CN114907349A

CN114907349A - Fused azatricyclo derivatives, preparation method and application thereof in medicines

Info

Publication number: CN114907349A
Application number: CN202210122439.6A
Authority: CN
Inventors: 李心; 陈阳; 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: 2021-02-10
Filing date: 2022-02-09
Publication date: 2022-08-16

Abstract

The present disclosure relates to fused azatricycles derivatives, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a fused azatricyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, especially an application of the derivative as a GR (GR) regulator and an application of the derivative in preparation of drugs for treating and/or preventing tumors.

Description

Fused azatricyclo derivatives, preparation method and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused azatricyclo derivative, a preparation method and application thereof in medicines. In particular, the disclosure relates to fused azatricyclo derivatives shown in the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and application of the fused azatricyclo derivatives as GR modulators and application of the fused azatricyclo derivatives in preparation of drugs for treating and/or preventing tumors.

Background

Glucocorticoid Receptor (GR) is a member of the nuclear Receptor family, and belongs to a class of steroid hormone receptors in the nuclear Receptor family, along with Mineralocorticoid Receptor (MR), Progestogen Receptor (PR), Androgen Receptor (AR), and Estrogen Receptor (ER). Glucocorticoids regulate gene expression by activating GR, regulating a variety of cellular functions such as metabolism, inflammation, cell growth and differentiation, etc. Physiologically, glucocorticoids regulate sugar metabolism, protein metabolism, and lipid metabolism in humans. The glucocorticoid excess caused by pathological factors can cause metabolic disturbance, developmental delay and the like, and becomes Cushing's Syndrome (CS for short) clinically; addison's disease, which is caused by pathological trauma or other factors, results in low glucocorticoid levels, which are manifested by anxiety, fatigue, muscle and joint pain, and depression, with some patients experiencing severe depression.

Due to the effective inhibition of immune response, GR receptor agonists such as steroid glucocorticoids are widely used clinically for the treatment of autoimmune diseases or allergies. Steroid glucocorticoids are also one of the combination therapies in hematological tumors with malignant proliferation of immune cells.

In the treatment of solid tumors, steroid glucocorticoids are approved as adjunctive therapy to alleviate symptoms of allergy, emesis, etc. in patients and to enhance tolerance to chemotherapy or targeted therapies. However, in recent years, more and more clinical and academic studies have shown that GR signaling pathway activation is directly associated with the progression, metastasis, drug resistance and poor prognosis of a variety of solid tumors.

In castration-resistant prostate cancer (CRPC), GR signaling pathway activation is directly associated with enzalutamide resistance. After administration of enzalutamide to patients (>8 weeks), GR levels were up-regulated in tumor tissues and responded poorly to enzalutamide. GR and AR can together regulate a series of genes associated with prostate cancer progression in prostate cancer cells, and GR pathway activation is a compensatory effect of prostate cancer cells on AR inhibition. On an in vivo efficacy model, GR gene knockout or GR antagonists can significantly inhibit the growth of in vivo tumor models.

In Triple Negative Breast Cancer (TNBC) patients, there is a statistically significant correlation between GR expression levels and poor survival in TNBC as well as ovarian cancer. GR signaling pathway activation is associated with cancer cell metastasis and resistance to paclitaxel. Paclitaxel-based chemotherapy is currently the mainstay of TNBC therapy. Researches find that GR agonist dexamethasone mediated GR activation leads to high expression of genes related to chemotherapy tolerance and tumor metastasis, and then chemotherapy tolerance and metastasis of TNBC tumor cells are promoted. Use of GR antagonists can enhance the sensitivity of chemotherapy and reduce metastasis.

Therefore, targeting GR and interfering with its signal transduction by antagonistic means is a new therapeutic approach for cancer. The mechanism of action has been validated effectively by a large body of literature data, particularly in prostate and breast cancer.

Patent applications which have now disclosed GR modulators include, among others, WO2005087769A1, WO2012027702A1, WO2013177559A2 and WO2015077530A 1.

Disclosure of Invention

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

wherein:

is absent or a chemical bond;

R ^4a and R ^4b Are identical or different and are each independently alkyl, or R ^4a And R ^4b Fused to the carbon atom to which it is attached to form a cycloalkyl or heterocyclyl group;

L ¹ and L ² Are the same or different and are each independently a bond or selected from the group consisting of an oxygen atom, a sulfur atom, -S (O) -, -S (O) ₂ -, -C (O) -, -C (O) O-, -C (O) NH-, alkylene, and heteroalkylene;

ring a is selected from the group consisting of heterocyclyl, aryl and heteroaryl;

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

or two adjacent R ¹ Fused to ring A to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently optionally substituted with a group selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy and hydroxyalkyl;

ring B is aryl or heteroaryl;

each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ^5a R ^5b Hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁷ R ⁸ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring C is aryl or heteroaryl;

