CN116829556A

CN116829556A - Fused azatricyclic derivatives, preparation method and medical application thereof

Info

Publication number: CN116829556A
Application number: CN202280012570.5A
Authority: CN
Inventors: 李心; 钟家鑫; 蔡国栋; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-02-03
Filing date: 2022-01-28
Publication date: 2023-09-29
Also published as: TW202246260A; WO2022166810A1

Abstract

The present disclosure relates to fused azatricyclic derivatives, methods for their preparation and their use in medicine. In particular, the present disclosure relates to a fused azatricyclic derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, particularly as a GR modulator and in the preparation of a medicament for treating and/or preventing tumors.

Description

Fused azatricyclic derivatives, preparation method and medical application thereof

Technical Field

The present disclosure relates to a fused azatricyclic derivative, a preparation method thereof and a medical application thereof, which belong to the field of medicine. In particular, the present disclosure relates to fused azatricyclic derivatives of general formula (I), to methods for their preparation and to pharmaceutical compositions containing them, and to their use as GR modulators and in the preparation of medicaments for the treatment and/or prophylaxis of tumors.

Background

Glucocorticoid receptor (Glucocorticoid Receptor, GR) is a member of the nuclear receptor family, belonging to the class of steroid hormone receptors in the nuclear receptor family, together with Mineralocorticoid Receptor (MR), progestogen Receptor (PR), androgen Receptor (AR), estrogen Receptor (ER). Glucocorticoids regulate gene expression by activating GR, regulating a variety of cellular functions such as metabolism, inflammation, cell growth and differentiation, and the like. Physiologically, glucocorticoids regulate human glycometabolism, protein metabolism and lipid metabolism. The excessive glucocorticoid caused by pathological factors can cause metabolic disorder, development retardation and the like, and is clinically called Cushing Syndrome (CS for short); however, excessive low glucocorticoid levels due to pathological trauma or other factors can lead to addison's disease, which is manifested mainly as anxiety, fatigue, muscle-joint pain and depression, and some patients can manifest as major depression.

Due to the potent inhibitory effect on immune responses, GR receptor agonists such as steroid glucocorticoids are widely used clinically in the treatment of autoimmune diseases or allergies. In hematological tumors in which immune cells proliferate maliciously, steroid glucocorticoids are also one of the combination therapies.

In the treatment of solid tumors, steroid glucocorticoids are approved as adjuvant therapy to alleviate symptoms such as allergy, emesis, etc. in patients, enhancing resistance to chemotherapy or targeted therapies. However, in recent years, increasing clinical and academic studies have shown that GR signaling pathway activation is directly related to progression, metastasis, resistance, and prognosis of a variety of solid tumors.

In castration-resistant prostate cancer (CRPC for short), GR signaling pathway activation is directly associated with enzalutamide resistance. After patient administration of enzalutamide (> 8 weeks), GR levels in tumor tissues were up-regulated and the response to enzalutamide was poor. GR and AR can co-regulate a range of genes associated with prostate cancer progression in prostate cancer cells, and GR pathway activation is compensatory action of the prostate cancer cells on AR inhibition. On an in vivo efficacy model, GR gene knockout or GR antagonists can significantly inhibit growth of an in vivo tumor model.

In patients with triple negative breast cancer (triple negative breast cancer, TNBC for short), there is a statistically significant correlation between the expression level of GR and poor survival in TNBC and ovarian cancer. GR signaling pathway activation is associated with cancer cell metastasis and drug resistance to paclitaxel. Paclitaxel-based chemotherapy is currently the primary means of treating TNBC. Studies have found that GR activation by the GR agonist, plug Mi Songjie, results in high expression of genes associated with chemotherapy tolerance and tumor metastasis, thereby promoting chemotherapy tolerance, and metastasis of TNBC tumor cells. The use of GR antagonists can enhance the sensitivity of chemotherapy and reduce metastasis.

Thus, targeting GR, interfering with its signal transduction with an antagonistic approach is a new tumor therapeutic approach. In particular, in prostate cancer and breast cancer, the mechanism of action has been effectively demonstrated by a large amount of literature data.

Patent applications for which GR modulators have been disclosed include WO2005087769A1, WO2012027702A1, WO2013177559A2, WO2015077530A1 and the like.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

is absent or a chemical bond;

ring a is selected from heterocyclyl, aryl and heteroaryl;

Each R is ¹ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ Hydroxy, -C (O) R ⁶ 、-C(O)OR ⁶ 、-C(O)NR ⁴ R ⁵ 、-S(O) _p R ⁶ Cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein the alkyl, alkoxy groups areThe radicals, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

alternatively, two adjacent R ¹ Condensed with ring A to form a heterocyclic group, wherein said heterocyclic group is optionally substituted with a member selected from the group consisting of halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy and hydroxyalkyl;

ring B is aryl or heteroaryl;

each R is ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ Hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring C is aryl or heteroaryl;

each R is ³ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ And hydroxyl;

R ⁶ and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

R ⁴ 、R ⁵ 、R ⁷ and R is ⁸ The alkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

or R is ⁴ And R is ⁵ Together with the attached nitrogen atom, form a heterocyclic group optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

Or R is ⁷ And R is ⁸ Together with the attached nitrogen atom, form a heterocyclic group optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

p is 0, 1 or 2;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4; and is also provided with

t is 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III):

Wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof is a compound of formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1) or 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 pyridinyl.

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

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (IV):

Wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1) or formula (IV) or a pharmaceutically acceptable salt thereof is a compound of formula (IV-1) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II-2) or formula (IV) or a pharmaceutically acceptable salt thereof is a compound of formula (IV-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof is a compound of formula (V):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (III-1) or formula (V) or a pharmaceutically acceptable salt thereof is a compound of formula (V-1) or a pharmaceutically acceptable salt thereof:

wherein:

Ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (III-2) or formula (V) or a pharmaceutically acceptable salt thereof is a compound of formula (V-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; preferably, ring a is a 5 or 6 membered heteroaryl; further preferred, ring a is a 5 membered nitrogen containing heteroaryl; more preferably, ring a is selected from pyrazolyl, imidazolyl, 1,2, 3-triazolyl and tetrazolyl; most preferably, ring A is 1,2, 3-triazolyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl and 1,2, 3-triazolyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, wherein each of said 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl is independently optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; preferably, each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, whereinThe 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; more preferably, each R ¹ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; preferably, R ¹ Is a hydrogen atom or C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein two adjacent R ¹ Condensed with ring A to form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; preferably, two adjacent R ¹ Condensed with ring A to form a 5-or 6-membered heterocyclic group, wherein said 5-or 6-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; betterOptionally, two adjacent R ¹ Fused to ring a to form a 5 or 6 membered heterocyclyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, wherein each of said 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl is independently optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; or two adjacent R ¹ Condensed with ring A to form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; or two adjacent R ¹ Fused to ring a to form a 5 or 6 membered heterocyclyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof,wherein the method comprises the steps ofSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting of More preferably, the process is carried out,is that

In some embodiments of the present disclosure, the compound of formula (II-1), formula (III-1), formula (IV-1) or formula (V -1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting of More preferably, the process is carried out,is that

In some embodiments of the present disclosure, the general formula (II-2), a compound represented by the general formula (III-2), the general formula (IV-2) or the general formula (V-2) or a pharmaceutically acceptable salt thereofSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting of More preferably, the process is carried out,is that

In the present disclosureIn some embodiments, the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting ofMore preferably, the process is carried out,is that

In some embodiments of the present disclosure, the compound of formula (II-1), formula (III-1), formula (IV-1) or formula (V-1) or a pharmaceutically acceptable salt thereofA salt, whereinSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting ofMore preferably, the process is carried out,is that

In some embodiments of the present disclosure, the compound of formula (II-2), formula (III-2), formula (IV-2) or formula (V-2) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of Wherein R is ⁰ Selected from hydrogen atoms, halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and C _1-6 Hydroxyalkyl, s is 0, 1, 2, 3 or 4, R ¹ 、R ⁷ And R is ⁸ As defined in formula (I); preferably, the method comprises the steps of,selected from the group consisting ofMore preferably, the process is carried out,is that

