Fused azatricyclic derivatives, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to fused azatricyclic derivatives, processes for their preparation and their use in medicine. In particular, the present disclosure relates to a fused azatricyclic derivative of general formula (I), processes for its preparation, pharmaceutical compositions containing the derivative and its use as a therapeutic agent, in particular as a GR modulator and in the manufacture of a medicament for the treatment and / or prevention of a tumor.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused azatricyclic derivative, its preparation method, and its pharmaceutical applications. In particular, this disclosure relates to a fused azatricyclic derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a GR modifier and in the preparation of medicaments for the treatment and / or prevention of tumors. Background Technology

[0002] The glucocorticoid receptor (GR) is a member of the nuclear receptor family, belonging to the steroid hormone receptor class along with the mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and estrogen receptor (ER). Glucocorticoids regulate gene expression and various cellular functions, such as metabolism, inflammation, cell growth, and differentiation, by activating the GR. Physiologically, glucocorticoids regulate human glucose metabolism, protein metabolism, and lipid metabolism. Pathologically caused hyperglycemia can lead to metabolic disorders and developmental delays, clinically known as Cushing's syndrome (CS). Conversely, hypoglycemia caused by pathological trauma or other factors can lead to Addison's disease, primarily manifested as anxiety, fatigue, muscle and joint pain, and depression; some patients may experience severe depression.

[0003] Due to their effective suppression of the immune response, GR receptor agonists, such as corticosteroids, are widely used clinically to treat autoimmune diseases or allergies. In hematologic malignancies characterized by malignant proliferation of immune cells, corticosteroids are also a component of combination therapy.

[0004] In the treatment of solid tumors, corticosteroids are approved as adjuvant therapy to alleviate symptoms such as allergies and vomiting, and to enhance tolerance to chemotherapy or targeted therapy. However, in recent years, an increasing number of clinical and academic studies have shown that activation of the GR signaling pathway is directly related to the progression, metastasis, drug resistance, and poor prognosis of various solid tumors.

[0005] In castration-resistant prostate cancer (CRPC), GR signaling pathway activation is directly associated with enzalutamide resistance. After enzalutamide treatment (>8 weeks), GR levels in tumor tissue are upregulated, and the response to enzalutamide is poor. GR and AR can co-regulate a series of genes related to prostate cancer progression in prostate cancer cells; GR pathway activation is a compensatory response of prostate cancer cells to AR inhibition. In in vivo pharmacodynamic models, GR gene knockout or GR antagonists can significantly inhibit tumor growth.

[0006] In patients with triple-negative breast cancer (TNBC), the expression level of GR (grapevine) is statistically significantly correlated with poor survival in both TNBC and ovarian cancer. GR signaling pathway activation is associated with cancer cell metastasis and paclitaxel resistance. Paclitaxel-based chemotherapy is currently the primary treatment for TNBC. Studies have found that GR activation mediated by the GR agonist dexamethasone leads to high expression of genes related to chemotherapy resistance and tumor metastasis, thereby promoting chemotherapy resistance and the metastasis of TNBC tumor cells. Using GR antagonists can enhance chemotherapy sensitivity and reduce metastasis.

[0007] Therefore, targeting GR and interfering with its signal transduction through antagonism is a novel approach to cancer treatment. Its mechanism of action has been effectively confirmed by a large body of literature, particularly in prostate and breast cancer.

[0008] Patent applications for GR regulators that have been published include WO2005087769A1, WO2012027702A1, WO2013177559A2 and WO2015077530A1, etc. Summary of the Invention

[0009] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] It is either non-existent or a chemical bond;

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

[0014] Each R 1 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5hydroxyl group, -C(O)R 6 -C(O)OR 6 -C(O)NR 4 R 5 -S(O) p R 6 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7 R 8 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0015] Or, two adjacent R 1 Fusing with ring A to form a heterocyclic group, wherein the heterocyclic group is optionally selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7 R 8 It is substituted by one or more substituents selected from nitro, hydroxy, and hydroxyalkyl;

[0016] Ring B is aryl or heteroaryl;

[0017] Each R 2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 hydroxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7 R 8 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0018] The ring C is aryl or heteroaryl;

[0019] Each R 3 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 4 R 5 and hydroxyl groups;

[0020] R 6The same or different in each occurrence, and each independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each independently optionally replaced by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0021] R 4 R 5 R 7 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0022] Or R 4 and R 5 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0023] Or R 7 and R 8 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0024] p is 0, 1, or 2;

[0025] m can be 0, 1, 2, 3, or 4;

[0026] n is 0, 1, 2, 3, or 4; and

[0027] t can be 0, 1, 2, 3 or 4.

[0028] 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:

[0029]

[0030] in:

[0031] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0032] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II-1) or general formula (II-2), or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0036] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0037]

[0038] in:

[0039] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0040] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (III), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-1) or general formula (III-2), or a pharmaceutically acceptable salt thereof:

[0041]

[0042] in:

[0043] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0044] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring B is pyridyl.

[0045] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, the ring C is a phenyl.

[0046] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:

[0047]

[0048] in:

[0049] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0050] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (II), general formula (II-1) or general formula (IV) is a compound or pharmaceutically acceptable salt thereof represented by general formula (IV-1):

[0051]

[0052] in:

[0053] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0054] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (II), general formula (II-2) or general formula (IV) is a compound or pharmaceutically acceptable salt thereof represented by general formula (IV-2):

[0055]

[0056] in:

[0057] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0058] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof:

[0059]

[0060] in:

[0061] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0062] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (III), general formula (III-1) or general formula (V) is a compound or pharmaceutically acceptable salt thereof represented by general formula (V-1):

[0063]

[0064] in:

[0065] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0066] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (III), general formula (III-2) or general formula (V) is a compound or pharmaceutically acceptable salt thereof represented by general formula (V-2):

[0067]

[0068] in:

[0069] Rings A and R 1 To R 3 m, n and t are as defined in general formula (I).

[0070] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are wherein ring A is selected from 3- to 12-membered heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; preferably, ring A is a 5- or 6-membered heteroaryl group; more preferably, ring A is a 5-membered nitrogen-containing heteroaryl group; more preferably, ring A is selected from pyrazolyl, imidazolyl, 1,2,3-triazolyl, and tetrazolyl; most preferably, ring A is a 1,2,3-triazolyl group.

[0071] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula (V-2), or pharmaceutically acceptable salts thereof, wherein ring A is selected from pyrazolyl, imidazolyl and 1,2,3-triazolyl.

[0072] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups, wherein the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclic groups are each optionally selected independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 One or more substituents in the hydroxyalkyl group are substituted; preferably, each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups, wherein the 3- to 6-membered cycloalkyl groups and the 3- to 6-membered heterocyclic groups are each independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted with one or more substituents; more preferably, each R 1 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups.

[0073] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, R 1 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0074] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are wherein two adjacent R 1 Fusing with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted by one or more substituents; preferably, two adjacent R groups are substituted by one or more substituents. 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted by one or more substituents; more preferably, two adjacent R groups are substituted by one or more substituents. 1 It fuses with ring A to form a 5- or 6-membered heterocyclic group.

[0075] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups, wherein the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclic groups are each optionally selected independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; or by two adjacent R groups. 1 Fusing with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 It is substituted by one or more substituents in the haloalkoxy group.

[0076] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein each R 1 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; or two adjacent R groups. 1 It fuses with ring A to form a 5- or 6-membered heterocyclic group.

[0077] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V), or their pharmaceutically acceptable salts, wherein... Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0078] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (II-1), (III-1), (IV-1), or (V-1) are wherein... Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0079] In some embodiments of this disclosure, the compounds represented by general formula (II-2), general formula (III-2), general formula (IV-2) or general formula (V-2), or pharmaceutically acceptable salts thereof, wherein Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0080] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V), or their pharmaceutically acceptable salts, wherein... Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0081] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (II-1), (III-1), (IV-1), or (V-1) are wherein... Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0082] In some embodiments of this disclosure, the compounds represented by general formula (II-2), general formula (III-2), general formula (IV-2) or general formula (V-2), or pharmaceutically acceptable salts thereof, wherein Selected from Where R 0 Selected from hydrogen atoms, halogens, C 1-6Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, -NR 7 R 8 nitro, hydroxyl and C 1-6 Hydroxyalkyl, where s is 0, 1, 2, 3 or 4, R 1 R 7 and R 8 As defined in general formula (I); preferably, Selected from More preferably, for

[0083] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, 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, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, 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; more preferably, R 2 C 1-6 Halogenated alkyl; most preferably, R 2 It is trifluoromethyl.

[0084] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; preferably, 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 C1-6 Halogenated alkyl; more preferably, R 3 It is a halogen; most preferably, R 3 It is a fluorine atom.

[0085] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), or (V-2) are used, wherein m is 0, 1, or 2; preferably, m is 1 or 2; more preferably, m is 1.

[0086] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula (V-2) is used, wherein n is 0, 1 or 2; preferably, n is 1.

[0087] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt thereof represented by general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1) or general formula (V-2) is used, wherein t is 0, 1 or 2; preferably, t is 1.

[0088] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3- to 12-membered heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; ring C is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups, wherein the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclic groups are each optionally selected independently from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, hydroxyl and C 1-6The hydroxyalkyl group is substituted by one or more substituents; or by two adjacent R groups. 1 Fusing with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; 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, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0089] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 3- to 12-membered heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; ring B is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; ring C is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; or two adjacent R groups 1 Fusing with ring A to form a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; 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, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkyl groups and C 1-6 Haloalkoxy; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0090] In some embodiments of this disclosure, the compound represented by general formula (II), general formula (II-1), or general formula (II-2), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, 1,2,3-triazolyl, and tetrazolyl; ring B is pyridyl; ring C is phenyl; and each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups, wherein the 3- to 6-membered cycloalkyl groups and the 3- to 6-membered heterocyclic groups are each independently selected from halogens, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; or by two adjacent R groups. 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; 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 groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0091] In some embodiments of this disclosure, the compound represented by general formula (II), general formula (II-1), or general formula (II-2), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, and 1,2,3-triazolyl; ring B is pyridinyl; ring C is phenyl; and each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group; or two adjacent R groups 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C1-6 One or more substituents in the haloalkoxy group are substituted; 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 groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0092] In some embodiments of this disclosure, the compound represented by general formula (III), general formula (III-1), or general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, 1,2,3-triazolyl, and tetrazolyl; ring B is pyridyl; ring C is phenyl; and each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; or two adjacent R groups. 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; 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 groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0093] In some embodiments of this disclosure, the compound represented by general formula (III), general formula (III-1), or general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, and 1,2,3-triazolyl; ring B is pyridyl; ring C is phenyl; and each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group; or two adjacent R groups 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C1-6 Halogenated alkyl groups and C 1-6 One or more substituents in the haloalkoxy group are substituted; 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 groups; each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

[0094] In some embodiments of this disclosure, the compound represented by general formula (IV), general formula (IV-1), or general formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heteroaryl group; each R 1 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, or two adjacent R groups 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group; R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; m is 1 or 2; n is 1; t is 1.

[0095] In some embodiments of this disclosure, the compound represented by general formula (IV), general formula (IV-1), or general formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered nitrogen-containing heteroaryl group; each R 1 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; m is 1; n is 1; t is 1.

