-((tert-butyldiphenylsilyl)oxy)-7-azaspiro[3.5]non-7-yl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid methyl ester 12c

[0815] Compound 12b (1.0 g, 2.40 mmol), methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (400 mg, 1.63 mmol, prepared by the method disclosed in Example 6-24 on page 18 of patent application “US2015111747”), palladium acetate (180 mg, 802 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.0 g, 1.61 mmol), and cesium carbonate (1.60 g, 4.91 mmol) were dissolved in 1,4-dioxane (30 mL) and reacted at 90 °C for 16 hours. After the reaction solution cooled to room temperature, it was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 12c (260 mg, yield: 29.4%).

[0816] MS m / z(ESI): 545.5 [M+1].

[0817] Step 3

[0818] 5-(2-((tert-butyldiphenylsilyl)oxy)-7-azaspiro[3.5]non-7-yl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid 12d

[0819] Compound 12c (260 mg, 486.5 μmol) was dissolved in tetrahydrofuran (5 mL) and water (3 mL), and lithium hydroxide monohydrate (125 mg, 2.98 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 (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 the crude title compound 12d (260 mg), which was used directly in the next reaction without purification.

[0820] MS m / z(ESI): 531.5 [M+1].

[0821] Step 4

[0822] 5-(2-((tert-butyldiphenylsilyl)oxy)-7-azaspiro[3.5]non-7-yl)-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide 12e

[0823] Crude compound 12d (260 mg, 490 μmol) and compound 1e (147 mg, 466 μmol) were dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (285 mg, 2.2 mmol) and n-butylphosphine anhydride (529 mg, 735 μmol, 50% ethyl acetate solution) were added. The mixture was stirred for 1 hour, the reaction solution was concentrated under reduced pressure, water was added, 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. The residue was purified by silica gel column chromatography using eluent system B to give title compound 12e (224 mg, yield: 57.8%).

[0824] MS m / z(ESI): 791.7 [M+1].

[0825] Step 5

[0826] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide 12f

[0827] Compound 12e (224 mg, 283 μmol) was dissolved in tetrahydrofuran (5 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (710 μL) was added. The mixture was stirred at 33 °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 using eluent system B to give the title compound 12f (150 mg, yield: 95.8%).

[0828] MS m / z(ESI): 553.4 [M+1].

[0829] Step 6

[0830] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-methyl-6-oxo-5-(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]diazepeptide-4-yl)phenoxy)-7-azaspiro[3.5]non-7-yl)-1,6-dihydropyridine-2-carboxamide 12

[0831] Compound 12f (110 mg, 199 μmol), compound 2j (90 mg, 222 μmol), and triphenylphosphine (105 mg, 400 μmol) were dissolved in tetrahydrofuran (5 mL). Diisopropyl azodicarbonate (81 mg, 400 μmol) was added under ice bath conditions, and the mixture was heated to 70 °C and stirred 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, 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 (40 mg, yield: 21.4%).

[0832] MS m / z(ESI): 940.6 [M+1].

[0833] H NMR (500MHz, CD3OD): δ7.91(s,1H),7.73(dd,1H),7.33(d,2H),7.14(s,2H),6.99(dd,1H ),6.88(d,1H),6.83(d,2H),6.53(d,1H),4.82-4.77(m,1H),4.76-4.72(m,1H),4.28(s,1 H),4.11(s,1H),4.04-3.92(m,2H),3.58(s,3H),3.13-3.00(m,4H),2.72(s,3H),2.54-2 .48(m,5H),1.98-1.91(m,2H),1.87-1.77(m,4H),1.72(s,3H),1.29(s,6H),1.23(s,6H).

[0834] Example 13

[0835] N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13

[0836] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13-p1

[0837] N-((1r,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13-p2

[0838] first step

[0839] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 13b

[0840] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride 13a (2.35 g, 7.56 mmol, prepared by the method disclosed in Example 101 on page 103 of patent application "WO2024146617") and crude compound 4c (4.35 g, 8.42 mmol) were dissolved in dichloromethane (40 mL), and N,N-diisopropyl 5.45 g of methyl ethylamine (42.2 mmol) and 9.10 g of butylphosphine (12.6 mmol, 50% ethyl acetate solution) were stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 13b (3.96 g, yield: 60.8%).

[0841] MS m / z(ESI): 773.7 [M+1].

[0842] Step 2

[0843] N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 13c

[0844] Compound 13b (3.96 g, 5.12 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (12.8 mL) was added. The mixture was stirred at 40 °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 using eluent system B to give the title compound 13c (2.61 g, yield: 95.3%).

[0845] MS m / z(ESI): 535.5 [M+1].

[0846] Step 3

[0847] N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13

[0848] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13-p1

[0849] N-((1r,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 13-p2

[0850] Compound 13c (2.57 g, 4.81 mmol) and compound 2j (2.04 g, 5.03 mmol) were dissolved in toluene (50 mL), and cyanomethylenetri-n-butylphosphine (5.0 g, 20.7 mmol) was added. The mixture was stirred at 125 °C for 2 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: 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 13 (3.1 g, yield: 69.9%).

[0851] MS m / z(ESI): 922.8 [M+1].

[0852] 1H NMR (500MHz, CD3OD): δ8.20(d,1H),7.91(d,1H),7.54(d,1H),7.34(d,2H),7.24 (d,1H),7.16-7.13(m,1H),6.84(d,2H),6.64(d,1H),6.56(dd,1H),4.80-4.72(m ,2H),4.26(s,1H),4.14(s,1H),4.04-3.93(m,5H),2.72(s,3H),2.62-2.57(m,1H ),2.48(s,3H),2.41-2.36(m,1H),2.00-1.63(m,14H),1.30(s,6H),1.24(s,6H).

[0853] Compound 13 (3.1 g) was resolved by a chiral column (column: CHIRALPAK IH, 10 μm, 50 mm * 250 mm; mobile phase A: methanol, mobile phase B: acetonitrile, gradient ratio: A:B = 90:10, flow rate: 60 mL / min) to give title compounds 13-p2 (1.3 g, yield: 41.9%) and 13-p1 (1.3 g, yield: 41.9%).