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; preferably, each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ² Is C _1-6 A haloalkyl group; most preferably, R ² Is trifluoromethyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, each R ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, R ³ Is halogen; most preferably, R ³ Is a fluorine atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; preferably, m is 1 or 2; more preferably, m is 1.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 1.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2; preferably, t is 1.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; ring B is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; ring C is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, wherein each of said 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl is independently optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; or two adjacent R ¹ Condensed with ring A to form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a salt thereofA pharmaceutically acceptable salt, wherein ring a is selected from the group consisting of 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; ring B is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; ring C is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; or two adjacent R ¹ Condensed with ring A to form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; m is 0, 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, 1,2, 3-triazolyl and tetrazolyl; ring B is pyridinyl; ring C is phenyl; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, wherein each of said 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl is independently optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; or two adjacent R ¹ Condensed with ring A to form a 5-or 6-membered heterocyclic group, wherein said 5-or 6-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl and 1,2, 3-triazolyl; ring B is pyridinyl; ring C is phenyl; each R is ¹ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; or two adjacent R ¹ Condensed with ring A to form a 5-or 6-membered heterocyclic group, wherein said 5-or 6-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl, 1,2, 3-triazolyl and tetrazolyl; ring B is pyridinyl; ring C is phenyl; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; or two adjacent R ¹ Condensed with ring A to form a 5-or 6-membered heterocyclic group, wherein said 5-or 6-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, imidazolyl and 1,2, 3-triazolyl; ring B is pyridinyl; ring C is phenyl; each R is ¹ Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; or two adjacent R ¹ Condensed with ring A to form a 5-or 6-membered heterocyclic group, wherein said 5-or 6-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; each R is ² Identical or different and are each independently selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1 or 2; n is 0, 1 or 2; t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-or 6-membered heteroaryl; each R is ¹ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3-to 6-membered cycloalkyl, or two adjacent R ¹ Fused to ring a to form a 5 or 6 membered heterocyclyl; r is R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; m is 1 or 2; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV), formula (IV-1) or formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-membered nitrogen containing heteroaryl; each R is ¹ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; r is R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; m is 1; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V), formula (V-1) or formula (V-2), or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-or 6-membered heteroaryl; each R is ¹ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; or two adjacent R ¹ Fused to ring a to form a 5 or 6 membered heterocyclyl; r is R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; m is 1 or 2; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Selected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV-2) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (IV-2) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V-2) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of R ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V-1) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

In some embodiments of the present disclosure, the compound of formula (V-2) or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting ofR ² Is C _1-6 A haloalkyl group; r is R ³ Is halogen; n is 1; t is 1.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a salt thereof,

wherein:

R ^w is an amino protecting group; preferably, R ^w Is tert-butyldimethylsilyl (TBS);

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined for the compounds of formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (II-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-2A):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (II-2).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIA):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1A):

Wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (III-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-2A):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (III-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (IVA):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a compound represented by the general formula (IV-1A):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IV-2A):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (VA):

Wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V).

Another aspect of the present disclosure relates to a compound represented by the general formula (V-1A):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (V-2A):

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-2).

Table B typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

deamination of protecting group R by Compounds of general formula (IA) or salts thereof ^w Obtaining a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

Deamination protecting group R of compound represented by general formula (IIA) or salt thereof ^w Obtaining the compound represented by the general formula (II)A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises:

deamination protecting group R of compound represented by general formula (II-1A) or salt thereof ^w Obtaining a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, which comprises:

deamination protecting group R of compound represented by general formula (II-2A) or salt thereof ^w Obtaining a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III):

deamination of a protecting group R by a Compound or a salt thereof represented by the general formula (IIIA) ^w Obtaining a compound shown in a general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

deamination of the protecting group R by the compound represented by the general formula (III-1A) or a salt thereof ^w Obtaining a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

deamination of the protecting group R by the compound represented by the general formula (III-2A) or a salt thereof ^w Obtaining a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

deamination of a protecting group R by a compound represented by the general formula (IVA) or a salt thereof ^w Obtaining a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, which comprises:

deamination protecting group R of compound represented by general formula (IV-1A) or salt thereof ^w Obtaining a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises:

Deamination protecting group R of compound represented by general formula (IV-2A) or salt thereof ^w Obtaining a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

deamination protecting group R of compound represented by general formula (VA) or salt thereof ^w Obtaining a compound shown in a general formula (V) or pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, which comprises:

deamination protecting group R of compound represented by general formula (V-1A) or salt thereof ^w Obtaining a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, which comprises:

deamination protecting group R of compound represented by general formula (V-2A) or salt thereof ^w Obtaining a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-2).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), and table a, or a pharmaceutically acceptable salt thereof, in accordance with the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of a disease or disorder by modulating GR.

The present disclosure further relates to the use of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of a disease or disorder by antagonizing GR.

The disclosure further relates to the use of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2) and formula A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for 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; preferably, the use in the manufacture of a medicament for the treatment and/or prophylaxis of a condition selected from cancer, obesity, diabetes, hypertension, syndrome X, depression (e.g. psychotic depression, post-partum depression), allergy, anxiety, glaucoma, alzheimer's disease, parkinson's disease, huntington's disease, cognitive enhancement, cushing's syndrome (also known as hypercortisolism), addison's disease, osteoporosis, frailty, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, diseases associated with adrenal function, viral infections (e.g. Human Immunodeficiency Virus (HIV)), immunodeficiency (e.g. acquired immunodeficiency syndrome (AIDS)), immunomodulation, allergy, wound healing, compulsive behaviour, addiction, psychosis (e.g. post-partum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous retinopathy, alcohol dependence, stress disorders (e.g. post-traumatic stress disorder), delirium, chronic pain, premature infant neurological disorders and migraine; more preferably, the use in the preparation of a medicament for the treatment and/or prophylaxis of a cancer selected from the group consisting of breast cancer, prostate cancer, adrenal cortex cancer, fallopian tube cancer (e.g. recurrent fallopian tube cancer), pancreatic cancer (e.g. metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (e.g. recurrent primary peritoneal cancer), skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer (e.g. non-small cell lung cancer and small cell lung cancer), leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma and ovarian cancer (e.g. recurrent ovarian cancer); most preferably in the manufacture of a medicament for the treatment and/or prophylaxis of a disease selected from the group consisting of breast cancer, prostate cancer, cushing's syndrome, adrenocortical cancer, fallopian tube cancer (e.g. recurrent fallopian tube cancer), pancreatic cancer (e.g. metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (e.g. recurrent primary peritoneal cancer) and ovarian cancer (e.g. recurrent ovarian cancer).

The present disclosure also relates to a method of treating and/or preventing a disease or disorder by modulating GR comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing a disease or disorder by antagonizing GR comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present 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 patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound represented by general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2) and Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for use as a medicament.

The present disclosure further relates to compounds of general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of diseases or disorders by modulating GR.

The present disclosure further relates to compounds of general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of diseases or disorders by antagonizing GR.

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

The disease or condition described in the present disclosure is selected from cancer, obesity, diabetes, hypertension, syndrome X, depression (e.g., psychotic depression, post partum depression), allergy, anxiety, glaucoma, alzheimer's disease, parkinson's disease, huntington's disease, cognitive enhancement, cushing's syndrome, addison's disease, osteoporosis, frailty, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, diseases associated with adrenal function, viral infections (e.g., human Immunodeficiency Virus (HIV)), immunodeficiency (e.g., acquired immunodeficiency syndrome (AIDS)), immunomodulation, allergy, wound healing, compulsive behavior, addiction, psychosis (e.g., postpartum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders (e.g., post-traumatic stress disorder), delirium, chronic pain, premature infant neurological disorders, and migraine; preferably, the cancer is selected from the group consisting of breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer (e.g., recurrent fallopian tube cancer), pancreatic cancer (e.g., metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (e.g., recurrent primary peritoneal cancer), skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma, and ovarian cancer (e.g., recurrent ovarian cancer); more preferably, the disease or condition is selected from the group consisting of breast cancer, prostate cancer, cushing's syndrome, adrenocortical cancer, fallopian tube cancer (e.g., recurrent fallopian tube cancer), pancreatic cancer (e.g., metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (e.g., recurrent primary peritoneal cancer), and ovarian cancer (e.g., recurrent ovarian cancer).

