CN115232131A

CN115232131A - Nitrogen-containing heterocyclic compound, preparation method and medical application thereof

Info

Publication number: CN115232131A
Application number: CN202210428960.2A
Authority: CN
Inventors: 陈敬金; 姜治涛; 张军龙; 宋明娟; 徐铭键; 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: 2021-04-23
Filing date: 2022-04-22
Publication date: 2022-10-25

Abstract

The disclosure relates toAnd nitrogen-containing heterocyclic compounds, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to nitrogen-containing heterocyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds as therapeutic agents, especially application of the compounds as BET inhibitors and application of the compounds in preparation of drugs for treating and/or preventing BET-mediated or dependent diseases or symptoms.

Description

Nitrogen-containing heterocyclic compound, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to a nitrogen-containing heterocyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a therapeutic agent, in particular an application of the compound as a BET inhibitor and an application of the compound in preparation of a medicament for treating and/or preventing BET mediated or dependent diseases or symptoms.

Background

Bromodomain and extra-terminal domain (BET) family proteins are a widely expressed epigenetic reader, including ubiquitously expressed BRD2, BRD3, BRD4, and BRDT expressed only in germ cells. The BET family of proteins each contain two bromodomains (BD 1 and BD 2) in tandem with a highly homologous ET domain, BRD4 also having a specific C-terminal domain.

BET proteins are mainly distributed in the vicinity of histone acetylation sites on chromatin, recognize and bind acetylated lysine on histone by using BD1 and BD2 domains, and recruit other proteins such as transcription factors to promoters and enhancers as skeleton proteins, thereby playing an important role in normal development and diseases such as tumor, inflammation, and viral infection. BRD4 recruits a transcriptional elongation factor b (P-TEFb) primarily through the C-terminal domain. The P-TEFb protein can interact with cell cycle dependent protein kinase 9 (CDK 9), increase the transcription activity of RNA polymerase II through phosphorylation and activate the expression of downstream genes. BRD2, BRD3 and BRDT play a role in transcriptional regulation mainly by recruiting other transcriptional activators such as HDAC, GATA1 and the like through the ET domain.

The primary physiological functions of BET proteins are to regulate the cell cycle, inflammatory response, and maintain high-order chromatin structure. Knockout of the BRD2 and BRD4 genes resulted in early embryonic death of the mice. Adult mice develop epidermal hyperplasia, hair loss, decreased small intestinal cell diversity and decreased stem cells after BRD4 knockdown.

BET family proteins are closely related to tumors, and some important protooncogenes such as MYC, BCL2 and CDK6 are all regulated and controlled by the BET proteins. Research shows that the BET inhibitor can reduce the expression of protooncogene and has obvious effect of inhibiting tumor growth.

The first generation BET inhibitors have the same affinity for the BD1 and BD2 domains, limiting their clinical applications due to side effects and short duration of clinical response. The selective BET inhibitors show good efficacy and low toxicity in preclinical studies, and are becoming a new direction of development. Such as the selective BD2 inhibitor ABBV-744, is currently in clinical use for the treatment of Myelofibrosis (MF) at stage 1. Preclinical data show that ABBV-744 is mainly effective in Acute Myeloid Leukemia (AML) and androgen receptor positive prostate cancer cells, while normal small intestine cells are not affected. ABBV-744 significantly inhibited tumor growth at lower doses in the enzalutamide sensitive and resistant tumor model (ACS Chem Biol,2015,10 (8): 1770-1777 nat Rev cancer,2012,12 (7): 465-77 Nature,2020,578 (7794): 306-310.

It is an object of the present disclosure to provide a class of selective BD2 inhibitors for use in therapy targeting malignancies.

Patent applications for BET inhibitors that have been disclosed include WO2017177955A1 and

WO2015058160A1。

disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

x is a nitrogen atom or CR ⁵ ；

R ⁵ Selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, and hydroxyalkyl groups;

G ⁴ is a nitrogen atom or CR ^6a ；

G ¹ 、G ² And G ³ Are the same or different and are each independently a nitrogen atom or CR ⁶ ；

R ^6a And R ⁶ Identical or different, each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ Hydroxy and

l is selected from covalent bond, oxygen atom, sulfur atom, (CH) ₂ ) _r And NH;

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ^x The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxy, hydroxyalkyl, -NR ⁷ R ⁸ 、-C(O)R ⁹ 、-C(O)OR ⁹ 、-C(O)NR ⁷ R ⁸ 、-S(O) _t R ⁷ R ⁸ and-S (O) _t NR ⁷ R ⁸ ；