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

R ⁶ selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups, wherein said alkyl groups, cycloalkyl groups, and heterocyclic groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkoxy groups, haloalkyl groups, and haloalkoxy groups;

R ^5a 、R ^5b 、R ⁷ and R ⁸ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, whereinEach of the 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 ^5a And R ^5b 、R ⁷ And R ⁸ Together with the nitrogen atom to which they are attached form a heterocyclic group, which heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, 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

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

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Is a chemical bond.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^4a And R ^4b Are the same or different and are each independently C _1-6 Alkyl, or R ^4a And R ^4b Fused to the carbon atom to which it is attached to form a 3 to 6 membered cycloalkyl group; preferably, R ^4a And R ^4b Are both methyl, or R ^4a And R ^4b Condensed with the carbon atom to which it is attached to form a cyclopropyl group.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L ¹ is-C (O) -.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L ² is-S (O) ₂ -。

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L ¹ is-C (O) -, and L ² is-S (O) ₂ -。

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

wherein:

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

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

wherein:

ring A, ring B, ring C, R ¹ ～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 pyridyl.

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 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring C is phenyl.

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

wherein:

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

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

wherein:

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

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

wherein:

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

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

wherein:

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

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

wherein:

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

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

wherein:

ring A, R ¹ ～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), 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 5 or 6 membered heteroaryl; more preferably, ring a is a 5-membered heteroaryl; most preferably, ring a is pyrazolyl or 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), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein each R is R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; preferably, each R ¹ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; more preferably, R ¹ Is C _1-6 An alkyl group; most preferably, R ¹ Is methyl.

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), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein

Is composed of

R ¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; preferably, the first and second electrodes are formed of a metal,

is composed of

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), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein each R is R ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; preferably, each R ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, each R ² Are the same or different and are each independently a hydrogen atom or C _1-6 A haloalkyl group; even 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), formula (V-2) or a pharmaceutically acceptable salt thereof, wherein each R is R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group; preferably, each R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably, each R ³ Are the same or different and are each independently a hydrogen atom or a halogen; even more preferably, R ³ Is halogen; most preferably, R ³ Is a fluorine atom.

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

Is composed of

Each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 Haloalkoxy, n is as defined in formula (I); preferably, it is

R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably

In some embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein

Is composed of

R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, it is

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) or a pharmaceutically acceptable salt thereofSalts of, wherein

Is composed of

Each R is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Haloalkoxy, t is as defined in formula (I); preferably a

R ³ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably

Is composed of

R ³ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably a

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), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; 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), 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), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2; preferably, t is 1.

Is a chemical bond; r ^4a And R ^4b Are both methyl, or R ^4a And R ^4b Condensed with the attached carbon atom to form a cyclopropyl group; l is ¹ is-C (O) -; l is a radical of an alcohol ² is-S (O) ₂ -; ring a is selected from 3-to 12-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; ring B is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; ring C is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; each R is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2.

In some embodiments of the present disclosure, the compounds of formula (II), formula (II-1), formula (II-2), formula (III-1), formula (III-2) are as describedA compound of formula (la) or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-to 6-membered heteroaryl; ring B is pyridyl; ring C is phenyl; each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group; each R is ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 0, 1 or 2; n is 0, 1 or 2; and t is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein ring A is pyrazolyl or 1,2, 3-triazolyl; each R is ¹ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; each R is ² Are the same or different and are each independently a hydrogen atom or C _1-6 A haloalkyl group; each R is ³ Are the same or different and are each independently a hydrogen atom or a halogen; m is 1; n is 1; and t is 1.

In some embodiments of the present disclosure, the compound of formula (IV), formula (IV-1), formula (IV-2), formula (V-1), formula (V-2), or a pharmaceutically acceptable salt thereof, wherein ring A is pyrazolyl or 1,2, 3-triazolyl; r ¹ Is C _1-6 An alkyl group; r ² Is C _1-6 A haloalkyl group; r ³ Is halogen; m is 1; n is 1; and 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 ^4a 、R ^4b 、L ¹ ring B, ring C, R ² 、R ³ N and t are as defined in formula (I).

Another aspect of the present disclosure relates to a compound of formula (IIA) or a salt thereof,

wherein:

ring B, ring C, R ² 、R ³ 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) or a salt thereof,

wherein:

ring B, ring C, R ² 、R ³ N and t are as defined in the general formula (II-1).

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

wherein:

ring B, ring C, R ² 、R ³ N and t are as defined in the general formula (II-2).

Another aspect of the present disclosure relates to a compound of formula (IIIA) or a salt thereof,

wherein:

ring B, ring C, R ² 、R ³ 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) or a salt thereof,

wherein:

ring B, ring C, R ² 、R ³ N and t are as defined in the general formula (III-1).