[0854] Single configuration compound (shorter retention time): 13-p2 (1.3 g, yield: 41.9%).

[0855] MS m / z(ESI): 922.8 [M+1].

[0856] Chiral HPLC analysis: retention time 22.474 min, purity: 99.9% (column: ChiralPak ID, 4.6*150mm, 5μm; mobile phase A: ethanol (0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0857] 1H NMR(500MHz,CD3OD)δ:8.20(d,1H),7.91(d,1H),7.54(d,1H),7.34(d,2H),7.24 (d,1H),7.16-7.13(m,1H),6.84(d,2H),6.64(d,1H),6.56(dd,1H),4.80-4.72(m ,2H),4.26(s,1H),4.14(s,1H),4.04-3.93(m,5H),2.72(s,3H),2.62-2.57(m,1H ),2.48(s,3H),2.41-2.36(m,1H),2.00-1.63(m,14H),1.30(s,6H),1.24(s,6H).

[0858] Single configuration compound (longer retention time): 13-p1 (1.3 g, yield: 41.9%).

[0859] MS m / z(ESI): 922.8 [M+1].

[0860] Chiral HPLC analysis: retention time 26.749 min, purity: 99.9% (column: ChiralPak ID, 4.6*150mm, 5μm; mobile phase A: ethanol (0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0861] 1 H NMR(500MHz,CD3OD)δ:8.20(d,1H),7.91(d,1H),7.54(d,1H),7.34(d,2H),7.24 (d,1H),7.16-7.13(m,1H),6.84(d,2H),6.64(d,1H),6.56(dd,1H),4.80-4.72(m ,2H),4.26(s,1H),4.14(s,1H),4.04-3.93(m,5H),2.72(s,3H),2.62-2.57(m,1H ),2.48(s,3H),2.41-2.36(m,1H),2.00-1.63(m,14H),1.30(s,6H),1.24(s,6H).

[0862] Example 14

[0863] N-((1r,3r)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14

[0864] N-((1r,3S)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14-p1

[0865] N-((1r,3R)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14-p2

[0866] first step

[0867] 1-(2-((tert-butyldiphenylsilyl)oxy)spiro[3.5]non-7-yl)-N-((1r,3r)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 14b

[0868] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethoxy)benzonitrile hydrochloride 14a (320 mg, 877 μmol, prepared by the method disclosed in Example 41 on page 313 of patent application "WO2025085738") and crude compound 4c (500 mg, 968 μmol) were dissolved in dichloromethane (10 mL), and N,N-di Isopropyl ethylamine (626 mg, 4.84 mmol) and n-butylphosphine anhydride (1.05 g, 1.46 mmol, 50% ethyl acetate solution) were stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture 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. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 14b (590 mg, yield: 73.7%).

[0869] MS m / z(ESI): 827.7 [M+1].

[0870] Step 2

[0871] N-((1r,3r)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 14c

[0872] Compound 14b (590 mg, 713 μmol) was dissolved in tetrahydrofuran (10 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (1.6 mL) was added. The mixture was stirred at 40 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 14c (380 mg, yield: 90.5%).

[0873] MS m / z(ESI): 589.5 [M+1].

[0874] Step 3

[0875] N-((1r,3r)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14

[0876] N-((1r,3S)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2S,4R,7S)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14-p1

[0877] N-((1r,3R)-3-(4-cyano-3-(trifluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-oxo-1-((2R,4S,7R)-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)spiro[3.5]non-7-yl)-1,6-dihydropyridazine-4-carboxamide 14-p2

[0878] Compound 14c (380 mg, 646 μmol) and compound 2j (290 mg, 715 μmol) were dissolved in toluene (10 mL), and cyanomethylenetri-n-butylphosphine (640 mg, 2.65 mmol) was added. The mixture was stirred at 125 °C for 2 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: 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 14 (450 mg, yield: 71.4%).

[0879] MS m / z(ESI): 976.8 [M+1].

[0880] 1H NMR (500MHz, CD3OD): δ8.21(d,1H),7.92(d,1H),7.81(d,1H),7.34(d,2H),7.25(s,1H), 7.16-7.13(m,1H),7.06(d,1H),7.02(s,1H),6.84(d,2H),4.80-4.72(m,2H),4.30(s,1H ),4.17(s,1H),4.05-3.93(m,2H),2.73(s,3H),2.64-2.55(m,1H),2.48(s,3H),2.42-2. 35(m,1H),2.00-1.78(m,9H),1.73(s,3H),1.70-1.59(m,2H),1.30(s,6H),1.24(s,6H).

[0881] Compound 14 (450 mg) was resolved by a chiral column (column: CHIRALPAK IA, 10 μm, 50 mm * 250 mm; mobile phase A: ethanol, mobile phase B: acetonitrile, gradient ratio: A:B = 90:10, flow rate: 30 mL / min) to give the title compound (200 mg, yield: 44.4%) and (200 mg, yield: 44.4%).

[0882] Single configuration compound (shorter retention time): (200 mg, yield: 44.4%).

[0883] MS m / z(ESI): 976.8 [M+1].

[0884] Chiral HPLC analysis: retention time 3.873 min, purity: 99.9% (column: ColumnTek IA, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.0 mL / min).

[0885] 1H NMR (500MHz, CD3OD): δ8.21(d,1H),7.92(d,1H),7.81(d,1H),7.34(d,2H),7.25(s,1H), 7.16-7.13(m,1H),7.06(d,1H),7.02(s,1H),6.84(d,2H),4.80-4.72(m,2H),4.30(s,1H ),4.17(s,1H),4.05-3.93(m,2H),2.73(s,3H),2.64-2.55(m,1H),2.48(s,3H),2.42-2. 35(m,1H),2.00-1.78(m,9H),1.73(s,3H),1.70-1.59(m,2H),1.30(s,6H),1.24(s,6H).

[0886] Single-configuration compound (longer retention time): (200 mg, yield: 44.4%).

[0887] MS m / z(ESI): 976.8 [M+1].

[0888] Chiral HPLC analysis: retention time 5.019 min, purity: 99.6% (column: ColumnTek IA, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.0 mL / min).