R ¹ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, and hydroxyalkyl groups;

R ² selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ Hydroxy, -C (O) R ⁹ 、-C(O)OR ⁹ 、-C(O)NR ⁷ R ⁸ 、-S(O) _t R ⁷ R ⁸ 、-S(O) _t NR ⁷ R ⁸ 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 ¹⁰ R ¹¹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ³ and R ⁴ The same or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ¹⁰ R ¹¹ Nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ³ And R ⁴ Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, wherein each of said cycloalkyl or heterocyclyl groups is independently optionally substituted by a group selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ¹⁰ R ¹¹ Nitro, hydroxy and hydroxyalkyl;

R ⁷ 、R ⁸ 、R ¹⁰ and R ¹¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl groupAlkyl, cycloalkyl and heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; or R ⁷ And R ⁸ 、R ¹⁰ And R ¹¹ 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;

R ⁹ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

r is 0, 1,2,3,4, 5 or 6;

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

t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein G ⁴ Is CR ^6a And R is ^6a Is composed of

L, ring A, R ^x And n is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is an oxygen atom.

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

wherein:

x, ring A, G ¹ To G ³ 、R ¹ To R ⁴ 、R ^x And n is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, cyano, -NR ⁷ R ⁸ Hydroxy and-C (O) NR ⁷ R ⁸ ，R ⁷ And R ⁸ As defined in formula (I); preferably, R ² is-C (O) NR ⁷ R ⁸ ，R ⁷ And R ⁸ As defined in formula (I); more preferably, R ² is-C (O) NR ⁷ R ⁸ ；R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; further preferably, R ² is-C (O) NR ⁷ R ⁸ ；R ⁷ And R ⁸ One of them is a hydrogen atom and the other is C _1-6 An alkyl group; most preferably, R ² is-C (O) NR ⁷ R ⁸ ；R ⁷ And R ⁸ One of which is a hydrogen atom and the other is an ethyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein G ¹ 、G ² And G ³ Are all CR ⁶ (ii) a And R is ⁶ Is a hydrogen atom.

In some preferred 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 (III) or a pharmaceutically acceptable salt thereof:

wherein:

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ^x And n is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, ring a is phenyl or pyridyl; more preferably, ring a is phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom or CR ⁵ (ii) a And R is ⁵ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ¹ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ¹ Is C _1-6 An alkyl group; more preferably, R ¹ Is methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ³ And R ⁴ Same or different, each independently selected from hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ³ And R ⁴ Are all C _1-6 An alkyl group; more preferably, R ³ And R ⁴ Are all methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is ^x 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, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 A hydroxyalkyl group; preferably, each R ^x 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 and C _1-6 A hydroxyalkyl group; more preferably, each R ^x Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is ^x Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 A hydroxyalkyl group; and n is 0, 1,2 or 3; preferably, each R ^x Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; and n is 1,2 or 3; more preferably, each R ^x Are identical or different and are each independently halogen or C _1-6 An alkyl group; and n is 3; most preferably, each R ^x Identical or different and are each independently a fluorine atom or a methyl group; and n is 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein R is ⁷ And R ⁸ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, wherein said C is _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy; preferably, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; more preferably, R ⁷ And R ⁸ One of which is a hydrogen atom and the other is C _1-6 An alkyl group; most preferably, R ⁷ And R ⁸ One of which is a hydrogen atom and the other is a methyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein n is 1,2 or 3; preferably, n is 3.

In some preferred embodiments of the present disclosure, the compound represented by the formula (III)Or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom or CR ⁵ (ii) a And R is ⁵ Is a hydrogen atom; ring A is phenyl; r ¹ Is C _1-6 An alkyl group; r ³ And R ⁴ Are all C _1-6 An alkyl group; r ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; each R is ^x 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 and C _1-6 A hydroxyalkyl group; n is 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom or CR ⁵ (ii) a And R is ⁵ Is a hydrogen atom; ring A is phenyl; r ¹ Is methyl; r ³ And R ⁴ Are all methyl; r ⁷ And R ⁸ One of them is a hydrogen atom and the other is C _1-6 An alkyl group; each R is ^x Are identical or different and are each independently halogen or C _1-6 An alkyl group; and n is 3.

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

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

wherein:

R ^y selected from hydroxy, C _1-6 Alkoxy and halogen; preferably, R ^y Is C _1-6 An alkoxy group;

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ^x And n is as defined in formula (III).

