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 carbohydrate, protein, and lipid metabolism in humans. Pathologically elevated glucocorticoid levels can lead to metabolic disorders and developmental delays, clinically known as Cushing's syndrome (CS). Conversely, hypoglycemic levels 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] R 4a and R 4b Same or different, and each independently is an alkyl group, or R 4a and R 4b It fuses with the attached carbon atom to form a cycloalkyl or heterocyclic group;

[0014] L 1and L 2 They may be the same or different, and each is independently a chemical bond or selected from oxygen atom, sulfur atom, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NH-, alkylene and heteroalkylene;

[0015] Ring A is selected from heterocyclic, aryl, and heteroaryl groups;

[0016] Each R 1 They may be the same or different, and each is independently selected from hydrogen atom, halogen, oxo group, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR 5a R 5b hydroxyl group, -C(O)R 6 -C(O)OR 6 -C(O)NR 5a R 5b -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, oxo, 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;

[0017] Or, two adjacent R 1 Fusing with ring A to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl group is independently and optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR 7 R 8 It is substituted by one or more substituents selected from nitro, hydroxy, and hydroxyalkyl;

[0018] Ring B is aryl or heteroaryl;

[0019] 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 5a R 5b 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;

[0020] The ring C is aryl or heteroaryl;

[0021] 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 5a R 5b and hydroxyl groups;

[0022] R 6 The group is selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl and heterocyclic groups, wherein each of the alkyl, cycloalkyl and heterocyclic groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

[0023] R 5a R 5b R 7 and R 8 The same or different, and each independently selected from hydrogen atoms, alkyl, hydroxyalkyl, cycloalkyl, and heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; or R 5a and R 5b R 7 and R 8 Together with the attached nitrogen atom, a heterocyclic group is formed, wherein the formed heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, alkyl, 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, wherein It is a chemical bond.

[0029] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b The same or different, and each independently is C. 1-6 Alkyl, or R 4a and R 4bFusing with the attached carbon atom to form a 3- to 6-membered cycloalkyl group; preferably, R 4a and R 4b All are methyl, or R 4a and R 4b It fuses with the attached carbon atom to form a cyclopropyl group.

[0030] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 It is -C(O)-.

[0031] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 2 It is -S(O)2-.

[0032] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 It is -C(O)-, and L 2 It is -S(O)2-.

[0033] 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:

[0034]

[0035] in:

[0036] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (I).

[0037] 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:

[0038]

[0039] in:

[0040] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (I).

[0041] 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:

[0042]

[0043] in:

[0044] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (I).

[0045] 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:

[0046]

[0047] in:

[0048] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (I).

[0049] 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.

[0050] 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.

[0051] 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:

[0052]

[0053] in:

[0054] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0055] 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):

[0056]

[0057] in:

[0058] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0059] 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):

[0060]

[0061] in:

[0062] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0063] 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:

[0064]

[0065] in:

[0066] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0067] 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):

[0068]

[0069] in:

[0070] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0071] 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):

[0072]

[0073] in:

[0074] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (I).

[0075] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or pharmaceutically acceptable salts 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; preferably, ring A is a 5- or 6-membered heteroaryl group; more preferably, ring A is a 5-membered heteroaryl group; most preferably, ring A is a pyrazolyl or 1,2,3-triazolyl.

[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), and (V-2) are described, 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, each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 1 C 1-6 Alkyl; most preferably, R 1 It is a methyl group.

[0077] 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), and (V-2) are used, wherein... for R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C1-6 Halogenated alkoxy groups; preferably, for

[0078] 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), and (V-2) are described, 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 groups; more preferably, each R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Halogenated alkyl; more preferably, R 2 C 1-6 Halogenated alkyl; most preferably, R 2 It is trifluoromethyl.

[0079] 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), and (V-2) are described, 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 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 C 1-6 Halogenated alkyl groups; more preferably, each R 3 They may be the same or different, and each is independently a hydrogen atom or a halogen; more preferably, R 3 It is a halogen; most preferably, R 3 It is a fluorine atom.

[0080] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts represented by general formulas (I), (II), (II-1), (II-2), (III), (III-1), and (III-2) are wherein... for 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 The haloalkoxy group, n, is as defined in general formula (I); preferably... R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably alkyl

[0081] In some embodiments of this disclosure, the compounds represented by general formulas (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or their pharmaceutically acceptable salts, wherein... for R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably

[0082] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts represented by general formulas (I), (II), (II-1), (II-2), (III), (III-1), and (III-2) are wherein... for 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 and C 1-6 Haloalkoxy group, t as defined in general formula (I); preferably R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably alkyl

[0083] In some embodiments of this disclosure, the compounds represented by general formulas (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or their pharmaceutically acceptable salts, wherein... for R 3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably

[0084] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or pharmaceutically acceptable salts thereof, wherein m is 0, 1, or 2; preferably, m is 1.