[0889] 1 H NMR (500MHz, CD3OD): δ8.21(d,1H),7.92(d,1H),7.81(d,1H),7.34(d,2H),7.25(s,1H), 7.16-7.13(m,1H),7.06(d,1H),7.02(s,1H),6.84(d,2H),4.80-4.72(m,2H),4.30(s,1H ),4.17(s,1H),4.05-3.93(m,2H),2.73(s,3H),2.64-2.55(m,1H),2.48(s,3H),2.42-2. 35(m,1H),2.00-1.78(m,9H),1.73(s,3H),1.70-1.59(m,2H),1.30(s,6H),1.24(s,6H).

[0890] Example 15

[0891] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 15

[0892] first step

[0893] 1-(2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester 15a

[0894] 1-((2R,4r,7R)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester 15a-1

[0895] 1-((2S,4S,7S)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester 15a-2

[0896] Compound 4b (31 g, 58.41 mmol) was dissolved in methanol (300 mL), and a solution of 1,4-dioxane with 4 M hydrogen chloride (40 mL) was added in an ice bath. The mixture was stirred for 40 hours. The pH of the reaction mixture was adjusted to approximately 5 by adding saturated sodium bicarbonate solution, followed by the addition of ice water (500 mL). The mixture was extracted with dichloromethane (200 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 B to give the title compound 15a (15.7 g, yield: 91.9%).

[0897] MS m / z(ESI):293.4[M+1].

[0898] Compound 15a (15.7 g) was resolved by a chiral column (column: CHIRALCEL OZ, 10 μm, 5.0 cm * 25 cm; mobile phase A: n-hexane, mobile phase B: methanol, gradient ratio: A:B = 0:100, flow rate: 60 mL / min) to give title compounds 15a-1 (7.5 g, yield: 47.8%) and 15a-2 (7.5 g, yield: 47.8%).

[0899] Single configuration compound (shorter retention time): 15a-1 (7.5 g, yield: 47.8%).

[0900] MS m / z(ESI):293.4[M+1].

[0901] Chiral HPLC analysis: retention time 4.798 min, purity: 99.7% (column: CHIRALPAK IM 150*4.6mm, 10μm; mobile phase A: ethanol (0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B = 50:50, flow rate: 1.0 mL / min).

[0902] Single configuration compound (longer retention time): 15a-2 (7.5 g, yield: 47.8%).

[0903] MS m / z(ESI):293.4[M+1].

[0904] Chiral HPLC analysis: retention time 6.877 min, purity: 99.3% (column: CHIRALPAK IM 150*4.6mm, 10μm; mobile phase A: ethanol (0.1% diethylamine), mobile phase B: n-hexane, gradient ratio: A:B = 50:50, flow rate: 1.0 mL / min).

[0905] Step 2

[0906] 1-((2R,4r,7R)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid 15b

[0907] Compound 15a-1 (7.5 g, 25.66 mmol) was dissolved in tetrahydrofuran (100 mL) and water (50 mL), and lithium hydroxide monohydrate (2.8 g, 66.72 mmol) was added. The mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution was extracted with dichloromethane (100 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 to obtain crude title compound 15b (7 g), which was used directly in the next reaction without purification.

[0908] MS m / z(ESI):279.3[M+1].

[0909] Step 3

[0910] N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4r,7R)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 15c

[0911] Crude compound 15b (1 g, 3.59 mmol) and compound 1e (1.25 g, 3.97 mmol) were dissolved in N,N-dimethylformamide (25 mL). N,N-diisopropylethylamine (2.8 g, 21.66 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.05 g, 5.39 mmol) were added under ice bath conditions. The mixture was stirred for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane (25 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 title compound 15c (1.8 g, yield: 92.9%).

[0912] MS m / z(ESI): 539.6 [M+1].

[0913] Step 4

[0914] 4-Bromo-3-cyclopropylphenol 15e

[0915] Compound 4-bromo-3-iodophenol 15d (200 mg, 669 μmol), cyclopropylboronic acid (70 mg, 815 μmol), tetrakis(triphenylphosphine)palladium (78 mg, 67 μmol), and sodium hydroxide (81 mg, 2.03 mmol) were dissolved in tetrahydrofuran (3 mL) and water (1 mL), and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 15e (72 mg, yield: 50.5%). MS m / z (ESI): 211.0 [M-1].

[0916] Step 5

[0917] 3-Cyclopropyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenol 15f

[0918] Compound 15e (72 mg, 338 μmol), pinacol diborate (130 mg, 512 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30 mg, 35 μmol), and potassium acetate (135 mg, 1.38 mmol) were dissolved in dioxane (5 mL), and the mixture was stirred at 85 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 15f (42 mg, yield: 47.8%).

[0919] MS m / z(ESI):259.1[M-1].

[0920] Step 6

[0921] (S)-3-Cyclopropyl-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)phenol 15h

[0922] Compound 15f (42 mg, 161 μmol), compound (S)-2-((4-chloro-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptide-6-yl)methyl)oxazole 15 g (45 mg, 129 μmol, prepared by the method disclosed in Example 37 on page 461 of patent application "WO2024054603"), tris(dibenzylideneacetone)palladium (19 mg, 21 μmol), tricyclohexylphosphine (12 mg, 43 μmol) and potassium phosphate (83 mg, 391 μmol) were dissolved in dioxane (3 mL) and water (1 mL), and the mixture was stirred at 90 °C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 15h (46 mg, yield: 79.8%).

[0923] MS m / z(ESI):446.5[M+1].

[0924] Step 7

[0925] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 15

[0926] Compound 15h (46 mg, 103 μmol) and compound 15c (55 mg, 102 μmol) were dissolved in toluene (4 mL), and cyanomethylenetri-n-butylphosphine (150 mg, 622 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60-95%, flow rate: 30 mL / min) to give title compound 15 (30 mg, yield: 31.0%).

[0927] MS m / z(ESI): 966.9 [M+1].