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

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

a compound represented by the general formula (IIIa) or a salt thereof and a compound NHR ⁷ R ⁸ Or salts thereof to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salts thereof;

wherein:

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ^x And n is as defined in formula (III).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III) 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), formula (III) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for the inhibition of BET.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting BD1 and/or BD2, preferably for inhibiting BD 2.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of a disease or condition selected from the group consisting of a tumor, a cardiovascular disease, an inflammatory disease, an autoimmune disease, a renal disease, a viral infection and a neurological disease.

The disclosure also relates to a method of inhibiting BET comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of inhibiting BD1 and/or BD2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of inhibiting BD2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing a disease or condition selected from the group consisting of tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, kidney diseases, viral infections, and neurological diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to compounds of formula (I), formula (II), formula (III) 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), formula (III) and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as BET inhibitors.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as BD1 and/or BD2 inhibitors.

The disclosure further relates to compounds of formula (I), formula (II), formula (III) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as BD2 inhibitors.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III) and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of a disease or condition selected from the group consisting of a tumor, a cardiovascular disease, an inflammatory disease, an autoimmune disease, a renal disease, a viral infection and a neurological disease.

A disease or condition described in the present disclosure is a disease or condition mediated by BET, preferably a disease or condition mediated by BD1 and/or BD2, more preferably a disease or condition mediated by BD 2.

The disease or condition described in the present disclosure is preferably selected from: <xnotran> , , , , , , , , (COPD), , , , ( ), , , , , , ( ), , , , , , , , , , , , , , , , , , I , , , , , , , (AIDS), , , , , , , II , , , , , , , , , , , , , HIV , , igA , , ; </xnotran> The inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.

Wherein said cancer is preferably selected from: prostate cancer (e.g., hormone-insensitive prostate cancer), acute leukemia (e.g., acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia), myelogenous leukemia, myelofibrosis, erythroleukemia, acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, embryonic carcinoma, endometrial carcinoma, endothelial sarcoma (e.g., lymphatic endotheliosarcoma, ependymoma, epithelial carcinoma, esophageal carcinoma, ewing's tumor, fibrosarcoma, follicular lymphoma germ cell testicular cancer, gliomas (such as glioblastoma, gliosarcoma, and oligodendroglioma), heavy chain disease, hemangioblastoma, liver cancer, leiomyosarcoma, liposarcoma, lung cancer (such as non-small cell lung cancer (such as lung adenocarcinoma and lung squamous carcinoma) and small cell lung cancer), lymphangiosarcoma, hodgkin's lymphoma, non-hodgkin's lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma, bone carcinoma, nasopharyngeal carcinoma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, thyroid cancer, pineal tumor, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sebaceous carcinoma, seminoma, neuroblastoma, skin cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, waldenstrom's macroglobulinemia, and wilms' tumor; more preferably, the cancer is selected from the group consisting of prostate cancer, acute myeloid leukemia, and myelofibrosis; the myeloma is preferably multiple myeloma.

The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may 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.

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 from 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: 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.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. 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 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 or mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, 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, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of 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 solution and microemulsion 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 used to prepare injections.

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

As is well known to those skilled in the art, the dosage of the drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal 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, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group containing 1 to 12 (e.g., 1,2,3,4, 5,6,7, 8, 9, 10, 11, and 12) carbon atoms _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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 3638-zxft 3724-dimethylpentyl, 4924-pentyl, 4924-dimethylpentyl, 4924-dimethylbutyl, 3-methylbutyl, 3282-methylbutyl, and mixtures thereofFurther, the term "alkyl" refers to a group selected from the group consisting of alkyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl 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 a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1,2,3,4, 5,6,7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -), 1,1-ethylene (-CH (CH) ₃ ) -), 1,2-ethylene (-CH) ₂ CH ₂ ) -, 1,1-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-butylidene (-CH) ₂ CH ₂ CH ₂ CH ₂ -) and the like. Alkylene groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any available point of attachment, preferably the substituents are independently optionally one or more substituents selected from 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 "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3,4, 5,6,7, 8, 9, 10, 11 and 12, carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 2 to 12 (e.g., 2,3,4, 5,6,7, 8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from one or more of alkoxy, halogen, 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 containing 3 to 20 carbon atoms (i.e., 3 to 20 membered cycloalkyl), preferably 3 to 12 (e.g., 3,4, 5,6,7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds (i.e., a 5 to 20 membered spirocycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, according to the number of spiro atoms shared between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused cyclic alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. They may be classified into polycyclic fused alkyl groups such as bicyclic, tricyclic, tetracyclic, etc., according to the number of constituent rings, preferably bicyclic or tricyclic, 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 bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 membered bridged cycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, and preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

said cycloalkyl ring includes a cycloalkyl (including monocycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged ring alkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl

Tetrahydronaphthyl

And benzocycloheptalkyl

Etc.; indanyl is preferred

And tetrahydronaphthyl

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, heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted and when substituted are preferably 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 "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e., a 3 to 20 membered heterocyclyl) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include a cyclic portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5,6,7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3,4, 5,6,7 and 8), wherein 1-3 is a heteroatom (e.g., 1,2 and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1-3 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 (i.e., 5 to 20 membered heterocyclyl) 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., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 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 double-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a double-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 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 group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members (i.e., a 5 to 20 member fused heterocyclyl group), each ring in the system sharing an adjacent pair of atoms with the other rings in the system, 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), but does not include the ring portion of-O-, -O-S-, or-S-, and the remaining ring atoms are carbon. Preferably 6 to 14 membered (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic, and other polycyclic fused heterocyclic groups according to the number of constituent rings, and are preferably bicyclic or tricyclic, 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 heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 14 membered bridged heterocyclyl), 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), but does not include the ring portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably 6 to 14 (i.e. 6 to 14 bridged heterocyclyl) and more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 bridged heterocyclyl). They may be classified into polycyclic bridged heterocyclic groups such as bicyclic, tricyclic, tetracyclic, etc., depending on the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

and so on.

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 all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably 6 to 10 membered (e.g., 6,7, 8, 9 or 10 membered) (i.e., 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, heteroaryl.

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

heteroaryl groups may be substituted or unsubstituted, and when substituted, 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, heteroaryl.

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

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsiloxy) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), acetyl, 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 derivative of a hydroxyl group that is commonly used to block or protect the hydroxyl group while the reaction is carried out on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, 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 "aryloxy" refers to aryl-O-wherein aryl is as defined above.

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

The term "alkylthio" refers to an alkyl-S-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.

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 made of

Or

Or at the same timeIncluded

And

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

The configuration is not specified, i.e., either Z or E or both are contemplated.

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: such as keto-enol tautomerism, imine-enamine tautomerism, lactam-lactam tautomerism, 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 at least one atomA compound substituted with 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, etc., 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 for each 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 per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium 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 for each 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" 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 a pharmaceutically acceptable salt or prodrug thereof, in admixture with 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" 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 compound, 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 recipient 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 tests.

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 following technical solutions are adopted in the present disclosure:

scheme one

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

a compound represented by the general formula (IIIa) or a salt thereof and a compound NHR ⁷ R ⁸ Or salts thereof react under heating to obtain a compound shown in a general formula (III) or pharmaceutically acceptable salts thereof;

wherein:

In the above synthesis scheme, the reaction temperature is 50-100 ℃, preferably 60-70 ℃.

The above synthetic schemes are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below 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 (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using Bruker AVANCE NEO 400M in 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 1290-6125 single quadrupole (ESI) mass spectrometer.

High Performance Liquid Chromatography (HPLC) analysis used an Agilent 1290DAD high pressure liquid chromatograph and a Thermo U3000 high pressure liquid chromatograph (Waters Sunfire C18.6X 75mm,3.5 μm column).

The thin layer chromatography Silica Gel plate is HPTLC Silica Gel 60GF254 or PLC Silica Gel 60GF254 Silica Gel plate of Shanghai hong biological medicine science and technology Limited company, the specification of the Silica Gel plate used by the Thin Layer Chromatography (TLC) is 0.2 mm-0.25 mm, and the specification of the thin layer chromatography separation and purification product is 0.9 mm-1.0 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel from Futai Huanghai silica gel as a carrier.

Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril 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 hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

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: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

N-Ethyl-7- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5-methyl-4-oxo-4,5-dihydropyrazolo [1,5-a ] pyrazine-2-carboxamide 1

First step of

2- (4- (4-fluoro-2,6-dimethylphenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol 1b

Compound 2- (3-bromo-4- (4-fluoro-2,6-dimethylphenoxy) phenyl) propan-2-ol 1a (4 g,11.4mmol, prepared using the method disclosed in patent application WO2017177955A1, page 95, example 35 c) and 1,4-dioxane (40 mL) were added to a reaction flask, stirred uniformly, pinacol diborate (4.3g, 17mmol, shanghai meier chemical limited), [1,1' -bis (diphenylphosphine) ferrocene ] palladium (0.8g, 1.1mmol, sienna kelim new material limited) and potassium acetate (3.2g, 32.6mmol) were added to the reaction system, nitrogen was replaced three times, the reaction was warmed to 95 ℃ for 4 hours, allowed to cool naturally to room temperature, filtered, dioxane was washed, the filtrate was concentrated, the cake was purified by silica gel column chromatography to give the title compound 1a (1.54 g, 2.54% yield).