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

wherein:

ring B, ring C, R ² 、R ³ N and t are as defined in the general formula (III-2).

Another aspect of the present disclosure relates to a compound of formula (IVA) or a salt thereof,

wherein:

R ² 、R ³ 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) or a salt thereof,

wherein:

R ² 、R ³ n and t are as defined in the general formula (IV-1).

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

wherein:

R ² 、R ³ n and t are as defined in the general formula (IV-2).

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

wherein:

R ² 、R ³ 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) or a salt thereof,

wherein:

R ² 、R ³ n and t are as defined in the general formula (V-1).

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

wherein:

R ² 、R ³ n and t are as defined in the general formula (V-2).

Typical intermediate compounds of the present disclosure include, but are not limited to:

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

reacting a compound represented by the general formula (IA) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

L ² is a chemical bond or is selected from-S (O) ₂ -, -C (O) -and C _1-6 An alkylene group; preferably, L ² is-S (O) ₂ -；

X is halogen; preferably, X is a chlorine atom;

R ^4a 、R ^4b 、L ¹ ring A, ring B, ring C, R ¹ ～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-1) and general formula (II-2), or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound shown in a general formula (IIA) or a salt thereof with a compound shown in a general formula (VI) to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof, optionally, splitting the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof to obtain a compound shown in a general formula (II-1) and a general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, ring B, ring C, R ¹ ～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 (III-1) and the general formula (III-2), or a pharmaceutically acceptable salt thereof, which comprises:

reacting the compound shown in the general formula (IIIA) or the salt thereof with the compound shown in the general formula (VI) to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof, optionally, splitting the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (III-1) and the general formula (III-2) or the pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (IV-1) and the general formula (IV-2), or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound represented by the general formula (IVA) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, and optionally, splitting the compound represented by the general formula (IV) or the pharmaceutically acceptable salt thereof to obtain a compound represented by the general formula (IV-1) or the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, R ¹ ～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 (V-1) and the general formula (V-2), or a pharmaceutically acceptable salt thereof, which comprises:

reacting a compound represented by the general formula (VA) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, and optionally, splitting the compound represented by the general formula (V) or the pharmaceutically acceptable salt thereof to obtain a compound represented by the general formula (V-1) or the general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, R ¹ ～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 (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

reacting a compound represented by the general formula (II-1A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in the general formula (II-1).

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, the method comprising:

reacting a compound represented by the general formula (II-2A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in the general formula (II-2).

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

reacting a compound represented by the general formula (III-1A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in the general formula (III-1).

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

reacting the compound shown in the general formula (III-2A) or the salt thereof with the compound shown in the general formula (VI) to obtain the compound shown in the general formula (III-2) or the pharmaceutically acceptable salt thereof,

wherein:

L ² is a chemical bond or a selectionfrom-S (O) ₂ -, -C (O) -and C _1-6 An alkylene group; preferably, L ² is-S (O) ₂ -；

X is halogen; preferably, X is a chlorine atom;

ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in the general formula (III-2).

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, the method comprising:

reacting a compound represented by the general formula (IV-1A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, R ¹ ～R ³ M, n and t are as defined in the general 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:

reacting a compound represented by the general formula (IV-2A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

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:

reacting a compound represented by the general formula (V-1A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

ring A, R ¹ ～R ³ M, n and t are as defined in the general 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:

reacting a compound represented by the general formula (V-2A) or a salt thereof with a compound represented by the general formula (VI) to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by 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, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of compounds 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 shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for the treatment and/or prevention of a disease or condition by modulation of GR.

The disclosure further relates to the use of compounds 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 pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for the treatment and/or prevention of a disease or condition 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 shown in 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 tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ocular diseases and neurodegenerative diseases; preferably in the preparation of a medicament for the treatment and/or prevention of a disease selected from the group consisting of cancer, obesity, diabetes, hypertension, syndrome X, depression (e.g. psychotic depression, postpartum depression), allergy, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognition enhancement, Cushing's syndrome (also known as hypercortisolism), Addison's disease, osteoporosis, frailty (muscle weakness), osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal function-related disorders, viral infections (e.g. Human Immunodeficiency Virus (HIV)), immunodeficiency (e.g. acquired immunodeficiency syndrome (AIDS)), immunomodulation, allergy, wound healing, obsessive-compulsive behaviour, addiction, psychosis (e.g. postpartum psychosis), anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, Alcohol dependence, stress disorders (such as posttraumatic stress disorder), delirium, chronic pain, neurological disorders of premature infants and migraine; more preferably for the manufacture of a medicament for the treatment and/or prevention of a cancer 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, endometrial 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 for the manufacture of a medicament for the treatment and/or prevention of a cancer selected from the group consisting of breast cancer, prostate cancer, cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer (such as recurrent fallopian tube cancer), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer) and ovarian cancer (such as recurrent ovarian cancer).

