CN115232123A

CN115232123A - Nitrogen-containing heterocyclic compound, preparation method and medical application thereof

Info

Publication number: CN115232123A
Application number: CN202210428922.7A
Authority: CN
Inventors: 陈敬金; 姜治涛; 张军龙; 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 to nitrogen-containing heterocyclic compounds, a preparation method thereof and application thereof in medicine. In particular to a nitrogen-containing heterocyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a therapeutic agent, in particular to a BET inhibitorUse and use for the manufacture of a medicament for the treatment and/or prevention of a BET-mediated or dependent disease or condition.

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. 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.

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 distributed mainly 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 backbone 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 transcriptional regulatory role primarily through the ET domain, recruiting other transcriptional activators such as HDACs, GATA1, etc.

The primary physiological functions of BET proteins are to regulate the cell cycle, inflammatory responses and maintain high-order chromatin structure. BRD2 and BRD4 gene knock-outs result in early embryonic death of 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.

First generation BET inhibitors have the same affinity for the BD1 and BD2 domains, limiting their clinical utility due to side effects and short duration of clinical response. Selective BET inhibitors exhibit good pharmacological effects and low toxic effects in preclinical studies, and are becoming a new direction of development. Such as the selective BD2 inhibitor ABBV-744, is currently used clinically in stage 1 for the treatment of Myelofibrosis (MF). 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 targeted therapy of malignancies.

Patent applications for BET inhibitors that have been disclosed include US20150148372A1, 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:

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

R ² selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, 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 selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ A hydroxyl group and

l is selected from a covalent bond, an oxygen atom, a sulfur atom, and (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 ⁴ Selected from hydrogen atom, alkyl group,Haloalkyl and hydroxyalkyl radicals;

R ⁵ and R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ Nitro, hydroxy, 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 and hydroxyalkyl;

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, 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

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 R ³ Is composed of

And L, ring A, R ^x And n is as in formula (I)And (4) defining.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 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 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 represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):

wherein:

l, ring A, R ^x 、R ¹ 、R ⁴ To R ⁸ 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 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.

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond.

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 ⁵ 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:

R ^x 、R ¹ 、R ⁴ 、R ⁶ to R ⁸ 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 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 ⁴ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ⁴ Is C _1-6 An alkyl group; more preferably, R ⁴ 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 ⁶ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ⁶ Is C _1-6 A hydroxyalkyl group.

In some preferred implementations of the present disclosureIn the scheme, the compound shown in the general formula (I), the general formula (II) or the general formula (III) or pharmaceutically acceptable salt thereof is shown in the specification, 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 all hydrogen atoms.

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 them 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 an ethyl 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.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein n is 0.

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 isR ^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 identical or different and are each independently halogen or C _1-6 An alkyl group; and n is 0, 1,2 or 3; most preferably, n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, 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 Haloalkyl and C _1-6 A hydroxyalkyl group; r ¹ Is C _1-6 An alkyl group; r is ⁴ Is C _1-6 An alkyl group; r ⁶ Selected from hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; r is ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl 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 R ¹ Is C _1-6 An alkyl group; r ⁴ Is C _1-6 An alkyl group; r ⁶ Is C _1-6 A hydroxyalkyl group; r ⁷ And R ⁸ One of them is a hydrogen atom and the other is C _1-6 An alkyl group; and n is 0.

Table a typical 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 (I) or a pharmaceutically acceptable salt thereof, comprising:

carrying out Suzuki coupling reaction on the compound shown in the general formula (VI) or salt thereof and the compound shown in the general formula (Ia) or salt thereof to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

R ¹ to R ⁶ As defined in formula (I).

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

carrying out Suzuki coupling reaction on a compound shown in a general formula (VII) or a salt thereof and a compound shown in a general formula (IIa) or a salt thereof to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

l, ring A, R ^x 、R ¹ 、R ⁴ To R ⁸ And n is as defined in formula (II).

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:

carrying out Suzuki coupling reaction on the compound shown in the general formula (VII) or salt thereof and the compound shown in the general formula (IIIa) or salt thereof to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

R ^x 、R ¹ 、R ⁴ 、R ⁶ to R ⁸ 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 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 preparation of a medicament for inhibiting 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.