[0085] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or pharmaceutically acceptable salts thereof, wherein n is 0, 1, or 2; preferably, n is 1.

[0086] 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), and (V-2) are used, wherein t is 0, 1, or 2; preferably, t is 1.

[0087] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein It is a chemical bond; R 4a and R 4b All are methyl, or R 4a and R 4b It fuses with the attached carbon atom to form a cyclopropyl group; L 1 -C(O)-; L 2 The ring is -S(O)2-; 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 1-6Alkoxy and C 1-6 Halogenated alkoxy groups; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, 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 and C 1-6 Haloalkoxy group; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2.

[0088] In some embodiments of this disclosure, the compounds of general formulas (II), (II-1), (II-2), (III), (III-1), and (III-2), or pharmaceutically acceptable salts thereof, wherein ring A is a 5- to 6-membered heteroaryl group; 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 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl 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 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2.

[0089] In some embodiments of this disclosure, the compounds represented by general formulas (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or pharmaceutically acceptable salts thereof, wherein ring A is pyrazolyl or 1,2,3-triazolyl; each R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups; each R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Halogenated alkyl groups; each R 3 They may be the same or different, and each is independently a hydrogen atom or a halogen; m is 1; n is 1; and t is 1.

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (IV), (IV-1), (IV-2), (V), (V-1), and (V-2), or pharmaceutically acceptable salts thereof, wherein ring A is pyrazolyl or 1,2,3-triazolyl; R 1 C 1-6 Alkyl; R 2 C 1-6 Halogenated alkyl; R 3 It is a halogen; m is 1; n is 1; and t is 1.

[0091] Table A lists typical compounds disclosed herein, including but not limited to:

[0092]

[0093]

[0094]

[0095]

[0096]

[0097] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0098]

[0099] in:

[0100] R 4a R 4b L 1 Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (I).

[0101] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof.

[0102]

[0103] in:

[0104] Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (II).

[0105] Another aspect of this disclosure relates to compounds of general formula (II-1A) or salts thereof.

[0106]

[0107] in:

[0108] Ring B, Ring C, R 2 R 3 , n and t are defined as in general formula (II-1).

[0109] Another aspect of this disclosure relates to compounds of general formula (II-2A) or salts thereof.

[0110]

[0111] in:

[0112] Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (II-2).

[0113] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof.

[0114]

[0115] in:

[0116] Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (III).

[0117] Another aspect of this disclosure relates to compounds of general formula (III-1A) or salts thereof.

[0118]

[0119] in:

[0120] Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (III-1).

[0121] Another aspect of this disclosure relates to compounds of general formula (III-2A) or salts thereof.

[0122]

[0123] in:

[0124] Ring B, Ring C, R 2 R 3 , n and t are as defined in general formula (III-2).

[0125] Another aspect of this disclosure relates to compounds of general formula (IVA) or salts thereof.

[0126]

[0127] in:

[0128] R 2 R 3 , n and t are as defined in general formula (IV).

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

[0130]

[0131] in:

[0132] R 2 R 3 , n and t are as defined in general formula (IV-1).

[0133] Another aspect of this disclosure relates to compounds of general formula (IV-2A) or salts thereof.

[0134]

[0135] in:

[0136] R 2 R 3 , n and t are as defined in general formula (IV-2).

[0137] Another aspect of this disclosure relates to compounds of general formula (VA) or salts thereof.

[0138]

[0139] in:

[0140] R 2 R 3 , n and t are as defined in general formula (V).

[0141] Another aspect of this disclosure relates to compounds of general formula (V-1A) or salts thereof.

[0142]

[0143] in:

[0144] R 2 R 3 , n and t are defined as in general formula (V-1).

[0145] Another aspect of this disclosure relates to compounds of general formula (V-2A) or salts thereof.

[0146]

[0147] in:

[0148] R 2 R 3 , n and t are defined as in general formula (V-2).

[0149] Typical intermediate compounds disclosed herein include, but are not limited to:

[0150]

[0151]

[0152]

[0153] 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:

[0154]

[0155] The compound of general formula (IA) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (I) or its pharmaceutically usable salt.

[0156] in:

[0157] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0158] X is a halogen; preferably, X is a chlorine atom;

[0159] R 4a R 4b L 1 Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (I).

[0160] Another aspect of this disclosure relates to a method for preparing compounds of general formulas (II-1) and (II-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0161]

[0162] A compound of general formula (IIA) or a salt thereof reacts with a compound of general formula (VI) to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof, and optionally, a compound of general formula (II) or a pharmaceutically acceptable salt thereof is resolved to give compounds of general formula (II-1) and general formula (II-2) or pharmaceutically acceptable salts thereof.

