CN109678803A - A kind of preparation and application of novel 4,6- disubstituted amido miazines jak kinase inhibitor - Google Patents

Abstract

The present invention discloses the preparation and application of a novel 4,6-disubstituted aminopyrimidine JAK kinase inhibitor, and provides a method that can be used to prevent, treat and/or improve autoimmune diseases (eg, psoriasis, rheumatoid joints) Inflammation, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), etc.), it has excellent JAK kinase (janus kinase) inhibitory activity. The present invention also provides pharmaceutically acceptable compositions comprising the compounds and methods for preparing these compounds.

Description

Preparation and application of novel 4, 6-disubstituted aminopyrimidine JAK kinase inhibitor

The technical field is as follows:

the present invention relates to a heterocyclic compound having a JAK kinase inhibitory action, which is useful as an agent for preventing, treating and/or improving autoimmune diseases (e.g., Psoriasis (Psoriasis), rheumatoid arthritis (rheumatoid arthritis), inflammatory bowel disease (inflammatory bowel disease), sjogren's syndrome (sjogren's syndrome), behcet's disease, multiple sclerosis (multiple sclerosis), systemic lupus erythematosus (systemic lupus erythematosis) and the like), and a pharmaceutical composition containing the same, and the like.

Background art:

JAK kinase (janus kinase) and its downstream effector, signal transduction and transcriptional activator proteins (STATs) form an important cytokine signaling pathway, the JAK-STAT pathway (Science, 1994, 264: 1415-. The discovery of the pathway greatly improves the knowledge of researchers on gene regulation, and the researches discover that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors and participates in the processes of cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like (World JGastroenterol, 2007, 13: 6478-.

The JAK kinase family plays a role in the cytokine-dependent regulation of cellular functions associated with growth and immune responses. In mammals, there are four JAK kinases: JAK-1 (also known as janus kinase 1), JAK-2 (also known as janus kinase 2), JAK-3 (also known as janus kinase 3), and TYK-2 (also known as tyrosine kinase 2). The JAK-STAT signaling pathway is a signaling pathway stimulated by multiple cytokine receptors, JAK kinases mediate signaling of most cytokines in cells (Prog Med Chem, 2013, 52: 153-. Among them, JAK-3 regulates cell signaling by binding to the gamma chain (yc) in the type I cytokine receptor complex such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Severe Combined Immunodeficiency (SCID) can result when JAK-3 is defective or gammac mutated, manifested as immune-restricted symptoms of T-cell and natural killer cell (NK) depletion, loss of B-cell function, etc. (Chinese J New Drug, 2015, 24: 39-45). When present in suitable amounts, these cytokines play an important role in the immune response. However, their overproduction is thought to be associated with a number of autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus and the like (Journal of Allergy and clinical Tmmurmmurgy 127, 3, 701-721.e70(2011), Cytoki ne & Growth Factor Reviews19, 41-52(2008), Invest Ophthalmol Vis Sci.2008Jul; 49 (7): 3058 3064, Ann Rheum Dis.2010Jul; 69 (7): 1325) 1328). For example, in Europe, Ustekinumab, which is an anti-IL-12/23 monoclonal antibody, has been approved as a therapeutic drug for patients with moderate to severe psoriasis, and in addition, clinical trials for various diseases involved in the IL-12/23 signaling pathway have been conducted. From the above, JAK kinase inhibitors are potential therapeutic drugs for various autoimmune diseases (Front biosci.2011Jun 1; 17: 3214-32).

Examples of the compounds having a structure similar to that of the compounds described in the present specification include the following compounds.

(1) A compound represented by the formula:

(non-patent document 1).

(2) A compound represented by the formula:

(non-patent document 2).

List of documents

Non-patent document

[ non-patent document 1] Li Tan, Koshi Akahane, Randall McNally, et aJ. development of Selective compatibility Janus Kinase 3 Inhibitors [ J ]. Journal of medicinal chemistry, 2015, 58 (16): 6589-6606.

[ non-patent document 2] Zhou W, et al.novel mutant-selective EGFR kinase inhibitors against EGFR T790M [ J ]. Nature.2009, 462 (7276): 1070-4.

Summary of the invention

Problems to be solved by the invention

It is an object of the present invention to provide a medicament for preventing, treating and/or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus and the like) and the like, which has an excellent JAK-1 and/or JAK-3 inhibitory effect.

