CN113045560B

CN113045560B - Amide derivative and preparation method and application thereof

Info

Publication number: CN113045560B
Application number: CN202110341819.4A
Authority: CN
Inventors: 季鸣; 林松文; 金晶
Original assignee: Gangke Penghe Biology Suzhou Co ltd
Current assignee: Gangke Penghe Biology Suzhou Co ltd
Priority date: 2021-03-30
Filing date: 2021-03-30
Publication date: 2022-09-06
Anticipated expiration: 2041-03-30
Also published as: CN113045560A

Abstract

The invention relates to an amide derivative and a preparation method and application thereof, wherein the structure of the amide derivative is shown as a formula (I), wherein n is selected from any integer of 3-10; ring a is a 5-membered heteroaromatic ring containing 1-4 nitrogen atoms. The invention develops a novel amide derivative structure, and the compound has remarkable effect of simultaneously inhibiting RIPK1 and HDAC (high-order fatty acid) and can be applied to preventing and/or treating RIPK1 and/or HDAC (high-order fatty acid) mediated diseases, such as inflammatory diseases, autoimmune diseases, proliferative disorders, neurodegenerative diseases and the like.

Description

Amide derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, particularly relates to an amide derivative, and a preparation method and application thereof, and particularly relates to an amide derivative with inhibitory activity on RIPK1 and HDAC, and a preparation method and application thereof.

Background

The programmed necrosis process, also called necroptosis, is an important physiological process closely related to cell death, innate immunity and inflammation. Receptor-interacting protein 1 kinase (RIPK1), a key upstream regulator of necrotic apoptosis, is associated with a variety of pathologies such as ischemic injury, inflammatory diseases, autoimmune diseases, and neurological diseases. Numerous studies have shown that inhibition of RIPK1 kinase activity can ameliorate various diseases, including inflammatory diseases (such as colitis and dermatitis), autoimmune diseases (such as rheumatoid arthritis), and neurological diseases (such as Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)). Research shows that the inhibition of the activity of RIPK1 kinase can regulate tumor-associated macrophages, thereby improving the anti-tumor immunity, and the RIPK1 can also be used as a new immunoregulation target for developing anti-cancer drugs. Therefore, inhibition of RIPK1 kinase activity may be a promising therapeutic approach to treat these diseases.

Acetylation modification of proteins is a common post-translational modification. Histidine Deacetylase (HDAC) is an enzyme that hydrolyzes and removes the lysine N-acetyl group of Histone, and plays an important role in the structural modification of chromosome and the regulation of gene transcription. Besides having higher expression level in various tumor cells and promoting the generation and development of tumors, HDACs are also proved to play important roles in various diseases such as neurological diseases, inflammatory diseases, autoimmune diseases and the like. HDAC inhibitors have been proved to show therapeutic effects in various animal models such as asthma, colitis, multiple sclerosis and rheumatoid arthritis, and the HDAC inhibitors have potential to be developed into other disease therapeutic drugs besides antitumor drugs. Research has shown that HDAC has the function of treating autoimmune diseases, inflammatory diseases and other diseases, is closely related to the regulation of the expression of various cytokines, and the inhibition of HDAC can obviously reduce the expression of proinflammatory factors such as IL-1 beta, TNF, MCP-1 and the like.

The existing research shows that the diseases such as inflammatory diseases, autoimmune diseases and the like are closely related to various cytokines and inflammatory factors. Blocking one of the cytokines may act to relieve symptoms, while blocking two or more cytokines may have a significant synergistic effect. The simultaneous inhibition of RIPK1 and HDAC has the potential to have better prevention and/or treatment effects on diseases mediated by RIPK1 and/or HDAC, such as inflammatory diseases, autoimmune diseases, proliferative disorders and neurodegenerative diseases, so the development of a dual RIPK1 and HDAC inhibitor has important value.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an amide derivative and a preparation method and application thereof, and particularly provides an amide derivative with inhibitory activity on RIPK1 and HDAC (Histone-like kinase), and a preparation method and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides an amide derivative, wherein the structure of the amide derivative is represented by formula (i):

wherein n is selected from any integer of 3-10 (for example, n ═ 3,4,5, 6, 7, 8, 9, 10); ring a is a 5-membered heteroaromatic ring containing 1-4 nitrogen atoms (e.g., 1 nitrogen atom, 2 nitrogen atoms, 3 nitrogen atoms, 4 nitrogen atoms).