MS m/z(ESI):383.2.2[M-17]。

Second step of

5- ((2,2-Dimethoxyethyl) (methyl) aminocarbonyl) -1H-pyrazole-3-carboxylic acid ethyl ester 1c

Tetrahydrofuran (150 mL) was added to a reaction flask, the temperature was reduced to 0. + -. 5 ℃ and trimethylaluminum (70 mL) was added dropwise to the reaction system, after completion of the addition, 2,2-dimethoxy-N-methylethane-1-amine (17g, 0.14mol, shanghai Han hong chemical science Co., ltd.) was added dropwise, 1H-pyrazole-3,5-dicarboxylic acid diethyl ester (10g, 47.2mmol, lemo) was added dropwise, the reaction was stirred at room temperature for 12 hours, water (30 mL) was added and the reaction was quenched, ethyl acetate (100 mL) was added and extracted, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1c (10.2 g, yield: 75.8%).

MS m/z(ESI):285.9[M+1]。

The third step

7-hydroxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester 1d

Compound 1c (10.2 g,35.1 mmol), 3M hydrochloric acid (10.2 mL) and acetone (51 mL) were added to a reaction flask, dissolved with stirring, warmed to 50 ℃, reacted with stirring for 4 hours, naturally cooled to room temperature, adjusted to pH 7-8 with an aqueous solution of sodium carbonate, concentrated under reduced pressure, added with ethyl acetate (100 mL) for liquid separation, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 1d (1.7 g, yield: 20.3%).

MS m/z(ESI):240.1[M+1]。

The fourth step

5-methyl-4-oxo-4,5-dihydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester 1e

Compound 1d (2g, 8.4 mmol), p-methylphenylsulfonyl chloride (2.4 g,12.6mmol, michelin), 1,8-diazabicyclo [5.4.0] undec-7-ene (5.1g, 33.6mmol, shanghai Michelle chemical technology Co., ltd.) and methylene chloride (20 mL) were charged into a reaction flask, stirred at room temperature for reaction for 6 hours, quenched with water (50 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 1e (1.7 g, yield: 91.8%).

MS m/z(ESI):222.0[M+1]。

The fifth step

7-bromo-5-methyl-4-oxo-4,5-dihydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester 1f

Compound 1e (1g, 4.5 mmol) was added to N, N-dimethylformamide (6 mL), and replaced with nitrogen three times; n-bromosuccinimide (0.81g, 4.5mmol, ramule) dissolved in N, N-dimethylformamide (4 mL) was added dropwise to the above reaction system, the reaction was stirred for 30 minutes, a saturated sodium bicarbonate solution (40 mL) and dichloromethane (20 mL) were added to separate the solution, dichloromethane (30 mL) was added to extract the aqueous phase, the organic phases were combined, the organic phase was successively washed with water (100 mL. Times.4), saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1f (1.1 g, yield: 78.57%).

MS m/z(ESI):300.0[M+1]。

The sixth step

7- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -5-methyl-4-oxo-4,5-dihydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester 1g

Compound 1f (1g, 3.3mmol), compound 1b (1.6g, 4.0mmol), tetrakis (triphenylphosphine) palladium (0.4g, 0.33mmol, rake), and potassium carbonate (1.4g, 9.9mmol) were added to 1,4-dioxane (10 mL) and water (1.5 mL), nitrogen was replaced three times, the temperature was raised to 85 ℃ for reaction for 5 hours, natural cooling was performed to room temperature, filtration was performed, the filter cake was washed with 1,4-dioxane, the filtrates were combined, after the filtrate was concentrated under reduced pressure, water (20 mL) and ethyl acetate (20 mL) were added for separation, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure to give the title product 1g (1.5 g, yield: 91.46%).

MS m/z(ESI):476.1[M-17]。

Seventh step

Compound 1g (0.15g, 0.3mmol) was added to 70% aqueous ethylamine (5 mL), warmed to 65 ℃ for half an hour for reaction, cooled to room temperature, ethylamine was removed under reduced pressure, water (5 mL) was added, pH was adjusted to 5 with 3M hydrochloric acid, ethyl acetate (20 mL × 2) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography with eluent system a to give the title compound 1 (28 mg, yield: 18.67%).