Means for solving the problems

The present inventors have conducted intensive studies in an attempt to solve the above problems, and have found that a compound (TM) represented by the following formula has an excellent JAK-1 and/or JAK-3 inhibitory effect, thereby completing the present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the formula (TM):

wherein

X₁Is a nitrogen atom or-CH-;

X₂is a nitrogen atom or-CH-;

w isSubstituted or unsubstituted C_3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;

y is independently selected from substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8A 4-, 5-or 6-membered heteroaryl group substituted or unsubstituted with a heterocycloalkyl group;

R₁is independently selected from hydrogen atom, halogen, cyano, hydroxyl, Wherein,

z is independently selected from hydrogen atom, halogen, cyano, hydroxyl;

R₇、R₈、R₉and R₁₀Independently selected from hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6Heterohydrocarbyl or substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;

R₂is a hydrogen atom, unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6Heterohydrocarbyl or substituted or unsubstituted C_3-8A cyclic hydrocarbon group;

R₃is a hydrogen atom, a halogen atom, a cyano group, an amino group, an optionally substituted C_1-6A hydrocarbyl group;

R₄is a hydrogen atom, a halogen atom, a substituted or unsubstituted 4-, 5-, 6-, 7-or 8-membered heterocyclic ring;

R₅is optional and when present is a bond, optionally substituted or unsubstituted C_1-6A hydrocarbyl group;

R₆is optional and when present is a bond, optionally substituted or unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6A heterohydrocarbyl group;

[2] a compound according to claim [1], or a salt thereof, wherein the compound has the formula (I), (II),

[3]according to claim [1]]-[2]A compound of any one of (1), wherein R₁Is a cyano group,

[4]According to claim [1]]-[3]A compound of any one of (1), wherein R₄Is a hydrogen atom, a fluorine atom, a substituted or unsubstituted 4-, 5-or 6-membered nitrogen-containing heterocyclic ring.

[5] The compound according to any one of claims [1] to [4], wherein Y is a nitrogen-containing five-membered heteroaromatic ring.

[6]According to claim [1]]-[5]A compound of any one of (1), wherein R₆Is that

(1) Methyl radical

(2) C optionally substituted with 1 to 3 substituents selected from the group consisting of_1-6Alkyl groups: (a) halogen atom, (b) hydroxyl group, (C) C_1-6Alkoxy group, (d) C_3-8Cycloalkyl, (e) C_1-6Alkyl-carbonyl mono-or di-substituted amino.

[7] The pharmaceutical agent as claimed in claims [1] to [6], which is a JAK-1 and/or JAK-3 inhibitor.

[8] The compound or a salt thereof according to claim [7], which is an agent for preventing, treating and/or ameliorating an autoimmune disease.

[9] The medicament according to claim [8], wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis or systemic lupus erythematosus.

Effects of the invention

The compound (I) has an excellent JAK-1 and/or JAK-3 inhibitory action and is useful as an agent for preventing, treating or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis, etc.), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), and the like.

Detailed description of the invention

In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, "C" or "C" is used_1-6By "hydrocarbyl (group)" is meant C_1-6Alkyl radical, C_2-7Alkenyl radical, C_1-6Alkoxy radical, C_2-6Alkenyloxy radical, C_1-6Alkyl-carbonyl mono-or di-substituted aminoaryl, and the like.

In the present specification, "C" or "C" is used_1-6Alkyl (group) "means, for example, methyl, ethyl, isopropyl, butyl, sec-butyl, pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, isohexyl, 1-dimethylbutyl, 3-dimethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, 1, 2-dimethylpropyl, and the like.

In the present specification, "C" or "C" is used_2-7Alkenyl "means, for example, ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 4-methyl-3-pentenyl, 3-hexenyl, 5-hexenyl, and the like.

In the present specification, "C" or "C" is used_2-7Alkynyl "means, for example, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 1-pentynyl, 1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.

In the present specification, "C" or "C" is used_1-6Alkoxy "means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxyRadicals, and the like.

In the present specification, "C" or "C" is used_2-6The "alkenyloxy group" means, for example, an ethyleneoxy group, a 1-propylenyloxy group, a 2-methyl-1-propylenyloxy group, a 1-butenyloxy group, a 2-butenyloxy group, a 4-methyl-3-pentenyloxy group, a 1-hexenyloxy group, a 3-hexenyloxy group, a 5-hexenyloxy group, etc.