[0096] In some embodiments of this disclosure, the compound represented by general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heteroaryl group; each R 1 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; or two adjacent R groups. 1 Fusing with ring A to form a 5- or 6-membered heterocyclic group; R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; m is 1 or 2; n is 1; t is 1.

[0097] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0098] In some embodiments of this disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0099] In some embodiments of this disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0100] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0101] In some embodiments of this disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0102] In some embodiments of this disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0103] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0104] In some embodiments of this disclosure, the compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0105] In some embodiments of this disclosure, the compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0106] In some embodiments of this disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0107] In some embodiments of this disclosure, the compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0108] In some embodiments of this disclosure, the compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; n is 1; t is 1.

[0109] Table A lists typical compounds disclosed herein, including but not limited to:

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0120]

[0121] in:

[0122] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0123] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined for compounds of general formula (I).

[0124] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof:

[0125]

[0126] in:

[0127] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0128] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II).

[0129] Another aspect of this disclosure relates to compounds of general formula (II-1A) or salts thereof:

[0130]

[0131] in:

[0132] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0133] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-1).

[0134] Another aspect of this disclosure relates to compounds of general formula (II-2A) or salts thereof:

[0135]

[0136] in:

[0137] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0138] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-2).

[0139] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof:

[0140]

[0141] in:

[0142] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0143] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III).

[0144] Another aspect of this disclosure relates to compounds of general formula (III-1A) or salts thereof:

[0145]

[0146] in:

[0147] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0148] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-1).

[0149] Another aspect of this disclosure relates to compounds of general formula (III-2A) or salts thereof:

[0150]

[0151] in:

[0152] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0153] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-2).

[0154] Another aspect of this disclosure relates to compounds of the general formula (IVA) or salts thereof:

[0155]

[0156] in:

[0157] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0158] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV).

[0159] Another aspect of this disclosure relates to compounds of general formula (IV-1A) or salts thereof:

[0160]

[0161] in:

[0162] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0163] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV-1).

[0164] Another aspect of this disclosure relates to compounds of general formula (IV-2A) or salts thereof:

[0165]

[0166] in:

[0167] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0168] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV-2).

[0169] Another aspect of this disclosure relates to compounds of general formula (VA) or salts thereof:

[0170]

[0171] in:

[0172] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0173] Rings A and R 1 To R 3 m, n and t are as defined in general formula (V).

[0174] Another aspect of this disclosure relates to compounds of general formula (V-1A) or salts thereof:

[0175]

[0176] in:

[0177] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0178] Rings A and R 1 To R 3 m, n and t are defined as in general formula (V-1).

[0179] Another aspect of this disclosure relates to compounds of general formula (V-2A) or salts thereof:

[0180]

[0181] in:

[0182] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0183] Rings A and R 1 To R 3m, n and t are as defined in general formula (V-2).

[0184] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0195]

[0196] The compound represented by general formula (IA) or its salt after deamino protecting group R w This yields compounds of general formula (I) or their pharmaceutically usable salts.

[0197] in:

[0198] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0199] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0200] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0201]

[0202] Compounds of general formula (IIA) or their salts after deamino protecting group R wThis yields compounds of general formula (II) or their pharmaceutically usable salts.

[0203] in:

[0204] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0205] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II).

[0206] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0207]

[0208] The compound represented by general formula (II-1A) or its salt, after deamino protecting group R w This yields compounds of general formula (II-1) or their pharmaceutically usable salts.

[0209] in:

[0210] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0211] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-1).

[0212] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0213]

[0214] The compound represented by general formula (II-2A) or its salt, after deamino protecting group R w This yields compounds of general formula (II-2) or their pharmaceutically usable salts.

[0215] in:

[0216] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0217] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-2).

[0218] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0219]

[0220] Compounds of general formula (IIIA) or their salts after deamino protecting group R w This yields the compound represented by general formula (III) or its pharmaceutically usable salt.

[0221] in:

[0222] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0223] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III).

[0224] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0225]

[0226] The compound represented by general formula (III-1A) or its salt, after deamino protecting group R w This yields compounds of general formula (III-1) or their pharmaceutically usable salts.

[0227] in:

[0228] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0229] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-1).

[0230] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0231]

[0232] The compound represented by general formula (III-2A) or its salt, after deamino protecting group R w This yields compounds of general formula (III-2) or their pharmaceutically usable salts.

[0233] in:

[0234] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0235] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-2).

[0236] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0237]

[0238] Compounds of general formula (IVA) or their salts after deamino protecting group R w This yields compounds of general formula (IV) or their pharmaceutically usable salts.

[0239] in:

[0240] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0241] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV).

[0242] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0243]

[0244] Compounds of general formula (IV-1A) or their salts after deamino protecting group R w This yields compounds of general formula (IV-1) or their pharmaceutically usable salts.

[0245] in:

[0246] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0247] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV-1).

[0248] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0249]

[0250] Compounds of general formula (IV-2A) or their salts after deamino protecting group R w This yields compounds of general formula (IV-2) or their pharmaceutically usable salts.

[0251] in:

[0252] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0253] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV-2).

[0254] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0255]

[0256] Compounds of general formula (VA) or their salts after deamino protecting group R w This yields compounds of general formula (V) or their pharmaceutically usable salts.

[0257] in:

[0258] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0259] Rings A and R 1 To R 3 m, n and t are as defined in general formula (V).

[0260] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0261]

[0262] Compounds of general formula (V-1A) or their salts after deamino protecting group R w This yields compounds of general formula (V-1) or their pharmaceutically usable salts.

[0263] in:

[0264] R wIt is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0265] Rings A and R 1 To R 3 m, n and t are defined as in general formula (V-1).

[0266] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0267]

[0268] Compounds of general formula (V-2A) or their salts after deamino protecting group R w This yields compounds of general formula (V-2) or their pharmaceutically usable salts.

[0269] in:

[0270] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0271] Rings A and R 1 To R 3 m, n and t are as defined in general formula (V-2).

[0272] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and the compound shown in Table A, 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 formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions by regulating GR.

[0274] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions by antagonizing GR.

[0275] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), and the compounds shown in 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, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases, and neurodegenerative diseases; preferably In the preparation of treatments and / or preventative measures for cancer, obesity, diabetes, hypertension, Syndrome X, depression (such as psychotic depression, postpartum depression), allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome (also known as hypercortisolism), Addison's disease, osteoporosis, weakness, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related disorders, viral infections (such as human immunodeficiency virus (HIV)), and immunodeficiency (such as acquired immunodeficiency). Use in the preparation of medicines for the treatment and / or prevention of breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as AIDS), immune modulation, allergies, wound healing, compulsive behaviors, addictions, psychosis (such as postpartum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders (such as post-traumatic stress disorder), delirium, chronic pain, neurological disorders in premature infants, and migraines; more preferably in the preparation of medicines for the treatment and / or prevention of breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as Use in the preparation of medicines for the treatment and / or prevention of breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer), and ovarian cancer (such as recurrent ovarian cancer); most preferably, use in the preparation of medicines for the treatment and / or prevention of breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer), and ovarian cancer (such as recurrent ovarian cancer).

[0276] This disclosure also relates to a method of treating and / or preventing disease or condition by modulating GR, comprising administering to a patient a therapeutically effective amount of the compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds thereof.

[0277] This disclosure also relates to a method of treating and / or preventing disease or condition by antagonizing GR, comprising administering to a desired patient a therapeutically effective amount of the compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds thereof.

[0278] This disclosure also relates to a method of treating and / or preventing tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases, and neurodegenerative diseases, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0279] This disclosure further relates to a compound of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2), and the compound shown in Table A, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the thereof, which is used as a medicine.

[0280] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions by regulating GR.

[0281] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions by antagonizing GR.

[0282] This disclosure further relates to compounds of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurodegenerative diseases.

[0283] The diseases or conditions described in this disclosure are selected from cancer, obesity, diabetes, hypertension, Syndrome X, depression (such as psychotic depression, postpartum depression), allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, weakness, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related disorders, viral infections (such as human immunodeficiency virus (HIV)), immunodeficiency (such as acquired immunodeficiency syndrome (AIDS)), immune regulation, allergies, wound healing, compulsive behaviors, addiction, psychosis (such as postpartum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders (such as post-traumatic stress disorder). The cancers are selected from breast cancer, prostate cancer, adrenocortical carcinoma, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer), skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer (such as non-small cell lung cancer and small cell lung cancer), leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma, and ovarian cancer (such as recurrent ovarian cancer); more preferably, the diseases or conditions are selected from breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer), and ovarian cancer (such as recurrent ovarian cancer).

[0284] Compared with the positive control compound Relacorilant (CORT-125134, WO2013177559A2, Example 18), the compound of Example 1-P1 of this disclosure has better safety and significant pharmacokinetic advantages. Specific data can be found in the biological evaluation section. The structural formula of Relacorilant is as follows:

[0285]

[0286] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0287] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 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] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0290] 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.

[0291] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used 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.

[0292] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0293] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0298] 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, weight, health status, behavior, diet, timing of administration, route of administration, rate of excretion, combination of drugs, and severity of disease. Furthermore, optimal treatment modalities, such as treatment regimens, daily dosage of compounds, or types of pharmaceutically acceptable salts, can be validated based on conventional treatment protocols.

[0299] Terminology Explanation

[0300] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0301] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 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. The most preferred are lower alkyl groups having 1 to 6 carbon atoms, and 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, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably 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.

[0302] 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 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to: methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0303] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the alkyl group is defined as described above as an alkenyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C14). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0304] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the alkyl group is defined as described above and is an alkynyl group (i.e., C14) having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0305] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably 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.

[0306] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent 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) carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably having 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), more preferably having 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably having 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0307] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members) of monocyclic rings sharing a single carbon atom (called a spiro atom), and may contain one or more double bonds. Preferred are 6 to 14-membered spirocycloalkyl groups, more preferably 7 to 10-membered spirocycloalkyl groups. Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (e.g., bispirocycloalkyl) based on the number of shared spiro atoms between rings, with monospirocycloalkyl or bispirocycloalkyl groups being preferred. More preferred are 3 / 5, 3 / 6, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, 6 / 4, 6 / 5, or 6 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0308]

[0309] The term "fused cycloalkyl" refers to a polycyclic aromatic hydrocarbon group consisting of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members) sharing a pair of adjacent carbon atoms, wherein one or more rings may contain one or more double bonds. Preferred are 6 to 14-membered fused cycloalkyl groups, more preferably 7 to 10-membered fused cycloalkyl groups. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic or tricyclic fused cycloalkyl groups being preferred, and more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0310]

[0311] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group consisting of any two rings sharing two non-directly connected carbon atoms, ranging from 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members), which may contain one or more double bonds. Preferred are 6- to 14-membered bridged cycloalkyl groups, more preferably 7- to 10-membered bridged cycloalkyl groups. Depending on the number of rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, etc., with bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups being preferred, and bicyclic or tricyclic bridged cycloalkyl groups being more preferred. Non-limiting examples of bridged cycloalkyl groups include:

[0312]

[0313] 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... etc.; preferred

[0314] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0315] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent 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, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, the ring group has 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, or 4) are heteroatoms (i.e., 3 to 12-membered heterocyclic groups); more preferably, it has 3 to 8 ring atoms, of which 1 to 3 are heteroatoms (e.g., 1, 2, or 3) (i.e., 3 to 8-membered heterocyclic groups); more preferably, it has 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6-membered heterocyclic groups); and most preferably, it has 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6-membered heterocyclic groups). Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0316] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members) of monocyclic rings sharing a single atom (called a spiroatom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. 6 to 14 member spiroheterocyclic groups are preferred, and 7 to 10 member spiroheterocyclic groups are more preferred. Spiroheterocyclic groups are classified into monospirocyclic groups or polyspirocyclic groups (e.g., bispirocyclic groups) according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, 5 / 6, or 6 / 6 monospirocyclic heterocyclic groups are preferred. Non-limiting examples of spirocyclic groups include:

[0317]

[0318] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 members) sharing an adjacent pair of atoms. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Fused heterocyclic groups of 6 to 14 members are preferred, and 7 to 10 members are more preferred. Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, and tetracyclic groups, among others. Bicyclic or tricyclic fused heterocyclic groups are preferred, and 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 groups are more preferred. Non-limiting examples of fused heterocyclic groups include:

[0319]

[0320] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group consisting of any two rings sharing two non-directly connected atoms, ranging from 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members). It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferred are 6- to 14-membered bridged heterocyclic groups, more preferably 7- to 10-membered bridged heterocyclic groups. Based on the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, and other polycyclic bridged heterocyclic groups, with bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups being preferred, and bicyclic or tricyclic bridged heterocyclic groups being more preferred. Non-limiting examples of bridged heterocyclic groups include:

[0321]

[0322] 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:

[0323] wait.