[0928] 1 H NMR (500MHz, CD3OD): δ8.20(s,1H),7.91(s,1H),7.74(d,1H),7.24(s,1H),7.18-7.12(m, 2H),7.04-6.95(m,2H),6.67-6.60(m,1H),6.43(s,1H),4.79-4.59(m,2H),4.29(s,1H),4 .15(s,1H),4.10-4.02(m,1H),3.93-3.86(m,1H),2.74(s,3H),2.58-2.51(m,1H),2.43(s ,3H),2.38-2.31(m,1H),1.97-1.59(m,15H),1.29(s,6H),1.23(s,6H),0.67-0.30(m,4H).

[0929] Example 16

[0930] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyano-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4])

[0931] (diazaheptan-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 16

[0932] first step

[0933] (4-((tert-butyldimethylsilyl)oxy)-2-cyanophenyl)boronic acid 16b

[0934] Compound 2-bromo-5-((tert-butyldimethylsilyl)oxy)benzonitrile 16a (200 mg, 640 μmol, prepared by the method of compound 10 disclosed on page 114 of patent application "WO2015166370") was dissolved in tetrahydrofuran (2 mL), cooled to -78 °C, and then a 2.5 M n-butyllithium solution in n-hexane (45 mg, 281 μL, 703 μmol) was added. After stirring for 5 minutes, trimethyl borate (87 mg, 837 μmol) was added, and the reaction was stirred for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, extracted with dichloromethane (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 16b (78 mg, yield: 43.9%).

[0935] MS m / z(ESI):276.3[M-1].

[0936] Step 2

[0937] (S)-5-hydroxy-2-(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)benzonitrile 16c

[0938] Compound 16b (78 mg, 281 μmol), compound 15 g (75 mg, 216 μmol), tris(dibenzylacetone)palladium (30 mg, 33 μmol), tricyclohexylphosphine (20 mg, 71 μmol), and potassium phosphate (138 mg, 650 μmol) were dissolved in dioxane (4 mL) and water (1 mL), and the mixture was stirred at 90 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 16c (18 mg, yield: 19.4%).

[0939] MS m / z(ESI):431.5[M+1].

[0940] Step 3

[0941] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyano-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4])

[0942] (diazaheptan-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 16

[0943] Compound 16c (15 mg, 35 μmol) and compound 15c (18 mg, 33 μmol) were dissolved in toluene (2 mL), and cyanomethylenetri-n-butylphosphine (34 mg, 141 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 16 (15 mg, yield: 45.2%).

[0944] MS m / z(ESI): 952.0 [M+1].

[0945] 1 H NMR (500MHz, CD3OD): δ8.20(d,1H),7.90(s,1H),7.74(d,1H),7.48-7.44(m,1H),7.26-7.23 (m,1H),7.21-7.17(m,2H),7.16-7.14(m,1H),7.13-7.11(m,1H),7.01-6.97(dd,1H),4.86-4 .81(m,2H),4.29(s,1H),4.15(s,1H),4.05-4.00(m,2H),2.71(s,3H),2.65-2.58(m,1H),2.4 6(s,3H),2.44-2.38(m,1H),2.02-1.79(m,8H),1.77-1.63(m,6H),1.29(s,6H),1.23(s,6H).

[0946] Example 17

[0947] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-methoxy-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 17

[0948] first step

[0949] (S)-3-methoxy-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)phenol 17b

[0950] Compound 3-methoxy-4-boronic acid pinacol ester phenol 17a (60 mg, 240 μmol, Shanghai Leyan), compound 15 g (75 mg, 216 μmol), tris(dibenzylacetone)dipalladium (30 mg, 33 μmol), tricyclohexylphosphine (20 mg, 71 μmol), and potassium phosphate (138 mg, 650 μmol) were dissolved in dioxane (3 mL) and water (1 mL), and the mixture was stirred at 90 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 17b (45 mg, yield: 47.9%).

[0951] MS m / z(ESI):436.4[M+1].

[0952] Step 2

[0953] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-methoxy-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 17

[0954] Compound 17b (45 mg, 103 μmol) and compound 15c (55 mg, 102 μmol) were dissolved in toluene (3 mL), and cyanomethylenetri-n-butylphosphine (125 mg, 518 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 17 (35 mg, yield: 35.8%).

[0955] MS m / z(ESI): 956.9 [M+1].

[0956] 1H NMR (500MHz, CD3OD): δ8.21(s,1H),7.93(s,1H),7.74(d,1H),7.25(s,1H),7.23-7.17(m,1H ),7.17-7.13(m,2H),7.01-6.98(m,1H),6.49-6.45(m,1H),6.42(s,1H),4.80-4.74(m,2H),4 .29(s,1H),4.15(s,1H),4.04-3.90(m,2H),3.54(s,3H),2.73(s,3H),2.62-2.56(m,1H),2.4 3(s,3H),2.41-2.35(m,1H),2.01-1.77(m,8H),1.73-1.62(m,6H),1.30(s,6H),1.23(s,6H).

[0957] Example 18

[0958] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 18

[0959] first step

[0960] 2-Cyclopropyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenol 18b

[0961] Compound 4-bromo-2-cyclopropylphenol 18a (40 mg, 188 μmol, prepared by the method disclosed in Example 33 on page 71 of patent application "WO2015153720"), pinacol diboronate (60 mg, 236 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (20 mg, 27 μmol), and potassium acetate (60 mg, 611 μmol) were dissolved in dioxane (5 mL), and the mixture was stirred at 85 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 18b (30 mg, yield: 61.4%).

[0962] MS m / z(ESI):259.2[M-1].

[0963] Step 2

[0964] (S)-2-Cyclopropyl-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 18c

[0965] Compound 18b (25 mg, 96 μmol), compound 15 g (35 mg, 101 μmol), tris(dibenzylacetone)palladium (20 mg, 22 μmol), tricyclohexylphosphine (10 mg, 36 μmol), and potassium phosphate (65 mg, 306 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and the mixture was stirred at 90 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 18c (15 mg, yield: 35.0%).

[0966] MS m / z(ESI):446.5[M+1].