The diseases or disorders described in the present disclosure are diseases or disorders mediated by BET, preferably diseases or disorders mediated by BD1 and/or BD2, more preferably diseases or disorders mediated by BD 2.

The disease or condition described in the present disclosure is preferably selected from: cancer, addison's disease, gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, chronic Obstructive Pulmonary Disease (COPD), dermatitis, eczema, giant cell arteritis, glomerulonephritis (such as membranous glomerulonephritis), hepatitis, autoimmune hypophysitis, inflammatory bowel disease, kawasaki disease, multiple sclerosis, myositis (such as myocarditis), organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, haynaud's arteritis, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, primary thrombocytosis, polycythemia vera, wegener's granulomatosis, acquired Immune Deficiency Syndrome (AIDS), obesity, dyslipidemia, hypercholesterolemia, alzheimer's disease, interstitial metabolic syndrome, hepatic syndrome, hepatitis II, insulin intervention, insulin-induced nephropathy, kidney reperfusion induced nephropathy, kidney diseases induced nephropathy induced by percutaneous glomerulonephritis, glomerulonephritis induced nephropathy, reperfusion induced nephropathy of drugs, kidney diseases, kidney reperfusion induced nephropathy of renal macrosclerosis, kidney diseases induced nephropathy induced by renal glomerulonephritis, kidney diseases induced nephropathy induced by drugs, and reperfusion induced nephropathy induced by drugs; 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 the active compound 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, dragees, 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 the preparation of 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 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 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 an antioxidant.

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 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.

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 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 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). 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, and 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-heptylpropyl2-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-dimethylhexyl, 2, 3-dimethylpentyl, 2-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 23, 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 chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, 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-ethylene (-CH (CH) ₃ ) -), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) -), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) -), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ -) 1, 4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, 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 groups (i.e., C) containing 2 to 12 (e.g., 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 groups (i.e., C) 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 containing 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 of the following groups, independently selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl,One or more of heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4,5, 6,7, 8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 20 membered cycloalkyl), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), 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 monocyclic 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, preferably a single spirocycloalkyl group and a double spirocycloalkyl 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-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring 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 the other rings in the system, and in which one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused ring 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 an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 member bridged cycloalkyl). Preferably 6 to 14 (i.e. 6 to 14 bridged cycloalkyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 7 to 10 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:

the cycloalkyl ring includes a cycloalkyl ring (including monocycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) 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 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 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 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 mono-or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e. a 3 to 20 membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulphur, which sulphur 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. 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 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). 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 preferably 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 monospiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused heterocyclyl) polycyclic heterocyclic group in which each ring in the system shares 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., 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 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, etc. polycyclic fused heterocyclic groups according to the number of constituting 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 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 membered (i.e. 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged heterocyclyl). They may be divided 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 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 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, 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 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 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-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removing one hydrogen atom from the parent ring atom, or those derived by removing two hydrogen atoms from the parent ring atom or from 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 (trimethylsilyl) 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 the 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-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 this disclosure, a bond

Denotes an unspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond

Can be that

Or

Or at the same time contain

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 the Z configuration or the E configuration, or both configurations 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 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 (i.e., at least 15% incorporation of deuterium) than the natural abundance of deuterium (which is 0.015%). 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 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 for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% of 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 per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optionally" or "optionally" 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 ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. 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 physiologically/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 being used in the body of a mammal, 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 will vary from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one skilled in the art in the light of routine experimentation.

The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and/or dosage forms 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 method for preparing the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

R ¹ to R ⁶ As defined in formula (I).

Scheme two

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

carrying out Suzuki coupling reaction on the compound shown in the general formula (VII) or salt thereof and the compound shown in the general formula (IIa) or salt thereof to obtain a compound shown in the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

l, ring A, R ^x 、R ¹ 、R ⁴ To R ⁸ And n is as defined in formula (II).

Scheme three

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

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

R ^x 、R ¹ 、R ⁴ 、R ⁶ to R ⁸ And n is as defined in formula (III).

In the above synthesis schemes, the Suzuki coupling reaction is preferably carried out in the presence of a base and a metal catalyst.