[0324] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0325] The term "aryl" refers to a 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered) all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered aryl, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0326]

[0327] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0328] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms and 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably, 5 to 10-membered heteroaryls are used; more preferably, 5- or 6-membered heteroaryls are used, such as furanyl, thiopheneyl, pyridyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl), tetrazolyl, etc.; most preferably, 5-membered nitrogen-containing heteroaryls are used, such as pyrazolyl, imidazolyl, 1,2,3-triazolyl, and tetrazolyl. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0329]

[0330] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0331] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene".

[0332] 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), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, p-methoxybenzyl, tert-butyldimethylsilyl (TBS), etc. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups.

[0333] The term "hydroxyl protecting group" refers to a group introduced onto a hydroxyl group that is easily removed, typically used to block or protect the hydroxyl group so that reactions can proceed on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 alkoxy-substituted C 1-6 alkyl or phenyl substituted C 1-6 Alkyl groups (such as methoxymethyl (MOM) and ethoxyethyl), (C 1-10 Alkyl or aromatic group) acyl group (e.g., formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6 to 10 aryl) sulfonyl, (C 1-6 Alkyl or 6 to 10 aryloxy groups, carbonyl, allyl, 2-tetrahydropyranyl (THP), etc.

[0334] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0335] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0336] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0337] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0338] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0339] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0340] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0341] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0342] 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.

[0343] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0344] The term "hydroxyl group" refers to -OH.

[0345] The term "thiol" refers to -SH.

[0346] The term "amino" refers to -NH2.

[0347] The term "cyano" refers to -CN.

[0348] The term "nitro" refers to -NO2.

[0349] The term "oxo" or "oxo" refers to "=O".

[0350] The term "carbonyl" refers to C=O.

[0351] The term "carboxyl group" refers to -C(O)OH.

[0352] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0353] 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.

[0354] 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.

[0355] 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:

[0356]

[0357] 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:

[0358]

[0359] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0360] 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 Grade I, with deuterium as the preferred grade.

[0361] 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.

[0362] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0363] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally (optionally) C substituted with halogen or cyano groups..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0364] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0365] "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.

[0366] "Pharmaceutical-grade salt" or "pharmaceutically 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. The salt 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.

[0367] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the age and general condition of the subject, as well as the specific active substance. The appropriate therapeutic effective amount in a particular case can be determined by a person skilled in the art based on routine experimental procedures.

[0368] 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.

[0369] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0370] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably 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.

[0371] The method for synthesizing the compounds disclosed herein

[0372] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0373] Option 1

[0374] A method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0375]

[0376] Compounds of general formula (IA) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (I) or their pharmaceutically usable salts.

[0377] in:

[0378] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0379] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (I).

[0380] Option 2

[0381] A method for preparing the compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0382]

[0383] Compounds of general formula (IIA) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (II) or their pharmaceutically usable salts.

[0384] in:

[0385] R w It is an amino protecting group; preferably, R wIt is tert-butyldimethylsilyl (TBS);

[0386] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II).

[0387] Option 3

[0388] This disclosure includes a method for preparing the compound of formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0389]

[0390] Compounds of general formula (II-1A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (II-1) or their pharmaceutically usable salts.

[0391] in:

[0392] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0393] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-1).

[0394] Option 4

[0395] This disclosure includes a method for preparing the compound of formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0396]

[0397] Compounds of general formula (II-2A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (II-2) or their pharmaceutically usable salts.

[0398] in:

[0399] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0400] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (II-2).

[0401] Option 5

[0402] A method for preparing the compound of formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0403]

[0404] Compounds of general formula (IIIA) or their salts undergo deamino protecting group R under acidic conditions. w This yields the compound represented by general formula (III) or its pharmaceutically usable salt.

[0405] in:

[0406] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0407] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III).

[0408] Option Six

[0409] This disclosure includes a method for preparing the compound of formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0410]

[0411] Compounds of general formula (III-1A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (III-1) or their pharmaceutically usable salts.

[0412] in:

[0413] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0414] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-1).

[0415] Option 7

[0416] This disclosure includes a method for preparing the compound of formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0417]

[0418] Compounds of general formula (III-2A) or their salts undergo deamino protecting group R under acidic conditions. wThis yields compounds of general formula (III-2) or their pharmaceutically usable salts.

[0419] in:

[0420] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0421] Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in general formula (III-2).

[0422] Option 8

[0423] A method for preparing the compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0424]

[0425] Compounds of general formula (IVA) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (IV) or their pharmaceutically usable salts.

[0426] in:

[0427] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0428] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV).

[0429] Option Nine

[0430] This disclosure discloses a method for preparing the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0431]

[0432] Compounds of general formula (IV-1A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (IV-1) or their pharmaceutically usable salts.

[0433] in:

[0434] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0435] Rings A and R 1To R 3 m, n and t are as defined in general formula (IV-1).

[0436] Option 10

[0437] The present disclosure includes a method for preparing the compound of formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0438]

[0439] Compounds of general formula (IV-2A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (IV-2) or their pharmaceutically usable salts.

[0440] in:

[0441] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0442] Rings A and R 1 To R 3 m, n and t are as defined in general formula (IV-2).

[0443] Option 11

[0444] A method for preparing the compound of formula (V) or a pharmaceutically acceptable salt thereof, comprising:

[0445]

[0446] Compounds of general formula (VA) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (V) or their pharmaceutically usable salts.

[0447] in:

[0448] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0449] Rings A and R 1 To R 3 m, n and t are as defined in general formula (V).

[0450] Option Twelve

[0451] This disclosure discloses a method for preparing the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0452]

[0453] Compounds of general formula (V-1A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (V-1) or their pharmaceutically usable salts.

[0454] in:

[0455] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0456] Rings A and R 1 To R 3 m, n and t are defined as in general formula (V-1).

[0457] Option Thirteen

[0458] This disclosure discloses a method for preparing the compound of formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0459]

[0460] Compounds of general formula (V-2A) or their salts undergo deamino protecting group R under acidic conditions. w This yields compounds of general formula (V-2) or their pharmaceutically usable salts.

[0461] in:

[0462] R w It is an amino protecting group; preferably, R w It is tert-butyldimethylsilyl (TBS);

[0463] Rings A and R 1 To R 3 m, n and t are as defined in general formula (V-2).

[0464] In the above deprotection reaction, the acid in the acidic conditions includes organic acids and inorganic acids. The organic acids include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf, with trifluoroacetic acid being preferred. The inorganic acids include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, with hydrochloric acid being preferred.

[0465] The above reaction is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. Detailed Implementation

[0466] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0467] Example

[0468] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (d) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0469] Mass spectrometry (MS) measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0470] 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.

[0471] Chiral HPLC analysis was performed using an Agilent 1260 DAD liquid chromatograph.

[0472] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2545-2767, Waters 2767-SQD2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0473] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0474] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0475] 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.

[0476] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0477] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0478] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0479] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0480] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0481] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0482] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0483] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0484] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0485] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0486] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0487] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and 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.

[0488] Examples 1-P1, 1-P2

[0489] ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P1

[0490] ((R)-1-(4-fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P2

[0491]

[0492] first step

[0493] 2-Methyl-2H-1,2,3-triazole-4-sulfonamide 1b

[0494] Compound 2-methyl-2H-1,2,3-triazol-4-sulfonyl chloride 1a (4 g, 11.07 mmol, prepared by a known method, "Journal of Medicinal Chemistry, 2017, 60(8), 3405-3421") was dissolved in ammonia in methanol (7 M, 30 mL). After stirring for 3 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to give title compound 1b (1.9 g, yield: 53.2%).

[0495] MS m / z(ESI): 163.1 [M+1].

[0496] Step 2

[0497] N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonamide 1c

[0498] Dissolve 1b (5 g, 30.83 mmol) and tert-butyldimethylchlorosilane (7 g, 46.64 mmol) in N,N-dimethylformamide. Add triethylamine (10 g, 98.8 mol) and 4-dimethylaminopyridine (760 mg, 6.22 mmol) at 0 °C. Allow the mixture to rise naturally to room temperature and stir for 16 hours. Concentrate the reaction solution under reduced pressure, add 100 mL of water, and extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product 1c (2.6 g, yield: 30.5%). The product was directly used for the next reaction without purification.

[0499] MS m / z (ESI): 277.1 [M+1].

[0500] Step 3

[0501] ((R)-6-((R)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1e

[0502] ((R)-6-((S)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1f

[0503] Dichlorotriphenylphosphine (2.85 g, 8.55 mmol) was dissolved in 20 mL of chloroform. Triethylamine (2.2 g, 21.74 mmol) was added at 0 °C. After stirring for 5 minutes, 1c (1.43 g, 5.17 mmol) was added. After stirring for another 10 minutes, 1d (1.9 g, 4.29 mol, prepared by the method disclosed in intermediate 78 on page 101 of patent application "WO2013177559A2") was added. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give a mixture of title compounds 1e and 1f (1.5 g, yield: 49.8%).

[0504] MS m / z (ESI): 701.1 [M+1].

[0505] Step 4

[0506] ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P1

[0507] ((R)-1-(4-fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P2

[0508] A mixture of 1e and 1f (60 mg, 85.6 μmol) was dissolved in 3 mL of tetrahydrofuran, and 2 mL of 1 M hydrochloric acid was added. The mixture was stirred for 0.5 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 3), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25%-42%) to give title compounds 1-P1 (6 mg, yield: 11.9%) and 1-P2 (8 mg, yield: 15.9%).

[0509] Compound 1-P1 (shorter retention time):

[0510] MS m / z (ESI): 587.2 [M+1].