[0967] Step 3

[0968] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 18

[0969] Compound 18c (15 mg, 34 μmol) and compound 15c (20 mg, 37 μmol) were dissolved in toluene (2 mL), and cyanomethylenetri-n-butylphosphine (50 mg, 207 μmol) was added. The mixture was stirred at 125 °C for 2 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 Prep C18 5 μm 30*150 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 65-95%, flow rate: 30 mL / min) to give title compound 18 (3 mg, yield: 9.2%).

[0970] MS m / z(ESI): 966.8 [M+1].

[0971] 1H NMR (500MHz, CD3OD): δ8.18(s,1H),7.91(s,1H),7.73(d,1H),7.22(s,1H), 7.14-7.12(m,2H),7.06-7.04(m,1H),6.99-6.97(m,1H),6.92(s,1H),6.71-

[0972] 6.69(m,1H),4.85-4.79(m,1H),4.77-4.68(m,1H),4.26(s,1H),4.13(s,1H ),3.99-3.94(m,1H),3.92-3.86(m,1H),2.71(s,3H),2.60-2.56(m,1H),2. 45(s,3H),2.43-2.35(m,1H),2.21-2.15(m,1H),2.01-1.86(m,6H),1.80-1 .61(m,8H),1.29(s,6H),1.21(s,6H),0.91-0.89(m,2H),0.58-0.55(m,2H).

[0973] Example 19

[0974] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyano-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4])

[0975] (diazaheptan-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 19

[0976] first step

[0977] (S)-2-hydroxy-5-(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)benzonitrile 19b

[0978] Compound 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzonitrile 19a (65 mg, 265 μmol, prepared by the method disclosed in compound 78 on page 115 of patent application "WO2020009176"), compound 15 g (75 mg, 216 μmol), tris(dibenzylacetone)dipalladium (30 mg, 33 μmol), tricyclohexylphosphine (20 mg, 71 μmol), and potassium phosphate (140 mg, 660 μmol) were dissolved in dioxane (3 mL) and water (1 mL), and the mixture was stirred at 90 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 19b (38 mg, yield: 40.9%). MS m / z (ESI): 431.4 [M+1].

[0979] Step 2

[0980] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyano-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4])

[0981] (diazaheptan-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 19

[0982] Compound 19b (35 mg, 81 μmol) and compound 15c (43 mg, 80 μmol) were dissolved in toluene (3 mL), and cyanomethylenetri-n-butylphosphine (100 mg, 414 μmol) was added. The mixture was stirred at 125 °C for 2 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 (Gilson-GX-281, column: prePulite XP tC18-AX 5 μm 30*150 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 19 (26 mg, yield: 34.3%).

[0983] MS m / z(ESI): 951.8 [M+1].

[0984] 1H NMR (500MHz, CD3OD): δ8.20(d,1H),7.92(s,1H),7.74(d,1H),7.69-7.63(m,2H),7.2 4(d,1H),7.17-7.13(m,2H),7.01(dd,2H),4.97-4.92(m,1H),4.81-4.76(m,1H),4.2 9(s,1H),4.15(s,1H),4.06-3.94(m,2H),2.73(s,3H),2.69-2.62(m,1H),2.49(s,3H ),2.48-2.42(m,1H),2.08-1.84(m,8H),1.79-1.61(m,6H),1.29(s,6H),1.23(s,6H).

[0985] Example 20

[0986] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyano-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 20

[0987] first step

[0988] N-((1r,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4r,7R)-2-hydroxyspiro[3.5]nonane-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 20a

[0989] Crude compound 15b (3.5 g, 12.6 mmol) and compound 13a (4.3 g, 13.8 mmol, prepared by the method disclosed in Example 101 on page 103 of patent application "WO2024146617") were dissolved in N,N-dimethylformamide (100 mL). N,N-diisopropylethylamine (9.7 g, 75.1 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (7.0 g, 18.4 mmol) were added under ice bath conditions. The mixture was stirred for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane (100 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 title compound 20a (6.7 g, yield: 99.6%).

[0990] MS m / z(ESI): 535.5 [M+1].

[0991] Step 2

[0992] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyano-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 20

[0993] Compound 20a (30 mg, 56 μmol) and compound 16c (25 mg, 58 μmol) were dissolved in toluene (2 mL), and cyanomethylenetri-n-butylphosphine (70 mg, 290 μmol) was added. The mixture was stirred at 125 °C for 2 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 (Gilson-GX-281, column: Welch Xtimate Prep C18 5 μm 30*150 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 20 (15 mg, yield: 28.2%).

[0994] MS m / z(ESI): 947.8 [M+1].

[0995] 1H NMR (500MHz, CD3OD): δ8.20(d,1H),7.90(s,1H),7.54(d,1H),7.46(d,1H),7.24(d,1H), 7.22-7.17(m,2H),7.13(s,1H),6.64(s,1H),6.57(dd,1H),4.86-4.80(m,2H),4.26(s,1 H),4.14(s,1H),4.05-4.01(m,2H),3.95(s,3H),2.71(s,3H),2.65-2.59(m,1H),2.46(s ,3H),2.45-2.38(m,1H),2.02-1.79(m,8H),1.73-1.62(m,6H),1.30(s,6H),1.24(s,6H).

[0996] Example 21

[0997] N-((1r,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4S,7R)-2-(3-cyano-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 21

[0998] first step

[0999] 1-((2S,4S,7S)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid 21a

[1000] Compound 15a-2 (4.0 g, 13.7 mmol) was dissolved in tetrahydrofuran (60 mL) and water (30 mL), and lithium hydroxide monohydrate (1.5 g, 35.7 mmol) was added. The mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to approximately 5 with 1 M hydrochloric acid solution. The solution was extracted with dichloromethane (50 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 to obtain crude title compound 21a (3.8 g), which was used directly in the next reaction without purification.

[1001] MS m / z(ESI):279.4[M+1].

[1002] Step 2

[1003] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4S,7S)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 21b

[1004] Crude compound 21a (3.73 g, 13.4 mmol) and compound 13a (5.0 g, 16.1 mmol) were dissolved in N,N-dimethylformamide (150 mL). Under ice bath conditions, N,N-diisopropylethylamine (8.7 g, 67.3 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (7.65 g, 20.1 mmol) were added and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water and extracted with dichloromethane (100 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 title compound 21b (7.0 g, yield: 97.7%).