[0163] in:

[0164] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0165] X is a halogen; preferably, X is a chlorine atom;

[0166] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II).

[0167] Another aspect of this disclosure relates to a method for preparing compounds of general formulas (III-1) and (III-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0168]

[0169] A compound of general formula (IIIA) or a salt thereof reacts with a compound of general formula (VI) to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof, and optionally, a compound of general formula (III) or a pharmaceutically acceptable salt thereof is resolved to give compounds of general formula (III-1) and general formula (III-2) or pharmaceutically acceptable salts thereof.

[0170] in:

[0171] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0172] X is a halogen; preferably, X is a chlorine atom;

[0173] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (III).

[0174] Another aspect of this disclosure relates to a method for preparing compounds of general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0175]

[0176] A compound of general formula (IVA) or a salt thereof reacts with a compound of general formula (VI) to give a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, and optionally, the compound of general formula (IV) or a pharmaceutically acceptable salt thereof is resolved to give compounds of general formula (IV-1) and general formula (IV-2) or pharmaceutically acceptable salts thereof.

[0177] in:

[0178] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0179] X is a halogen; preferably, X is a chlorine atom;

[0180] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV).

[0181] Another aspect of this disclosure relates to a method for preparing compounds of general formulas (V-1) and (V-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0182]

[0183] A compound of general formula (VA) or a salt thereof reacts with a compound of general formula (VI) to give a compound of general formula (V) or a pharmaceutically acceptable salt thereof, and optionally, the compound of general formula (V) or a pharmaceutically acceptable salt thereof is resolved to give compounds of general formula (V-1) and general formula (V-2) or pharmaceutically acceptable salts thereof.

[0184] in:

[0185] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0186] X is a halogen; preferably, X is a chlorine atom;

[0187] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (V).

[0188] 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:

[0189]

[0190] The compound of general formula (II-1A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (II-1) or its pharmaceutically usable salt.

[0191] in:

[0192] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0193] X is a halogen; preferably, X is a chlorine atom;

[0194] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II-1).

[0195] 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:

[0196]

[0197] The compound of general formula (II-2A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (II-2) or its pharmaceutically usable salt.

[0198] in:

[0199] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0200] X is a halogen; preferably, X is a chlorine atom;

[0201] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II-2).

[0202] 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:

[0203]

[0204] The compound of general formula (III-1A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (III-1) or its pharmaceutically usable salt.

[0205] in:

[0206] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0207] X is a halogen; preferably, X is a chlorine atom;

[0208] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (III-1).

[0209] 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:

[0210]

[0211] The compound of general formula (III-2A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (III-2) or its pharmaceutically usable salt.

[0212] in:

[0213] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0214] X is a halogen; preferably, X is a chlorine atom;

[0215] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (III-2).

[0216] 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:

[0217]

[0218] A compound of general formula (IV-1A) or a salt thereof reacts with a compound of general formula (VI) to give a compound of general formula (IV-1) or a pharmaceutically usable salt thereof.

[0219] in:

[0220] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0221] X is a halogen; preferably, X is a chlorine atom;

[0222] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV-1).

[0223] 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:

[0224]

[0225] The compound of general formula (IV-2A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (IV-2) or its pharmaceutically usable salt.

[0226] in:

[0227] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0228] X is a halogen; preferably, X is a chlorine atom;

[0229] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV-2).

[0230] 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:

[0231]

[0232] The compound of general formula (V-1A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (V-1) or its pharmaceutically usable salt.

[0233] in:

[0234] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0235] X is a halogen; preferably, X is a chlorine atom;

[0236] Rings A and R 1 ~R 3 m, n and t are defined as in general formula (V-1).

[0237] 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:

[0238]

[0239] The compound of general formula (V-2A) or its salt reacts with the compound of general formula (VI) to give the compound of general formula (V-2) or its pharmaceutically usable salt.

[0240] in:

[0241] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0242] X is a halogen; preferably, X is a chlorine atom;

[0243] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (V-2).

[0244] 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.

[0245] 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 treating and / or preventing diseases or conditions by regulating GR.

[0246] 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 treating and / or preventing diseases or conditions by antagonizing GR.

[0247] This disclosure further relates to the use of compounds of general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), and 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... Available for the treatment and / or prevention of a range of conditions including 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 impairment, 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 syndrome). 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 recurrent primary cancer), 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 recurrent primary cancer), and other cancers selected from breast cancer, prostate cancer, adrenocortical cancer, fallopian tube ... metastatic pancreatic ductal adenocarcinoma), and peritoneal cancer (such as recurrent primary cancer). 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).