[0511] HPLC analysis: Retention time 1.45 min, purity: 96% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0512] 1 H NMR (1500MHz, CDCl3): δ8.93(d,1H),8.16(s,1H),7.88(s,1H),7.72(d,1H),7.47(dd,2H),7.33(s,1H),7.20(t ,2H),6.55(s,1H),5.73(d,1H),4.28(d,4H),4.07-3.95(m,1H),2.96(dd,2H),2.83(d,1H),2.63-2.51(m,3H).

[0513] Compound 1-P2 (longer retention time):

[0514] MS m / z (ESI): 587.2 [M+1].

[0515] HPLC analysis: Retention time 1.47 min, purity: 97% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0516] 1 H NMR (1500MHz, CDCl3): δ8.91(d,1H),8.18(s,1H),7.91(s,1H),7.76-7.72(m,1H),7.47(dd,2H),7.33(s,1H),7.20(t,2H),6.5 2(s,1H),5.59-5.53(m,1H),4.28(s,3H),4.02(d,2H),2.92(d,1H),2.85(d,1H),2.79-2.64(m,2H),2.51(d,1H),2.19(s,1H).

[0517] Examples 2-P1, 2-P2

[0518] ((R)-1-(4-fluorophenyl)-6-((S)-1-methyl-1H-pyrazole-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2-P1

[0519] ((R)-1-(4-fluorophenyl)-6-((R)-1-methyl-1H-pyrazole-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2-P2

[0520]

[0521]

[0522] first step

[0523] 1-Methyl-1H-pyrazole-4-sulfonamide 2b

[0524] Compound 1-methyl-1H-pyrazole-4-sulfonyl chloride 2a (2 g, 11.07 mmol) was dissolved in 150 mL of dichloromethane, and a methanol solution of ammonia (7 M, 3 mL) was added. After stirring for 14 hours, the reaction solution was concentrated under reduced pressure to obtain crude product 2b (1.8 g, yield: 98.6%), which was used directly in the next step without purification.

[0525] MS m / z (ESI): 161.8 [M+1].

[0526] Step 2

[0527] N-(tert-butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonamide 2c

[0528] Compound 2b (1.8 g, 11.16 mmol) and tert-butyldimethylchlorosilane (1.1 g, 13.35 mmol) were dissolved in N,N-dimethylformamide. Triethylamine (1.7 g, 16.8 mol) was added at 0 °C, and the mixture was allowed to rise naturally to room temperature with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and 150 mL of water was added. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2c (1 g, yield: 32.5%).

[0529] MS m / z (ESI): 276.1 [M+1].

[0530] Step 3

[0531] ((R)-6-((R)-N-(tert-butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2d

[0532] ((R)-6-((S)-N-(tert-butyldimethylsilyl)-1-methyl-1H-pyrazole-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2e

[0533] Dichlorotriphenylphosphine (120 mg, 360.15 μmol) was dissolved in 3 mL of chloroform. Triethylamine (91 mg, 820 μmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, 2c (75 mg, 272.28 μmol) was added, and the mixture was stirred for another 10 minutes. Finally, 1d (80 mg, 180.82 μmol) was added, and the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of title compounds 2d and 2e (100 mg, yield: 79.0%).

[0534] MS m / z (ESI): 700.1 [M+1].

[0535] Step 4

[0536] ((R)-1-(4-fluorophenyl)-6-((S)-1-methyl-1H-pyrazole-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2-P1

[0537] ((R)-1-(4-fluorophenyl)-6-((R)-1-methyl-1H-pyrazole-4-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 2-P2

[0538] A mixture of 2d and 2e (150 mg, 71.44 μmol) was dissolved in 3 mL of tetrahydrofuran, and 2 mL of 1 M hydrochloric acid was added. The mixture was stirred for 0.5 h. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 3), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) to give the title compounds 2-P1 (5 mg, yield: 11.9%) and 2-P2 (20 mg, yield: 47.8%).

[0539] Compound 2-P1 (shorter retention time):

[0540] MS m / z (ESI): 586.2 [M+1].

[0541] HPLC analysis: Retention time 2.68 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0542] 1H NMR (1500MHz, CDCl3): δ8.92(d,1H),8.18-8.15(m,1H),7.75(s,1H),7.7 4-7.70(m,2H),7.150-7.44(m,2H),7.31(s,1H),7.24-7.17(m,2H),6.53 (d,1H),5.56(dd,1H),4.26(d,1H),3.95(s,3H),3.94-3.88(m,1H),2.94 (d,1H),2.88-2.80(m,1H),2.62(d,1H),2.54(d,1H),2.43-2.29(m,2H).

[0543] Compound 2-P2 (longer retention time):

[0544] MS m / z (ESI): 586.2 [M+1].

[0545] HPLC analysis: Retention time 2.74 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0546] 1 H NMR (1500MHz, CDCl3): δ8.92(d,1H),8.20(s,1H),7.78(s,1H),7.75(d,2H),7.49-7.43(m,2H),7.32(s,1H),7.23-7.16(m,2H),6.150( d,1H),5.150(dd,1H),4.05(d,1H),3.97-4.10(m,5H),2.92(d,1H),2.82-2.72(m,1H),2.57(d,1H),2.52-2.45(m,1H),2.36(ddd,1H).

[0547] Examples 3-P1, 3-P2

[0548] ((R)-6-((S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3-P1

[0549] ((R)-6-((R)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3-P2

[0550]

[0551] first step

[0552] 3-Bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 3b

[0553] Compound 3a (200 mg, 1.84 mmol, Shanghai Leyan) was dissolved in acetonitrile (5 mL), and N-bromosuccinimide (3150 mg, 1.97 mmol) was added. The mixture was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and 15 mL of water was added. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was collected. The organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system C to give the title compound 3b (340 mg, yield: 98.2%).

[0554] MS m / z (ESI): 188.2 [M+1].

[0555] Step 2

[0556] 3-((4-methoxybenzyl)thio)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 3c

[0557] Compound 3b (2150 mg, 1.33 mmol) and compound 4-methoxybenzyl mercaptan (2150 mg, 1.62 mmol) were dissolved in 5 mL of 1,4-dioxane. Tris(dibenzylacetone)dipalladium (123 mg, 0.134 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (155 mg, 0.268 mmol), and N,N-diisopropylethylamine (3150 mg, 2.70 mmol) were added. The reaction was carried out under nitrogen atmosphere and microwaved at 120 °C for 1.5 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title product 3c (340 mg, yield: 97.7%).

[0558] MS m / z (ESI): 261.1 [M+1].

[0559] Step 3

[0560] 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonyl chloride 3d

[0561] Compound 3c (340 mg, 1.30 mmol) was dissolved in 6 mL of a mixture of acetic acid and water (V / V = 2:1), and N-chlorosuccinimide (700 mg, 5.24 mmol) was added. The mixture was stirred for 2 hours. 15 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed successively with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system C to give the title compound 3d (200 mg, yield: 74.1%).

[0562] MS m / z (ESI): 207.1 [M+1].

[0563] Step 4

[0564] 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonamide 3e

[0565] Compound 3d (370 mg, 1.79 mmol) was dissolved in a methanol solution of ammonia (7 M, 5 mL), and the reaction was stirred for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain the crude title product 3e (200 mg, yield: 59.66%), which was used directly in the next step without purification.

[0566] MS m / z (ESI): 188.2 [M+1].

[0567] Step 5

[0568] N-(tert-butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonamide 3f

[0569] 3e (300 mg, 1.62 mmol) and tert-butyldimethylchlorosilane (200 mg, 2.42 mmol, Shanghai Bide) were dissolved in N,N-dimethylformamide. Triethylamine (811 mg, 8.01 mmol) and 4-dimethylaminopyridine (10 mg, 324.7 μmol) were added at 0 °C, and the mixture was allowed to rise naturally to room temperature with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and 15 mL of water was added. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 3f (200 mg, yield: 41.4%). The product was used directly in the next reaction without purification.

[0570] MS m / z (ESI): 302.2 [M+1].

[0571] Step 6

[0572] ((R)-6-((R)-N-(tert-butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazololo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3g

[0573] ((R)-6-((S)-N-(tert-butyldimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazololo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3h

[0574] Dichlorotriphenylphosphine (57 mg, 717.0 μmol) was dissolved in 3 mL of chloroform. Triethylamine (60 mg, 592.9 mmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, 3f (40 mg, 132.6 μmol) was added, and the mixture was stirred for another 10 minutes. Finally, 1d (150 mg, 113.0 μmol) was added, and the mixture was allowed to rise naturally to room temperature and stirred for 16 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of 3 g and 3 h of the title compound (150 mg, yield: 60.9%).

[0575] MS m / z (ESI): 726.2 [M+1].

[0576] Step 7

[0577] ((R)-6-((S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3-P1

[0578] ((R)-6-((R)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazole[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 3-P2

[0579] The mixture of 3g and 3h (150mg, 60.88μmol) was dissolved in 3mL of tetrahydrofuran, and 2mL of 1M hydrochloric acid was added. The mixture was stirred for 0.5h. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: SharpSil-T, 30*150mm, 5μm; mobile phase: aqueous phase (10mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) to give the title compounds 3-P1 (6mg, yield: 14.2%) and 3-P2 (6mg, yield: 14.2%).

[0580] Compound 3-P1 (shorter retention time):

[0581] MS m / z (ESI): 612.2 [M+1].

[0582] HPLC analysis: Retention time 1.40 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0583] 1 H NMR (1500MHz, CDCl3): δ8.91(d,1H),8.16(s,1H),7.72(d,2H),7.150-7.44(m,2H),7.31(s,1H),7.20(t,2H),6.52(d,1H),5.58-5.52(m,1H) ),4.24(d,1H),4.18(q,2H),3.90(d,1H),3.09(tt,3H),2.94(d,1H), 2.88-2.79(m,1H),2.72-2.62(m,3H),2.54(d,1H),2.48-2.40(m,1H).

[0584] Compound 3-P2 (longer retention time):

[0585] MS m / z (ESI): 612.2 [M+1].

[0586] HPLC analysis: Retention time 1.43 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0587] 1H NMR (1500MHz, CDCl3): δ8.89(d,1H),8.17(s,1H),7.72(s,2H),7.47-7.41(m,2H),7.29(s,1H),7.18(t,2H),6.47(s,1H),5 .48(d,1H),4.18(t,2H),4.04(d,1H),3.91(s,1H),3.09(q,2H),2.90(d,1H),2.79-2.57(m,5H),2.47(d,1H),2.38(t,1H).

[0588] Examples 4-P1, 4-P2

[0589] ((4aR,8aS)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4-P1

[0590] ((4aR,8aS)-1-(4-fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4-P2

[0591]

[0592] first step

[0593] (4aR,8aS)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)pyridinyl)-1,4,4a,5,7,8,8a,9-octahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylic acid tert-butyl ester 4b

[0594] Compound 4a (400 mg, 737.3 μmol, prepared using the method disclosed in intermediate 82 on page 104 of patent application "WO2013177559A2") was dissolved in methanol (10 mL), and 200 mg of 10% wet palladium catalyst on carbon was added. The mixture was stirred for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 4b (400 mg, yield: 99.6%). The product was directly used in the next reaction without purification.

[0595] MS m / z (ESI): 545.0 [M+1].

[0596] Step 2

[0597] ((4aR,8aS)-1-(4-fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4c

[0598] Compound 4b (1 g, 1.84 mmol) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (2 g, 17.5 mmol) was added dropwise, followed by stirring for 1 hour. The system was neutralized to weakly alkaline with saturated sodium bicarbonate solution, and extracted with ethyl acetate (150 mL × 3). The organic phases were combined and concentrated under reduced pressure to give crude product 4c (0.5 g, yield: 61.3%), which was directly used in the next reaction without purification.