Compared with a positive control compound, namely Relacorizant (CORT-125134, WO 20131775599A 2, example 18), the compound in examples 1-P1 of the disclosure has better safety than the Relacorizant and obvious pharmacokinetic advantage, and specific data are shown in a biological evaluation part, wherein the structural formula of the Relacorizant is as follows:

the active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifying agents may be naturally occurring phosphatides. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated straight 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., C _1-20 Alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 3-methylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferably a lower alkyl group having 1 to 6 carbon atoms, non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 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., C _1-20 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.eC _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to: methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, which is alkenyl (i.e., C) having 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: ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above, which is a compound having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atomsAlkynyl (i.e. C) _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be substituted or unsubstituted and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring 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 groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (called a spiro atom) between single rings 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), which may contain one or more double bonds. Preferably a 6 to 14 membered spirocycloalkyl group, more preferably a 7 to 10 membered spirocycloalkyl group. The spirocycloalkyl group is classified into a single spirocycloalkyl group or a multiple spirocycloalkyl group (e.g., a double spirocycloalkyl group) according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group or a double spirocycloalkyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to an all-carbon polycyclic group sharing an adjacent pair of carbon atoms between rings 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), wherein one or more of the rings may contain one or more double bonds. Preferably a 6 to 14 membered fused ring alkyl group, more preferably a 7 to 10 membered fused ring alkyl group. The polycyclic condensed ring alkyl group such as a bicyclic ring, a tricyclic ring, a tetracyclic ring and the like may be divided according to the number of constituent rings, and is preferably a bicyclic or tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group 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) in which any two rings share two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably a 6 to 14 membered bridged cycloalkyl group, more preferably a 7 to 10 membered bridged cycloalkyl group. Polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like can be divided according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 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, which may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding ring moieties of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 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 heterocyclyl); further preferably 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (e.g., 1,2, or 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably having 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (called a spiro atom) shared between single rings 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), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably a 6 to 14 membered spiroheterocyclyl, more preferably a 7 to 10 membered spiroheterocyclyl. The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered) rings sharing an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably a 6 to 14 membered fused heterocyclic group, more preferably a 7 to 10 membered fused heterocyclic group. The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings of 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members) share two atoms that are not directly attached, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably a 6 to 14 membered bridged heterocyclyl, more preferably a 7 to 10 membered bridged heterocyclyl. Polycyclic bridged heterocyclic groups such as a bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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 being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 10 membered aryl group, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms, 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered) ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Preferably a 5 to 10 membered heteroaryl; more preferably a 5-or 6-membered heteroaryl group such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl (e.g., 1,2, 3-triazolyl and 1,2, 4-triazolyl), tetrazolyl, and the like; most preferred are 5-membered nitrogen containing heteroaryl groups such as pyrazolyl, imidazolyl, 1,2, 3-triazolyl and tetrazolyl. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, p-methoxybenzyl, t-butyldimethylsilyl (TBS), and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group, typically used to block or protect the hydroxy group to react with other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, t-butyl, C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl groups (e.g., methoxymethyl (MOM), ethoxyethyl, etc.) (C) _1-10 Alkyl or aryl) acyl (e.g.: nail armorAcyl, acetyl, benzoyl, p-nitrobenzoyl, and the like), (C _1-6 Alkyl or 6-to 10-membered aryl) sulfonyl, (C) _1-6 Alkoxy or 6 to 10 membered aryloxy) carbonyl, allyl, 2-Tetrahydropyranyl (THP), and the like.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present 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. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time contain Two configurations.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of lactam-lactam balances are shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Example packages of isotopes that can be incorporated into compounds of the present disclosure Stable and radioactive isotopes including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g. respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., deuterium is preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position of a compound of the present disclosure is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold greater than the natural abundance of deuterium (which is 0.015%), i.e., at least 15% deuterium incorporation. In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500-fold greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally (optionally) substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate 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 inorganic and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount will vary from person to person, depending on the age and general condition of the subject, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art from routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

deamination of the protecting group R under acidic conditions of a Compound represented by the general formula (IA) or a salt thereof ^w Obtaining a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (I).

Scheme II

A process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

Compounds of the formula (IIA)The salt thereof removes amino protecting group R under acidic condition ^w Obtaining a compound shown in a general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in formula (II).

Scheme III

A process for the preparation of a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound shown as general formula (II-1A) or salt thereof ^w Obtaining a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme IV

A process for the preparation of a compound of formula (II-2) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound shown as general formula (II-2A) or salt thereof ^w Obtaining a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme five

A process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound represented by general formula (IIIA) or salt thereof ^w Obtaining a compound shown in a general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

Scheme six

A process for preparing a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound shown in general formula (III-1A) or salt thereof ^w Obtaining a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme seven

A process for preparing a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound shown in general formula (III-2A) or salt thereof ^w Obtaining a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

Scheme eight

A process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound represented by general formula (IVA) or salt thereof ^w Obtaining a compound shown in a general formula (IV) or pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV).

Scheme nine

A process for the preparation of a compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

removing amino protecting group R under acidic condition by using compound shown in general formula (IV-1A) or salt thereof ^w Obtaining a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-1).

Scheme ten

A process for preparing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises:

Removing amino protecting group R under acidic condition by using compound shown in general formula (IV-2A) or salt thereof ^w Obtaining a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (IV-2).

Scheme eleven

A process for preparing a compound of formula (V) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises:

deamination of protecting group R under acidic conditions of Compound of formula (VA) or salt thereof ^w Obtaining a compound shown in a general formula (V) or pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V).

Scheme twelve

A process for producing a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, which comprises:

removing amino protecting group R under acidic condition by using compound shown as general formula (V-1A) or salt thereof ^w Obtaining a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-1).

Scheme thirteen

A process for producing a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, which comprises:

represented by the general formula (V-2A)Removing amino protecting group R from compound or salt thereof under acidic condition ^w Obtaining a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in formula (V-2).

In the deprotection reaction, the acid in the acidic condition comprises organic acid and inorganic acid, and the organic acid comprises trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid and Me ₃ SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, preferably hydrochloric acid.

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-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below in connection with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR Displacement (d) at 10 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE NEO 500.500M magnetonucleo-magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

Mass Spectra (MS) were measured using an Agilent 1200/1290 DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometer (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q exact (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260 DAD liquid chromatograph.

The high performance liquid chromatography used was performed by Waters 2545-2767, waters 2767-SQD2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparative chromatography used Shimadzu LC-20AP preparative chromatography.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: the volume ratio of the petroleum ether to the ethyl acetate is adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Examples 1 to P1,1 to P2

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

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

First step

2-methyl-2H-1, 2, 3-triazole-4-sulfonamide 1b

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

MS m/z(ESI):163.1[M+1]。

Second step

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

1b (5 g,30.83 mmol) and t-butyldimethylchlorosilane (7 g,46.64 mmol) were dissolved in N, N-dimethylformamide, triethylamine (10 g,98.8 mol) and 4-dimethylaminopyridine (760 mg,6.22 mmol) were added at 0℃and the reaction mixture was stirred at room temperature for 16 hours, 100mL of water was added after concentrating the reaction mixture under reduced pressure, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 1c (2.6 g, yield: 30.5%) which was directly subjected to the next reaction without purification.

MS m/z(ESI)：277.1[M+1]。

Third step

((R) -6- ((R) -N- (tert-Butyldimethylsilyl) -2-methyl-2H-1, 2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 1e

((R) -6- ((S) -N- (tert-Butyldimethylsilyl) -2-methyl-2H-1, 2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 1f

Triphenylphosphine dichloride (2.85 g,8.55 mmol) was dissolved in 20mL of chloroform, triethylamine (2.2 g,21.74 mmol) was added at 0deg.C, 1c (1.43 g,5.17 mmol) was added after stirring for 5 min, 1d (1.9 g,4.29mol, prepared by the procedure disclosed for intermediate 78 on page 101 of the specification in patent application "WO2013177559A 2") was added after stirring for ten minutes, and after stirring for 2 hours the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography with eluent system B to give a mixture of the title compounds 1e and 1f (1.5 g, yield: 49.8%).

MS m/z(ESI)：701.1[M+1]。

Fourth step

A mixture of 1e and 1f (60 mg, 85.6. Mu. Mol) was dissolved in 3mL of tetrahydrofuran, 2mL of 1M hydrochloric acid was added, and the reaction was stirred for 0.5 hour. The reaction solution was neutralized with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate (10 mL X3), and the organic phase was concentrated under reduced pressure and then purified by high performance liquid chromatography (column: sharpsil-T, 30X 150mM,5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25% -42%) to give the title compound 1-P1 (6 mg, yield: 11.9%) and 1-P2 (8 mg, yield: 15.9%).

Compound 1-P1 (shorter retention time):

MS m/z(ESI)：587.2[M+1]。

HPLC analysis: retention time 1.45 min, purity: 96% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

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

Compounds 1-P2 (longer retention time):

MS m/z(ESI)：587.2[M+1]。

HPLC analysis: retention time 1.47 min, purity: 97% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.91(d,1H),8.18(s,1H),7.91(s,1H),7.76-7.72(m,1H),7.47(dd,2H),7.33(s,1H),7.20(t,2H),6.52(s,1H),5.59-5.53(m,1H),4.28(s,3H),4.02(d,2H),2.92(d,1H),2.85(d,1H),2.79-2.64(m,2H),2.51(d,1H),2.19(s,1H)。

Examples 2-P1,2-P2

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

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

First step

1-methyl-1H-pyrazole-4-sulfonamide 2b

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

MS m/z(ESI)：161.8[M+1]。

Second step

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

2b (1.8 g,11.16 mmol) and t-butyldimethylchlorosilane (1.1 g,13.35 mmol) were dissolved in N, N-dimethylformamide, triethylamine (1.7 g,16.8 mol) was added at 0℃and the mixture was stirred at room temperature to react for 16 hours. The reaction mixture was concentrated under reduced pressure, 150mL of water was added, the mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2c (1 g, yield: 32.5%).