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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, and stress disorders (such as post-traumatic stress disorder). Delirium, chronic pain, neurological disorders in premature infants, and migraines; preferably, the cancer is 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, endometrial 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 disease or symptom is 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).

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] Oil suspensions are formulated by suspending active ingredients 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] Terminology Explanation

[0270] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0271] 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, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0272] 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 alkyl, 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.

[0273] The term "heteroalkylene" refers to one or more (preferably 1, 2, 3, 4, or 5) of an alkylene group whose -CH2- atoms are replaced by heteroatoms selected from N, O, and S; wherein the alkylene group is as defined above. The heteroalkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is 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.

[0274] 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 and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. 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 substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0275] 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 has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. 2-12The 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 alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0276] 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.

[0277] 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.

[0278] 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, 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:

[0279]

[0280] 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:

[0281]

[0282] 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:

[0283]

[0284] 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

[0285] 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.

[0286] 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 (e.g., 3, 4, 5, 6, 7, or 8), 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.

[0287] 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:

[0288]

[0289] 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:

[0290]

[0291] 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. Preferably, it consists of 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). 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:

[0292]

[0293] 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:

[0294] wait.

[0295] 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.

[0296] 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:

[0297]

[0298] 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.

[0299] 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, such as furanyl, thiophene, pyridinyl, 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:

[0300]

[0301] 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.

[0302] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups have one residue derived from removing a hydrogen atom from a parent ring atom, or two residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent ring, namely "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene".

[0303] 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 one to three substituents selected from halogens, alkoxy groups, or nitro groups.

[0304] 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.

[0305] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0306] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0307] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0308] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0309] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0310] 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.

[0311] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0312] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0313] The term "hydroxyl group" refers to -OH.

[0314] The term "thiol" refers to -SH.

[0315] The term "amino" refers to -NH2.

[0316] The term "cyano" refers to -CN.

[0317] The term "nitro" refers to -NO2.

[0318] The term "oxo" or "oxo" refers to "=O".

[0319] The term "carbonyl" refers to C=O.

[0320] The term "carboxyl group" refers to -C(O)OH.

[0321] 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.

[0322] 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.

[0323] 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 Or simultaneously include and Two configurations.

[0324] 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:

[0325]

[0326] 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:

[0327]

[0328] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0329] 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.

[0330] 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.

[0331] 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).

[0332] "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.

[0333] "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).

[0334] "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.

[0335] "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.

[0336] 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.

[0337] As used herein, the term "solvent" refers to the physical bond of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonds. In some cases, such as when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0338] "Prodrugs" refer to compounds that can be converted in the body to produce active drug compounds under physiological conditions, such as through hydrolysis in the blood.

[0339] 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.

[0340] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0341] 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.

[0342] The method for synthesizing the compounds disclosed herein

[0343] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0344] Option 1

[0345] The present disclosure discloses a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0346]

[0347] A compound of general formula (IA) or a salt thereof reacts with a compound of general formula (VI) under basic conditions to give a compound of general formula (I) or a pharmaceutically usable salt thereof.

[0348] in:

[0349] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0350] X is a halogen; preferably, X is a chlorine atom;

[0351] R 4a R 4b L 1 Ring A, Ring B, Ring C, R 1 ~R 3m, n and t are as defined in general formula (I).

[0352] Option 2

[0353] This disclosure discloses a method for preparing compounds of general formulas (II-1) and (II-2) or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0354]

[0355] A compound of general formula (IIA) or a salt thereof reacts with a compound of general formula (VI) under basic conditions to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof. Optionally, a compound of general formula (II) or a pharmaceutically acceptable salt thereof is chirally resolved to give compounds of general formula (II-1) and general formula (II-2) or pharmaceutically acceptable salts thereof.

[0356] in:

[0357] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0358] X is a halogen; preferably, X is a chlorine atom;

[0359] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II).

[0360] Option 3

[0361] This disclosure discloses a method for preparing compounds of general formulas (III-1) and (III-2) or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0362]

[0363] A compound of general formula (IIIA) or a salt thereof reacts with a compound of general formula (VI) under basic conditions to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof. Optionally, a compound of general formula (III) or a pharmaceutically acceptable salt thereof is chirally resolved to give compounds of general formula (III-1) and general formula (III-2) or pharmaceutically acceptable salts thereof.

[0364] in:

[0365] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2It is -S(O)2-;

[0366] X is a halogen; preferably, X is a chlorine atom;

[0367] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (III).

[0368] Option 4

[0369] The present disclosure discloses methods for preparing compounds or pharmaceutically acceptable salts thereof according to formulas (IV-1) and (IV-2), the methods comprising the following steps:

[0370]

[0371] A compound of general formula (IVA) or a salt thereof reacts with a compound of general formula (VI) under basic conditions to give a compound of general formula (IV) or a pharmaceutically acceptable salt thereof. Optionally, a compound of general formula (IV) or a pharmaceutically acceptable salt thereof is chirally resolved to give compounds of general formula (IV-1) and general formula (IV-2) or pharmaceutically acceptable salts thereof.