[0599] MS m / z (ESI): 445.0 [M+1].

[0600] Step 3

[0601] ((4aR)-6-((R)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4d

[0602] ((4aR)-6-((S)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonylimide)-1-(4-fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4e

[0603] Dichlorotriphenylphosphine (203 mg, 609.26 μmol) was dissolved in 5 mL of chloroform. Triethylamine (210 mg, 2.07 mmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, 1c (40 mg, 132.6 μmol) was added, and the mixture was stirred for another 10 minutes. Then, 4c (150 mg, 113.0 μmol) was added, and the mixture was allowed to rise naturally to room temperature. The mixture was stirred for 16 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of title compounds 4d and 4e (180 mg, yield: 70.3%).

[0604] MS m / z (ESI): 703.0 [M+1].

[0605] Step 4

[0606] ((4aR,8aS)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4-P1

[0607] ((4aR,8aS)-1-(4-fluorophenyl)-6-((R)-2-methyl-2H-1,2,3-triazol-4-sulfonylimino)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 4-P2

[0608] A mixture of compounds 4d and 4e (200 mg, 284.56 μmol) was dissolved in 3 mL of tetrahydrofuran, and 2 mL of 1 M hydrochloric acid was added. The mixture was stirred for 0.5 h, and the reaction solution was neutralized with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) to give the title compounds 4-P1 (20 mg, yield: 11.9%) and 4-P2 (20 mg, yield: 11.9%).

[0609] Compound 4-P1 (shorter retention time):

[0610] MS m / z(ESI): 589.0 [M+1].

[0611] HPLC analysis: Retention time 1.48 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0612] 1H NMR (1500MHz, CDCl3): δ8.91(d,1H),8.11(d,1H),7.88(s,1H),7.68(d,1H),7.53-7.47(m,2H),7.35(s,1H),7.17(dd,2H),5.78( dd,1H),4.31-4.25(m,4H),4.06(d,1H),3.43(dd,1H),2.75(dd,1H),2.63(d,1H),2.53(d,3H),2.43(tt,1H),1.86-1.74(m,2H).

[0613] Compound 4-P2 (longer retention time):

[0614] MS m / z (ESI): 589.0 [M+1].

[0615] HPLC analysis: Retention time 1.51 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0616] 1 H NMR (1500MHz, CDCl3): δ8.94(d,1H),8.12(s,1H),7.91(s,1H),7.72(d,1H),7.150(dd,2H),7.34(s,1H),7.18(t,2H),5.7 7(d,1H),4.30(s,3H),4.13-4.06(m,2H),3.43(dd,1H),2.75(dd,1H),2.60(t,2H),2.52-2.42(m,2H),1.87-1.73(m,3H).

[0617] Examples 5-P1, 5-P2

[0618] ((R)-6-(S)-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5-P1

[0619] ((R)-6-(R)-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5-P2

[0620]

[0621]

[0622] first step

[0623] 3-((4-methoxybenzyl)thio)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine 5b

[0624] Compound 3-bromo-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine 5a (300 mg, 1.47 mmol, WuXi AppTec) and compound 4-methoxybenzyl mercaptan (341 mg, 2.21 mmol, Shanghai Biotech) were dissolved in 6 mL of 1,4-dioxane. Tris(dibenzylacetone)dipalladium (135 mg, 0.147 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (170 mg, 0.293 mmol), and N,N-diisopropylethylamine (432 mg, 3.34 mmol) were added. The mixture was microwaved at 120 °C for 1.5 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system B to give the title compound 5b (300 mg, yield: 73.4%).

[0625] MS m / z (ESI): 277.1 [M+1].

[0626] Step 2

[0627] 5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonyl chloride 5c

[0628] Compound 5b (400 mg, 1.44 mmol) was dissolved in 13.5 mL of a mixture of acetic acid and water (V / V = 2:1), and N-chlorosuccinimide (773 mg, 5.78 mmol) was added. The mixture was stirred for 2 hours. 15 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system C to give the title compound 5c (100 mg, yield: 31.0%).

[0629] MS m / z (ESI): 223.2 [M+1].

[0630] Step 3

[0631] 5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonamide 5d

[0632] Compound 5c (100 mg, 449.1 μmol) was dissolved in a methanol solution of ammonia (7 M, 2 mL). After stirring for 1 hour, the reaction solution was concentrated under reduced pressure to obtain crude product 5d (90 mg, yield: 98.6%), which was used directly in the next step without purification.

[0633] MS m / z (ESI): 203.9 [M+1].

[0634] Step 4

[0635] N-(tert-butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonamide 5e

[0636] 5d (150 mg, 246.0 μmol) and tert-butyldimethylchlorosilane (40 mg, 485.7 μmol, Shanghai Bide) were dissolved in N,N-dimethylformamide. Triethylamine (74 mg, 731.3 μmol) and 4-dimethylaminopyridine (5 mg, 40.59 μmol) were added at 0 °C, and the mixture was allowed to rise naturally to room temperature with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and 5 mL of water was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5e (20 mg, yield: 25.6%). The product was directly used in the next reaction without purification.

[0637] MS m / z (ESI): 318.1 [M+1].

[0638] Step 5

[0639] ((R)-6-((R)-N-(tert-butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5f

[0640] ((R)-6-((S)-N-(tert-butyldimethylsilyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5g

[0641] Dichlorotriphenylphosphine (60 mg, 180.1 μmol) was dissolved in 3 mL of chloroform. Triethylamine (144 mg, 1.42 mmol) was added at 0 °C, and the mixture was stirred for 5 minutes. Then, 5e (28 mg, 88.2 μmol) was added, and the mixture was stirred for another 10 minutes. Then, 1d (40 mg, 90.4 μmol) was added, and the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloroform (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compound 5f and 5g (30 mg, yield: 44.7%).

[0642] MS m / z (ESI): 742.2 [M+1].

[0643] Step 6

[0644] ((R)-6-(S)-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5-P1

[0645] ((R)-6-(R)-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 5-P2

[0646] A mixture of 5f and 5g (30mg, 40.4μmol) was dissolved in 1mL of tetrahydrofuran, and 0.5mL of 1M hydrochloric acid was added. The mixture was stirred for 0.5 hours. The reaction solution was quenched with saturated sodium bicarbonate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: SharpSil-T, 30*150mm, 5μm; mobile phase: aqueous phase (10mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%) to give the title compounds 5-P1 (3mg, yield: 11.8%) and 5-P2 (2mg, yield: 7.88%).

[0647] Compound 5-P1 (shorter retention time):

[0648] MS m / z (ESI): 628.2 [M+1].

[0649] HPLC analysis: Retention time 1.82 min, purity: 98% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0650] 1 H NMR (1500MHz, CDCl3): δ8.84(d,1H),8.11(s,1H),7.74-7.64(m,1H),7.49-7.43(m, 2H),7.28(s,1H),7.18(t,2H),6.75(s,1H),6.56(d,1H),5.76-5.63(m,1H),4.87-4 .68(m,2H),4.35(dt,1H),4.24(d,1H),4.17(dd,1H),4.09-4.00(m,1H),3.94(t,2H ),3.53(d,1H),3.19(td,1H),2.98(d,1H),2.83(dt,1H),2.59(d,1H),2.01(d,1H).

[0651] Compound 5-P2 (longer retention time):

[0652] MS m / z (ESI): 628.2 [M+1].

[0653] HPLC analysis: Retention time 1.84 min, purity: 98% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0654] 1H NMR (1500MHz, CDCl3): δ8.84(d,1H),8.14(s,1H),7.71-7.66(m,1H),7.47-7.43(m, 2H),7.30(s,1H),7.19(d,2H),6.79(s,1H),6.53(s,1H),5.66-5.54(m,1H),4.82(d, 2H),4.41-4.31(m,1H),4.26(dt,1H),4.05(d,1H),3.97(t,2H),3.53(d,1H),3.21( t,1H),2.96(d,1H),2.82-2.67(m,1H),2.52(d,1H),2.25-2.13(m,1H),2.01(s,1H).

[0655] Examples 6-P1, 6-P2

[0656] ((R)-6-((S)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 6-P1

[0657] ((R)-6-((R)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 6-P2

[0658]

[0659]

[0660] first step

[0661] 3-Bromo-1-(2-Bromoethyl)-1H-pyrazole-5-carboxylic acid methyl ester 6b

[0662] methyl 3-bromo-1H-pyrazole-5-carboxylic acid ester 6a (10 g, 48.77 mmol, Shanghai Biotech) and dibromoethane (45.8 g, 45.8 mmol) were dissolved in acetonitrile (1150 mL), and anhydrous potassium carbonate (33.7 g, 243.9 mmol) was added. The mixture was reacted at 80 °C for 3 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 6b (10 g, yield: 65.7%).

[0663] MS m / z (ESI): 312.8 [M+1].

[0664] Step 2

[0665] (3-bromo-1-(2-bromoethyl)-1H-pyrazol-5-yl)methanol 6c

[0666] Compound 6b (9.2 g, 29.5 mmol) was dissolved in tetrahydrofuran (100 mL), and a solution of lithium borohydride in tetrahydrofuran (2 M, 40 mL) was added under ice bath conditions. The reaction was allowed to proceed naturally at elevated temperature for 5 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (150 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 6c (8 g, yield: 95.5%). The product was used directly in the next reaction without purification.

[0667] MS m / z (ESI): 284.8 [M+1].

[0668] Step 3

[0669] 2-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine 6d

[0670] Compound 6c (8 g, 28.17 mmol) and triethylamine (5.78 g, 57.1 mmol) were dissolved in N,N-dimethylformamide (80 mL) and reacted at 100 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 6d (1 g, yield: 17.48%).

[0671] MS m / z (ESI): 204.2 [M+1].

[0672] The synthetic routes in Examples 5-P1 and 5-P2 were subsequently used, replacing compound 5a in the first step with compound 6d to obtain title compounds 6-P1 (2 mg, yield: 4.22%) and 6-P2 (2 mg, yield: 4.22%). Compound 6-P1 (shorter retention time):

[0673] MS m / z (ESI): 628.0 [M+1].

[0674] HPLC analysis: Retention time 1.40 min, purity: 90% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0675] 1H NMR (1500MHz, CDCl3): δ8.91(d,1H),8.19(s,1H),7.75-7.70(m,1H),7.150-7.4 6(m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.51(s,1H),6.43(s,1H),5.61 -5.56(m,1H),4.85(s,2H),4.71(s,2H),4.27-4.23(m,1H),4.16(dt,2H),4.02( t,1H),2.95(d,1H),2.87(d,1H),2.77(m,1H),2.51(td,1H),2.40-2.31(m,1H).

[0676] Compound 6-P2 (longer retention time):

[0677] MS m / z (ESI): 628.0 [M+1].

[0678] HPLC analysis: Retention time 1.42 min, purity: 99% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0679] 1 H NMR (1500MHz, CDCl3): δ8.92(d,1H),8.16(d,1H),7.74-7.69(m,1H),7.49-7.45( m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.54(d,1H),6.41(s,1H),5.70(dd ,1H),4.84(s,2H),4.71(s,2H),4.27-4.25(m,1H),4.14(t,2H),3.98(td,1H),2. 95(d,1H),2.86-2.79(m,1H),2.64-2.56(m,1H),2.53(dd,1H),2.39-2.35(m,1H).