The 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 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 disclosure also relates to a method of treating and/or preventing tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ophthalmic 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), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to compounds 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 pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for use as a medicament.

The disclosure further relates to compounds 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 pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and/or preventing a disease or condition by modulating GR.

The disclosure further relates to compounds 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 pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and/or preventing a disease or condition by antagonizing GR.

The disclosure further relates to compounds 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 pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are useful for treating and/or preventing tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ophthalmic diseases and neurodegenerative diseases.

The disease or disorder described in the present disclosure is selected from cancer, obesity, diabetes, hypertension, syndrome X, depression (e.g., psychotic depression, postpartum depression), allergy, anxiety, glaucoma, alzheimer's disease, parkinson's disease, huntington's disease, cognition enhancement, cushing's syndrome, addison's disease, osteoporosis, weakness (muscle weakness), osteoarthritis, rheumatoid arthritis, asthma, rhinitis, disorders related to 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., posttraumatic stress disorder), delirium, chronic pain, neurological disorders of premature infants, and migraine; preferably, the cancer is selected from 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, endometrial 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 breast cancer, prostate cancer, cushing's syndrome, adrenocortical carcinoma, fallopian tube carcinoma (such as recurrent fallopian tube carcinoma), pancreatic cancer (such as metastatic pancreatic ductal adenocarcinoma), peritoneal cancer (such as recurrent primary peritoneal cancer) and ovarian cancer (such as recurrent ovarian cancer).

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers, to formulate the compositions of the disclosure by conventional means. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), 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, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. 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 a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed 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, the injection or microemulsion being injectable into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

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 the known art 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, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into 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 therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health condition 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 treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched chain 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 groups). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C) _1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl groups). 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexylHexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. Most preferred are lower alkyl groups 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. Alkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

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

The term "heteroalkylene" refers to one or more (preferably 1,2,3, 4, or 5) -CH groups in an alkylene group ₂ -is replaced by a heteroatom selected from N, O and S; wherein said alkylene is as defined above. The heteroalkylene group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, and which has an alkenyl (i.e., C) of 2 to 12 (e.g., 2,3, 4,5,6,7,8, 9, 10, 11, or 12) carbon atoms _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, and alkynyl (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 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. Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkyl, 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. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of D atoms, 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 groups), preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl groups), more preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), and most preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). 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 of 5 to 20 membered (e.g., 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered) monocyclic rings sharing one carbon atom (referred to as a spiro atom), which may contain one or more double bonds. Preferably 6 to 14 membered spirocycloalkyl, more preferably 7 to 10 membered spirocycloalkyl. Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bis-spiro cycloalkyl), preferably mono-or bis-spiro alkyl, depending on the number of spiro atoms shared between rings. 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 single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to an all-carbon polycyclic group in which the 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) share an adjacent pair of carbon atoms between the rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered fused ring alkyl, more preferably 7 to 10 membered fused ring alkyl. They may be classified into polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, tetracyclic, etc., preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 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 fused cycloalkyl groups, depending on the number of constituent rings. Non-limiting examples of fused ring alkyl groups include:

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

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

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with 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 mono-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 is a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur may optionally be oxo (i.e., to form a sulfoxide or sulfone), but does not include the ring moiety of-O-, -O-S-, or-S-, with 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. a 3 to 12 membered heterocyclyl); further preferably 3 to 8 ring atoms (e.g. 3,4, 5,6,7 or 8) 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. a 3 to 6 membered heterocyclyl); most preferably having 5 or 6 ring atoms of which 1 to 3 are heteroatoms (i.e. a 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 5 to 20 membered (e.g., 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 membered) polycyclic heterocyclic group having one atom (referred to as a spiro atom) in common between monocyclic rings, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 membered spiroheterocyclyl, more preferably 7 to 10 membered spiroheterocyclyl. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a bis-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a bis-spiro heterocyclic group, according to the number of spiro atoms shared between rings. 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 mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group in which the 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) share an adjacent pair of atoms between them, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14-membered fused heterocyclic group, more preferably 7 to 10-membered fused heterocyclic group. They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 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/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic 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 not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

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

and the like.

The heterocyclyl group may be substituted or unsubstituted and, when substituted, 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 "aryl" refers to a 6 to 14 membered (e.g., 6,7,8, 9, 10, 11, 12, 13 or 14 membered) all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 10 membered aryl such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, 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, may be substituted at any available point of attachment, with 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 comprising 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 5 to 10 membered heteroaryl, more preferably 5 or 6 membered heteroaryl, 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 a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with 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 above cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or 2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

The term "amino protecting group" refers to a group that is easily removed by introduction onto an amino group in order to keep the amino group unchanged during the reaction at other sites of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (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 "hydroxyl protecting group" refers to a group introduced on a hydroxyl group that is easily removed, typically to block or protect the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C _1-6 Alkoxy-substituted C _1-6 Alkyl or phenyl substituted C _1-6 Alkyl (e.g. methoxymethyl (MOM) and ethoxyethyl, etc.), (C) _1-10 Alkyl or aryl) acyl (e.g.: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (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 cycloalkyl-O-wherein cycloalkyl is as defined above.