In the present specification, "C" or "C" is used_1-6Alkyl-carbonyl mono-or di-substituted aminoaryl "means, for example, N, N-dimethylformyl, N, N-dimethylacetyl, and the like.

In the present specification, examples of the "monocyclic aromatic heterocyclic group" include 5 to 7-membered (preferably 5 or 6-membered) monocyclic aromatic heterocyclic groups containing, as ring constituting atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized), for example, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), and the like

In the present specification, "non-aromatic heterocyclic group" means a monocyclic non-aromatic heterocyclic group and a condensed non-aromatic heterocyclic group.

In the present specification, examples of the "monocyclic non-aromatic heterocyclic group" include 3 to 8-membered (preferably 5 or 6-membered) monocyclic non-aromatic heterocyclic groups containing, as a ring-constituting atom, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized) in addition to a carbon atom, for example, azetidinyl (e.g., 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), and the like.

In the present specification, examples of the "fused non-aromatic heterocyclic group" include 8 to 22-membered fused non-aromatic heterocyclic groups, specifically, groups derived from fused rings, wherein the ring corresponding to the above-mentioned 3 to 8-membered monocyclic non-aromatic heterocyclic group and C_6-14The fusion of aromatic hydrocarbons; a group derived from a condensed ring, wherein a ring corresponding to the above-mentioned 3 to 8-membered monocyclic non-aromatic heterocyclic group is a condensed ring; a group derived from a condensed ring wherein a ring corresponding to the above-mentioned 3 to 8-membered monocyclic non-aromatic heterocyclic group is condensed with a ring corresponding to the above-mentioned 5 to 7-membered monocyclic aromatic heterocyclic group; and the above groups are partially saturated groups, for example, indolinyl (e.g., 2, 3-dihydro-1H-indol-1-yl), isoindolyl (e.g., 1, 3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., 2, 3-dihydro-1-benzofuran-5-yl), and the like.

When compound (I) is in the form of a salt, examples thereof include: metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the metal salt include: alkali metal salts such as sodium salt, potassium salt, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; attract salt, and the like. Preferred examples of the salt with an organic base include salts with the following organic bases: trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N' -dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include: salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the organic acid include salts with the following organic acids: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), etc., ammonium salts, etc., and when the compound has a basic functional group, examples thereof include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts formed with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

Preparation method

The process for producing the compound (TM) or a salt thereof of the present invention is described below.

The compound (TM) and the starting compound can be prepared according to methods known per se, for example, the methods shown in the following reaction schemes, and the like. In each step of the following preparation method, "room temperature" generally means 5 to 40 ℃, unless otherwise specified, each symbol in the chemical formula described in the reaction scheme is as described above. In the compounds of the formula, each compound includes a salt, and examples of such a salt include a salt similar to the salt of the compound (TM), and the like.

In each reaction, when the raw material compound or the intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, in general, these groups may be protected with a protecting group used in peptide chemistry or the like. After the reaction, the protecting group is removed as necessary, whereby the target compound can be obtained. The introduction and removal of the protecting group can be carried out according to methods known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed", Wiley-Interscience, Inc. (2006) (Theodera W.Greene, Peter G.M.Wuts).

Examples of amino protecting groups include: formyl radical, C_1-6Alkyl-carbonyl, C_1-6Alkoxy-carbonyl, benzoyl, C_7-10Aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), C_7-12Aralkoxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, and the like), trityl, phthaloyl, N-dimethylaminomethylene, optionally substituted with C_1-6Alkyl-substituted silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl, etc.), C_2-6Alkenyl groups (e.g., 1-allyl, etc.), and the like. These radicals being optionally substituted by 1 to 3 atoms selected from halogen atoms, C_1-6Alkoxy and nitro.

Examples of carboxyl protecting groups include: c_1-6Alkyl radical, C_7-12Aralkyl (e.g., benzyl, etc.), phenyl, trityl, optionally substituted with C_1-6Alkyl-substituted silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl, etc.), C_2-6Alkenyl groups (e.g., 1-allyl, etc.), and the like.