[0680] Examples 7-P1, 7-P2

[0681] ((4aR,8aS)-6-((S)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 7-P1

[0682] ((4aR,8aS)-6-((R)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8,8a,9-octahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 7-P2

[0683]

[0684] Using the synthetic routes in Examples 4-P1 and 4-P2, the starting compound 1c in the third step was replaced with compound 6d to obtain title compounds 7-P1 (10 mg, yield: 23.6%) and 7-P2 (5 mg, yield: 11.8%).

[0685] Compound 7-P1 (shorter retention time):

[0686] MS m / z (ESI): 630.0 [M+1].

[0687] HPLC analysis: Retention time 1.42 min, purity: 97% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0688] 1 H NMR (1500MHz, CDCl3): δ8.86(d,1H),8.20-8.04(m,1H),7.68-7.61(m,1H),7.52-7.43(m,2H),7.32(s,1H),7.15(dd,2H),6.37(s,1H),5.67(dd, 1H),4.82(s,2H),4.32-4.20(m,3H),4.12(t,2H),4.02(dd,1H),3.42(dd ,1H),2.72(dd,1H),2.66-2.150(m,3H),2.38(d,2H),1.85-1.73(m,2H).

[0689] Compound 7-P2 (longer retention time):

[0690] MS m / z(ESI): 630.0 [M+1].

[0691] HPLC analysis: Retention time 1.45 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0692] 1 H NMR (1500MHz, CDCl3): δ8.89(d,1H),8.11-8.01(m,1H),7.72-7.60(m,1H),7.58-7.43(m,2H),7.32(s,1H),7.15(dd,2H),6.39(d,1H),5.69(dd, 1H),4.83(s,2H),4.26(t,2H),4.17-4.00(m,4H),3.42(dd,1H),2.72(d d,1H),2.59(td,2H),2.51(d,1H),2.47-2.32(m,2H),1.84-1.73(m,2H).

[0693] Examples 8-P1, 8-P2

[0694] ((R)-6-((S)-2-cyclopropyl-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 8-P1

[0695] ((R)-6-((R)-2-cyclopropyl-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 8-P2

[0696]

[0697] first step

[0698] 4-(benzylthio)-1H-1,2,3-triazole 8b

[0699] The sodium salt of 5-mercapto-1,2,3-triazole, 8a (10 g, 81.22 mmol, Shanghai Biotech), was dissolved in 100 mL of ethanol, and benzyl bromide (15.3 g, 89.45 mmol) was added dropwise. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product 8b (11 g, yield: 70.8%). The product was directly used in the next step of the reaction without purification.

[0700] MS m / z (ESI): 191.9 [M+1].

[0701] Step 2

[0702] 4-(benzylthio)-2-cyclopropyl-2H-1,2,3-triazole 8c

[0703] Compound 8b (3 g, 15.68 mmol) and cyclopropylboronic acid (2.7 g, 31.43 mmol) were dissolved in 1,2-dichloroethane (100 mL), and sodium carbonate (5 g, 47.17 mmol), copper acetate (3.13 g, 15.67 mmol), and 2,2'-bipyridine (3.7 g, 23.69 mmol) were added. The mixture was heated to 70 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 8c (1.2 g, yield: 33%). The product was directly used in the next reaction without purification.

[0704] MS m / z (ESI): 232.1 [M+1].

[0705] Step 3

[0706] 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonyl chloride 8d

[0707] Compound 8c (0.54 g, 2.33 mmol) was dissolved in 9 mL of a mixture of acetic acid and water (V:V = 2:1), and N-chlorosuccinimide (1.25 g, 9.36 mmol) was added. The mixture was stirred for 1 hour, and water (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 8d (0.4 g, yield: 82.5%). The product was directly used in the next reaction without purification.

[0708] MS m / z (ESI): 207.9 [M+1].

[0709] Step 4

[0710] 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamide 8e

[0711] At 0°C, 3 mL of 7 M ammonia-methanol solution was added to compound 8d (0.885 g, 4.26 mmol), and the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product 8e (0.4 g, yield: 82.5%). The product was directly used for the next reaction without purification.

[0712] MS m / z (ESI): 189.1 [M+1].

[0713] Step 5

[0714] N-(tert-butyldimethylsilyl)-2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide 8f

[0715] Compound 8e (0.8 g, 4.25 mmol) and 4-dimethylaminopyridine (0.1 g, 811.84 μmol) were dissolved in dichloromethane (50 mL). Tert-butyldimethylchlorosilane (528 mg, 6.4 mmol) was added at 0 °C. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 8f (0.5 g, yield: 38.8%).

[0716] MS m / z (ESI): 303.1 [M+1].

[0717] The synthetic routes in Examples 1-P1 and 1-P2 were then used, with the starting compound 1c in the third step replaced by compound 8f, to obtain the title compounds 8-P1 (2 mg, yield: 9.49%) and 8-P2 (2 mg, yield: 3.56%).

[0718] Compound 8-P1 (shorter retention time):

[0719] MS m / z (ESI): 613.0 [M+1].

[0720] HPLC analysis: Retention time 1.54 min, purity: 98.5% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0721] 1 H NMR (500MHz, CDCl3): δ8.93(s,1H),8.15(d,1H),7.83(s,1H),7.74-7.70(m,1H) ),7.53-7.42(m,2H),7.32(s,1H),7.24-7.17(m,1H),7.07(s,1H),6.55(d,1H) ,5.72(dd,1H),4.28(d,1H),4.10(tt,2H),4.03-3.95(m,1H),3.01-2.91(m,2H ),2.88-2.78(m,1H),2.64-2.51(m,2H),1.47-1.38(m,2H),1.22-1.14(m,2H).

[0722] Compound 8-P2 (longer retention time):

[0723] MS m / z (ESI): 613.0 [M+1].

[0724] HPLC analysis: Retention time 1.56 min, purity: 98.9% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0725] 1 H NMR (500MHz, CDCl3): δ8.90(d,1H),8.17(s,1H),7.86(s,1H),7.73(dd,1H),7.47(dd,2H),7.32(s,1H),7.20(t,2H),6.52(d, 1H),5.55(dd,1H),4.03(d,3H),2.92(d,1H),2.84(d,1H),2.79-2.63(m,3H),2.54-2.48(m,1H),1.42(dd,2H),1.18(dd,2H).

[0726] Examples 9-P1, 9-P2

[0727] ((R)-6-((S)-2-(difluoromethyl)-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 9-P1

[0728] ((R)-6-((R)-2-(difluoromethyl)-2H-1,2,3-triazol-4-sulfonylimino)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 9-P2

[0729]

[0730] first step

[0731] 4-(benzylthio)-2-(difluoromethyl)-2H-1,2,3-triazole 9a

[0732] Compound 8b (10 g, 52.28 mmol) was dissolved in N,N-dimethylformamide (80 mL), and cesium carbonate (34 g, 104.35 mmol) and sodium difluorochloroacetate (16 g, 104.94 mmol) were added. The mixture was heated to 100 °C and reacted for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography using eluent system A to give title compound 9a (2.92 g, yield: 23.1%).

[0733] MS m / z (ESI): 242.2 [M+1].

[0734] The synthetic routes in Examples 8-P1 and 8-P2 were then used, with the starting compound 8c in the third step replaced by compound 9a, to obtain title compounds 9-P1 (45 mg, yield: 26.6%) and 9-P2 (32 mg, yield: 18.9%).

[0735] Compound 9-P1 (shorter retention time):

[0736] MS m / z (ESI): 623.1 [M+1].

[0737] HPLC analysis: Retention time 3.11 min, purity: 96% (Column: ACQUITY) C18, 1.7μm, 2.1*50mm; Mobile phase: water (10mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0738] 1 H NMR (500MHz, CDCl3): δ8.90(d,1H),8.12(s,1H),8.06(s,1H),7.71(dd,1H),7.48-7.42(m,2H),7.33(t,1H),7.18(t,2H),6.54(d, 1H),5.77(dd,1H),4.25(d,1H),4.10-3.91(m,1H),3.08(d,1H),2.95(d,1H),2.90-2.78(m,1H),2.69(td,2H),2.62-2.47(m,1H).

[0739] Compound 9-P2 (longer retention time):

[0740] MS m / z (ESI): 623.1 [M+1].

[0741] HPLC analysis: Retention time 3.16 min, purity: 97% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0742] 1 H NMR (500MHz, CDCl3): δ8.86(d,1H),8.15(s,1H),8.10(d,1H),7.75-7.70(m,1H),7.48-7.42(m,2H),7.35(d,1H),7.18(dd,2H),6.50( d,1H),5.52(dd,1H),4.15-4.05(m,1H),3.96(d,1H),2.99-2.85(m,2H),2.81(td,1H),2.71(td,1H),2.56-2.48(m,1H),2.40(s,1H).

[0743] Examples 10-P1, 10-P2

[0744] ((R)-1-(4-fluorophenyl)-6-((S)-1-methyl-1H-tetrazole-5-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 10-P1

[0745] ((R)-1-(4-fluorophenyl)-6-((R)-1-methyl-1H-tetrazole-5-sulfonylimino)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 10-P2

[0746]

[0747] first step

[0748] 5-(benzylthio)-1-methyl-1H-tetrazole 10b

[0749] Compound 5-(benzylthio)-1H-tetrazole 10a (2 g, 10.4 mmol, Shanghai Biotech) was dissolved in tetrahydrofuran (20 mL), and trimethylsilyldiazomethane (2.39 g, 20.9 mmol) was added dropwise. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure to obtain crude product 10b (2 g, yield: 93.1%). The product was directly used for the next reaction without purification.

[0750] MS m / z (ESI): 207.2 [M+1].

[0751] The synthetic routes in Examples 8-P1 and 8-P2 were then used, with the starting compound 8c in the third step replaced by compound 10b, to obtain title compounds 10-P1 (4 mg, yield: 15.6%) and 10-P2 (4 mg, yield: 15.6%).

[0752] Compound 10-P1 (shorter retention time):

[0753] MS m / z (ESI): 588.2 [M+1].

[0754] HPLC analysis: Retention time 1.45 min, purity: 99% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0755] 1 H NMR (500MHz, CDCl3): δ8.91(d,1H),8.15(s,1H),7.72(dd,1H),7.51-7.44(m,2H),7.32(s,1H),7.20(t,2H),6. 57(d,1H),5.81(dd,1H),4.44(s,3H),4.28(d,1H),4.14(dq,1H),3.27(d,1H),3.09-2.82(m,4H),2.58(dd,1H).

[0756] Compound 10-P1 (longer retention time):

[0757] MS m / z (ESI): 588.2 [M+1].

[0758] HPLC analysis: Retention time 1.47 min, purity: 97% (Column: ACQUITY) C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0759] 1 H NMR (500MHz, CDCl3): δ8.88(d,1H),8.17(s,1H),7.72(d,1H),7.47(dd, 2H),7.33(s,1H),7.21(t,2H),6.54(s,1H),5.63(d,1H),4.45(s,3H),4.15(dd,1 H),4.04(d,1H),3.20(d,1H),3.03-2.89(m,2H),2.80-2.68(m,2H),2.55(d,1H).