MS m/z(ESI):475.1[M-17]。

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.09(m,1H),7.62(d,1H),7.48-7.46(m,1H),7.44(s,1H),7.41(s,1H),6.97(d,2H),6.30(d,1H),3.53(s,3H),3.29-3.22(m,2H),2.02(s,6H),1.46(s,6H),1.09-1.06(m,3H)。

Example 2

N-Ethyl-4- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -2-methyl-1-oxo-1,2-dihydropyrrolo [1,2-a ] pyrazine-7-carboxamide 2

First step of

2-cyano-N- (2,2-dimethoxyethyl) -N-methylacetamide 2a

Dissolving 2M trimethylaluminum (150mL, 300mmol) in dry tetrahydrofuran (250 mL), replacing with nitrogen three times, cooling to 0 ℃, dropwise adding the compound 2,2-dimethoxy-N-methylethan-1-amine (35g, 292.6mmol, an Naiji) into the reaction system, dropwise adding the compound 2-cyanomethyl acetate (10g, 100.9mmol) into the reaction system, dropwise adding, removing the ice bath, reacting for 16 to 18 hours, adding water (50 mL), quenching, adding ethyl acetate (100 mL), separating, extracting the aqueous phase with ethyl acetate (300 mL × 2), combining the organic phases, washing with saturated brine as eluent, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography with system B to obtain the title compound 2a (13 g, yield: 70.0%).

MS m/z(ESI):187.0[M+1]。

Second step of

5- ((2,2-Dimethoxyethyl) (methyl) aminocarbonyl) -1H-pyrrole-3-carboxylic acid ethyl ester 2b

Compound 2a (13g, 0.091mol), ethyl propiolate (6.9g, 70.4mmol, lesinum), 1,10-phenanthroline (5.0g, 27.7mmol, maireil) were added to 1,4-dioxane (130 mL), heated to 100 ℃, reacted for 2 hours, naturally cooled to room temperature, the solvent was removed under reduced pressure, then a saturated ammonium chloride solution (500 mL) was added, extracted with ethyl acetate (500 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified with silica gel column chromatography with eluent system a to give the title compound 2b (15 g, yield: 75.3%).

MS m/z(ESI):284.9[M+1]。

The third step

4-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo [1,2-a ] pyrazine-7-carboxylic acid ethyl ester 2c

Compound 2B (15g, 0.053 mol), 3M hydrochloric acid (20 mL) was added to acetone (150 mL), stirred well, warmed to 50 ℃ for reaction for 2.5 hours, naturally cooled to room temperature, the solvent was removed under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (500 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 2c (3 g, 23.7% yield).

MS m/z(ESI):239.2[M+1]。

The fourth step

2-methyl-1-oxo-1,2-dihydropyrrolo [1,2-a ] pyrazine-7-carboxylic acid ethyl ester 2d

Compound 2c (0.9 g, 3.8mmol), p-toluenesulfonyl chloride (1.1g, 5.78mmol, meclin) were added to dichloromethane (15 mL), 1,8-diazabicyclo-bicyclo (5,4,0) -7-undecene (2.29g, 15mmol) were slowly added dropwise, after stirring for reaction for 3 hours, water (15 mL) was added, dichloromethane (30 mL) was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 2d (0.6 g, yield: 71.0%).

MS m/z(ESI):221.1[M+1]。

The fifth step

4-bromo-2-methyl-1-oxo-1,2-dihydropyrrolo [1,2-a ] pyrazine-7-carboxylic acid ethyl ester 2e

Compound 2d (0.6 g,2.7 mmol), N-bromosuccinimide (0.48g, 2.7mmol, ramule) was added to methylene chloride (6 mL), reacted for 1 hour, and purified by thin layer chromatography using developer system B to give the title compound 2e (40 mg, yield: 4.9%).

MS m/z(ESI):299.0[M+1]。

The sixth step

4- (2- (4-fluoro-2,6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) phenyl) -2-methyl-1-oxo-1,2-dihydropyrrolo [1,2-a ] pyrazine-7-carboxylic acid ethyl ester 2f

Compound 2e (160mg, 0.54mmol), compound 1b (195mg, 0.65mmol), potassium carbonate (180mg, 1.62mmol) and tetrakis (triphenylphosphine) palladium (0.05g, 0.054mmol) were added to 1,4-dioxane (150 mL), water (20 mL) was added, nitrogen was replaced three times, the reaction was warmed to 85 ℃ for 18 hours, cooled naturally to room temperature, water (15 mL) was added for liquid separation, the aqueous phase was extracted with dichloromethane (70 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give crude title product 2f (230 mg), which was used in the next reaction without purification.