Wherein the metal catalyst comprises a metal palladium complex catalyst or a combination of a palladium-containing catalyst and a ligand. The metal palladium complex catalyst includes, but is not limited to, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, 1' -bis (dibenzylideneacetone) dichloropalladium, and tris (dibenzylideneacetone) dipalladium; tetrakis (triphenylphosphine) palladium is preferred. Such palladium-containing catalysts include, but are not limited to, palladium on carbon, palladium dichloride, and palladium acetate; the ligand includes but is not limited to triphenyl phosphine, tricyclohexyl phosphine, tri-n-butyl phosphine and trimethoxy phosphine.

Wherein the base includes organic bases and inorganic bases, said organic bases including but not limited to Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), N-butyllithium, t-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI), potassium bis (trimethylsilanyl) amide (KHMDS), and potassium t-butoxide; the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, and cesium carbonate, preferably potassium carbonate.

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 a mixture thereof.

Detailed Description

The following examples are presented to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

Examples

The structure of the compound being by Nuclear Magnetic Resonance (NMR) or/andmass 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 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 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, room temperature and is 20 ℃ to 30 ℃.

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, acetic acid and the like can be added for adjustment.

Example 1

N-ethyl-4- (6- (2-hydroxypropan-2-yl) -1-methyl-2-phenyl-1H-benzo [ d ] imidazol-4-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide 1

First step of

3-bromo-5- (methylamino) -4-nitrobenzoic acid methyl ester 1b

The compound methyl 3-bromo-5-fluoro-4-nitrobenzoate 1a (20g, 0.072mol, prepared as disclosed in example 15, step b, page 35 of the specification in patent application WO2009024615A 1), N, N-diisopropylethylamine (66.5g, 0.51mol, michelle) was added to dimethylacetamide (200 mL) and the temperature was reduced to below 10 ℃. Methylamine hydrochloride (14.7g, 0.22mol) was added to the reaction mixture and reacted for 21 to 23 hours, then water (600 mL) and petroleum ether (400 mL) were added thereto, the mixture was cooled to 10 ℃ and stirred to precipitate a large amount of solid, 9.7g of solid was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 1b (16.9 g, yield: 79.8%).

Second step of

4-amino-3-bromo-5- (methylamino) benzoic acid methyl ester 1c

Compound 1B (8.6 g,29.7 mmol) was added to 80mL of a mixed solution of methanol and water (V: V = 2.3.

MS m/z(ESI):259.1[M+1]。

The third step

4-bromo-1-methyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester 1d

Benzoic acid (5.0 g, 0.041mol) was dissolved in dichloromethane (50 mL), stirred and dissolved, thionyl chloride (15g, 0.126mol) and N, N-dimethylformamide (0.5 mL) were sequentially added thereto, the mixture was heated to 40 ℃ to react for 1.5 hours, naturally cooled to room temperature, methylene chloride and thionyl chloride were removed under reduced pressure, compound 1c (3.6 g, 0.014mol) was added to dichloromethane (20 mL) and dissolved under stirring, triethylamine (2g, 0.021mol) was added thereto, benzoyl chloride (1.95g, 0.014mol) dissolved in dichloromethane (15 mL) was added dropwise to the reaction system, the reaction was continued for 10 minutes after completion of dropwise addition, liquid separation was performed by adding water (50 mL), organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, acetic acid (30 mL) was added thereto, heated to 85 ℃ to react for 2 hours, naturally cooled to room temperature, the pH was adjusted to 8 with a saturated solution, extracted with ethyl acetate (30X 3 mL), combined organic phases were washed with water, concentrated under reduced pressure, filtered to give a yield, and concentrated over sodium sulfate to give the title compound (93.5 g).

MS m/z(ESI):345.2[M+1]。

The fourth step

2- (4-bromo-1-methyl-2-phenyl-1H-benzo [ d ] imidazol-6-yl) propan-2-ol 1e

Compound 1d (3g, 8.7mmol) was dissolved in dry tetrahydrofuran (30 mL), replaced with nitrogen three times, cooled to 0 deg.C, methyl magnesium bromide (12mL, 34.8mmol) was added dropwise, the ice bath was removed, the reaction was carried out for 90 minutes, a saturated ammonium chloride solution (30 mL) was added to quench the reaction, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, 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: 56.67%). MS m/z (ESI) 445.2[ 2 ], [ M ] +1].