[0760] Biological evaluation

[0761] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0762] Test Example 1: GR Receptor Reporter Gene Experiment

[0763] The following method was used to determine the effect of the disclosed compound on the transcriptional activity of the GR receptor in MDA-kb2 cells. The experimental method is briefly described below.

[0764] MDA-kb2 cells (ATCC, CRL-2713) were cultured in complete medium (i.e., Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141). On day 1, MDA-kb2 cells were seeded at a density of 30,000 cells / well in 96-well plates using incomplete medium (i.e., Leibovitz's L-15 medium (Gibco, 11415114) containing 5% activated charcoal-treated serum (Biosun, S-FBS-AU-045), with 80 μL of cell suspension per well. The plates were incubated overnight at 37°C in a CO2-free incubator. On day 2, 10 μL of serially diluted test compounds prepared in incomplete medium were added to each well. The final concentrations of the compounds were determined by five-fold serial dilutions starting from 10 μM, with a final DMSO concentration of 0.5%. Add 10 μL of dexamethasone (MCE, HY-14648) prepared with incomplete culture medium to each well, bringing the final concentration to 10 nM. Wells containing only 0.5% DMSO served as negative controls, and wells containing 10 nM dexamethasone served as positive controls. The plates were incubated at 37°C in a CO2-free incubator for 18 hours. On the third day, remove the 96-well cell culture plate and add 90 μL of the prepared ONE-Glo luciferase assay reagent (Promega, E6120) to each well. After incubating at room temperature for 10 minutes, read the luminescence signal values ​​using an EnVision (PerkinElmer) microplate reader. Calculate the inhibition rate using the luminescence values ​​from the compound concentrations and the negative and positive control wells. Calculate the IC50 (IC50) for inhibiting GR transcriptional activity using GraphPad Prism software based on the compound concentrations and corresponding inhibition rates. 50 value.

[0765] Table 1. Effects of the disclosed compounds on GR receptor transcriptional activity in MDA-kb2 cells.

[0766] Example number <![CDATA[IC 50 (nM)]]> 1-P1 10 1-P2 49 2-P1 270 2-P2 129 3-P1 153 4-P1 65 4-P2 159 5-P1 97 7-P1 157 8-P1 7 8-P2 16

[0767] 9-P1 6 9-P2 35 10-P1 20 10-P2 103

[0768] Conclusion: The compound disclosed herein exhibits good inhibitory activity against GR receptor transcription in MDA-kb2 cells.

[0769] Test Example 2: GR receptor binding assay

[0770] The following method is used to determine the competitive binding activity of the disclosed compound with the GR receptor. The experimental method is briefly described below.

[0771] This experiment uses GR receptor competitive binding assay kit (Invitrogen, A15901). First, prepare the experimental buffer by mixing Nuclear Receptor Buffer F (Invitrogen, PV4547), GR Stabilizing Peptide (10×) (Invitrogen, P2815), and DTT (Invitrogen, P2325) in a ratio of 179:20:1. Dilute the test compound with DMSO, performing a 4-fold serial dilution starting at 1 mM, for a total of 9 concentrations. Then, dilute the DMSO solution with the experimental buffer, adding 10 μL of the compound dilution to each well of a black 384-well plate (Corning, 4514), resulting in 9 final concentrations of the compound from the initial 4-fold serial dilutions at 10 μM. Wells containing 1% DMSO were used as negative controls, and wells containing 20 μM dexamethasone (MCE, HY-14648) were used as positive controls. Fluormone was prepared using the buffer. TM GS1Green (Invitrogen, PV6044) was diluted to a final concentration of 5 nM and added at 5 μL per well in a 384-well plate. GR-LBD (GST) (Invitrogen, A15668) and GR-LBD (GST) were prepared using buffer. A mixture of Tb-anti-GST antibody (Invitrogen, PV3550) was prepared to a final concentration of 2 nM for Tb anti-GST antibody and the final concentration of GR-LBD (GST) as specified in the batch instructions. 5 μL of this mixture was added to each well of a 384-well plate. After incubating the plates at room temperature for 2 hours, fluorescence values ​​were read using a Pherastar microplate reader (BMG LABTECH) at excitation wavelengths of 340 nm and emission wavelengths of 520 nm and 490 nm. The inhibition rate was calculated using the ratio of the fluorescence values ​​at 520 nm and 490 nm for each compound concentration to those of the negative and positive control wells. The IC50 of the competitive binding activity of the compound against the GR receptor was calculated using GraphPad Prism software based on the compound concentrations and corresponding inhibition rates. 50 value.

[0772] Table 2 Competitive binding activity of the disclosed compounds to the GR receptor

[0773] Example number <![CDATA[IC 50 (nM)]]> 1-P1 15 1-P2 22 2-P2 41 4-P1 43 5-P1 58

[0774] Conclusion: The compound disclosed herein exhibits good inhibitory activity through competitive binding to the GR receptor.

[0775] Test Example 3: MDA-MB-231 Cell Proliferation Experiment

[0776] The following method was used to determine the inhibitory effect of the disclosed compound on the proliferation of MDA-MB-231 cells in vitro. The experimental method is briefly described below.

[0777] MDA-MB-231 cells (ATCC, HTB-26) were cultured in complete medium (i.e., Leibovitz's L-15 medium (ThermoFisher, 11415-114) containing 10% fetal bovine serum (Gibco, 10099-141). On the first day of the experiment, MDA-MB-231 cells were seeded at a density of 1000 cells / well in 96-well 3D cell culture plates (Corning, CLS7007-24EA) using Leibovitz's L-15 incomplete medium containing 10% activated charcoal-treated fetal bovine serum (BioSun, S-FBS-AU-045), with 120 μL of cell suspension per well. After centrifugation at 2000 rpm for 3 minutes, the plates were incubated overnight at 37°C in a CO2-free cell culture incubator. On the second day, 15 μL of serially diluted test compounds prepared with incomplete culture medium were added to each well. The final concentrations of the compounds were determined by three-fold serial dilutions starting from 10 μM, resulting in nine concentration points. Then, 15 μL of dexamethasone (MCE, HY-14648) was added to each well, bringing the final concentration to 0.1 μM. Wells containing only 0.5% DMSO served as negative controls, and wells containing 0.1 μM dexamethasone served as positive controls. The plates were incubated at 37°C in a CO2-free cell culture incubator for 8 days. After 8 days, the 96-well 3D cell culture plates were removed, and 50 μL of [a specific reagent / component] was added to each well. The 3D Cell Viability Assay (Promega, G9683) was performed by shaking in the dark for 25 minutes. 100 μL of solution was then transferred to each well of a 96-well opaque white plate (PerkinElmer, 6005290). The luminescence signal values ​​were read using a PerkinElmer multi-functional microplate reader (VICTOR 3). The inhibition rate was calculated using the luminescence values ​​from the compound concentrations, negative controls, and positive controls. Based on the compound concentrations and corresponding inhibition rates, the IC50 (IC50) for inhibiting the proliferation of MDA-MB-231 cells was calculated using GraphPad Prism software. 50value.

[0778] Table 3. Inhibitory effect of the disclosed compounds on the proliferation of MDA-MB-231 cells in vitro.

[0779] Example number <![CDATA[IC 50 (nM)]]> 1-P1 205 1-P2 405 8-P1 53 8-P2 380 9-P1 47 9-P2 259

[0780] Conclusion: The compound disclosed herein exhibits good inhibitory effect on the proliferation of MDA-MB-231 cells in vitro.

[0781] Test Example 4: Inhibition of enzyme activity at the midazolam metabolite site of human liver microsomes by the disclosed compound. effect

[0782] The enzyme activity of the disclosed compound at the midazolam metabolite site of human liver microsomes was determined using the following experimental method.

[0783] I. Experimental Materials and Instruments

[0784] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0785] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0786] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 35)

[0787] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0788] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0789] 6. CYP probe substrate (midazolam, TRC, M343000 / 3μM)

[0790] 7. Quality control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG)

[0791] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0792] II. Experimental Procedure

[0793] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these series of solutions I 200 times with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute with PBS to a 15 μM concentration for midazolam working solution.

[0794] Take 40 μL of a 0.25 mg / mL microparticle solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 15 μM midazolam working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. Use ketoconazole of the same concentration instead of the compound for the quality control group. Simultaneously, pre-incubate with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubated samples should be in duplicate. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0795] The IC50 value for the drug at the CYP3A4 midazolam metabolite site was calculated using Graphpad Prism. 50 The values ​​are shown in Table 4.

[0796] Table 4 shows the IC50 values ​​of the disclosed compounds at the midazolam metabolite site in human liver microsomes CYP3A4. 50 value

[0797] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 10.4 Relacorilant 2.4

[0798] Conclusion: The compound of Example 1-P1 of this disclosure has a weak inhibitory effect on the midazolam metabolic site of human liver microsomes CYP3A4, and the risk of metabolic drug interaction based on the midazolam metabolic site of CYP3A4 is small. It shows better safety than the positive control compound Relacorilant.

[0799] Test Example 5: Inhibitory effect of the disclosed compound on the enzyme activity of the human liver microsomal CYP3A4 testosterone metabolism site.

[0800] The enzyme activity of the disclosed compound at the human liver microsomal CYP3A4 testosterone metabolism site was determined using the following experimental method.

[0801] I. Experimental Materials and Instruments

[0802] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0803] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0804] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002, Donor 35)

[0805] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0806] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0807] 6. CYP probe substrate (testosterone, Wokai, CAS No. [58-22-0] / 75μM)

[0808] 7. Quality control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG)

[0809] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0810] II. Experimental Procedure

[0811] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these solutions I 200-fold with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute with PBS to a testosterone working solution concentration of 375 μM.

[0812] Take 40 μL of a 0.25 mg / mL microsome solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 375 μM testosterone working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. The quality control group is replaced with ketoconazole at the same concentration. Simultaneously, pre-incubate the mixture with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0813] The IC50 value for the drug at the CYP3A4 testosterone metabolite site was calculated using Graphpad Prism. 50 The values ​​are shown in Table 5.

[0814] Table 5 shows the IC50 values ​​of the disclosed compounds at the testosterone metabolism site of human liver microsomal CYP3A4. 50 value

[0815] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 25.2 Relacorilant 2.5

[0816] Conclusion: The compound of Example 1-P1 of this disclosure has a weaker inhibitory effect on the testosterone metabolism site of human liver microsome CYP3A4 and exhibits better safety than the positive control compound Relacorilant.

[0817] Test Example 6: Inhibition of enzyme activity at the CYP2C9 diclofenac metabolic site in human liver microsomes by the disclosed compound. effect

[0818] The enzyme activity of the disclosed compound at the diclofenac metabolic site of human liver microsomes was determined using the following experimental method.

[0819] I. Experimental Materials and Instruments

[0820] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0821] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0822] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 35)

[0823] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0824] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0825] 6. CYP probe substrate (diclofenac, SIGMA, Cat No. D6899-10G / 4μM)

[0826] 7. Quality control inhibitor (sulfamethoxazole, SIGMA, Cat No. 526-08-9)

[0827] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0828] II. Experimental Procedure

[0829] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these series of solutions I 200 times with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute with PBS to a 20 μM diclofenac working solution.