[1005] MS m / z(ESI): 535.6 [M+1].

[1006] Step 3

[1007] N-((1r,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4S,7R)-2-(3-cyano-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 21

[1008] Compound 21b (30 mg, 56 μmol) and compound 16c (25 mg, 58 μmol) were dissolved in toluene (2 mL), and cyanomethylenetri-n-butylphosphine (70 mg, 290 μmol) was added. The mixture was stirred at 125 °C for 2 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 (Gilson-GX-281, column: Welch Xtimate Prep C18 5 μm 30*150 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 21 (22 mg, yield: 41.4%).

[1009] MS m / z(ESI): 947.8 [M+1].

[1010] 1 H NMR (500MHz, CD3OD): δ8.20(d,1H),7.90(s,1H),7.54(d,1H),7.46(d,1H),7.24(d,1H), 7.22-7.17(m,2H),7.13(s,1H),6.64(s,1H),6.57(dd,1H),4.86-4.80(m,2H),4.26(s,1 H),4.14(s,1H),4.05-4.01(m,2H),3.95(s,3H),2.71(s,3H),2.65-2.59(m,1H),2.46(s ,3H),2.45-2.38(m,1H),2.02-1.79(m,8H),1.73-1.62(m,6H),1.30(s,6H),1.24(s,6H).

[1011] Example 22

[1012] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 22

[1013] first step

[1014] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(2-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 22

[1015] Compound 18c (40 mg, 90 μmol) and compound 20a (50 mg, 94 μmol) were dissolved in toluene (4 mL), and cyanomethylenetri-n-butylphosphine (108 mg, 447 μmol) was added. The mixture was stirred at 125 °C for 2 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 Prep C18 5 μm 30*150 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60-95%, flow rate: 30 mL / min) to give title compound 22 (12 mg, yield: 13.9%).

[1016] MS m / z(ESI): 963.0 [M+1].

[1017] 1 H NMR (500MHz, CD3OD): δ8.18(s,1H),7.91(s,1H),7.53(d,1H),7.22(s,1H),7.14(s,1H),7.06-7.04(m,1H),6.92( s,1H),6.71-6.69(m,1H),6.62(d,1H),6.58-6.51(m,1H),4.79-4.75(m,1H),4.72-4.66(m,1H),4.24(s,1H),4.12 (s,1H),4.04-3.95(m,1H),3.93(s,3H),3.92-3.86(m,1H),2.71(s,3H),2.63-2.56(m,1H),2.45(s,3H),2.43-2. 35(m,1H),2.21-2.08(m,1H),2.01-1.61(m,14H),1.29(s,6H),1.22(s,6H),0.91-0.89(m,2H),0.58-0.55(m,2H).

[1018] Example 23

[1019] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 23

[1020] first step

[1021] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 23

[1022] Compound 15h (15 mg, 34 μmol) and compound 20a (18 mg, 34 μmol) were dissolved in toluene (1 mL), and cyanomethylenetri-n-butylphosphine (58 mg, 240 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 23 (9 mg, yield: 27.8%).

[1023] MS m / z(ESI): 963.0 [M+1].

[1024] 1 H NMR (500MHz, CD3OD): δ8.21(s,1H),7.92(s,1H),7.54(d,1H),7.24(s,1H),7.14(s,1H),7.01-6.95(m,1H),6 .67-6.60(m,2H),6.57(d,1H),6.43(s,1H),4.77-4.59(m,2H),4.26(s,1H),4.15(s,1H),4.10-4.02(m,1H), 3.95(s,3H),3.92-3.86(m,1H),2.74(s,3H),2.58-2.51(m,1H),2.43(s,3H),2.38-2.32(m,1H),2.08-2.02( m,1H),1.99-1.74(m,8H),1.72-1.59(m,6H),1.30(s,6H),1.24(s,6H),0.66-0.54(m,2H),0.49-0.28(m,2H).

[1025] Example 24

[1026] N-((1r,3S)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-4-((S)-2,3,9-trimethyl-6-(oxaz) ol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide twenty four

[1027] N-((1r,3S)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 24

[1028] first step

[1029] tert-butyl((1r,3r)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate 24b

[1030] tert-butyl((1r,3r)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate 24b

[1031] The compound tert-butyl ((1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate (200 mg, 822 μmol, Shanghai Adamas) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (50 mg, 1.30 mmol, 60% purity) was added under ice bath conditions. After stirring for 30 minutes, compound 2-(difluoromethoxy)-4-fluorobenzonitrile 24a (200 mg, 1.07 mmol, prepared by the method disclosed on page 74 of patent application "US2008261979A1") was added, and the mixture was heated to 70 °C and stirred for 1 hour. The reaction solution was quenched in ice water, 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. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 24b (100 mg, yield: 29.6%).

[1032] MS m / z(ESI):411.4[M+1].

[1033] Step 2

[1034] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(difluoromethoxy)benzonitrilehydrochloride 24c

[1035] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(difluoromethoxy)benzonitrile hydrochloride 24c

[1036] Compound 24b (100 mg, 244 μmol) was dissolved in dichloromethane (2 mL), and 4 M dioxane hydrochloride solution (2 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude title compound 24c (85 mg), which was used directly in the next reaction without purification.

[1037] MS m / z(ESI): 311.4 [M+1].

[1038] Step 3

[1039] N-((1r,3R)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4r,7R)-2-hydroxyspiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 24d

[1040] N-((1r,3R)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2R,4r,7R)-2-hydroxyspiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 24d

[1041] Crude compound 24c (85 mg, 245 μmol) and compound 15b (62 mg, 223 μmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, N,N-diisopropylethylamine (190 mg, 1.47 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg, 368 μmol) were added, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water 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 using eluent system A to give the title compound 24d (125 mg, yield: 89.4%).

[1042] MS m / z(ESI): 571.7 [M+1].