The invention develops a novel amide derivative structure, namely 5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] shown as a formula (I)][1,4]Oxazazem

The compound has the remarkable effect of simultaneously inhibiting RIPK1 and HDAC, and can be applied to preventing and/or treating RIPK1 and/or HDAC mediated diseases, such as inflammatory diseases, autoimmune diseases, proliferative disorders, neurodegenerative diseases and the like.

Preferably, the a ring is a 5-membered heteroaromatic ring containing 2-3 nitrogen atoms.

Further preferably, the A ring is selected from

Further preferably, the amide derivative is selected from the structures shown as follows:

in a second aspect, the present invention provides a process for producing an amide-based derivative according to the first aspect, the process comprising the steps of:

(1) removing Boc protecting group from the compound shown in the formula (V) through trifluoroacetic acid, and then reacting with the compound A to prepare a compound shown in the formula (IV);

(2) hydrolyzing the compound shown in the formula (IV) to prepare a compound shown in a formula (III);

(3) reacting a compound shown in a formula (III) with a compound B to obtain a compound shown in a formula (II);

(4) reacting a compound shown in a formula (II) with hydroxylamine to obtain a compound shown in a formula (I);

the reaction formula is shown as follows, wherein the limited range of the n and A rings is consistent with the range defined by the first aspect; r is methyl, ethyl or tert-butyl;

in a third aspect, the present invention provides a pharmaceutically acceptable salt, hydrate, solvate or crystal form compound of the amide derivative according to the first aspect.

The pharmaceutically acceptable salts are those salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are described in detail in j.pharma.sci.,1977,66,1-19 by Berge et al, which are incorporated herein by reference. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, dihydrogenphosphate, metaphosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprylate, or a mixture thereof, Citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

In a fourth aspect, the present invention provides a pharmaceutical composition, which includes the amide derivative according to the first aspect or the pharmaceutically acceptable salt, hydrate, solvate, crystal form compound of the amide derivative according to the third aspect, and a pharmaceutically acceptable excipient.

Preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.

The auxiliary materials related by the invention are listed in Remington: the Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Bucker, Marcel Dekker, New York, which disclose various carriers for The formulation of pharmaceutically acceptable compositions and known techniques for their preparation, The contents of which are incorporated herein by reference.

Preferably, the pharmaceutical composition further comprises other pharmaceutically active ingredients.

The other pharmaceutical active ingredients are one or more pharmaceutical active ingredients for preventing and/or treating inflammatory diseases, autoimmune diseases, proliferative disorders and neurodegenerative diseases except the compound shown in the formula (I). Such as IL-17 antibody drugs, immune sentinel inhibitor PD-1 monoclonal antibody, etc.

In a fifth aspect, the present invention provides an amide derivative according to the first aspect, a pharmaceutically acceptable salt, a hydrate, a solvate, a crystalline compound according to the third aspect, and a pharmaceutical composition according to the fourth aspect, for use in the preparation of a medicament for preventing and/or treating RIPK1 and/or HDAC mediated diseases.

Preferably, the RIPK1 and/or HDAC mediated disease comprises an inflammatory disease, an autoimmune disease, a proliferative disorder or a neurological disease.

Preferably, the dosage form of the drug comprises a parenteral, enteral or topical formulation.

Such parenteral formulations as injection solutions or suspensions; such enteral formulations as tablets or capsules; such as lotions, gels, ointments, creams, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.

The medicament may be administered by any route suitable for the condition to be treated. In particular by administration in the form: parenterally, e.g., in the form of injectable solutions or suspensions; enterally, e.g., orally, e.g., in tablet or capsule form; topically, e.g. in the form of a lotion, gel, ointment or cream or in the form of a nose or suppository. Topical application is, for example, application to the skin. Another form of topical administration is to the eye.

In a sixth aspect, the present invention provides an amide derivative according to the first aspect, a pharmaceutically acceptable salt, a hydrate, a solvate, a crystalline compound according to the third aspect, and a pharmaceutical composition according to the fourth aspect, for use in preparing an RIPK1 inhibitor and/or an HDAC inhibitor.