MS m/z(ESI)：276.1[M+1]。

Third step

((R) -6- ((R) -N- (tert-Butyldimethylsilyl) -1-methyl-1H-pyrazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 2d

((R) -6- ((S) -N- (tert-Butyldimethylsilyl) -1-methyl-1H-pyrazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 2e

Triphenylphosphine dichloride (120 mg, 360.15. Mu. Mol) was dissolved in 3mL chloroform, triethylamine (91 mg, 820. Mu. Mol) was added at 0℃and 2c (75 mg, 272.28. Mu. Mol) was added after stirring for 5 minutes, and 1d (80 mg, 180.82. Mu. Mol) was added after stirring was continued for ten minutes, and the mixture was allowed to naturally warm to room temperature and stirred for 2 hours. To the reaction solution was added 5. 5 mL water, extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compounds 2d and 2e (100 mg, yield: 79.0%).

MS m/z(ESI)：700.1[M+1]。

Fourth step

A mixture of 2d and 2e (150 mg, 71.44. Mu. Mol) was dissolved in 3mL of tetrahydrofuran, 2mL of 1M hydrochloric acid was added thereto, and the reaction was stirred for 0.5 hour. The reaction solution was neutralized with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate (10 mL. Times.3), and the organic phase was concentrated under reduced pressure and then purified by high performance liquid chromatography (column: sharpsil-T, 30X 150mM,5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25% -42%) to give the title compound 2-P1 (5 mg, yield: 11.9%) and 2-P2 (20 mg, yield: 47.8%).

Compound 2-P1 (shorter retention time):

MS m/z(ESI)：586.2[M+1]。

HPLC analysis: retention time 2.68 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.92(d,1H),8.18-8.15(m,1H),7.75(s,1H),7.74-7.70(m,2H),7.150-7.44(m,2H),7.31(s,1H),7.24-7.17(m,2H),6.53(d,1H),5.56(dd,1H),4.26(d,1H),3.95(s,3H),3.94-3.88(m,1H),2.94(d,1H),2.88-2.80(m,1H),2.62(d,1H),2.54(d,1H),2.43-2.29(m,2H)。

Compound 2-P2 (longer retention time):

MS m/z(ESI)：586.2[M+1]。

HPLC analysis: retention time 2.74 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.92(d,1H),8.20(s,1H),7.78(s,1H),7.75(d,2H),7.49-7.43(m,2H),7.32(s,1H),7.23-7.16(m,2H),6.150(d,1H),5.150(dd,1H),4.05(d,1H),3.97-4.10(m,5H),2.92(d,1H),2.82-2.72(m,1H),2.57(d,1H),2.52-2.45(m,1H),2.36(ddd,1H)。

Examples 3-P1,3-P2

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

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

First step

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

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

MS m/z(ESI)：188.2[M+1]。

Second step

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

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

MS m/z(ESI)：261.1[M+1]。

Third step

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

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

MS m/z(ESI)：207.1[M+1]。

Fourth step

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

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

MS m/z(ESI)：188.2[M+1]。

Fifth step

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

3e (300 mg,1.62 mmol) and t-butyldimethylchlorosilane (200 mg,2.42mmol, shanghai Bi) were dissolved in N, N-dimethylformamide, triethylamine (811 mg,8.01 mmol) and 4-dimethylaminopyridine (10 mg, 324.7. Mu. Mol) were added at 0℃and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 15mL of water was added, extraction was performed with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3f (200 mg, yield: 41.4%) which was used in the next reaction without purification.

MS m/z(ESI)：302.2[M+1]。

Sixth step

((R) -6- ((R) -N- (tert-Butyldimethylsilyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole-3-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 3g

((R) -6- ((S) -N- (tert-Butyldimethylsilyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole-3-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 3H

Triphenylphosphine dichloride (57 mg, 717.0. Mu. Mol) was dissolved in 3mL chloroform, triethylamine (60 mg,592.9 mmol) was added at 0deg.C, 3f (40 mg, 132.6. Mu. Mol) was added after stirring for 5 minutes, 1d (150 mg, 113.0. Mu. Mol) was added after stirring was continued for ten minutes, and the mixture was allowed to naturally warm to room temperature and stirred for 16 hours. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compound 3g and 3h (150 mg, yield: 60.9%).

MS m/z(ESI)：726.2[M+1]。

Seventh step

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

Compound 3-P1 (shorter retention time):

MS m/z(ESI)：612.2[M+1]。

HPLC analysis: retention time 1.40 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

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

Compound 3-P2 (longer retention time):

MS m/z(ESI)：612.2[M+1]。

HPLC analysis: retention time 1.43 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.89(d,1H),8.17(s,1H),7.72(s,2H),7.47-7.41(m,2H),7.29(s,1H),7.18(t,2H),6.47(s,1H),5.48(d,1H),4.18(t,2H),4.04(d,1H),3.91(s,1H),3.09(q,2H),2.90(d,1H),2.79-2.57(m,5H),2.47(d,1H),2.38(t,1H)。

Examples 4-P1,4-P2

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

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

First step

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

Compound 4a (400 mg, 737.3. Mu. Mol, prepared using the procedure disclosed for intermediate 82 at page 104 of the specification in patent application "WO2013177559A 2") was dissolved in methanol (10 mL), and 10% palladium on carbon catalyst (wet) (200 mg) was added and the reaction stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude title product 4b (400 mg, yield: 99.6%), which was directly subjected to the next reaction without purification.

MS m/z(ESI)：545.0[M+1]。

Second step

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

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

MS m/z(ESI)：445.0[M+1]。

Third step

((4 aR) -6- ((R) -N- (tert-Butyldimethylsilyl) -2-methyl-2H-1, 2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8a, 9-octahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 4d

((4 aR) -6- ((S) -N- (tert-Butyldimethylsilyl) -2-methyl-2H-1, 2, 3-triazole-4 sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8a, 9-octahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 4e

Triphenylphosphine dichloride (203 mg, 609.26. Mu. Mol) was dissolved in 5mL chloroform, triethylamine (210 mg,2.07 mmol) was added at 0deg.C, 1c (40 mg, 132.6. Mu. Mol) was added after stirring for 5 minutes, 4c (150 mg, 113.0. Mu. Mol) was added after continuing stirring for ten minutes, and the mixture was naturally warmed to room temperature and stirred for 16 hours. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compounds 4d and 4e (180 mg, yield: 70.3%).

MS m/z(ESI)：703.0[M+1]。

Fourth step

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

Compound 4-P1 (shorter retention time):

MS m/z(ESI):589.0[M+1]。

HPLC analysis: retention time 1.48 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

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

Compound 4-P2 (longer retention time):

MS m/z(ESI)：589.0[M+1]。

HPLC analysis: retention time 1.51 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.94(d,1H),8.12(s,1H),7.91(s,1H),7.72(d,1H),7.150(dd,2H),7.34(s,1H),7.18(t,2H),5.77(d,1H),4.30(s,3H),4.13-4.06(m,2H),3.43(dd,1H),2.75(dd,1H),2.60(t,2H),2.52-2.42(m,2H),1.87-1.73(m,3H)。

Examples 5-P1,5-P2

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

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

First step

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

The compound 3-bromo-5, 6-dihydro-8H-imidazo [5,1-c ] [1,4] oxazine 5a (300 mg,1.47 mmol, ming Kangde), the compound 4-methoxybenzyl mercaptan (3411 mg,2.21mmol, shanghai Bi) was dissolved in 6mL of 1, 4-dioxane, tris (dibenzylideneacetone) dipalladium (135 mg,0.147 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (170 mg,0.293 mmol), N-diisopropylethylamine (433 mg,3.34 mmol) were added and the reaction was carried out under a nitrogen atmosphere at 120℃for 1.5 hours by microwave. Cooled to room temperature, and the reaction mixture was concentrated under reduced pressure and purified by column chromatography using eluent system B to give the title compound 5B (300 mg, yield: 73.4%).

MS m/z(ESI)：277.1[M+1]。

Second step

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

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

MS m/z(ESI)：223.2[M+1]。

Third step

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

Compound 5c (100 mg, 449.1. Mu. Mol) was dissolved in a methanol solution of ammonia (7M, 2 mL), and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure to give the crude title product 5d (90 mg, yield: 98.6%) which was used in the next step without purification.