[1043] Step 4

[1044] N-((1r,3S)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-4-((S)-2,3,9-trimethyl-6-(oxaz) ol-2-ylmethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide twenty four

[1045] N-((1r,3S)-3-(4-cyano-3-(difluoromethoxy)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-cyclopropyl-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 24

[1046] Compound 15h (40 mg, 90 μmol) and compound 24d (50 mg, 88 μmol) were dissolved in toluene (3 mL), and cyanomethylenetri-n-butylphosphine (105 mg, 435 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 24 (45 mg, yield: 51.5%).

[1047] MS m / z(ESI): 999.1 [M+1].

[1048] Chiral HPLC analysis: retention time 6.788 min, purity: 95.5% (column: ChiralPak IC, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.0 mL / min).

[1049] Compound 24 (45 mg) was resolved by a chiral column (column: CHIRALPAK IC, 5 μm, 20 mm * 250 mm; mobile phase A: acetonitrile, mobile phase B: ethanol, gradient ratio: A:B = 15:85, flow rate: 20 mL / min) to give title compound 24 (27 mg, yield: 66.7%).

[1050] MS m / z(ESI): 999.1 [M+1].

[1051] Chiral HPLC analysis: retention time 6.771 min, purity: 99.9% (column: ChiralPak IC, 4.6*150mm, 5μm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B = 10:90, flow rate: 1.0 mL / min).

[1052] 1H NMR (400MHz, CD3OD): δ8.17(d,1H),7.88(s,1H),7.68(d,1H)7.22-7.19(m,1H),7.10(s,1H),7.04(t,1H,-OCH F2),6.98-6.91(m,1H),6.84(s,2H),6.60(d,1H),6.40(s,1H),4.76-4.52(m,2H),4.23(s,1H),4.12(s,1H),4. 07-3.98(m,1H),3.90-3.82(m,1H),2.70(s,3H),2.55-2.47(m,1H),2.40(s,3H),2.35-2.27(m,1H),1.94-1.71 (m,9H),1.67-1.54(m,6H),1.27(s,6H),1.20(s,6H),0.64-0.51(m,2H),0.46-0.38(m,1H),0.33-0.26(m,1H).

[1053] Example 25

[1054] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3 ,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 25

[1055] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 25

[1056] first step

[1057] tert-butyl 4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenol 25b

[1058] 4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptidyl-4-yl)phenol 25b

[1059] Compound 2-((4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazaphen-6-yl)methyl)-5-cyclopropyl-1,3,4-oxadiazole 25a (37 mg, 80 μmol) was prepared using the method disclosed for compound 20 on page 12 of patent application “CN109503618A”. The following solutions were prepared: methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 40 μmol, Shanghai Bide) and potassium hydroxide (30 mg, 535 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.75 mL), and the mixture was heated to 90 °C and stirred for 3 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 the title compound 25b (10 mg, yield: 28.1%).

[1060] MS m / z(ESI):447.1[M+1].

[1061] Step 2

[1062] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3 ,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 25

[1063] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 25

[1064] Compound 15c (13 mg, 24 μmol) and compound 25b (10 mg, 22 μmol) were dissolved in toluene (2 mL), and cyanomethylenetri-n-butylphosphine (60 mg, 249 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 25 (8 mg, yield: 36.9%).

[1065] MS m / z(ESI): 967.8 [M+1].

[1066] 1H NMR (500MHz, CD3OD): δ8.21(d,1H),7.74(s,1H),7.36(d,2H)7.24(s,1H),7.15(s, 1H),7.00(d,1H),6.86(d,2H),4.80-4.71(m,2H),4.29(s,1H),4.15(s,1H),4.04-3 .93(m,2H),2.73(s,3H),2.63-2.57(m,1H),2.48(s,3H),2.42-2.35(m,1H),2.00- 1.81(m,9H),1.76-1.65(m,6H),1.30(s,6H),1.25-1.21(m,8H),1.15-1.11(m,2H).

[1067] Example 26

[1068] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3 ,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 26

[1069] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 26

[1070] first step

[1071] 5-((4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)methyl)-3-cyclopropyl-1,2,4-oxadiazole 26b

[1072] 5-((4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptide-6-yl)methyl)-3-cyclopropyl-1,2,4-oxadiazole 26b

[1073] Compound tert-butyl(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepeptidyl-6-yl)acetate 26a (450 mg, 985 μmol, Shanghai Shaoyuan) and cyclopropylcarbamate oxime (1.0 g, 9.99 mmol) were dissolved in N-methylpyrrolidone (4 mL), and sodium methoxide (240 mg, 4.44 mmol) was added. The mixture was heated to 70 °C and stirred for 3 hours. The reaction mixture was poured into ice water 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 using eluent system A to give title compound 26b (170 mg, yield: 37.1%).

[1074] MS m / z(ESI): 465.5 [M+1].

[1075] Step 2

[1076] 4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenol 26c

[1077] 4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepeptide-4-yl)phenol 26c

[1078] Compound 26b (150 mg, 323 μmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (150 mg, 165 μmol, Shanghai Bide), and potassium hydroxide (115 mg, 2.05 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1.5 mL). The mixture was heated to 90 °C and stirred for 3 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 26c (28 mg, yield: 19.4%).

[1079] MS m / z(ESI):447.4[M+1].

[1080] Step 3

[1081] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3 ,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 26

[1082] N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4s,7S)-2-(4-(6-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazaheptane-4-yl)phenoxy)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 26

[1083] Compound 15c (18 mg, 33 μmol) and compound 26c (15 mg, 34 μmol) were dissolved in toluene (1 mL), and cyanomethylenetri-n-butylphosphine (60 mg, 249 μmol) was added. The mixture was stirred at 125 °C for 2 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: Ultimate C18, C18, 30*150 mm, 5 μm (Boston); mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55-95%, flow rate: 30 mL / min) to give title compound 26 (5 mg, yield: 15.4%).

[1084] MS m / z(ESI): 967.7 [M+1].

[1085] 1 H NMR (500MHz, CD3OD): δ8.21(d,1H),7.74(s,1H),7.33(d,2H)7.24(s,1H),7.15(s,1H),7.0 0(d,1H),6.85(d,2H),4.80-4.71(m,2H),4.29(s,1H),4.15(s,1H),4.10-4.03(m,1H),3.9 9-3.93(m,1H),2.73(s,3H),2.63-2.57(m,1H),2.48(s,3H),2.42-2.36(m,1H),2.06-1.76 (m,9H),1.74-1.61(m,6H),1.30(s,6H),1.23(s,6H),1.11-1.05(m,2H),1.00-0.90(m,2H).