[0372] in:

[0373] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0374] X is a halogen; preferably, X is a chlorine atom;

[0375] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV).

[0376] Option 5

[0377] This disclosure discloses a method for preparing compounds of general formulas (V-1) and (V-2) or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0378]

[0379] A compound of general formula (VA) or a salt thereof reacts with a compound of general formula (VI) under basic conditions to give a compound of general formula (V) or a pharmaceutically acceptable salt thereof. Optionally, a compound of general formula (V) or a pharmaceutically acceptable salt thereof is chirally resolved to give compounds of general formulas (V-1) and (V-2) or pharmaceutically acceptable salts thereof.

[0380] in:

[0381] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0382] X is a halogen; preferably, X is a chlorine atom;

[0383] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (V).

[0384] Option Six

[0385] This disclosure discloses a method for preparing the compound of formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0386]

[0387] The compound of general formula (II-1A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (II-1) or its pharmaceutically usable salt.

[0388] in:

[0389] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0390] X is a halogen; preferably, X is a chlorine atom;

[0391] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II-1).

[0392] Option 7

[0393] This disclosure discloses a method for preparing the compound of formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0394]

[0395] The compound of general formula (II-2A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (II-2) or its pharmaceutically usable salt.

[0396] in:

[0397] L 2It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0398] X is a halogen; preferably, X is a chlorine atom;

[0399] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (II-2).

[0400] Option 8

[0401] This disclosure discloses a method for preparing the compound of formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0402]

[0403] The compound of general formula (III-1A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (III-1) or its pharmaceutically usable salt.

[0404] in:

[0405] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0406] X is a halogen; preferably, X is a chlorine atom;

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

[0408] Option Nine

[0409] This disclosure discloses a method for preparing the compound of formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0410]

[0411] The compound of general formula (III-2A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (III-2) or its pharmaceutically usable salt.

[0412] in:

[0413] L 2It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0414] X is a halogen; preferably, X is a chlorine atom;

[0415] Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in general formula (III-2).

[0416] Option 10

[0417] This disclosure discloses a method for preparing the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0418]

[0419] The compound of general formula (IV-1A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (IV-1) or its pharmaceutically usable salt.

[0420] in:

[0421] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0422] X is a halogen; preferably, X is a chlorine atom;

[0423] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV-1).

[0424] Option 11

[0425] This disclosure discloses a method for preparing the compound of formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0426]

[0427] The compound of general formula (IV-2A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (IV-2) or its pharmaceutically usable salt.

[0428] in:

[0429] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0430] X is a halogen; preferably, X is a chlorine atom;

[0431] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (IV-2).

[0432] Option Twelve

[0433] This disclosure discloses a method for preparing the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0434]

[0435] The compound of general formula (V-1A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (V-1) or its pharmaceutically usable salt.

[0436] in:

[0437] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0438] X is a halogen; preferably, X is a chlorine atom;

[0439] Rings A and R 1 ~R 3 m, n and t are defined as in general formula (V-1).

[0440] Option Thirteen

[0441] This disclosure discloses a method for preparing the compound of formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0442]

[0443] The compound of general formula (V-2A) or its salt reacts with the compound of general formula (VI) under basic conditions to give the compound of general formula (V-2) or its pharmaceutically usable salt.

[0444] in:

[0445] L 2 It is a chemical bond or selected from -S(O)2-, -C(O)- and C 1-6 Alkylene; preferably, L 2 It is -S(O)2-;

[0446] X is a halogen; preferably, X is a chlorine atom;

[0447] Rings A and R 1 ~R 3 m, n and t are as defined in general formula (V-2).

[0448] The alkalis include organic alkalis and inorganic alkalis. The organic alkalis include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably triethylamine. The inorganic alkalis include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.

[0449] 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

[0450] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0451] Example

[0452] 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.

[0453] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-QExactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0454] 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.

[0455] Chiral HPLC analysis was performed using an Agilent 1260DAD liquid chromatograph.

[0456] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SDQ2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0457] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0458] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0459] 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.

[0460] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0461] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0462] 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.