MS m/z(ESI)：203.9[M+1]。

Fourth step

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

5d (150 mg, 246.0. Mu. Mol), t-butyldimethylchlorosilane (40 mg, 485.7. Mu. Mol, shanghai Bifide) was dissolved in N, N-dimethylformamide, triethylamine (74 mg, 731.3. Mu. Mol) and 4-dimethylaminopyridine (5 mg, 40.59. Mu. Mol) were added at 0℃and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, then 5mL of water was added, extraction was performed with ethyl acetate (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 5e (20 mg, yield: 25.6%) which was directly subjected to the next reaction without purification.

MS m/z(ESI)：318.1[M+1]。

Fifth step

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

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

Triphenylphosphine dichloride (60 mg, 180.1. Mu. Mol) was dissolved in 3mL chloroform, triethylamine (144 mg,1.42 mmol) was added at 0deg.C, 5e (28 mg, 88.2. Mu. Mol) was added after stirring for 5 minutes, 1d (40 mg, 90.4. Mu. Mol) was added after stirring for 10 minutes, and the mixture was naturally warmed to room temperature and stirred for 2 hours. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give a mixture of the title compound 5f and 5g (30 mg, yield: 44.7%).

MS m/z(ESI)：742.2[M+1]。

Sixth step

A mixture of 5f and 5g (30 mg, 40.4. Mu. Mol) was dissolved in 1mL of tetrahydrofuran, and 0.5mL of 1M hydrochloric acid was added thereto, followed by stirring for 0.5 hours. After the reaction solution was quenched with saturated sodium bicarbonate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: sharpsil-T, 30X 150mM,5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25% -42%) to give the title compound 5-P1 (3 mg, yield: 11.8%) and 5-P2 (2 mg, yield: 7.88%).

Compound 5-P1 (shorter retention time):

MS m/z(ESI)：628.2[M+1]。

HPLC analysis: retention time 1.82 min, purity: 98% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.84(d,1H),8.11(s,1H),7.74-7.64(m,1H),7.49-7.43(m,2H),7.28(s,1H),7.18(t,2H),6.75(s,1H),6.56(d,1H),5.76-5.63(m,1H),4.87-4.68(m,2H),4.35(dt,1H),4.24(d,1H),4.17(dd,1H),4.09-4.00(m,1H),3.94(t,2H),3.53(d,1H),3.19(td,1H),2.98(d,1H),2.83(dt,1H),2.59(d,1H),2.01(d,1H)。

Compound 5-P2 (longer retention time):

MS m/z(ESI)：628.2[M+1]。

HPLC analysis: retention time 1.84 min, purity: 98% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.84(d,1H),8.14(s,1H),7.71-7.66(m,1H),7.47-7.43(m,2H),7.30(s,1H),7.19(d,2H),6.79(s,1H),6.53(s,1H),5.66-5.54(m,1H),4.82(d,2H),4.41-4.31(m,1H),4.26(dt,1H),4.05(d,1H),3.97(t,2H),3.53(d,1H),3.21(t,1H),2.96(d,1H),2.82-2.67(m,1H),2.52(d,1H),2.25-2.13(m,1H),2.01(s,1H)。

Examples 6-P1,6-P2

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

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

First step

3-bromo-1- (2-bromoethyl) -1H-pyrazole-5-carboxylic acid methyl ester 6b

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

MS m/z(ESI)：312.8[M+1]。

Second step

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

Compound 6b (9.2 g,29.5 mmol) was dissolved in tetrahydrofuran (100 mL), and a solution of lithium borohydride in tetrahydrofuran (2M, 40 mL) was added thereto under ice bath, followed by reaction at a natural temperature for 5 hours. Saturated ammonium chloride was added to quench, extraction was performed with ethyl acetate (150 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 6c (8 g, yield: 95.5%) which was used directly in the next reaction without purification.

MS m/z(ESI)：284.8[M+1]。

Third step

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

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

MS m/z(ESI)：204.2[M+1]。

The synthetic routes in examples 5-P1 and 5-P2 were followed, substituting compound 5a of the first step with compound 6d, to give the title compounds 6-P1 (2 mg, yield: 4.22%) and 6-P2 (2 mg, yield: 4.22%). Compound 6-P1 (shorter retention time):

MS m/z(ESI)：628.0[M+1]。

HPLC analysis: retention time 1.40 min, purity: 90% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ )：δ8.91(d,1H),8.19(s,1H),7.75-7.70(m,1H),7.150-7.46(m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.51(s,1H),6.43(s,1H),5.61-5.56(m,1H),4.85(s,2H),4.71(s,2H),4.27-4.23(m,1H),4.16(dt,2H),4.02(t,1H),2.95(d,1H),2.87(d,1H),2.77(m,1H),2.51(td,1H),2.40-2.31(m,1H)。

Compound 6-P2 (longer retention time):

MS m/z(ESI)：628.0[M+1]。

HPLC analysis: retention time 1.42 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ )：δ8.92(d,1H),8.16(d,1H),7.74-7.69(m,1H),7.49-7.45(m,2H),7.33(s,1H),7.21(d,2H),6.98(s,1H),6.54(d,1H),6.41(s,1H),5.70(dd,1H),4.84(s,2H),4.71(s,2H),4.27-4.25(m,1H),4.14(t,2H),3.98(td,1H),2.95(d,1H),2.86-2.79(m,1H),2.64-2.56(m,1H),2.53(dd,1H),2.39-2.35(m,1H)。

Examples 7-P1,7-P2

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

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

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

Compound 7-P1 (shorter retention time):

MS m/z(ESI)：630.0[M+1]。

HPLC analysis: retention time 1.42 min, purity: 97% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

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

Compound 7-P2 (longer retention time):

MS m/z(ESI):630.0[M+1]。

HPLC analysis: retention time 1.45 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(1500MHz,CDCl ₃ ):δ8.89(d,1H),8.11-8.01(m,1H),7.72-7.60(m,1H),7.58-7.43(m,2H),7.32(s,1H),7.15(dd,2H),6.39(d,1H),5.69(dd,1H),4.83(s,2H),4.26(t,2H),4.17-4.00(m,4H),3.42(dd,1H),2.72(dd,1H),2.59(td,2H),2.51(d,1H),2.47-2.32(m,2H),1.84-1.73(m,2H)。

Examples 8-P1,8-P2

((R) -6- ((S) -2-cyclopropyl-2H-1, 2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 8-P1

((R) -6- ((R) -2-cyclopropyl-2H-1, 2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 8-P2

First step

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

The compound 5-mercapto-1, 2, 3-triazole sodium salt 8a (10 g,81.22mmol, shanghai Bifide) was dissolved in 100mL ethanol, benzyl bromide (15.3 g,89.45 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give crude title product 8b (11 g, yield: 70.8%) which was directly subjected to the next reaction without purification.

MS m/z(ESI)：191.9[M+1]。

Second step

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

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

MS m/z(ESI)：232.1[M+1]。

Third step

2-cyclopropyl-2H-1, 2, 3-triazole-4-sulfonyl chloride 8d

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

MS m/z(ESI)：207.9[M+1]。

Fourth step

2-cyclopropyl-2H-1, 2, 3-triazole-4-sulfonamide 8e

To compound 8d (0.885 g,4.26 mmol) was added 7M methanolic ammonia (3 mL), and the mixture was stirred at room temperature for 2 hours after natural temperature rise, and the reaction mixture was concentrated under reduced pressure to give the crude title product 8e (0.4 g, yield: 82.5%) which was directly subjected to the next reaction without purification.

MS m/z(ESI)：189.1[M+1]。

Fifth step

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

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

MS m/z(ESI)：303.1[M+1]。

The following synthetic routes in examples 1-P1 and 1-P2 were used, substituting compound 1c from the third step with compound 8f, to give the title compounds 8-P1 (2 mg, yield: 9.49%) and 8-P2 (2 mg, yield: 3.56%).

Compound 8-P1 (shorter retention time):

MS m/z(ESI)：613.0[M+1]。

HPLC analysis: retention time 1.54 min, purity: 98.5% (column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(500MHz,CDCl ₃ ):δ8.93(s,1H),8.15(d,1H),7.83(s,1H),7.74-7.70(m,1H),7.53-7.42(m,2H),7.32(s,1H),7.24-7.17(m,1H),7.07(s,1H),6.55(d,1H),5.72(dd,1H),4.28(d,1H),4.10(tt,2H),4.03-3.95(m,1H),3.01-2.91(m,2H),2.88-2.78(m,1H),2.64-2.51(m,2H),1.47-1.38(m,2H),1.22-1.14(m,2H)。

Compound 8-P2 (longer retention time):

MS m/z(ESI)：613.0[M+1]。

HPLC analysis: retention time 1.56 min, purity: 98.9% (column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

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

Examples 9-P1,9-P2

((R) -6- ((S) -2- (difluoromethyl) -2H-1,2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 9-P1

((R) -6- ((R) -2- (difluoromethyl) -2H-1,2, 3-triazole-4-sulfonylimino) -1- (4-fluorophenyl) -1,4,5,6,7, 8-hexahydro-4 aH-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 9-P2

First step

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

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

MS m/z(ESI)：242.2[M+1]。

The following synthetic routes in examples 8-P1 and 8-P2 were used, substituting compound 8c of the third starting material with compound 9a, to give the title compounds 9-P1 (45 mg, yield: 26.6%) and 9-P2 (32 mg, yield: 18.9%).