Examples of hydroxy protecting groups include: c_1-6Alkyl, phenyl, trityl radical, C_7-12Aralkyl (e.g., benzyl, etc.), formyl, C_1-6Alkyl-carbonyl, benzoyl, C_7-12Aralkyloxy-carbonyl (e.g., benzylcarbonyl, etc.), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, optionally substituted with C_1-6Alkyl-substituted silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl, t-butyldiethylsilyl, etc.), C_2-6Alkenyl groups (e.g., 1-allyl, etc.), and the like.

These radicals being optionally substituted by 1 to 3 atoms selected from halogen atoms, C_1-6Alkyl radical, C_1-6Alkoxy and nitro.

These protecting groups can be removed according to methods known per se, for example, the methods described in "Protective group organic Synthesis, 4th Ed", Wiley-Interscience, Inc. (2006) (Theodora w. Specifically, a method using an acid, a base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or the like can be employed.

If necessary, the reaction in the synthesis step may also be carried out under microwave irradiation using a microwave irradiation apparatus or the like.

The compound obtained in each step may be used directly in the next step in the form of a reaction mixture or crude product, or may be isolated from the reaction mixture according to a conventional method, and may be easily purified according to an isolation method such as recrystallization, distillation, chromatography and the like.

For example, compound (TM) can be prepared according to the following method A or a method similar thereto. The starting compounds in each process may be commercially available products or may also be prepared according to methods known per se or analogously thereto.

Among the compounds (TM), the compounds represented by the formula (TM-1)

Wherein W isEach symbol in the chemical formula is as described above,

(hereinafter, abbreviated as compound (TM)) can be prepared according to the following method A or a method similar thereto. In each step of the preparation process, the starting compounds may be in the form of salts. Examples of the salts include those similar to the salt of the compound (TM).

Method A

Wherein X is a halogen atom and the other symbols are as described above.

In this method, the compound (III) used as a starting material may be a commercially available product, or may also be prepared according to a method known per se or a method similar thereto.

Step A-1

The step is a step of converting the compound (III) into the compound (IV) by subjecting the compound (III) to a halogenation reaction with a halogenating agent.

The halogenating agent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (III).

Examples of the halogenated agents used include: POCl₃、POBr₃Etc., wherein POCl is preferred₃。

In this step, the solvent is not particularly limited, and a solvent may be used or may not be used as long as the reaction can proceed. Examples thereof include: hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane, and the like), halogenated hydrocarbons (e.g., chloroform, dichloromethane, and the like), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like), nitriles (e.g., acetonitrile, and the like), aprotic polar solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like), protic polar solvents (e.g., water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, and the like), and mixtures thereof.

In this step, the reaction temperature is usually from about-50 ℃ to about 200 ℃, preferably from about-10 ℃ to about 100 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.

The compound (IV) thus obtained can be isolated and purified by using a known separation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Step A-2

This step is a step of converting compound (IV) into compound (V) by reacting compound (IV) with a substituted benzylamine.

The substituted benzylamine is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (IV).

Examples of substituted benzylamines used include: 3-nitrobenzylamine, 3-aminobenzylamine and the like, and among them, 3-nitrobenzylamine is preferable.

In this step, the solvent is not particularly limited, and a solvent may be used or may not be used as long as the reaction can proceed. Examples thereof include: hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane, and the like), halogenated hydrocarbons (e.g., chloroform, dichloromethane, and the like), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like), nitriles (e.g., acetonitrile, and the like), aprotic polar solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like), protic polar solvents (e.g., water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, and the like), and mixtures thereof.

In this step, the reaction temperature is usually about-50 ℃ to about 250 ℃, preferably about 50 ℃ to about 250 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.

The compound (V) thus obtained can be isolated and purified by using a known separation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound (V) can be used directly in the next reaction without purification.

Step A-3

This step is a step of converting compound (V) into compound (VI) by reacting compound (V) with a substituting reagent.

The substitution reagent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (V).

In this step, the solvent is not particularly limited as long as the reaction can proceed. Examples thereof include: hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane, and the like), halogenated hydrocarbons (e.g., chloroform, dichloromethane, and the like), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like), nitriles (e.g., acetonitrile, and the like), aprotic polar solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like), protic polar solvents (e.g., water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, and the like), and mixtures thereof.

In this step, the reaction temperature is usually about-50 ℃ to about 200 ℃, preferably about 50 ℃ to about 200 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.