MS m/z(ESI):493.2[M+1]。

Seventh step

Compound 2f (65mg, 0.13mmol) was added to 70% aqueous ethylamine (7 mL), allowed to warm to 60 ℃ for reaction for 24 hours, naturally cooled to room temperature, the solvent was removed under reduced pressure, water was added, extraction was performed with ethyl acetate, washing was performed twice with water, washing was performed with saturated brine, drying was performed with anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and purification was performed by thin layer chromatography using developer system B to give the title compound 2 (22 mg, yield: 34.5%).

MS m/z(ESI):474.2[M-17]。

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.22(m,1H),7.62(d,1H),7.61(m,1H),7.52(s,1H),7.43(s,1H),7.08(s,1H),7.00(d,2H),6.40(d,1H),3.20(s,2H),3.45(s,3H),1.99(s,6H),1.46(s,6H),1.07(m,3H)。

Biological evaluation

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

Test example 1: BRD4 BD1 or BD2 binding inhibition assay

1. Purpose of experiment

Binding of the BD1 or BD2 domain of BRD4 to a substrate using HTRF, IC based on inhibition of binding by the compound ₅₀ The selectivity to BD1 or BD2 was evaluated.

2. Experimental methods

BRD4 BD1 (Pan superbio, prokaryotic expression) or BRD4 BD2 protein (Pan superbio, prokaryotic expression) and compounds were diluted with binding buffer (Cisbio, 62 DLBDDF), 384-well assay plates (Corning, 4513) were added, vortexed (Lin Beier, MH-I from Haimen, inc., L-530) and centrifuged at 1000rpm for 1 min, and incubated in a 25-degree incubator (Shanghai Macro laboratory facilities, inc., DMP-9052) for 30 min.

The substrate (BET Bromodomain Ligand, gill Biochemical Synthesis) was diluted with binding buffer, added to the incubated assay plate, vortexed and centrifuged at 1000rpm for 1 min. Eu anti-GST antibody (Cisbio, 61HI2 KLA) and APC-conjugated streptavidin (Cisbio, 611 SAXLA) were diluted with detection buffer (Cisbio, #62DB1 FDG), added to the incubated detection plates, shaken, mixed well, centrifuged at 1000rpm for 1 min, and incubated at 25 ℃ overnight.

After the incubation, the incubation was performed in a microplate reader (BMG, PHERAStar FS)

The reader block reads 665/620nm signals. Data were processed analytically using Graphpad Prism 6.

The inhibitory effect of the disclosed compounds on BRD4 BD1 or BD2 is shown in table 1.

Table 1 inhibitory effect of the disclosed compounds on BRD4 BD1 or BD 2.

And (4) conclusion: the compounds of the present disclosure have selective inhibitory effects on BRD4 BD 2.

Test example 2: cell proliferation inhibition assay

1. Purpose of the experiment

Testing the ability of a compound to inhibit proliferation of LNCap or MV-4-11 cells according to IC ₅₀ The activity of the compounds was evaluated.

2. Experimental methods

LNcap (ATCC, CRL-1740) or MV-4-11 (ATCC, CRL-9591) cells were digested with 0.25% pancreatin (Invitrogen, 25200-072) and counted. Cells were resuspended in RPMI-1640 (Gibco, 11875119) or IMDM (Gibco, 12440061) containing 10% fetal bovine serum (Gibco, 10099-141), respectively. Putting 2000 cells per well into a 96-well plate (Corning, 3903), incubating at 37 ℃ and 5% CO ₂ In an incubator (thermo scientific, HERAcell 240 i). After 24 hours of incubation, the compounds were added in a gradient, incubated at 37 ℃ and 5% CO ₂ Culturing in an incubator for 3 days. The plates were removed, cellTiter-Glo (Promega, G7573) was added, incubated for 10 min at room temperature in the dark, white background sticker (PE, 6005199) was applied to the bottom, and the cold light signal was read with microplate reader (BMG, PHERAstar FS). Data were analyzed using Graphpad Prism 6.

The inhibitory effect of the compounds of the present disclosure on LNCap or MV-4-11 cell proliferation is shown in table 2.