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

The term "alkylthio" refers to an alkyl-S-group 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 the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "═ 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 disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are structurally identical but differ in the arrangement of the 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, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as 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. One 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 diastereoisomeric salt is formed with an appropriate optically active acid or base, followed by diastereoisomeric resolution by conventional methods well known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

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 ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

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 in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, 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., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs 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, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

A compound of the present disclosure, when a position thereof is specifically designated as "deuterium" or "D", the position is understood to be at least 1000 times more abundant than deuterium naturally (which is 0.015%) i.e. at least 15% incorporation of deuterium. 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 for each 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 for each 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 for each 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 for each 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 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each 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 for each 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 for each 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 for each 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" means 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 substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the 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, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or pharmaceutically acceptable salts thereof and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group 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 acids as well as organic acids.

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

The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.

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 effective for the intended use.

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

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

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound shown in a general formula (IA) or a salt thereof with a compound shown in a general formula (VI) under an alkaline condition to obtain a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme two

Disclosed is a method for producing a compound represented by the general formula (II-1) or the general formula (II-2) below or a pharmaceutically acceptable salt thereof, which comprises the steps of:

reacting a compound shown in a general formula (IIA) or a salt thereof with a compound shown in a general formula (VI) under an alkaline condition to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof, and optionally, carrying out chiral preparation and resolution on the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof to obtain a compound shown in a general formula (II-1) and a general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme three

Disclosed is a method for producing a compound represented by the general formula (III-1) or (III-2) below or a pharmaceutically acceptable salt thereof, which comprises the steps of:

the compound shown in the general formula (IIIA) or the salt thereof reacts with the compound shown in the general formula (VI) under alkaline conditions to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof, and optionally, the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof is subjected to chiral preparation and resolution to obtain the compound shown in the general formula (III-1) and the general formula (III-2) or the pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme four

Disclosed herein is a method for preparing a compound represented by the general formula (IV-1) and the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises the steps of:

reacting a compound shown in a general formula (IVA) or a salt thereof with a compound shown in a general formula (VI) under an alkaline condition to obtain a compound shown in a general formula (IV) or a pharmaceutically acceptable salt thereof, and optionally, chiral preparing and splitting the compound shown in the general formula (IV) or the pharmaceutically acceptable salt thereof to obtain a compound shown in a general formula (IV-1) and a general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme five

Disclosed is a method for producing a compound represented by the general formula (V-1) or (V-2) below or a pharmaceutically acceptable salt thereof, which comprises the steps of:

reacting a compound shown in a general formula (VA) or a salt thereof with a compound shown in a general formula (VI) under an alkaline condition to obtain a compound shown in a general formula (V) or a pharmaceutically acceptable salt thereof, and optionally, carrying out chiral preparation and resolution on the compound shown in the general formula (V) or the pharmaceutically acceptable salt thereof to obtain a compound shown in a general formula (V-1) and a general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme six

The preparation method of the compound shown in the general formula (II-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (II-1A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme seven

The preparation method of the compound shown in the general formula (II-2) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (II-2A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme eight

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

reacting a compound represented by the general formula (III-1A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme nine

The preparation method of the compound shown in the general formula (III-2) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (III-2A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

Scheme ten

The preparation method of the compound shown in the general formula (IV-1) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (IV-1A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme eleven

The preparation method of the compound shown in the general formula (IV-2) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (IV-2A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme twelve

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

reacting a compound represented by the general formula (V-1A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

Scheme thirteen

The preparation method of the compound shown in the general formula (V-2) or the pharmaceutically acceptable salt thereof comprises the following steps:

reacting a compound represented by the general formula (V-2A) or a salt thereof with a compound represented by the general formula (VI) under an alkaline condition to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

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

The base comprises organic base and inorganic base, the organic base comprises but is not limited to triethylamine, N-diisopropylethylamine, N-butyl lithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and triethylamine is preferred; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide.

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 a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not 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 shift (d) at 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE NEO 500M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultrate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC analytical determination using Agilent 1260DAD liquid chromatograph.

High performance liquid preparation Waters 2545-2767, Waters 2767-SDQ2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Examples 1, 1-P1, 1-P2

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

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

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

First step of

5- (tert-butyl) 7-methyl 8-oxo-5-azaspiro [2.5] octane-5, 7-dicarboxylate 1b

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

MS m/z(ESI):284.3[M+1]。

Second step of

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

After compound 1b (3.0g, 10.6mmol) was dissolved in methanol (30mL), methylketene (1.48g, 21.1mmol) and triethylamine (1.07g, 10.6mmol) were added and stirred for reaction for 3 hours, the reaction solution was concentrated under reduced pressure to give crude title compound 1c (3.7g, yield: 98.8%), which was subjected to the next reaction without purification. MS M/z (ESI) 354.2[ M +1 ].