[1086] Example 27

[1087] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-(difluoromethyl)-4-((S)-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)phenoxy)spiro[3.5]nonan-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 27

[1088] N-((1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-((2S,4R,7S)-2-(3-(difluoromethyl)-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)spiro[3.5]non-7-yl)-6-oxo-1,6-dihydropyridazine-4-carboxamide 27

[1089] first step

[1090] 3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 27b

[1091] Compound 4-bromo-3-(difluoromethyl)phenol 27a (500 mg, 2.24 mmol, prepared by the method disclosed in Intermediate A-12 on page 475 of patent application "WO2023141432"), pinacol diboronate (875 mg, 3.45 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (190 mg, 224 μmol), and potassium acetate (882 mg, 8.99 mmol) w...

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from 5- or 6-membered heterocyclic groups, 6-membered aryl groups, and 5- or 6-membered heteroaryl groups, and ring A is substituted by an oxo group; 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, hydroxy, hydroxyalkyl, cyano, alkoxyalkyl, alkenyl, alkynyl, amino, cycloalkyl, heterocyclic and cycloalkylalkyl; or R a R b Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkylalkyl groups are each independently and optionally influenced by one or more R groups. 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 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, alkenyl, alkynyl, 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 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; Or two Rs 8 Together with the carbon atom attached thereto, they form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is independently and optionally converted by one or more R groups. 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 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 or 3; 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 according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 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 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 R 14 R 0 R 7 R 7b u, y, w, R d and R e As defined in claim 1; Preferably, E is selected from R 6 To R 9 R d R e u and y are as defined in claim 1; more preferably, E is selected from...

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridinone, pyridazinone, pyrimidinone, and pyridoxine groups; preferably, ring A is selected from... Or for 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II) or a pharmaceutically acceptable salt thereof: in, X 1 X 2 and X 3 Whether the same or different, and each independently constitutes a CR 3 Or N; 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 s1, s2, q, r, x, R 1 To R 5 R' and m are as defined in claim 1.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof: in, b3 is 0, 1, 2, 3, or 4; b4 is 0, 1, 2, 3, or 4; q1 is 0, 1, 2, 3 or 4; q2 is 0, 1 or 2; Rings C, E, L 2 L 3 s2, B 1 B 2 b1, b2, x, X 1 To X 3 R 1 m, R 2 R 4 R 5 and r as defined in claim 4.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 5, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (IV): in, R 1a and R 1b They may be the same or different, and each is independently a hydrogen atom or R. 1 ; R 1 To R 4 X 1 X 2 x, B 1 B 2 ,b1,b2,b3,b4,q1,q2,L 2 L 3 R 6 R 8 u, R 9 And y as defined in claim 5.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, 2, 5 or 6, wherein the compound or a pharmaceutically acceptable salt thereof is represented by general formula (V): in, R 1a R 1b R 2 X 1 x, B 1 B 2 b1, b2, b3, b4, R 4 q1, q2, L 2 and L 3 As defined in claim 5, R 9 And y as defined in claim 1.

8. The compound according to any one of claims 4 to 7, or a pharmaceutically acceptable salt thereof, wherein B 1 For CH or N, and / or B 2 For CH or N, and / or b1 is 0 or 1, and / or b2 is 0 or 1; preferably, B 1 For CH, and / or B 2 For CH, and / or b1 is 1, and / or b2 is 1.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein x is 0 or 1, and / or L 2 Selected from bond, O, C(O), (CR) a R b ) x C(O)-(CR) a R b ) x2 O-CR a R b And C(O)NH, and / or the ring C is a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocyclic group, and / or s2 is 0 or 1, and / or L 3 Selected from the following groups: bond, O, S, NH, CH2, CH(CH3), C(O), C(CH3)2, and propynyl group; 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; x2 is 0, 1, or 2; preferably, x is 0 or 1, and / or 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 s2 is 0 or 1, and / or L 3 Selected from bonds, O, S, NH, CH2, CH(CH3), C(O), C(CH3)2 and propynyl groups; more preferably, x is 0, and / or L 2 The C1 bond is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, and / or the S2 group is 0 or 1, and / or L. 3 Selected from bonds, CH2, C(O) and O.

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, C1-6 haloalkyl 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 Halogenated alkyl; preferably, R 2 C 1-6 Alkyl; more preferably, R 2 It is a methyl group.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 3 Selected from hydrogen atoms, F and methyl.

13. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 6, 8 to 10, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and / or 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; preferably, R 6 C 1-6 Alkyl groups; and / or each R 8 The same or different, and each independently is C. 1-6 Alkyl; more preferably, R 6 Methyl; and / or R 8 It is a methyl group.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 haloalkoxy, hydroxyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; preferably, each R 9 The same or different, and each independently selected from C 1-6 Alkoxy, cyano, and 3- to 6-membered cycloalkyl groups.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein L 3 It is O.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 9 It is a 3- to 6-membered cycloalkyl group; preferably, R 9 It is cyclopropyl.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 9 C 1-6 Halogenated alkyl; preferably, R 9 It is CHF2.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 9 It is a cyano group.

19. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein y is 0.

20. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein y is 1.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 20, wherein R 1a It is a cyano group.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 21, wherein R 1b It is a halogen; preferably, R 1b It is Cl.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 21, wherein R 1b It is an alkoxy group; preferably, R 1b It is a methoxy group.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 21, wherein R 1b C 1-6 Halogenated alkoxy group; preferably, R 1b It is either OCF3 or OCHF2.

25. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 24, wherein the compound is selected from the following compounds:

26. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, and one or more pharmaceutically acceptable carriers, diluents or excipients.

27. Use of the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 26 in the preparation of a medicament for the treatment and / or prevention of androgen receptor-mediated or dependent diseases or conditions.

28. Use of the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 26 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.

Images