The compound (VI) thus obtained can be isolated and purified by using a known isolation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-soluble base precipitation and the like. Further, the compound (VI) can be used directly in the next reaction without isolation.

Step A-4

This step is a step of converting the compound (VI) into the compound (VII) by reduction of the compound (VI).

The reducing agent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 20mol, per 1mol of the compound (VI).

In this step, the use of the reaction catalyst is not particularly limited, and may or may not be used as long as the reaction can proceed. The catalyst comprises: Pd/C, etc.

In this step, the solvent is not particularly limited as long as the reaction can proceed. Examples thereof include: hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane, and the like), halogenated hydrocarbons (e.g., chloroform, dichloromethane, and the like), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like), nitriles (e.g., acetonitrile, and the like), aprotic polar solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like), protic polar solvents (e.g., water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, and the like), and mixtures thereof.

In this step, the reaction temperature is generally from about-50 ℃ to about 250 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.

In this step, the reaction gas shielding is not particularly limited, and gas shielding may be performed or not, as long as the reaction can be performed. The shielding gas includes: nitrogen, argon, and the like.

The compound (VII) thus obtained can be isolated and purified using known isolation and purification methods, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-soluble base precipitation and the like. Further, the compound (VII) can be used directly in the next reaction without isolation.

Step A-5

This step is a step of converting compound (VII) into compound (TM-1) by subjecting compound (VII) to an amide-forming reaction with a substituting reagent.

The substitution reagent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (VII).

In this step, the solvent is not particularly limited as long as the reaction can proceed. Examples thereof include: hydrocarbons (e.g., benzene, toluene, xylene, hexane, heptane, and the like), halogenated hydrocarbons (e.g., chloroform, dichloromethane, and the like), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like), nitriles (e.g., acetonitrile, and the like), aprotic polar solvents (e.g., N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, and the like), protic polar solvents (e.g., water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-2-propanol, and the like), and mixtures thereof.

In this step, the reaction temperature is usually from about-50 ℃ to about 200 ℃, preferably from about-50 ℃ to about 150 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.

In this step, the reaction gas shielding is not particularly limited, and gas shielding may be performed or not, as long as the reaction can be performed. The shielding gas includes: nitrogen, argon, and the like.

The compound (TM-1) thus obtained can be isolated and purified using known isolation and purification methods, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-base precipitation, and the like.

When the compound (TM) has an optical isomer, a stereoisomer, a regioisomer or a rotamer, these isomers are also included in the scope of the compound (TM), and a single product form can be obtained according to a synthesis method and a separation method known per se (for example, concentration, solvent extraction, column chromatography, recrystallization and the like). For example, when the compound (TM) has an optical isomer, the optical isomer resolved by the compound also has a range within the compound (TM).

The optical isomers can be prepared according to methods known per se. Specifically, optical isomers are obtained using optically active synthetic intermediates or optically resolving racemic end products according to known methods.

The optical resolution method may be a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method, or the like.

1) Fractional recrystallization method

In this method, a racemic salt is formed with an optically active compound (e.g., (+) -mandelic acid, (-) -mandelic acid, (+) -tartaric acid, (-) -tartaric acid, (+) -1-phenylethylamine, (-) -1-phenylethylamine, cinchonine, (-) -cinchonidine, brucine, etc.), which is separated by fractional recrystallization and, if necessary, the free optical isomer is obtained by a neutralization step.

2) Chiral column method

In this method, the racemate or a salt thereof is applied to a column for separating optical isomers (chiral column) to perform separation. For example, in the case of liquid chromatography, a mixture of optical isomers is applied to a chiral column, for example, CHIRA1 series (manufactured by Daicel Chemical Industries, 1 td.) and the like, and developed with water alone, various buffers (for example, phosphate buffers and the like), and organic solvents (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, triethylamine and the like) or a mixture thereof as eluents, to separate the optical isomers. For example, in the case of gas chromatography, the separation is carried out using a chiral column.

3) Non-corresponding isomer process

In this method, a racemic mixture is prepared as a mixture of diastereomers by a chemical reaction of the racemic mixture with an optically active agent, which is converted into a single substance by a typical separation method (e.g., fractional recrystallization method, chromatography method, etc.), and subjected to a chemical treatment such as hydrolysis, etc., to separate an optically active agent moiety, thereby obtaining an optical isomer.

Compound (I) may be crystalline.