The fifth step

4-bromo-7-methoxy-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid isopropyl ester 1g

The compound 4-bromo-7-methoxy-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridine 1f (3g, 8mmol, prepared by the method disclosed in example fifth step on page 87 of the specification in WO2016077378A 1) was added to dry tetrahydrofuran (30 mL), replaced with nitrogen three times, cooled to-78 deg.C, lithium diisopropylamide (6 mL,12mmol, triturated), stirred for 10 minutes after completion of dropwise addition, isopropyl chloride (1.5g, 12mmol) was added dropwise, the reaction was continued for 30 minutes after completion of dropwise addition, naturally warmed to room temperature, water (20 mL) was added, pH was adjusted to 3-4 with 3M hydrochloric acid, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1g (4.3 g) of the crude title compound, which was used in the next step without purification.

MS m/z(ESI):467.2[M+1]。

The sixth step

4-bromo-7-oxo-1-p-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid isopropyl ester 1H

Adding 1g (3.3g, 7.1mmol) of the compound into isopropanol (30 mL), stirring uniformly, adding p-toluenesulfonic acid monohydrate (6.7g, 35.5mmol, annaiji) and lithium chloride (0.6g, 14.2mmol, lemo), heating to 85 ℃, reacting for 1.5 hours, naturally cooling to room temperature, removing the solvent under reduced pressure, adding water (20 mL) and ethyl acetate (20 mL) for separating, extracting the aqueous phase with ethyl acetate (20 mL), combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the crude compound for 1h (4 g), and directly using the crude compound in the next step without purification.

MS m/z(ESI):453.2[M+1]。

Seventh step

4-bromo-6-methyl-7-oxo-1-p-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid isopropyl ester 1i

Compound 1h (4g, 8.8mmol), potassium carbonate (3.7g, 26.4mmol) were added to N, N-dimethylformamide (40 mL), iodomethane (2.4g, 16.72mmol) was added dropwise with stirring, after 1 hour of reaction, water (80 mL) and ethyl acetate (40 mL) were added for separation, the aqueous phase was extracted with ethyl acetate (40 mL), and the organic phases were combined, washed successively with water (40 mL. Times.3), a 5% lithium chloride solution (40 mL. Times.3), a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1i (3.9 g, yield: 92.86%).

MS m/z(ESI):467.2[M+1]。

Eighth step

4-bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide 1j

Compound 1i (3.9g, 8.4 mmol) was added to 70% aqueous ethylamine (60 mL), the reaction was stirred at 60 ℃ for 18-20 hours, cooled to room temperature, adjusted to pH 3-4 with 3M hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent system A to give the title compound 1j (1.6 g, yield: 62.50%).

MS m/z(ESI):298.2[M+1]。

The ninth step

N-Ethyl-6-methyl-7-oxo-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide 1k

Compound 1j (0.5g, 1.7mmol) was dissolved in 1, 4-dioxane (5 mL), stirred well, pinacol diboron (1.3g, 5.1mmol, mirel) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.13g, 0.17mmol) were added, the temperature was raised to 95 ℃ for reaction for 4 hours, naturally cooled to room temperature, filtered, the cake was washed with dioxane, the filtrates were combined, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 1k (0.3 g, yield: 51.72%).

MS m/z(ESI):346.4[M+1]。

The tenth step

Compound 1e (0.25g, 0.7mmol), compound 1k (0.3g, 0.084mmol), potassium carbonate (0.3g, 2.1mmol) and tetrakis (triphenylphosphine) palladium (0.08g, 0.07mmol) were added to 1, 4-dioxane (5 mL), water (0.5 mL) was added, nitrogen was replaced three times, the reaction was warmed to 85 ℃ for 7 hours, cooled naturally to room temperature, filtered, the cake was washed with 1, 4-dioxane, the filtrates were combined, concentrated under reduced pressure, and purified by thin layer chromatography using developer system A to give the title compound 1 (32 mg, yield: 9.14%).