In a seventh aspect, the present invention provides a RIPK1 and HDAC dual inhibitor, where the RIPK1 and HDAC dual inhibitor includes an amide derivative according to the first aspect, a pharmaceutically acceptable salt, hydrate, solvate, crystalline compound of the amide derivative according to the third aspect, or a pharmaceutical composition according to the fourth aspect.

In an eighth aspect, the present invention provides a method for preventing and/or treating an inflammatory disease, an autoimmune disease, a proliferative disorder or a neurodegenerative disease, the method comprising: administering to the subject a prophylactically and/or therapeutically effective amount of an amide-based derivative according to the first aspect, a pharmaceutically acceptable salt, hydrate, solvate, crystalline form compound of an amide-based derivative according to the third aspect, or a pharmaceutical composition according to the fourth aspect.

The compounds to which the invention relates also include isotopically-labelled compounds thereof, in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass number different from the atomic mass number usually found in nature. Examples of isotopes suitable for the invention include, but are not limited to: isotopes of hydrogen ² H and ³ h; isotopes of carbon ¹¹ C、 ¹³ C and ¹⁴ c; isotopes of chlorine ³⁶ Cl; isotopes of fluorine ¹⁸ F; isotope of iodine ¹²³ I and ¹²⁵ i; isotopes of nitrogen ¹³ N and ¹⁵ n; isotopes of oxygen ¹⁵ O、 ¹⁷ O and ¹⁸ o; isotopes of phosphorus ³² Isotopes of P and sulfur ³⁵ S。

Prodrugs of the compounds to which the present invention relates are also included within the scope of the present invention. Some derivatives of the compounds described in the present invention have weak pharmacological activity or no pharmacological activity themselves, but when these derivatives are administered into or onto the body, they may be converted into the compounds described in the present invention having pharmacological activity by means of, for example, hydrolytic cleavage, and the like, and these derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, vol.14, ACS Symposium Series (t.higuchi and w.stella) and Bioreversible Carriers in Drug Design, Pergamon Press,1987(ed.e.b.roche, American Pharmaceutical Association).

Compared with the prior art, the invention has the following beneficial effects:

the invention develops a novel amide derivative structure, and the preparation method is simple and easy to operate and is very suitable for industrial production. The compound has remarkable effect of simultaneously inhibiting RIPK1 and HDAC, and thus can be applied to preventing and/or treating RIPK1 and/or HDAC mediated diseases, such as inflammatory diseases, autoimmune diseases, proliferative disorders, neurodegenerative diseases and the like.

Detailed Description

To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

The sources of the raw materials referred to in the following preparations and examples are as follows:

methyl aminobutyric acid hydrochloride, methyl aminopentanoate hydrochloride, methyl aminocaproate hydrochloride, methyl aminoheptanoate hydrochloride, methyl aminocaprylate hydrochloride, methyl aminononanoate hydrochloride, methyl aminodecanoate hydrochloride are commercially available from common reagent suppliers, such as Shanghai Bigdi pharmaceutical science and technology, Inc., Hadamard reagent, Inc., Shanghai Arlatin Biotechnology, Inc.; or prepared by conventional synthetic technical principles and methods well known to those skilled in the art.

Preparation example 1

General intermediate (S) -3- ((tert-butyloxycarbonyl) amino) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of benzyl 8-carboxylate (IM-1), whose structure is shown below:

prepared according to the synthesis method disclosed in the literature (J.Med.chem.2018,61, 2384-: MS (ESI +) M/z 427.1[ M + H ]] ⁺ 。

Preparation example 2

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazem

-synthesis of benzyl 8-carboxylate (IM-2a), whose structure is shown below:

a mixed solution of intermediate IM-1(10mmol) and trifluoroacetic acid (10mL) in dichloromethane (30mL) was stirred at 25 ℃ for 4 hours and then evaporated to dryness under reduced pressure. The residue was redissolved with 30mL of dichloromethane and evaporated to dryness under reduced pressure, and the procedure was repeated 3 times. To the residue were added dichloromethane (50mL), 1-benzyl-1H-pyrazole-3-carboxylic acid in that order