The crystals of compound (I) can be prepared according to crystallization methods known per se.

Examples of crystallization methods include: solution crystallization methods, vapor crystallization methods, melt crystallization methods, and the like.

The "solution crystallization method" is generally a method of converting a non-saturated state into a supersaturated state, which changes factors (solvent composition, pH, temperature, ionic strength, redox state, etc.) related to the solubility of a compound or changes the amount of a solvent. Specific examples thereof include: concentration, slow cooling, reaction (diffusion, electrolysis), hydrothermal growth, molten salt growth, and the like. Examples of the solvent used include: aromatic hydrocarbons (e.g., toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), amides (e.g., N-dimethylformamide, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc.), water, etc. These solvents may be used alone, or in combination of two or more solvents in an appropriate ratio (for example, 1: 1 to 1: 100 (volume ratio)). If necessary, a seed crystal may be used.

The "vapor crystallization method" is, for example, a vaporization method (a sealed tube method, a gas flow method), a gas phase reaction method, a chemical transfer method, or the like.

The "melt crystallization method" is, for example, a normal condensation method (single crystal control method, temperature gradient method, British method), a zone melting method (zone equilibrium method, suspension zone method), a specific growth method (V1S method, liquid phase epitaxy method), or the like.

Preferred examples of the crystallization method include the following methods: compound (I) is dissolved in a suitable solvent (e.g., an alcohol such as ethanol, isopropanol, etc.) at-20 ℃ to 120 ℃, and the resulting solution is cooled to a temperature below the dissolution temperature (e.g., -10-50 ℃, preferably-10-20 ℃), and the like.

The crystals of the present invention thus obtained may be isolated, for example, filtered, and the like.

The analysis method of the obtained crystal is generally a crystal analysis method utilizing powder X-ray diffraction. As a method of measuring the crystal orientation, a mechanical method or an optical method, or the like can also be used.

The crystals of the compound (TM) obtained by the above-mentioned production method (hereinafter, abbreviated as "the crystals of the present invention") have high purity, high quality and high stability, and are not denatured even after long-term storage under ordinary conditions. Furthermore, it is also advantageous in terms of biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), expression of effects, etc.), especially for use as a medicament.

In the present specification, the specific optical rotation ([ α ] D) means a specific optical rotation measured by a polarimeter.

In the present specification, the melting point means, for example, a melting point measured using a microscopic melting point measuring apparatus, a DSC (differential scanning calorimetry) apparatus, or the like.

The compound (TM) may be used in prodrug form. The prodrug of the compound (TM) means a compound which can be converted into the compound (TM) by a reaction caused by an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound which is converted into the compound (TM) by an enzymatic oxidation, reduction, hydrolysis reaction or the like; a compound which is converted into the compound (TM) by hydrolysis reaction or the like (due to gastric acid), and the like.

Examples of prodrugs of compound (TM) include:

(1) a compound obtained by acylating, alkylating or phosphorylating an amino group of the compound (TM) (for example, a compound obtained by subjecting an amino group of the compound (TM) to eicosanoylation, alanoylation, pentylaminocarbonylation, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation or cyclopropylcarbonylation, or the like);

(2) a compound obtained by subjecting a hydroxyl group of the compound (TM) to acylation, alkylation, phosphorylation or boronation (for example, a compound obtained by subjecting a hydroxyl group of the compound (TM) to acetylation, palmitoylation, propionylation, pivaloylation, succinylation, fumarylation, alanoylation or dimethylaminomethylcarbonylation, or the like);

(3) a compound obtained by esterifying or amidating a carboxyl group of the compound (TM) (for example, a compound obtained by esterifying a carboxyl group of the compound (TM) with ethyl, phenyl, carboxymethyl, dimethylaminomethyl, pivaloyloxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl, cyclohexyloxycarbonylethyl, formylation or the like), and the like. These compounds can be prepared from the compounds (TM) according to methods known per se.

The prodrug of compound (TM) may also be a compound which is converted to compound (TM) under physiological conditions, as described in the following references: "IYAKUKIN no KAIHATSU (Development of Pharmaceuticals)", Vol.7, Design of Molecules, p 163-.

In the present specification, the compound (TM) and the prodrug of the compound (TM) are sometimes collectively abbreviated as "the compound of the present invention".

Compound (TM) may be a hydrate, a non-hydrate, a solvate or a non-solvate.