[0830] Take 40 μL of a 0.25 mg / mL microparticle solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 15 μM diclofenac working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. The quality control group is replaced with sulfamethoxazole at the same concentration. Simultaneously, pre-incubate the mixture with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubated samples are prepared in duplicate. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0831] The IC50 value for the drug at the CYP2C9 diclofenac metabolite site was calculated using Graphpad Prism. 50 The values ​​are shown in Table 6.

[0832] Table 6. IC50 of the disclosed compounds against the CYP2C9 diclofenac metabolite site in human liver microsomes. 50 value

[0833] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 >30 Relacorilant 4.2

[0834] Conclusion: Compound P1 of Example 1 of this disclosure does not exhibit metabolic drug interactions based on the CYP2C9 diclofenac metabolite site in the concentration range of 30 μM, and shows better safety than the positive control compound Relacorilant.

[0835] Test Example 7: The enzyme activity of the disclosed compound on the human liver microsomal CYP2C19(S)-methphenytoin metabolite site. Inhibition

[0836] The enzyme activity of the disclosed compound at the human liver microsomal CYP2C19(S)-methphenytoin metabolic site was determined using the following experimental method.

[0837] I. Experimental Materials and Instruments

[0838] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0839] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0840] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 35)

[0841] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0842] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0843] 6. CYP probe substrate ((S)-Mphenytoin / 20μM, powder purchased from Bailingwei Technology Co., Ltd., Cat No. 303768)

[0844] 7. Quality control inhibitor (ticlopidine, powder purchased from SIGMA, Cat No. T6654-1G)

[0845] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0846] II. Experimental Procedure

[0847] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these series of solutions I 200 times with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute with PBS to a 100 μM concentration of (S)-metphenytoin working solution.

[0848] Take 40 μL of a 0.25 mg / mL microparticle solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 15 μM (S)-mphenytoin working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. The quality control group is replaced with thiaclopidogrel at the same concentration instead of the compound. Simultaneously, pre-incubate the mixture with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubated samples are duplicated. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0849] The IC50 of the drug at the CYP2C19(S)-mephenytoin metabolite was calculated using Graphpad Prism. 50 The values ​​are shown in Table 7.

[0850] Table 7 shows the IC50 values ​​of the disclosed compounds at the human liver microsomal CYP2C19(S)-mephenytoin metabolite site. 50 value

[0851] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 >30 Relacorilant 6.9

[0852] Conclusion: Compound P1 of Example 1 of this disclosure does not exhibit metabolic drug interactions based on the CYP2C19(S)-mephenytoin metabolite site in the concentration range of 30 μM, and shows better safety than the positive control compound Relacorilant.

[0853] Test Example 8: Inhibition of enzyme activity at the phenacetin metabolite site of CYP1A2 in human liver microsomes by the disclosed compound. effect

[0854] The enzyme activity of the disclosed compound at the phenacetin metabolic site of human liver microsome CYP1A2 was determined using the following experimental method.

[0855] I. Experimental Materials and Instruments

[0856] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0857] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0858] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 35)

[0859] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0860] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0861] 6. CYP probe substrate (phenacetin / 12μM, National Institutes for Food and Drug Control, Cat No. 100095-200204)

[0862] 7. Quality control inhibitor (α-naphthylflavonoid, SIGMA, Cat No. N5757-1G)

[0863] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0864] II. Experimental Procedure

[0865] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these series of solutions I 200 times with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute with PBS to a 60 μM working solution of phenacetin.

[0866] Take 40 μL of a 0.25 mg / mL microparticle solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 15 μM phenacetin working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. The quality control group is replaced with α-naphthylflavonoid of the same concentration. Simultaneously, pre-incubate the mixture with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubated samples are duplicated. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0867] The IC50 value for the drug at the CYP1A2 phenacetin metabolite site was calculated using Graphpad Prism. 50 The values ​​are shown in Table 8.

[0868] Table 8 shows the IC50 values ​​of the disclosed compounds at the phenacetin metabolite site of human liver microsomes CYP1A2. 50 value

[0869] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 >30

[0870] Conclusion: Compound P1 of Example 1 of this disclosure does not exhibit metabolic drug interactions based on the CYP1A2 phenacetin metabolite site within the concentration range of 30 μM.

[0871] Test Example 9: Inhibition of enzyme activity at the dextromethorphan metabolite site of CYP2D6 in human liver microsomes by the disclosed compound. effect

[0872] The enzyme activity of the disclosed compound at the dextromethorphan metabolite site of human liver microsomes was determined using the following experimental method.

[0873] I. Experimental Materials and Instruments

[0874] 1. Phosphate buffer (20×PBS, purchased from Sangon Biotech)

[0875] 2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)

[0876] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 9050002, Donor, 35)

[0877] 4. ABI QTrap 4000 LC-MS / MS (AB Sciex)

[0878] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA)

[0879] 6. CYP probe substrate (dextromethorphan / 4μM, Sigma, Cat No. D9684-5G)

[0880] 7. Quality control inhibitor (quinidine, SIGMA, Q0750-5G)

[0881] 8. Positive control compound Relacorilant (CORT-125134, synthesized according to Example 18 of WO2013177559A2)

[0882] II. Experimental Procedure

[0883] Prepare a 100 mM PBS buffer. Use this buffer to prepare a 7.5 mM MgCl2 and a 5 mM NADPH solution. Then, use the 7.5 mM MgCl2 to prepare a 0.25 mg / mL microsomal solution. Dilute the 30 mM stock solution of the compound from Example 1-P1 or the positive control compound Relacorilant with DMSO to prepare a series of solutions I with concentrations of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, and 0 mM. Then, dilute these solutions I 200 times with phosphate-buffered saline (PBS) to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0 μM). Dilute the dextromethorphan working solution to a concentration of 20 μM with PBS.

[0884] Take 40 μL of a 0.25 mg / mL microparticle solution prepared in 7.5 mM MgCl2, and then take 20 μL each of 15 μM dextromethorphan working solution and compound working solutions (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM), and mix thoroughly. The quality control group is replaced with quinidine of the same concentration. Simultaneously, pre-incubate the mixture with 5 mM NADPH solution at 37 °C for 5 minutes. After 5 minutes, add 20 μL of NADPH to each well, start the reaction, and incubate for 30 minutes. All incubated samples are prepared as duplicate samples. After 30 minutes, add 250 μL of acetonitrile containing the internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of the supernatant, mix it with 80 μL of ultrapure water, and transfer to LC-MS / MS for analysis.

[0885] The IC50 of the drug at the CYP2D6 dextromethorphan metabolite site was calculated using Graphpad Prism. 50 The values ​​are shown in Table 9.

[0886] Table 9 shows the IC50 values ​​of the disclosed compounds at the CYP2D6 dextromethorphan metabolite site in human liver microsomes. 50 value

[0887] compound <![CDATA[IC 50 (μM)]]> Example 1-P1 >30 Relacorilant 9.0

[0888] Conclusion: Compound P1 of Example 1 of this disclosure does not exhibit metabolic drug interactions based on the CYP2D6 dextromethorphan metabolite site in the concentration range of 30 μM, and shows better safety than the positive control compound Relacorilant.

[0889] Example 10: Pharmacokinetic assay of the compounds disclosed herein

[0890] 1. Abstract

[0891] Nude mice were used as test animals. The plasma drug concentration of the test compound at different time points after gavage administration was determined by LC / MS / MS. The pharmacokinetic behavior of the compound disclosed herein in nude mice was studied, and its pharmacokinetic characteristics were evaluated.

[0892] 2. Experimental Design

[0893] 2.1 Experimental reagents

[0894] Example 1 - P1 compound, Relacorilant.

[0895] 2.2 Laboratory Animals

[0896] Twenty-seven female nude mice, divided into three groups, were purchased from Vital River Laboratory Animal Co., Ltd.

[0897] 2.3 Drug Preparation

[0898] Weigh a certain amount of the drug and add 10% DMSO, 0.1% Tween 80 and 89.9% HPMC (0.5%) to prepare a clear solution.

[0899] 2.4 Administration

[0900] Nude mice were fasted overnight and then administered the drugs by gavage at doses of 10 mg / kg and 30 mg / kg, with a volume of 0.2 mL / 10 g for both doses.

[0901] 3. Operation

[0902] Nude mice were administered the test compound via gavage. 0.1 mL blood samples were collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions.

[0903] To determine the content of the target compound in the plasma of nude mice after gavage administration of different concentrations of the drug: 20 μL of nude mouse plasma was collected at each time point after administration, 50 μL of internal standard solution (camptothecin 100 ng / mL) and 200 μL of acetonitrile were added, the mixture was vortexed for 5 minutes and centrifuged for 10 minutes (3700 rpm), and 1 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[0904] 4. Pharmacokinetic Parameter Results

[0905] Table 10 Pharmacokinetic parameters of the compounds disclosed herein

[0906]

[0907] Conclusion: The compound 1-P1 of this disclosure has good pharmacokinetic absorption and has a significant pharmacokinetic advantage over the positive control compound Relacorilant.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: It is either non-existent or a chemical bond; Ring A is a 5-membered nitrogen-containing heteroaryl group; Each R 1 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; Or, two adjacent R 1 It fuses with ring A to form a 5- or 6-membered heterocyclic group; Ring B is pyridinyl; Each R 2 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 Halogenated alkyl groups; The ring C is phenyl; Each R 3 They may be the same or different, and each is independently selected from hydrogen atoms and halogens; m is 0, 1, or 2; n is 1; and t is 1.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

3. The compound of general formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by general formula (II) is a compound represented by general formula (II-1) or general formula (II-2): or in: Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

4. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) or a pharmaceutically acceptable salt thereof is: in: Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by general formula (III) is a compound represented by general formula (III-1) or general formula (III-2): or in: Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

6. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IV) or a pharmaceutically acceptable salt thereof: in: Rings A and R 1 To R 3 m, n and t are as defined in claim 1.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by the general formula (IV) is a compound represented by general formula (IV-1) or general formula (IV-2): or in: Rings A and R 1 To R 3 m, n and t are as defined in claim 1.

8. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein the compound is a compound of general formula (V) or a pharmaceutically acceptable salt thereof: in: Rings A and R 1 To R 3 m, n and t are as defined in claim 1.

9. The compound of general formula (I) according to claims 8 to 9, wherein, The compound represented by the general formula (V) is a compound represented by general formula (V-1) or general formula (V-2): or in: Rings A and R 1 To R 3 m, n and t are as defined in claim 1.

10. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, 1,2,3-triazolyl and tetrazolyl.

11. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is 1,2,3-triazolyl.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , , , , and .

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

14. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 It is trifluoromethyl.

15. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a fluorine atom.

16. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

17. A compound of general formula (IA) or a salt thereof, in: R w It is an amino protecting group; Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

18. The compound or a salt thereof according to claim 17, wherein R w It is tert-butyldimethylsilyl (TBS).

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

20. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by general formula (IA) or its salt, after deamino protecting group R w This yields compounds of general formula (I) or their pharmaceutically usable salts. in: R w It is an amino protecting group; Ring A, Ring B, Ring C, R 1 To R 3 m, n and t are as defined in claim 1.

21. The method of claim 20, wherein R w It is tert-butyldimethylsilyl (TBS).

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

23. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

24. Use of the compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22 or 23, in the preparation of a medicament for the treatment and / or prevention of breast cancer, prostate cancer.

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