(12mmol) and HATU (12 mmol). To the resulting mixture was added triethylamine (40mmol) dropwise at 0 ℃. The resulting reaction mixture was stirred at 25 ℃ for 24 hours. 50mL of water was added and extracted three times with dichloromethane. The combined organic layers were washed with water (twice) and saturated brine (twice), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography to give the product. The characterization result is as follows: MS (ESI +) M/z 512.2[ M + H ]] ⁺ 。

Preparation example 3

(S) -3- (1-benzyl-1H-imidazolyl-4-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of benzyl 8-carboxylate (IM-2b), whose structure is shown below:

the preparation method is different from the preparation example 2 only in that: will be provided with

By replacing with equimolar amounts

The characterization result is as follows: MS (ESI +) M/z 511.1[ M + H ]] ⁺ 。

Preparation example 4

(S) -3- (1-benzyl-1H-pyrazol-4-ylamino) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of benzyl 8-carboxylate (IM-2c), whose structure is shown below:

By replacing with equimolar amounts

The characterization result is as follows: MS (ESI +) M/z 511.2[ M + H ]] ⁺ 。

Preparation example 5

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-carboxylic acid (IM-3a), whose structure is shown below:

a mixture of intermediate IM-2a (5mmol), lithium hydroxide (7.5mmol), methanol (15mL), tetrahydrofuran (15mL) and water (5mL) was stirred at 25 ℃ for 24 h. 100mL of water was added, extracted with ethyl acetate (2 times), and the ethyl acetate layer was discarded. Acidifying the remaining water layerThe pH was 3 and extracted with ethyl acetate (3 times). The ethyl acetate layers were combined, washed with water (2 times) and saturated brine (2 times), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the product as a white solid. The characterization result is as follows: MS (ESI +) M/z 422.1[ M + H ]] ⁺ 。

Preparation example 6

(S) -3- (1-benzyl-1H-imidazole-4-carboxamido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-carboxylic acid (IM-3b), whose structure is shown below:

the preparation method comprises the following steps: intermediate IM-2b was subjected to the same treatment as in preparation example 5. The characterization result is as follows: MS (ESI +) M/z 421.1[ M + H ]] ⁺ 。

Preparation example 7

-synthesis of 8-carboxylic acid (IM-3c), whose structure is shown below:

the preparation method comprises the following steps: intermediate IM-2c was subjected to the same treatment as in preparation example 5. The characterization result is as follows: MS (ESI +) M/z 421.1[ M + H ]] ⁺ 。

Example 1

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-acylamino) -N- (4- (hydroxyamino) -4-oxobutyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine

-8-amides (Compounds)1) The structure of the synthesis of (1) is shown below:

(1) (S) -4- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) butyrate (1 a):

IM-3a (1mmol), methyl aminobutyric acid hydrochloride (1.2mmol), HATU (1.2mmol) and triethylamine (3mmol) were added successively to dichloromethane (5mL) at 25 ℃. The resulting reaction mixture was stirred at 25 ℃ for 24 hours. 30mL of water was added and extracted with dichloromethane (3 times). The combined organic layers were washed with water (2 times) and brine (2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to give product (1a) as a pale yellow solid. The characterization result is as follows: MS (ESI +) M/z 521.2[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (4- (hydroxyamino) -4-oxobutyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (1):

intermediate 1a (0.5mmol) was dissolved in anhydrous methanol (10mL), potassium hydroxide (5mmol) and 50% aqueous hydroxylamine solution (15mmol) were added, reacted at 25 ℃ for 2 hours, the reaction was placed in an ice bath, acidified to pH 6, and filtered to give the product as a solid. The characterization result is as follows: MS (ESI +) M/z 522.2[ M + H ]] ⁺ 。

Example 2

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (5- (hydroxyamino) -5-oxopentyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazem

-synthesis of 8-amide (compound 2), whose structure is shown below:

(1) (S) -5- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine

-synthesis of 8-acylamino) methyl valerate (2 a):

the preparation was carried out with reference to the preparation process in example 1, except that the methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminopentanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 535.2[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (5- (hydroxyamino) -5-oxopentyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazem

-synthesis of 8-amide (2):

intermediate 2a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 536.2[ M + H ]] ⁺ 。

Example 3

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (6- (hydroxyamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-Synthesis of 8-amide (Compound 3), whose structure is shown below:

(1) (S) -6- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine

-synthesis of methyl 8-amido) hexanoate (3 a):

the preparation was carried out with reference to the preparation process in example 1, except that methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminocaproate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 549.2[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (6- (hydroxyamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (3):

intermediate 3a (0.5mmol) was processed as in example 1. The characterization result is as follows: MS (ESI +) M/z 550.2[ M + H ]] ⁺ 。

Example 4

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-carboxamide) -N- (7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (compound 4), whose structure is shown below:

(1) (S) -7- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) heptanoate (4 a):

the preparation was carried out with reference to the preparation process in example 1, except that methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminoheptanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 563.3[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-carboxamide) -N- (7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (4):

intermediate 4a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 564.2[ M + H ]] ⁺ 。

Example 5

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (8- (hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (compound 5), whose structure is shown below:

(1) (S) -8- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of 8-amido) methyl octanoate (5 a):

the preparation was carried out with reference to the preparation process in example 1, except that the methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminocaprylate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 577.3[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (8- (hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (5):

intermediate 5a (0.5mmol) was processed as in example 1. The characterization result is as follows: MS (ESI +) M/z 578.2[ M + H ]] ⁺ 。

Example 6

(S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-carboxamide) -N- (9- (hydroxyamino) -9-oxononyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (compound 6), whose structure is shown below:

(1) (S) -9- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) nonanoate (6 a):

the preparation was carried out with reference to the preparation process in example 1, with the only difference that methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminononanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 591.3[ M + H ]] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-carboxamide) -N- (9- (hydroxyamino) -9-oxononyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (6):

intermediate 6a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 592.3[ M + H ] +.

Example 7

(S) -3- (5-benzyl-1H-12, 4-Triazol-3-amido) -N- (10- (hydroxyamino) -10-oxodecyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazem

-synthesis of 8-amide (compound 7), whose structure is shown below:

(1) (S) -10- (3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine

-synthesis of methyl 8-amido) decanoate (7 a):

the preparation was carried out with reference to the preparation process in example 1, except that the methyl aminobutyric acid hydrochloride was replaced with an equimolar amount of methyl aminodecanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 605.3[ M + H] ⁺ 。

(2) (S) -3- (5-benzyl-1H-1, 2, 4-triazole-3-amido) -N- (10- (hydroxyamino) -10-oxodecyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (7):

intermediate 7a (0.5mmol) was processed as in example 1. The characterization result is as follows: MS (ESI +) M/z 606.3[ M + H ]] ⁺ 。

Example 8

(S) -3- (1-benzyl-1H-imidazole-4-carboxamide) -N- (6- (hydroxyamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-Synthesis of 8-amide (Compound 8), whose structure is shown below:

(1) (S) -6- (3- (1-benzyl-1H-imidazole-4-carboxamido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) hexanoate (8 a):

the preparation was carried out with reference to the preparation process in example 1, with the only difference that IM-3a was replaced by an equimolar amount of IM-3b and methyl aminobutyric acid hydrochloride was replaced by an equimolar amount of methyl aminocaproate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 548.2[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-imidazol-4-ylamino) -N- (6- (hydroxyamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazem

-synthesis of 8-amide (8):

intermediate 8a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 549.2[ M + H ]] ⁺ 。

Example 9

(S) -3- (1-benzyl-1H-imidazole-4-amido) -N-(7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-Synthesis of 8-amide (Compound 9), whose structure is shown below:

(1) (S) -7- (3- (1-benzyl-1H-imidazole-4-carboxamido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) heptanoate (9 a):

the preparation was carried out with reference to the preparation process in example 1, with the only difference that IM-3a was replaced by an equimolar amount of IM-3b and methyl aminobutyrate hydrochloride was replaced by an equimolar amount of methyl aminoheptanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 562.2[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-imidazole-4-carboxamido) -N- (7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (9):

intermediate 9a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 563.3[ M + H ]] ⁺ 。

Example 10

(S) -3- (1-benzyl-1H-imidazole-4-amido) -N- (8-(hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine

-synthesis of 8-amide (compound 10), whose structure is shown below:

(1) (S) -8- (3- (1-benzyl-1H-imidazole-4-carboxamido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) octanoate (10 a):

the preparation was carried out with reference to the preparation process in example 1, with the only difference that IM-3a was replaced by an equimolar amount of IM-3b and methyl aminobutyric acid hydrochloride was replaced by an equimolar amount of methyl aminocaprylate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 576.3[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-imidazole-4-carboxamido) -N- (8- (hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (10):

intermediate 10a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 577.3[ M + H ]] ⁺ 。

Example 11

(S) -3- (1-benzyl-1H-pyrazol-4-carboxamide) -N- (6)- (hydroxylamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (compound 11), whose structure is shown below:

(1) (S) -6- (3- (1-benzyl-1H-pyrazol-4-ylamino) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine

-synthesis of methyl 8-amido) hexanoate (11 a):

the preparation was carried out with reference to the preparation process in example 1, with the only difference that IM-3a was replaced by an equimolar amount of IM-3c and methyl aminobutyric acid hydrochloride was replaced by an equimolar amount of methyl aminocaproate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 548.2[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-pyrazol-4-ylamino) -N- (6- (hydroxyamino) -6-oxohexyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (11):

intermediate 11a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 549.2[ M + H ]] ⁺ 。

Example 12

(S) -3- (1-benzyl-1H-pyrazole-4-carboxamide) -N- (1-benzyl-1H-amide7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (compound 12), whose structure is shown below:

(1) (S) -7- (3- (1-benzyl-1H-pyrazol-4-ylamino) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) heptanoate (12 a):

the preparation was carried out with reference to the preparation process in example 1, except that IM-3a was replaced by an equimolar amount of IM-3c and methyl aminobutyrate hydrochloride was replaced by an equimolar amount of methyl aminoheptanoate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 562.2[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-pyrazol-4-ylamino) -N- (7- (hydroxyamino) -7-oxoheptyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (12):

intermediate 12a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 563.3[ M + H ]] ⁺ 。

Example 13

(S) -3- (1-benzyl-1H-pyrazole-4-amido) -N-(8- (hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazem

-synthesis of 8-amide (compound 13), whose structure is shown below:

(1) (S) -8- (3- (1-benzyl-1H-pyrazol-4-ylamino) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazem

-synthesis of methyl 8-amido) octanoate (13 a):

the preparation was carried out with reference to the preparation process in example 1, except that IM-3a was replaced by an equimolar amount of IM-3c and methyl aminobutyric acid hydrochloride was replaced by an equimolar amount of methyl aminocaprylate hydrochloride. The characterization result is as follows: MS (ESI +) M/z 576.3[ M + H ]] ⁺ 。

(2) (S) -3- (1-benzyl-1H-pyrazol-4-ylamino) -N- (8- (hydroxyamino) -8-oxooctyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazem

-synthesis of 8-amide (13):

intermediate 13a (0.5mmol) was treated according to the method in example 1. The characterization result is as follows: MS (ESI +) M/z 577.3[ M + H ]] ⁺ 。

Test example 1

RIPK1 inhibitory activity assay:

the compounds synthesized in examples 1-13 were tested for their enzymatic inhibitory activity against RIPK1 using an in vitro method. The RIPK1 test kit was purchased from BPS Biosciences, 384-well plates from COSTAR. Compounds were formulated in DMSO as 10mM stock solutions diluted with deionized water. The assay system included 1 × assay buffer, 0.5 μ l ATP (500 μ M), 1 μ l RIPK1 substrate (MBP), and 8 μ l deionized water. After adding 2.5. mu.l of test compound solution or control solution (DMSO) to each well, RIPK1 enzyme was added and incubated at 37 ℃ for 1 hour. 25 μ l of ADP-Glo solution was added and incubated at 37 ℃ for 45 minutes. Then 50. mu.l of kinase assay solution was added and incubated for another 45 minutes at 37 ℃ before measuring chemiluminescence using a BioTEK multifunctional microplate reader (with the drug GSK2982772 as a positive control).

Percent inhibition was calculated based on the following equation:

inhibition% (Max-Signal)/(Max-Min) × 100

Wherein, Signal is the reading under the given compound concentration, Min is the reading of DMSO control, Max is the reading of enzyme activity control. The results are shown in table 1 (data is the average of the results of the 6 replicates):

TABLE 1

As can be seen from the data in Table 1: the inhibition rate of the tested 13 compounds to RIPK1 kinase is more than or equal to 80% under the concentration of 1 mu M, and the compounds show obvious RIPK1 inhibition activity.