The third step

2' - (Tert-butyl) 8a ' -methyl 6' -oxo-7 ',8' -dihydro-1 ' H-spiro [ cyclopropane-1, 4' -isoquinoline ] -2',8a ' (3' H, 6' H) -dicarboxylate 1d

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

MS m/z(ESI):336.4[M+1]。

The fourth step

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

Compound 1d (1.2g, 3.58mmol) was dissolved in tetrahydrofuran (15mL), lithium bistrimethylsilylamide (17.8mL, 1M tetrahydrofuran solution) was added at-78 deg.C, after stirring for 0.5 hour, 2,2, 2-trifluoroethylformate (2.28g, 17.8mmol) was added, slowly warmed to room temperature for 15 hours, 30mL of saturated ammonium chloride solution was added, ethyl acetate was extracted (50 mL. times.3), the organic phases were combined and concentrated under reduced pressure to give crude title compound 1e (1.3g, yield: 100%) which was used in the next reaction without purification.

MS m/z(ESI):364.2[M-1]。

The fifth step

6'- (tert-butyl) 4a' -methyl 1'- (4-fluorophenyl) -1',4 '-dihydrospiro [ cyclopropane-1, 8' -pyrazolo [3,4-g ] isoquinoline ] -4a ',6' (5'H,7' H) -dicarboxylate 1f

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

MS m/z(ESI):454.3[M+1]。

The sixth step

1' - (4-fluorophenyl) -4a ' - (4- (trifluoromethyl) picolinoyl) -1',4',4a ',5' -tetrahydrospiro [ cyclopropane-1, 8' -pyrazolo [3,4-g ] isoquinoline ] -6' (7' H) -carboxylic acid tert-butyl ester 1g

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

MS m/z(ESI):569.6[M+1]。

Seventh step

(1'- (4-fluorophenyl) -1',4',6',7 '-tetrahydrospiro [ cyclopropane-1, 8' -pyrazolo [3,4-g ] isoquinolin ] -4a '(5' H) -yl) (4- (trifluoromethyl) pyridin-2-yl) methanone 1H

After dissolving 1g (130mg, 0.23mmol) of the compound in 2mL of dichloromethane, 0.7mL of trifluoroacetic acid was added and the reaction was stirred for 2 hours, the reaction was concentrated under reduced pressure to give the crude title compound 1h (130mg, yield: 97.6%) which was used in the next step without purification.

MS m/z(ESI):469.2[M+1]。

Eighth step

Dissolving the crude compound 1H (75mg, 0.13mmol) in 2mL of dichloromethane, adding triethylamine (65mg, 0.64mmol), 2-methyl-2H-1, 2, 3-triazole-4-sulfonyl chloride 1i (46mg, 0.25mmol, prepared by a known method "Journal of Medicinal Chemistry,2017,60,3405-, 20% ethanol ratio elution, flow rate: 20mL/min), the corresponding fractions were collected and concentrated under reduced pressure to give the title compound 15mg, 15mg, yield: 18.9 percent and 18.9 percent. Single configuration compounds (shorter retention time)

MS m/z(ESI):614.6[M+1]。

Chiral HPLC analysis: a chromatographic column: CHIRALCEL OD, 150 × 4.6mm, 5 μm, mobile phase: ethanol (0.1% DEA): 15% of n-hexane, flow rate: 1mL/min, retention time 7.146 minutes, purity: 99.35 percent. ¹ H NMR(500MHz,Methanol-d ₄ ):δ8.94(d,1H),8.00(s,1H),7.92(s,1H),7.89(d,1H),7.45(dd,2H),7.31(dd,3H),6.36(s,1H),5.41(d,1H),4.29(d,1H),4.23(s,3H),3.05(t,3H),2.95(d,1H),0.88-0.85(m,3H),0.67(d,1H)。

Single configuration compounds (longer retention time)

MS m/z(ESI):614.6[M+1]。

Chiral HPLC analysis: a chromatographic column: CHIRALCEL OD, 150 × 4.6mm, 5 μm, mobile phase: ethanol (0.1% DEA): 15% n-hexane, flow rate: 1mL/min, retention time 8.185 minutes, purity: 99.35 percent. ¹ H NMR(500MHz,Methanol-d ₄ ):δ8.94(d,1H),8.00(s,1H),7.94-7.86(m,2H),7.45(t,2H),7.31(d,3H),6.36(s,1H),5.41(d,1H),4.29(d,1H),4.23(s,3H),3.10-3.01(m,3H),2.95(d,1H),0.89-0.86(m,3H),0.67(d,1H)。

Example 2

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

After compound 1H (25mg, 53. mu. mol) was dissolved in 2mL of dichloromethane and triethylamine (27mg, 155. mu. mol), 1-methyl-1H-pyrazole-4-sulfonyl chloride 2a (27mg, 266. mu. mol) was added and the reaction was stirred for 2 hours, the reaction mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T, 30X 150mM, 5. mu.m; mobile phase: aqueous phase (10mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase: 30% -55%, flow rate: 30mL/min) to obtain the title compound 2(8mg, yield: 24.5%).