Compound 9-P1 (shorter retention time):

MS m/z(ESI)：623.1[M+1]。

HPLC analysis: retention time 3.11 min, purity: 96% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(500MHz,CDCl ₃ ):δ8.90(d,1H),8.12(s,1H),8.06(s,1H),7.71(dd,1H),7.48-7.42(m,2H),7.33(t,1H),7.18(t,2H),6.54(d,1H),5.77(dd,1H),4.25(d,1H),4.10-3.91(m,1H),3.08(d,1H),2.95(d,1H),2.90-2.78(m,1H),2.69(td,2H),2.62-2.47(m,1H)。

Compound 9-P2 (longer retention time):

MS m/z(ESI)：623.1[M+1]。

HPLC analysis: retention time 3.16 min, purity: 97% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(500MHz,CDCl ₃ ):δ8.86(d,1H),8.15(s,1H),8.10(d,1H),7.75-7.70(m,1H),7.48-7.42(m,2H),7.35(d,1H),7.18(dd,2H),6.50(d,1H),5.52(dd,1H),4.15-4.05(m,1H),3.96(d,1H),2.99-2.85(m,2H),2.81(td,1H),2.71(td,1H),2.56-2.48(m,1H),2.40(s,1H)。

Examples 10-P1, 10-P2

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

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

First step

5- (benzylthio) -1-methyl-1H-tetrazole 10b

Compound 5- (benzylthio) -1H-tetrazole 10a (2 g,10.4mmol, shanghai Bifide) was dissolved in tetrahydrofuran (20 mL), trimethylsilyl diazomethane (2.39 g,20.9 mmol) was added dropwise, and after stirring for 2 hours, the reaction mixture was concentrated under reduced pressure to give crude title product 10b (2 g, yield: 93.1%) which was then reacted directly without purification.

MS m/z(ESI)：207.2[M+1]。

The following synthetic routes in examples 8-P1 and 8-P2 were used, substituting compound 8c from the third step with compound 10b, to give the title compounds 10-P1 (4 mg, yield: 15.6%) and 10-P2 (4 mg, yield: 15.6%).

Compound 10-P1 (shorter retention time):

MS m/z(ESI)：588.2[M+1]。

¹ H NMR(500MHz,CDCl ₃ ):δ8.91(d,1H),8.15(s,1H),7.72(dd,1H),7.51-7.44(m,2H),7.32(s,1H),7.20(t,2H),6.57(d,1H),5.81(dd,1H),4.44(s,3H),4.28(d,1H),4.14(dq,1H),3.27(d,1H),3.09-2.82(m,4H),2.58(dd,1H)。

Compound 10-P1 (longer retention time):

MS m/z(ESI)：588.2[M+1]。

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

Biological evaluation

The present disclosure is explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: GR receptor reporter Gene experiments

The following methods were used to determine the effect of the compounds of the present disclosure on GR receptor transcriptional activity in MDA-kb2 cells, and are briefly described below.

MDA-kb2 cells (ATCC, CRL-2713) were cultured in complete medium, namely Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141). On the first day of the experiment, MDA-k was assayed using incomplete medium, leibovitz' S L-15 medium (Gibco, 11415114) containing 5% charcoal-treated serum (Biosun, S-FBS-AU-045) b2 cells were seeded at a density of 30000 cells/well in 96 well plates with 80 μl of cell suspension per well, the well plates were placed at 37deg.C without CO ₂ The cell culture incubator was incubated overnight. The next day, 10 μl of the test compound was added per well, diluted in a gradient with incomplete medium, the final concentration of the compound being 8 concentration points at 5-fold gradient dilution starting from 10 μΜ, the final DMSO concentration being 0.5% DMSO. Each well was further charged with 10. Mu.L of dexamethasone (MCE, HY-14648) in incomplete medium at a final concentration of 10nM. Wells containing only 0.5% dmso were set as negative controls, and plugs Mi Songkong containing 10nM were set as positive controls. The pore plate is placed at 37 ℃ and has no CO ₂ The cells were cultured in an incubator for 18 hours. On the third day, 96-well cell culture plates were removed, 90. Mu.L of the formulated ONE-Glo luciferase assay reagent (Promega, E6120) was added to each well, and after 10 minutes at room temperature, the luminescence signal value was read in the microplate reader EnVision (PerkinElmer). Inhibition was calculated using the compound concentrations and the luminescence values of the negative control and positive control wells. IC of compounds to inhibit GR transcriptional activity was calculated using GraphPad Prism software based on the concentrations of compounds and the corresponding inhibition rates ₅₀ Values.

TABLE 1 Effect of the compounds of the present disclosure on GR receptor transcriptional Activity in MDA-kb2 cells

Examples numbering	IC ₅₀ (nM)
1-P1	10
1-P2	49
2-P1	270
2-P2	129
3-P1	153
4-P1	65
4-P2	159
5-P1	97
7-P1	157
8-P1	7
8-P2	16

9-P1	6
9-P2	35
10-P1	20
10-P2	103

Conclusion: the compound disclosed by the disclosure has better inhibition activity on GR receptor transcription in MDA-kb2 cells.

Test example 2: GR receptor binding assay

The following methods are used to determine competitive binding activity of the compounds of the present disclosure to the GR receptor, and are briefly described below.

The experiment usesGR receptor competitive binding assay kit (Invitrogen, A15901). First Nuclear Receptor Buffer F (Invitrogen, PV 4547), GR Stabilizing Peptide (10×) (Invitrogen, P2815) and DTT (Invitrogen, P2325) in the kit were mixed in a ratio of 179:20:1 to form an assay buffer. The test compound was diluted with DMSO and subjected to 4-fold gradient dilution at a concentration of 1mM, for a total of 9 concentration points. The compound DMSO solution was diluted with assay buffer and 10 μl of compound dilution was added to each well of a black 384 well plate (Corning, 4514) at a final concentration of 9 concentrations of 10 μΜ starting 4-fold gradient dilution. Buffer wells containing 1% DMSO were set as negative controls and wells with a final concentration of 20. Mu.M dexamethasone (MCE, HY-14648) were added as positive controls. Preparation of Fluormene with buffer ^TM GS1Green (Invitrogen, PV 6044) was added to a final concentration of 5nM, and a 384-well plate was added at 5. Mu.L per well. GR-LBD (GST) (Invitrogen, A15668) and was formulated with buffer Tb-anti-GST anti-ibody (Invitrogen, PV 3550) was mixed so that the final concentration of Tb-anti-GST anti-ibody was 2nM, the final concentration of GR-LBD (GST) was as shown in each batch specification,the mixture was added at 5 μl per well to 384 well plates. After the well plate was left at room temperature for 2 hours, fluorescence values with excitation light wavelength of 340nm and emission light wavelength of 520nm and 490nm were read by a PHARMASTAR microplate reader (BMG LABECH), and inhibition ratios were calculated using ratios of the compound concentrations and the fluorescence values of 520nm and 490nm of the negative control and positive control wells. IC of competitive binding activity of compounds to GR receptor was calculated using GraphPad Prism software based on each concentration of compound and corresponding inhibition ₅₀ Values.

TABLE 2 competitive binding Activity of the compounds of the present disclosure with GR receptor

Examples numbering	IC ₅₀ (nM)
1-P1	15
1-P2	22
2-P2	41
4-P1	43
5-P1	58

Conclusion: the compound disclosed by the invention has better inhibition activity on competitive binding with GR receptor.

Test example 3: MDA-MB-231 cell proliferation assay

The following methods were used to determine the inhibition of MDA-MB-231 cell proliferation in vitro by the compounds of the present disclosure, and are briefly described below.