[0463] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0464] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0465] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0466] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0467] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0468] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0469] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0470] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0471] 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. The volume ratio of the solvent was adjusted according to the polarity of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0472] Example 1, 1-P1, 1-P2

[0473] (1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0474] (S)-(1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P1

[0475] (R)-(1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P2

[0476]

[0477]

[0478] first step

[0479] 5-(tert-butyl)7-methyl-8-oxo-5-azaspiro[2.5]octane-5,7-dicarboxylic acid ester 1b

[0480] Compound tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid 1a (5 g, 22.1 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydride (1.7 g, 44.3 mmol, 60%) was added, and the mixture was stirred for 0.5 hours. Then, dimethyl carbonate (19.9 g, 220 mmol) was added, and the mixture was reacted at 70 °C for 15 hours. After cooling to room temperature, 30 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography with eluent system A to give the title compound 1b (6.2 g, yield: 98.6%).

[0481] MS m / z(ESI):284.3[M+1].

[0482] Step 2

[0483] 5-(tert-butyl)7-methyl-8-oxo-7-(3-oxobutyl)-5-azaspiro[2.5]octane-5,7-dicarboxylic acid ester 1c

[0484] Compound 1b (3.0 g, 10.6 mmol) was dissolved in methanol (30 mL), and methyl ketene (1.48 g, 21.1 mmol) and triethylamine (1.07 g, 10.6 mmol) were added. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure to obtain crude title compound 1c (3.7 g, yield: 98.8%). The product was directly used for the next reaction without purification. MS m / z (ESI): 354.2 [M+1].

[0485] Step 3

[0486] 2'-(tert-butyl)8a'-methyl6'-oxo-7',8'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2',8a'(3'H,6'H)-dicarboxylic acid ester 1d

[0487] The crude compound 1c (3.7 g, 10.4 mmol) was dissolved in toluene (40 mL), and tetrahydropyrrole (1.02 g, 10.4 mmol) was added. The mixture was reacted at 110 °C for 15 hours, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography with eluent system A to give the title compound 1d (2.4 g, yield: 68.3%).

[0488] MS m / z(ESI): 336.4 [M+1].

[0489] Step 4

[0490] 2'-(tert-butyl)8a'-methyl(Z)-7'-(hydroxymethylene)-6'-oxotetrahydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2',8a'(3'H,4a'H)-dicarboxylic acid ester 1e

[0491] Compound 1d (1.2 g, 3.58 mmol) was dissolved in tetrahydrofuran (15 mL), and bis(trimethylsilylaminolithium) (17.8 mL, 1 M tetrahydrofuran solution) was added at -78 °C. After stirring for 0.5 hours, 2,2,2-trifluoroethyl carbamate (2.28 g, 17.8 mmol) was added, and the mixture was slowly heated to room temperature and reacted for 15 hours. 30 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure to give crude title compound 1e (1.3 g, yield: 100%), which was used directly in the next reaction without purification.

[0492] MS m / z(ESI): 364.2 [M-1].

[0493] Step 5

[0494] 6'-(tert-butyl)4a'-methyl1'-(4-fluorophenyl)-1',4'-dihydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a',6'(5'H,7'H)-dicarboxylic acid ester 1f

[0495] The crude compound 1e (1.3 g, 3.58 mmol) was dissolved in 15 mL of glacial acetic acid, and sodium acetate (440 mg, 5.37 mmol) and 4-fluorophenylhydrazine (756 mg, 4.65 mmol) were added. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A to give the title compound 1f (1.4 g, yield: 86.3%).

[0496] MS m / z(ESI):454.3[M+1].

[0497] Step 6

[0498] 1'-(4-fluorophenyl)-4a'-(4-(trifluoromethyl)pyridinyl)-1',4',4a',5'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-6'(7'H)-tert-butyl carboxylate 1g

[0499] 2-Bromo-4-(trifluoromethyl)pyridine (996 mg, 4.4 mmol) was dissolved in 9 mL of anhydrous diethyl ether, and isopropyl magnesium bromide (4.4 mL, 4.4 mmol, 1.0 M tetrahydrofuran solution) was added. After stirring for 0.5 hours, 1 f (200 mg, 0.44 mmol) of tetrahydrofuran solution (2 mL) was added. After reacting for 3 hours, 30 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography with eluent system A to give 1 g (50 mg, yield: 19.9%) of the title compound.

[0500] MS m / z(ESI): 569.6 [M+1].

[0501] Step 7

[0502] (1'-(4-fluorophenyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1h

[0503] 1 g (130 mg, 0.23 mmol) of the compound was dissolved in 2 mL of dichloromethane, and 0.7 mL of trifluoroacetic acid was added. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure to obtain crude title compound 1h (130 mg, yield: 97.6%). The product was used directly in the next step without purification.

[0504] MS m / z(ESI):469.2[M+1].