MS m/z(ESI):613.6[M+1]。

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

Example 3

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

Using the synthetic route described in example 1, substituting the starting material compound 1a for tert-butyl 3, 3-dimethyl-4-oxopiperidine-1-carboxylate in the first step and substituting the starting material compound 1i for 1-methyl-1H-pyrazole-4-sulfonyl chloride in the seventh step, the title compound 3(16mg, yield: 10.2%) was obtained.

MS m/z(ESI):614.8[M+1]。

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

Example 4

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

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

¹ H NMR(500MHz,CDCl ₃ ):δ8.87(d,1H),8.05(s,1H),7.84(s,1H),7.72-7.71(m,1H),7.50-7.47(m,2H),7.30-7.29(m,1H),7.25-7.22(m,2H),6.75(s,1H),5.79(d,1H),4.27-4.24(m,4H),3.43(d,1H),3.033(d,1H),2.85(d,1H),2.65(d,1H),1.27(d,6H)。

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test example 1: GR receptor reporter gene assay

The following protocol was used to determine the effect of the compounds of the present disclosure on GR receptor transcriptional activity in MDA-kb2 cells, and the experimental protocol is 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). Experiment the first day, MDA-kb2 cells were plated at 30000 cells/well in incomplete medium, Leibovitz' S L-15 medium (Gibco, 11415114) containing 5% charcoal treated serum (Biosun, S-FBS-AU-045)The cell suspension is cultured in a 96-well plate with a density of 80 μ L cell suspension per well, the plate is placed at 37 ℃ and is free of CO ₂ The cell culture box was cultured overnight. The following day, 10 μ L of test compound diluted in a gradient of incomplete medium was added to each well, the final concentration of compound being 8 concentration points with 5-fold gradient dilution from 10 μ M, the final concentration of DMSO being 0.5% DMSO. mu.L of dexamethasone (MCE, HY-14648) in incomplete medium was added to each well to a final concentration of 10 nM. Wells containing only 0.5% DMSO were set as negative controls and wells containing 10nM dexamethasone were set as positive controls. The pore plate is placed at 37 ℃ without CO ₂ The cell culture box was incubated for 18 hours. On the third day, the 96-well cell culture plate was removed, 90. mu.L of the formulated ONE-Glo luciferase assay reagent (Promega, E6120) was added to each well, and after standing at room temperature for 10 minutes, the luminescence signal value was read in a microplate reader EnVision (Perkinelmer). The inhibition was calculated using the concentration of the compound and the luminescence values of the negative and positive control wells. IC of compounds for inhibition of GR transcriptional activity was calculated using GraphPad Prism software based on compound concentrations and corresponding inhibition ₅₀ The value is obtained.

TABLE 1 Effect of Compounds of the disclosure on GR receptor transcriptional activity in MDA-kb2 cells

Example numbering	IC ₅₀ (nM)
		Compounds corresponding to longer retention times in 1-P1 and 1-P2	26
2	102
		3	179
4	79

And (4) conclusion: the compound disclosed by the invention has better inhibitory activity on GR receptor transcription in MDA-kb2 cells.

Test example 2: MDA-MB-231 cell proliferation assay

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on MDA-MB-231 cell proliferation in vitro, and the experimental methods are briefly described below:

MDA-MB-231 cells (ATCC, HTB-26) were cultured with complete medium, namely Leibovitz's L-15 medium (ThermoFisher, 11415-114) containing 10% fetal bovine serum (Gibco, 10099-141). The first day of experiment, MDA-MB-231 cells were seeded at a density of 1000 cells/well in 96-well 3D cell culture plates (Corning, CLS7007-24EA) using Leibovitz' S L-15 incomplete medium containing 10% charcoal-treated fetal bovine serum (BioSun, S-FBS-AU-045), 120. mu.L of cell suspension per well, and the well plates were left to stand at 37 ℃ after centrifugation for 3 minutes at 2000 rpm in a centrifuge, without CO ₂ The cell culture box was incubated overnight. The following day, 15 μ L of test compound diluted in a gradient of incomplete medium was added to each well, the final concentration of compound being 9 concentration points with a 3-fold gradient dilution from 10 μ M start. Then 15. mu.L dexamethasone (MCE, HY-14648) was added to each well to a final concentration of 0.1. mu.M. Wells containing only 0.5% DMSO were set as negative controls, and wells containing 0.1 μ M dexamethasone were set as positive controls. The pore plate is placed at 37 ℃ without CO ₂ The cell culture box is cultured for 8 days. After 8 days, the 96-well 3D cell culture plates were removed and 50. mu.L of CellTiter-