Table 2 inhibitory effect of compounds of the present disclosure on LNCap or MV-4-11 cell proliferation.

And (4) conclusion: the compounds of the present disclosure have inhibitory effects on LNCap and MV-4-11 cell proliferation.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

x is a nitrogen atom or CR ⁵ ；

G ⁴ is a nitrogen atom or CR ^6a ；

R ^6a And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ A hydroxyl group and

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ² selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxyHydroxyalkyl, cyano, -NR ⁷ R ⁸ Hydroxy, -C (O) R ⁹ 、-C(O)OR ⁹ 、-C(O)NR ⁷ R ⁸ 、-S(O) _t R ⁷ R ⁸ 、-S(O) _t NR ⁷ R ⁸ 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 ¹⁰ R ¹¹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ³ and R ⁴ The same or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ¹⁰ R ¹¹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ 、R ⁸ 、R ¹⁰ and R ¹¹ The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group; or R ⁷ And R ⁸ 、R ¹⁰ And R ¹¹ Together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group formed optionallySubstituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

r is 0, 1,2,3,4, 5 or 6;

n is 0, 1,2,3 or 4; and is

t is 0, 1 or 2.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein G ⁴ Is CR ^6a And R is ^6a Is composed of

L, ring A, R ^x And n is as defined in claim 1.

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

wherein:

x, ring A, G ¹ To G ³ 、R ¹ To R ⁴ 、R ^x And n is as defined in claim 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, cyano, -NR ⁷ R ⁸ A hydroxyl group and-C (O) NR ⁷ R ⁸ ；R ⁷ And R ⁸ As defined in claim 1.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein G ¹ 、G ² And G ³ Are all CR ⁶ (ii) a And R is ⁶ Is a hydrogen atom.

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

wherein:

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ^x And n is as defined in claim 1.

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 a is selected from a 3-to 8-membered cycloalkyl group, a 3-to 8-membered heterocyclic group, a 6-to 10-membered aryl group and a 5-to 10-membered heteroaryl group.

8. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein X is a nitrogen atom or CR ⁵ (ii) a And R is ⁵ Is a hydrogen atom.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group.

10. A compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereofIn R ³ And R ⁴ Are the same or different and are each independently selected from hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R ^x 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, C _1-6 Haloalkoxy, cyano, hydroxy and C _1-6 A hydroxyalkyl group.

12. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R ⁷ And R ⁸ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl, wherein said C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Haloalkoxy is substituted with one or more substituents.

13. A compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

14. a compound represented by the general formula (IIIa) or a salt thereof,

wherein:

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ^x And n is as defined in claim 6.

15. A compound or salt thereof according to claim 14, selected from the following compounds:

16. a process for preparing a compound of formula (III) according to claim 6, or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (IIIa) or a salt thereof and a compound NHR ⁷ R ⁸ Or salts thereof react to obtain a compound shown in a general formula (III) or pharmaceutically acceptable salts thereof;

wherein:

x, ring A, R ¹ 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ^x And n is as defined in claim 6.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for inhibiting BET.

19. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the inhibition of BD1 and/or BD2, preferably for the manufacture of a medicament for the inhibition of BD 2.

20. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition selected from a tumour, a cardiovascular disease, an inflammatory disease, an autoimmune disease, a renal disease, a viral infection and a neurological disease.

21. The use according to claim 20, wherein, wherein the disease or condition is selected from the group consisting of cancer, addison's disease, gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, chronic obstructive pulmonary disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, autoimmune hypophysitis, inflammatory bowel disease, kawasaki disease, multiple sclerosis, myositis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, primary thrombocytosis, polycythemia vera, wegener's granulomatosis, acquired immunodeficiency syndrome, obesity, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, interstitial steatosis, type II diabetes mellitus, insulin, interventional neuro-induced nephropathy, renal neuropathy, renal hypertension induced nephropathy, glomerulonephritis induced nephropathy, glomerulonephritis induced hypersensitivity, glomerulonephritis induced nephropathy, glomerulonephritis induced hypersensitivity diseases, glomerulonephritis induced nephropathy induced focal nephropathy, and glomerulonephritis induced nephropathy; the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.

22. The use according to claim 21, wherein the cancer is selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , , B- , , , , , , , , , , , , , , , , , , , , , T- B- , , , , , , , , , NUT , , , , , , , , , , , , , , , , , , , ; </xnotran> Preferably, the cancer is selected from prostate cancer, acute myeloid leukemia, and myelofibrosis; the myeloma is preferably multiple myeloma.