[0505] Step 8

[0506] (1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0507] (S)-(1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P1

[0508] (R)-(1'-(4-fluorophenyl)-6'-(2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P2

[0509] The crude compound 1h (75 mg, 0.13 mmol) was dissolved in 2 mL of dichloromethane, and triethylamine (65 mg, 0.64 mmol) and 2-methyl-2H-1,2,3-triazol-4-sulfonyl chloride 1i (46 mg, 0.25 mmol) were added using a known method. (Journal of Medicinal (Prepared by Chemistry, 2017, 60, 3405-3421) After stirring for 3 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T, 30*150mm, 5μm; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 30%-55%, flow rate: 30mL / min) to obtain compound 1 (40mg, yield: 50.1%). Then, chiral preparation was performed (separation conditions: Shimadzu LC-20AP; column: CHIRALPAK IG 20*250mm; mobile phase: n-hexane; ethanol (10mM ammonia), 20% ethanol ratio elution, flow rate: 20mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compound 15mg, 15mg, yield: 18.9%, 18.9%. Single-configuration compounds (shorter retention time)

[0510] MS m / z(ESI): 614.6 [M+1].

[0511] Chiral HPLC analysis: Column: CHIRALCEL OD, 150*4.6mm, 5μm; Mobile phase: ethanol (0.1% DEA): n-hexane = 15%; Flow rate: 1mL / min; Retention time: 7.146 min; Purity: 99.35%. 1 H NMR (500MHz, Methanol-d4): δ8.94(d,1H),8.00(s,1H),7.92(s,1H),7.89(d,1H),7.45(dd,2H),7.31(dd,3H), 6.36(s,1H),5.41(d,1H),4.29(d,1H),4.23(s,3H),3.05(t,3H),2.95(d,1H),0.88-0.85(m,3H),0.67(d,1H).

[0512] Single-configuration compounds (longer retention time)

[0513] MS m / z(ESI): 614.6 [M+1].

[0514] Chiral HPLC analysis: Column: CHIRALCEL OD, 150*4.6mm, 5μm; Mobile phase: ethanol (0.1% DEA): n-hexane = 15%; Flow rate: 1mL / min; Retention time: 8.185 min; Purity: 99.35%. 1 H NMR (500MHz, Methanol-d4): δ8.94(d,1H),8.00(s,1H),7.94-7.86(m,2H),7.45(t,2H),7.31(d,3H),6.36(s ,1H),5.41(d,1H),4.29(d,1H),4.23(s,3H),3.10-3.01(m,3H),2.95(d,1H),0.89-0.86(m,3H),0.67(d,1H).

[0515] Example 2

[0516] (1'-(4-fluorophenyl)-6'-(1-methyl-1H-pyrazol-4-yl)sulfonyl)-1',4',6',7'-tetrahydrospiro[cyclopropane-1,8'-pyrazolo[3,4-g]isoquinoline]-4a'(5'H)-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0517]

[0518] Compound 1h (25 mg, 53 μmol) was dissolved in 2 mL of dichloromethane, and triethylamine (27 mg, 155 μmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride 2a (27 mg, 266 μmol) were added. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 30%-55%, flow rate: 30 mL / min) to give title compound 2 (8 mg, yield: 24.5%).

[0519] MS m / z(ESI): 613.6 [M+1].

[0520] 1 H NMR (500MHz, CDCl3): δ8.86(d,1H),8.09(s,1H),7.72-7.62(m,3H),7.44-7.37(m,2H),7.29(s,1H),7.18(t,2H),6.29(s,1H) ,5.42(dd,1H),4.23(d,1H),3.92(s,3H),3.00-2.87(m,3H),2.83(dd,1H),1.16(d,1H),0.91-0.89(m,2H),0.59-0.57(m,1H).

[0521] Example 3

[0522] (1-(4-fluorophenyl)-8,8-dimethyl-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0523]

[0524] Using the synthetic route in Example 1, the starting material 1a in the first step was replaced with compound 3,3-dimethyl-4-oxopiridine-1-carboxylic acid tert-butyl ester, and the starting material 1i in the seventh step was replaced with compound 1-methyl-1H-pyrazole-4-sulfonyl chloride to obtain title compound 3 (16 mg, yield: 10.2%).

[0525] MS m / z(ESI): 614.8 [M+1].

[0526] 1H NMR (500MHz, CDCl3): δ8.87(d,1H),8.05(m,1H),7.72-7.67(m,3H),7.50-7.47(m,2H),7.30-7.29(m,1H),7.24-7.21(m,2 H),6.74(s,1H),5.63(d,1H),4.23(d,1H),3.95(s,3H),3.33(dd,1H),2.83(d,1H),2.71(d,1H),2.36(d,1H),1.27(d,6H).

[0527] Example 4

[0528] (1-(4-fluorophenyl)-8,8-dimethyl-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0529]

[0530] Using the synthetic route in Example 1, the starting material 1a in the first step was replaced with tert-butyl 3,3-dimethyl-4-oxopiridine-1-carboxylate (Shanghai Bide) to obtain title compound 4 (20 mg, yield: 12.3%). MS m / z (ESI): 615.8 [M+1].