3DCell visual Assay (Promega, G9683), shaking the shaker for 25 minutes in the dark, transferring 100. mu.L of the solution per well to a 96-well opaque white plate (PerkinElmer, 6005290), and reading the luminescence signal using a multifunctional microplate reader VICTOR 3 (PerkinElmer). By using the respective concentrations and anions of the compoundsThe inhibition was calculated from the luminescence values of the positive control and the positive control wells. IC of the compound for inhibiting MDA-MB-231 cell proliferation activity was calculated using GraphPad Prism software based on the concentration of the compound and the corresponding inhibition ₅₀ The value is obtained.

TABLE 2 inhibition of MDA-MB-231 cell proliferation by compounds of the present disclosure in vitro

Example numbering	IC ₅₀ (nM)
		Compounds corresponding to longer retention times in 1-P1 and 1-P2	54
4	125

And (4) conclusion: the compound disclosed by the invention has a better inhibiting effect on MDA-MB-231 cell proliferation in vitro.

Claims

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

wherein:

is absent or a chemical bond;

L ¹ and L ² Are the same or different and are each independently selected from the group consisting of a bond, an oxygen atom, a sulfur atom, -S (O) -, -S (O) ₂ -, -C (O) -, -C (O) O-, -C (O) NH-, alkylene, and heteroalkylene;

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

ring B is aryl or heteroaryl;

ring C is aryl or heteroaryl;

R ⁶ the same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

R ^5a 、R ^5b 、R ⁷ and R ⁸ The same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

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

or R ⁷ And R ⁸ Together with the nitrogen atom to which they are attached form a heterocyclic group, which is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, 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

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

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^4a And R ^4b Are the same or different and are each independently C _1-6 Alkyl, or R ^4a And R ^4b Fused to the carbon atom to which it is attached to form a 3 to 6 membered cycloalkyl group.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L ¹ is-C (O) -, and L ² is-S (O) ₂ -。

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 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 ～R ³ M, n and t are as defined in claim 1.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2):

wherein:

ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in claim 1.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring B is a 6-to 10-membered aryl group or a 5-to 10-membered heteroaryl group; preferably, ring B is pyridyl.

7. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring C is phenyl.

8. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3,6 to 7, which is a compound represented by the general formula (IV), the general formula (IV-1) or the general formula (IV-2) or a pharmaceutically acceptable salt thereof:

wherein:

ring A, R ¹ ～R ³ M, n and t are as defined in claim 1.

9. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3,6 to 7, 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 ～R ³ M, n and t are as defined in claim 1.

10. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein ring a is selected from 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein each R ² Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _1-6 A haloalkoxy group.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein each R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group.

14. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein m is 0, 1 or 2.

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

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein t is 0, 1 or 2.

17. A compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

18. a compound represented by the general formula (IA) or a salt thereof,

wherein:

R ^4a 、R ^4b 、L ¹ ring B, ring C, R ² 、R ³ N and t are as defined in claim 1.

19. A compound or salt thereof according to claim 18, selected from the following compounds:

20. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the steps of:

reacting a compound represented by the general formula (IA) or a salt thereof with a compound represented by the general formula (V) to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

X is halogen; preferably, X is a chlorine atom;

R ^4a 、R ^4b 、L ¹ ring A, ring B, ring C, R ¹ ～R ³ M, n and t are as defined in claim 1.

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

22. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 21 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition by modulation of GR.

23. Use of a compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 for the preparation of a medicament for the treatment and/or prevention of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, ocular diseases and neurodegenerative diseases; preferably for the manufacture of a medicament for the treatment and/or prevention of a disease 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, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, diseases related to adrenal function, human immunodeficiency virus, acquired immunodeficiency syndrome, immunomodulation, allergy, wound healing, compulsive behavior, addiction, psychosis, anorexia, cachexia, mild cognitive impairment, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders, delirium, chronic pain, neuropathy of prematurity, and migraine; more preferably for the manufacture of a medicament for the treatment and/or prevention of a cancer selected from the group consisting of breast cancer, prostate cancer, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, endometrial cancer, liver cancer, lung cancer, leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma and ovarian cancer; most preferably for the manufacture of a medicament for the treatment and/or prevention of a cancer selected from the group consisting of breast cancer, prostate cancer, cushing's syndrome, adrenocortical carcinoma, fallopian tube carcinoma, pancreatic cancer, peritoneal carcinoma and ovarian cancer.