MS m/z(ESI):484.2[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.29(m,1H),8.35(m,1H),7.85(s,2H),7.78(s,1H),7.59(m,4H),6.95(s,1H),6.76(s,1H),3.93(m,3H),3.63(s,3H),1.59(s,6H),1.13(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 superbiol, prokaryotic expression) or BRD4 BD2 protein (Pan superbiol, prokaryotic expression) and compounds were diluted with binding buffer (Cisbio, 62 DLBDDF), 384-well assay plates (Corning, 4513) were added, vortexed (Nenbel, MH-I, haimen), centrifuged at 1000rpm (Hunan instruments centrifuge Co., ltd., L-530) for 1 min, and incubated in a 25-degree incubator (Shanghai sperm macro laboratory devices Co., ltd., 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 plate 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 experiment

The ability of the compounds to inhibit the proliferation of MV-4-11 cells was examined, according to IC ₅₀ The activity of the compounds was evaluated.

2. Experimental method

MV-4-11 (ATCC, CRL-9591) cells were digested with 0.25% pancreatic enzyme (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 a microplate reader (BMG, PHERAstar FS). Data were processed analytically using Graphpad Prism 6.

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

TABLE 2 inhibition of MV-4-11 cell proliferation by compounds of the present disclosure.

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

Claims

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

wherein:

R ² selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, 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, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ³ selected from the group consisting of hydrogen, 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;

R ⁴ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, and hydroxyalkyl groups;

R ⁵ and R ⁶ Identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ⁷ R ⁸ Nitro, hydroxy, 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, hydroxyl and hydroxyalkyl;

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 <xnotran> , , , , , , , , , , , , , </xnotran>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 R ³ Is composed of

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

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ² Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 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.

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) or a pharmaceutically acceptable salt thereof:

wherein:

l, ring A, R ^x 、R ¹ 、R ⁴ To R ⁸ And n is 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 4, 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; preferably, ring a is phenyl or pyridyl.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein L is a covalent bond.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ⁵ Is a hydrogen atom.

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

wherein:

R ^x 、R ¹ 、R ⁴ 、R ⁶ to R ⁸ And n is as defined in claim 1.

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. The compound of formula (I) according to any one of claims 1 to 9, wherein R is ⁴ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group.

11. General formula according to any one of claims 1 to 10(I) A compound of the formula or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl 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 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.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, 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 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 Haloalkoxy is substituted with one or more substituents.

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

15. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

x is

R is a hydrogen atom or C _1-6 An alkyl group; preferably, X is

Y is halogen; preferably, Y is a bromine atom;

R ¹ to R ⁶ As defined in claim 1.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the manufacture of a medicament for inhibiting BET.

18. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting BD1 and/or BD2, preferably for inhibiting BD 2.

19. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition selected from a tumour, a cardiovascular disease, an inflammatory disease, an autoimmune disease, a renal disease, a viral infection and a neurological disease.

20. The use according to claim 19, wherein the disease or disorder 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, haynaud's arteritis, toxic shock, thyroiditis, type I diabetes, uveitis, vitiligo, vasculitis, primary thrombocytosis, polycythemia vera, wegener's granulomatosis, acquired immune deficiency syndrome, obesity, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, interstitial disease, hepatic steatosis, II, insulin intervention, insulin resistance, kidney diseases induced by percutaneous angiography, glomerulonephritis induced nephropathy, interstitial nephropathy induced reperfusion induced nephropathy, coronary heart disease, interstitial nephritis induced nephropathy, and reperfusion induced nephropathy induced by drugs for the kidney diseases; the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.

21. The use according to claim 20, wherein the cancer is selected from the group consisting of: <xnotran> , , , , , , , , , , , , , , , , , , , , B- , , , , , , , , , , , , , , , , , , , , , T- B- , , , , , , , , , NUT , , , , , , , , , , , , , , , , , , , ; </xnotran> Preferably, the cancer is selected from the group consisting of prostate cancer, acute myeloid leukemia, and myelofibrosis; the myeloma is preferably multiple myeloma.