[0531] 1 H NMR (500MHz, CDCl3): δ8.87(d,1H),8.05(s,1H),7.84(s,1H),7.72-7.71(m,1H),7.50-7.47(m,2H),7.30-7.29(m,1H),7.25- 7.22(m,2H),6.75(s,1H),5.79(d,1H),4.27-4.24(m,4H),3.43(d,1H),3.033(d,1H),2.85(d,1H),2.65(d,1H),1.27(d,6H).

[0532] Biological evaluation

[0533] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0534] Test Example 1: GR Receptor Reporter Gene Experiment

[0535] 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.

[0536] 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.

[0537] Table 1. Effects of the disclosed compounds on GR receptor transcriptional activity in MDA-kb2 cells.

[0538] Example number <![CDATA[IC 50 (nM)]]> Compounds with longer retention times in 1-P1 and 1-P2 26 2 102 3 179 4 79

[0539] Conclusion: The compound disclosed herein exhibits good inhibitory activity against GR receptor transcription in MDA-kb2 cells.

[0540] Test Example 2: MDA-MB-231 Cell Proliferation Experiment

[0541] 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:

[0542] 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 CellTiter- was added to each well. The 3DCell Viability Assay (Promega, G9683) was used. After shaking in the dark for 25 minutes, 100 μL of solution was transferred to each well of a 96-well opaque white plate (PerkinElmer, 6005290). The luminescence signal values ​​were read using a Victor 3 (PerkinElmer) microplate reader. The inhibition rate was calculated using the luminescence values ​​of the compound at various concentrations and the negative and positive control wells. Based on the compound concentrations and corresponding inhibition rates, the IC50 of the compound inhibiting the proliferation of MDA-MB-231 cells was calculated using GraphPad Prism software. 50 value.

[0543] Table 2. Inhibitory effect of the disclosed compounds on the proliferation of MDA-MB-231 cells in vitro.

[0544] Example number <![CDATA[IC 50 (nM)]]> Compounds with longer retention times in 1-P1 and 1-P2 54 4 125

[0545] Conclusion: The compound disclosed herein exhibits good inhibitory effect on the proliferation of MDA-MB-231 cells in vitro.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: It is a single bond; R 4a and R 4b It fuses with the attached carbon atom to form a cyclopropyl group; L 1 For -C(O)-, L 2 It is -S(O)2-; Ring A is selected from 5- to 10-membered heteroaryl groups; Each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, oxo groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and cyano groups; Ring B is a 5- to 10-membered heteroaryl group; 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 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and cyano groups; The ring C is a 6- to 10-membered aryl group; 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 Haloalkyl, C 1-6 Halogenated alkoxy and cyano groups; m can be 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, or 4; and t can be 0, 1, 2, 3 or 4.

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

3. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is pyridyl.

4. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the ring C is phenyl.

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

6. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is pyrazolyl or 1,2,3-triazolyl.

8. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

9. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 alkyl.

10. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

11. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 Halogenated alkyl groups.

12. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

13. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen.

14. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

15. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

16. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2.

17. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , and .

18. A compound of general formula (IA) or a salt thereof, in: R 4a R 4b L 1 Ring B, Ring C, R 2 R 3 , n and t are as defined in claim 1.

19. The compound of claim 18 or a salt thereof, wherein the compound is selected from the group consisting of: , and .

20. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound represented by general formula (IA) or its salt reacts with the compound represented by general formula (V) to give the compound represented by general formula (I) or its pharmaceutically usable salt. in: L 2 -S(O)2-; X is a halogen; R 4a R 4b L 1 Ring A, Ring B, Ring C, R 1 ~R 3 m, n and t are as defined in claim 1.

21. The method of claim 20, wherein X is a chlorine atom.

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

23. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for treating and / or preventing a disease or condition by regulating GR.

24. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment and / or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases, and neurodegenerative diseases.

25. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically usable salt thereof, or the pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment and / or prevention of cancer, obesity, diabetes, hypertension, syndrome X, depression, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, asthenia, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related diseases, human immunodeficiency virus, acquired immunodeficiency syndrome, immune modulation, wound healing, compulsive behavior, addiction, psychosis, anorexia, cachexia, mild cognitive impairment, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorder, delirium, neurological disorders of premature infants, and migraine.

26. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment and / or prevention of allergies, dementia, and chronic pain.

27. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically usable salt thereof, or the pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment and / or prevention of breast cancer, prostate cancer, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, endometrial cancer, liver cancer, lung cancer, leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma, and ovarian cancer.

28. Use of the compound of general formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment and / or prevention of breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, and ovarian cancer.

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