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 1000 cells/well in 96 well 3D cell culture plates (Corning, CLS7007-24 EA) using Leibovitz' S L-15 incomplete medium with 10% activated charcoal to treat fetal bovine serum (BioSun, S-FBS-AU-045), 120. Mu.L of cell suspension per well, and after centrifugation at 2000 rpm for 3 minutes, the well plates were placed at 37℃in the absence of CO ₂ The cell culture incubator was incubated overnight. The next day, 15 μl of the test compound was added per well, diluted in a gradient with incomplete medium, the final concentration of the compound being 9 concentration points from 10 μΜ at 3-fold gradient dilution. Then 15. Mu.L of dexamethasone (MCE, HY-14648) was added to each well at a final concentration of 0.1. Mu.M. Wells containing only 0.5% dmso were set as negative controls, and plugs Mi Songkong containing 0.1 μm were set as positive controls. The pore plate is placed at 37 ℃ and has no CO ₂ The cells were cultured in an incubator for 8 days. After 8 days, the 96-well 3D cell culture plate was removed and 50. Mu.L of the medium was added to each well3D Cell Viability Assay (Promega, G9683), after shaking for 25 minutes in the absence of light by an oscillator, 100. Mu.L of solution was transferred to a 96-well opaque white plate (Perkinelmer, 6005290) per well and the luminescence signal was read using a multifunctional microplate reader VICTOR 3 (Perkinelmer). Inhibition was calculated using the compound concentrations and the luminescence values of the negative control and positive control wells. IC of the compounds for inhibiting MDA-MB-231 cell proliferation activity was calculated using GraphPad Prism software based on the respective concentrations of the compounds and the corresponding inhibition rates ₅₀ Values.

TABLE 3 inhibition of MDA-MB-231 cell proliferation by the compounds of the present disclosure in vitro

Examples numbering	IC ₅₀ (nM)
1-P1	205
1-P2	405
8-P1	53
8-P2	380
9-P1	47
9-P2	259

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on MDA-MB-231 cell proliferation in vitro.

Test example 4: the compounds of the present disclosure have enzymatic activity on human liver microsomal CYP3A4 midazolam metabolic sites Inhibition effect

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP3A4 midazolam metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

3. Human liver microsomes (Corning Gentest, cat No,452161,Lot No.9050002,Donor, 35)

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate (Midazolam, TRC, M343000/3. Mu.M)

7. Quality control inhibitor (ketoconazole, SIGMA, cat No. K1003-100 MG)

8. Positive control compound, relacorilant (CORT-125134, cf. WO2013177559A2, example 18 Synthesis)

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). The midazolam working solution was diluted to a concentration of 15 μm with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ In the above solution, 40. Mu.L of 0.25mg/mL microsome solution was mixed with 20. Mu.L of each of 15. Mu.M midazolam working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M). The quality control group replaced the compound with the same concentration of ketoconazole. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. Taking 100 mu L of supernatant80. Mu.L of ultrapure water was mixed and transferred to LC-MS/MS analysis.

The numerical value is calculated by Graphpad Prism to obtain the IC of the drug to CYP3A4 midazolam metabolic site ₅₀ The values are shown in Table 4.

TABLE 4 IC of the compounds of the present disclosure for the midazolam metabolic site of human liver microsome CYP3A4 ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	10.4
Relacorilant	2.4

Conclusion: the compound of the embodiment 1-P1 has weak inhibitory effect on the midazolam metabolic site of human liver microsome CYP3A4, has smaller risk of metabolic drug interaction based on the CYP3A4 metabolic midazolam metabolic site, and shows better safety than a positive control compound, namely, a Relacorizant.

Test example 5: inhibition of enzymatic Activity of human liver microsomal CYP3A4 testosterone Metabolic sites by Compounds of the present disclosure Action

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP3A4 testosterone metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

3. Human liver microsomes (Corning Gentest, cat No,452161,Lot No.905002,Donor35)

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate (testosterone, walker, CAS No. [58-22-0 ]/75. Mu.M)

7. Quality control inhibitor (ketoconazole, SIGMA, cat No. K1003-100 MG)

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). Testosterone working solution diluted to 375 μm concentration with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ 40. Mu.L of the microsome solution of 0.25mg/mL, and 375. Mu.M testosterone working solution and 20. Mu.L of compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M) respectively were mixed uniformly. The quality control group replaced the compound with the same concentration of ketoconazole. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. 100. Mu.L of the supernatant was mixed with 80. Mu.L of ultrapure water and transferred to LC-MS/MS analysis.

The IC of the medicine to CYP3A4 testosterone metabolic site is obtained by calculating the numerical value through Graphpad Prism ₅₀ The values are shown in Table 5.

TABLE 5 IC of the compounds of the present disclosure for testosterone metabolic sites of human liver microsomal CYP3A4 ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	25.2
Relacorilant	2.5

Conclusion: the compound of example 1-P1 of the present disclosure showed weaker inhibition of testosterone metabolic site of human liver microsome CYP3A4, and better safety than the positive control compound, repaicorilant.

Test example 6: the compounds of the present disclosure have enzymatic activity on human liver microsomal CYP2C9 diclofenac metabolic sites Inhibition effect

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP2C9 diclofenac metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

3. Human liver microsomes (Corning Gentest, cat No,452161,Lot No.9050002,Donor,35)

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate (diclofenac, SIGMA, cat No. D6899-10G/4. Mu.M)

7. Quality control inhibitor (sulfadiazine, SIGMA, cat No. 526-08-9)

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). Diclofenac working solution diluted to 20 μm concentration with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ 40. Mu.L of the microsome solution of 0.25mg/mL, and 20. Mu.L of each of the diclofenac working solution and the compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M) of 15. Mu.M were taken and mixed uniformly. The quality control group uses sulfanilamide pyrazole with the same concentration to replace the compound. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. 100. Mu.L of the supernatant was mixed with 80. Mu.L of ultrapure water and transferred to LC-MS/MS analysis.

The numerical value is calculated by Graphpad Prism to obtain the IC of the drug to CYP2C9 diclofenac metabolic site ₅₀ The values are shown in Table 6.

TABLE 6 IC of the compounds of the present disclosure for human liver microsomal CYP2C9 diclofenac metabolic sites ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	>30
Relacorilant	4.2

Conclusion: the compound of example 1-P1 of the present disclosure does not undergo metabolic drug interactions based on CYP2C9 diclofenac metabolic sites over a 30 μm concentration range, showing better safety than the positive control compound, repaicorilant.

Test example 7: enzyme Activity of Compounds of the present disclosure on human liver microsomal CYP2C19 (S) -Methophenytoin Metabolic sites Sex inhibitory effect

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP2C19 (S) -mephenytoin metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate ((S) -Meifenthin/20. Mu.M, powder was purchased from carboline technologies Co., ltd., cat No. 303768)

7. Quality control inhibitor (ticlopidine, powder from SIGMA, cat No. T6654-1G)

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). (S) -Mephenytoin working solution diluted to 100. Mu.M concentration with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ 40. Mu.L of the microsome solution of 0.25mg/mL, and then 20. Mu.L of each of 15. Mu.M of (S) -Mephenytoin working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M) were taken and mixed uniformly. The quality control group replaced the compound with ticlopidine at the same concentration. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. 100. Mu.L of the supernatant was mixed with 80. Mu.L of ultrapure water and transferred to LC-MS/MS analysis.

The numerical value is calculated by Graphpad Prism to obtain the IC of the drug to CYP2C19 (S) -mephenytoin metabolic site ₅₀ The values are shown in Table 7.

TABLE 7 IC of the compounds of the present disclosure for human liver microsomal CYP2C19 (S) -mephenytoin metabolic site ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	>30
Relacorilant	6.9

Conclusion: the compound of example 1-P1 of the present disclosure does not undergo metabolic drug interactions based on the CYP2C19 (S) -mephenytoin metabolic site over a 30 μm concentration range, showing better safety than the positive control compound, reloroilant.

Test example 8: the compounds of the present disclosure have enzymatic activity on human liver microsomal CYP1A2 phenacetin metabolic sites Inhibition effect

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP1A2 phenacetin metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate (phenacetin/12 mu M, chinese medicine biological products institute, cat No. 100095-200204)

7. Quality control inhibitor (alpha-naphthaceneflavone, SIGMA, cat No. N5757-1G)

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). The phenacetin working solution was diluted to a concentration of 60. Mu.M with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ 40. Mu.L of the microsome solution of 0.25mg/mL, and 20. Mu.L of each of the phenacetin working solution and the compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M) of 15. Mu.M were taken and mixed uniformly. The quality control group uses alpha-naphthoflavone with the same concentration to replace the compound. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. 100. Mu.L of the supernatant was mixed with 80. Mu.L of ultrapure water and transferred to LC-MS/MS analysis.

The numerical value is calculated by Graphpad Prism to obtain the IC of the drug to CYP1A2 phenacetin metabolic site ₅₀ The values are shown in Table 8.

TABLE 8 IC of the presently disclosed compounds against human liver microsomal CYP1A2 phenacetin metabolic sites ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	>30

Conclusion: the compounds of examples 1-P1 of the present disclosure do not undergo metabolic drug interactions based on the CYP1A2 phenacetin metabolic site over a concentration range of 30 μm.

Test example 9: the compounds of the present disclosure have enzymatic activity on human liver microsomal CYP2D6 dextromethorphan metabolic sites Inhibition effect

The enzymatic activity of the compounds of the present disclosure on human liver microsomal CYP2D6 dextromethorphan metabolic sites was determined using the following experimental method.

1. Experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Producer)

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

4. ABI QTrap 4000 liquid and mass dual-purpose instrument (AB Sciex)

5. ZORBAX Expend-C18, 3X 50mm,3.5 μm (Agilent Co., USA)

6. CYP probe substrate (dextromethorphan/4. Mu.M, sigma, cat No. D9684-5G)

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

2. Experimental procedure

Preparing 100mM PBS buffer solution, and preparing 7.5mM MgCl with the buffer solution ₂ And 5mM NADPH solution, followed by the use of the 7.5mM MgCl ₂ A microsomal solution of 0.25mg/mL was prepared, and a stock solution of the compound of example 1-P1 or the positive control compound, relacorizant, was diluted with DMSO to a concentration of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, and 0mM to give a series of solutions I (150, 50, 15, 5, 1.5, 0.15, 0.015, and 0. Mu.M) to be tested, and the series of solutions I were diluted 200-fold with Phosphate Buffer (PBS). Dextromethorphan working solution diluted to a concentration of 20 μm with PBS.

The preparation of MgCl was carried out at 7.5mM ₂ 40. Mu.L of the microsome solution of 0.25mg/mL, and 20. Mu.L of each of 15. Mu.M dextromethorphan working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. Mu.M) were taken and mixed uniformly. The quality control group replaced the compound with quinidine at the same concentration. While 5mM NADPH solution was preincubated together at 37℃for 5 minutes. After 5 minutes 20. Mu.L of NADPH was added to each well, the reaction was started and incubated for 30 minutes. All incubation samples were double-sampled. After 30 minutes 250. Mu.L of acetonitrile containing an internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and centrifuged at 3700rpm for 10 minutes. 100. Mu.L of the supernatant was mixed with 80. Mu.L of ultrapure water and transferred to LC-MS/MS analysis.

The numerical value is calculated by Graphpad Prism to obtain the IC of the drug to CYP2D6 dextromethorphan metabolic site ₅₀ The values are shown in Table 9.

Table 9 IC of compounds of the present disclosure for human liver microsomal CYP2D6 dextromethorphan metabolic sites ₅₀ Value of

Compounds of formula (I)	IC ₅₀ (μM)
Example 1-P1	>30
Relacorilant	9.0

Conclusion: the compound of example 1-P1 of the present disclosure does not undergo metabolic drug interactions based on the CYP2D6 dextromethorphan metabolic site over a 30 μm concentration range, and exhibits better safety than the positive control compound, palacorilant.

b test example 10: pharmacokinetic testing of compounds of the present disclosure

1. Summary

The drug concentration in the plasma at different moments after the compound to be tested is administrated by the nude mice by lavage is determined by using the LC/MS/MS method by taking the nude mice as the tested animals. Pharmacokinetic behavior of the compounds of the present disclosure in nude mice was studied and their pharmacokinetic profile was assessed.

2. Experimental protocol

2.1 Experimental drugs

Example 1-P1 Compound, relacorilant.

2.2 laboratory animals

The nude mice, 27 females, were divided into 3 groups and purchased from Vetolihua laboratory animal Co.

2.3 pharmaceutical formulation

A certain amount of the drug was weighed, and 10% dmso, 0.1% tween 80, and 89.9% hpmc (0.5%) were added to prepare Cheng Chengming solution.

2.4 administration of drugs

The nude mice are fed by stomach injection after being fasted overnight, the dosage of the feed is 10mg/kg and 30mg/kg respectively, and the dosage volume of the feed is 0.2mL/10g.

3. Operation of

The compound to be tested is administrated by lavage of nude mice, 0.1mL of blood is collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours before and after administration, and the compound to be tested is placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000 revolutions per minute for 1 minute (4 ℃), plasma is separated in 1 hour, and the compound to be tested is stored at-20 ℃. The blood collection to centrifugation process was operated under ice bath conditions.

Determining the content of a compound to be detected in the blood plasma of nude mice after the gastric lavage administration of the medicaments with different concentrations: the naked mouse plasma at each time after administration was taken at 20. Mu.L, 50. Mu.L of an internal standard solution (100 ng/mL of camptothecin) and 200. Mu.L of acetonitrile were added, and the mixture was vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and the plasma sample was taken at 1. Mu.L of the supernatant for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 10 pharmacokinetic parameters of the compounds of the present disclosure

Conclusion: the compound of the embodiment 1-P1 of the disclosure has good drug absorption and obvious pharmacokinetic advantage compared with a positive control compound, namely, a Relacorizant.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

is absent or a chemical bond;

ring a is selected from heterocyclyl, aryl and heteroaryl;

each R is ¹ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ Hydroxy, -C (O) R ⁶ 、-C(O)OR ⁶ 、-C(O)NR ⁴ R ⁵ 、-S(O) _p R ⁶ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

alternatively, two adjacent R ¹ Condensed with ring A to form a heterocyclic group, wherein said heterocyclic group is optionally substituted with a member selected from the group consisting of halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy and hydroxyalkyl;

ring B is aryl or heteroaryl;

each R is ² Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ Hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ One or more substituents selected from the group consisting of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring C is aryl or heteroaryl;

each R is ³ Identical or different and each independentlySelected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁴ R ⁵ And hydroxyl;

R ⁶ and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

R ⁴ 、R ⁵ 、R ⁷ And R is ⁸ The alkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl and heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

or R is ⁴ And R is ⁵ Together with the attached nitrogen atom, form a heterocyclic group optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

or R is ⁷ And R is ⁸ Together with the attached nitrogen atom, form a heterocyclic group optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

p is 0, 1 or 2;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4; and is also provided with

t is 0, 1, 2, 3 or 4.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II), the general formula (II-1) or the general formula (II-2):

Wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in claim 1.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III), formula (III-1) or formula (III-2):

wherein:

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in claim 1.
A compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring B is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; preferably, ring B is pyridinyl.
A compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring C is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; preferably, ring C is phenyl.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, 4 to 5, which is a compound represented by the general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ To R ³ M, n and t are as defined in claim 1.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 5, which is a compound represented by the general formula (V), the general formula (V-1) or the general formula (V-2), or a pharmaceutically acceptable salt thereof:

Wherein:

ring A, R ¹ To R ³ M, n and t are as defined in claim 1.
A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; preferably, ring a is a 5 or 6 membered heteroaryl; further preferred, ring a is a 5 membered nitrogen containing heteroaryl; more preferably, ring a is selected from pyrazolyl, imidazolyl, 1,2, 3-triazolyl and tetrazolyl; most preferably, ring A is 1,2, 3-triazolyl.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl, wherein each of said 3-to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl is independently optionally substituted with a member selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 One or more substituents in the hydroxyalkyl group are substituted; or two adjacent R ¹ Condensed with ring A to form a 3-to 8-membered heterocyclic group, wherein said 3-to 8-membered heterocyclic group is optionally substituted with a halogen, C _1-6 Alkyl, oxo, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups.
A compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
a compound represented by the general formula (IA) or a salt thereof,

wherein:

R ^w is an amino protecting group; preferably, R ^w Is tert-butyldimethylsilyl (TBS);

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in claim 1.
A compound of formula (IA) according to claim 13, or a salt thereof, selected from the following compounds:
a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

Deamination of protecting group R by Compounds of general formula (IA) or salts thereof ^w Obtaining a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

R ^w is an amino protecting group; preferably, R ^w Is tert-butyldimethylsilyl (TBS);

ring a, ring B, ring C, R ¹ To R ³ M, n and t are as defined in claim 1.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition by modulating GR.
Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the manufacture of a medicament for the treatment and/or prophylaxis of tumours, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases and neurodegenerative diseases; preferably, the use in the manufacture of a medicament for the treatment and/or prophylaxis of a condition selected from the group consisting of cancer, obesity, diabetes, hypertension, syndrome X, depression, allergy, anxiety, glaucoma, alzheimer's disease, parkinson's disease, huntington's disease, cognition enhancement, cushing's syndrome, addison's disease, osteoporosis, frailty, muscular frailty, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, diseases associated with adrenal function, human immunodeficiency virus, acquired immunodeficiency syndrome, immunomodulation, allergy, wound healing, compulsive behaviour, addiction, psychosis, anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous retinopathy, alcohol dependence, stress disorders, delirium, chronic pain, premature infant neurological disorders and migraine; more preferably in the manufacture of a medicament for the treatment and/or prophylaxis of a cancer selected from the group consisting of breast cancer, prostate cancer, adrenocortical cancer, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer, leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma and ovarian cancer; most preferably in the manufacture of a medicament for the treatment and/or prophylaxis of a cancer selected from the group consisting of breast cancer, prostate cancer, cushing's syndrome, adrenocortical cancer, fallopian tube cancer, pancreatic cancer, peritoneal cancer and ovarian cancer.