Test example 2

HDAC1 inhibitory activity assay:

the compounds synthesized in examples 1 to 13 were tested for their enzymatic inhibitory activity against HDAC1 using an in vitro method. HDAC1 fluorescence detection kit was purchased from BPS Biosciences, 384-well plate from COSTAR. Compounds were formulated in DMSO as 10mM stock solutions diluted with deionized water. The assay system included 30. mu.l HDAC detection buffer, 5. mu.l BSA (1mg/mL) and 5. mu.l HDAC1 substrate (200. mu.M). Mu.l of test compound or control solution (DMSO) was added to each well followed by 5. mu.l of diluted HDAC1 enzyme and incubation at 37 ℃ for 30 min. Then 50. mu.l of the substrate solution was added to each well, incubated at 37 ℃ for 15 minutes, and the fluorescence signal value was measured using a BioTEK multifunctional plate reader under conditions of 350nM excitation light and 450mM emission light (drug SAHA was used as a positive control).

Percent inhibition was calculated based on the following equation:

inhibition% ((Max-Signal)/(Max-Min) × 100)

Wherein, Signal is the reading under the given compound concentration, Min is the reading of DMSO control, Max is the reading of enzyme activity control. The results are shown in table 2 (data is the average of the results of 6 parallel tests):

TABLE 2

Compound numbering	HDAC1 inhibition% @ 1. mu.M
		Example 1	65
Example 2	71
		Example 3	81
Example 4	89
		Example 5	85
Example 6	83
		Example 7	64
Example 8	85
		Example 9	90
Example 10	82
		Example 11	83
Example 12	88
		Example 13	84
SAHA	80

As can be seen from the data in Table 2: all 13 tested compounds showed more than 64% inhibition rate to HDAC1 at 1 μ M concentration, and showed good HDAC1 inhibitory activity.

The applicant states that the invention is illustrated by the above examples to show one amide derivative of the invention, its preparation method and application, but the invention is not limited to the above examples, i.e. it does not mean that the invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims

1. An amide derivative is characterized in that the structure of the amide derivative is shown as the formula (I):

wherein n is selected from any integer of 3-10; ring a is a 5-membered heteroaromatic ring containing 1-4 nitrogen atoms.

2. The amide-based derivative according to claim 1, wherein the ring a is a 5-membered heteroaromatic ring containing 2 to 3 nitrogen atoms.

3. The amide-based derivative according to claim 1, wherein the a ring is selected from the group consisting of

4. The amide-based derivative according to claim 1, wherein the amide-based derivative is selected from the structures shown as follows:

5. the process for producing amide-based derivatives according to any one of claims 1 to 4, characterized by comprising the steps of:

(1) removing Boc protecting group from the compound shown in the formula (V) by trifluoroacetic acid, and then reacting with the compound A to prepare a compound shown in the formula (IV);

the reaction formula is shown as follows, wherein the limited range of n and A ring is consistent with the range defined in any one of claims 1-4; r is methyl, ethyl or tert-butyl;

6. a pharmaceutically acceptable salt of the amide-based derivative according to claim 1.

7. A pharmaceutical composition, which comprises the amide-based derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt of the amide-based derivative according to claim 6, and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7, wherein the excipient is any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a colorant, a pH regulator, an antioxidant, a bacteriostatic agent, or a buffer.

9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises an additional pharmaceutically active ingredient.

10. Use of an amide-based derivative according to any one of claims 1 to 4, a pharmaceutically acceptable salt of an amide-based derivative according to claim 6, or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention and/or treatment of RIPK1 and/or HDAC mediated diseases.

11. The use according to claim 10, wherein the RIPK1 and/or HDAC mediated disease is an inflammatory disease, autoimmune disease, proliferative disorder, or neurological disease.

12. The use of claim 10, wherein the medicament is in the form of a parenteral, enteral or topical formulation.

13. Use of an amide derivative according to any one of claims 1 to 4, a pharmaceutically acceptable salt of an amide derivative according to claim 6, or a pharmaceutical composition according to claim 7 for the preparation of an RIPK1 inhibitor and/or an HDAC inhibitor.