The compound (TM) also includes isotopes (e.g.,³H、¹⁴C、³⁵S、¹²⁵i, etc.) and the like.

Compounds (TM) also include deuterium-converted forms, in which the transition is to²H(D)。

The compound (TM) also includes tautomers thereof.

Compound (TM) may be a pharmaceutically acceptable co-crystal or salt thereof. A co-crystal or salt thereof refers to a crystalline substance that is composed of two or more specific solids at room temperature, each solid having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility and stability, etc.). The co-crystals or salts thereof may be prepared according to per se known co-crystallization methods.

The compound (TM) may also be used as a PET tracer.

Since the compounds of the present invention have excellent JAK-1 and/or JAK-3 inhibitory activity, they are also useful as safe drugs based on this effect.

For example, the pharmaceutical agent of the present invention containing the compound of the present invention can be used in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) as a prophylactic or therapeutic agent for JAK-1 and JAK-3-related diseases, more specifically, diseases described in (1) to (4) below (particularly (2)).

(1) Inflammatory diseases (e.g., acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, Systemic Inflammatory Response Syndrome (SIRS), post-operative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, and the like),

(2) autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis, etc.), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, Dermatomyositis (DM), Periarthritis Nodosa (PN), Mixed Connective Tissue Disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves ' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft versus host disease, Addison's disease, abnormal immune responses, arthritis, dermatitis, radiodermatitis, etc.) (particularly psoriasis, rheumatoid arthritis, atopic dermatitis, psoriasis, chronic inflammation, multiple sclerosis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, and systemic lupus erythematosus),

(3) degenerative diseases of the bone and joints (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis, etc.)

(3) Neoplastic diseases [ e.g., malignant tumor, angiogenic glaucoma, infantile hemangioma, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple myeloma, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastatic lesions of breast cancer, lung cancer (e.g., non-small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (e.g., pancreatic ductal cancer, etc.), gastric cancer (e.g., mucinous adenocarcinoma, adenosquamous carcinoma, etc.), papillary adenocarcinoma, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer, etc.), ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian low-malignant potential tumor, etc.), prostate cancer (e.g., hormone-dependent prostate cancer, Hormone-independent prostate cancer and the like), liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer and the like), thyroid cancer (e.g., medullary thyroid cancer and the like), kidney cancer (e.g., renal cell carcinoma, metastatic cell carcinoma of the kidney and urinary duct, and the like), uterine cancer, brain tumor (e.g., astrocytoma of pineal body, fibroastrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and the like), melanoma, sarcoma, bladder cancer, blood cancer and the like, including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, liver cancer, pancreatic endocrine tumor, bile duct cancer, gall bladder cancer, penile cancer, urinary duct cancer, testicular tumor, vulval cancer, cervical cancer, endometrial cancer, pancreatic cancer, and the like, Uterine sarcoma, chorionic disease, vaginal cancer, skin cancer, mycoderma, basal cell tumor, soft tissue sarcoma, malignant lymphoma, hodgkin's disease, myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrohistiocytoma, leiomyosarcoma, rhabdomyosarcoma, unknown primary cancer).

Preferably, the medicament of the present invention can be used as a medicament for preventing, treating and/or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), inflammatory diseases, osteoarticular degenerative diseases or neoplastic diseases, particularly preferably psoriasis, rheumatoid arthritis, inflammatory bowel diseases (preferably crohn's disease or ulcerative colitis), sjogren's syndrome, behcet's disease, multiple sclerosis or systemic lupus erythematosus.

As used herein, the term "prevention" of a disease refers to, for example, administration of a drug containing a compound of the present invention to a patient who is at a high risk of developing a disease due to some disease-related factor but who has not yet developed a disease, or who has developed a disease but has no subjective symptoms, or administration of a drug containing a compound of the present invention to a patient who is afraid of recurrence of a disease after treatment of a disease.

The drugs of the invention show superior pharmacokinetics (e.g., half-life of the drug in plasma), low toxicity (e.g., HERG inhibition, CYP induction), low drug interaction profile. The compound of the present invention can be used as a medicament directly, or a pharmaceutical composition can be prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier as a medicament of the present invention by a method known per se and a method for preparing a pharmaceutical preparation generally used. The pharmaceutical of the present invention can be safely administered orally or parenterally to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, and goats).

The medicaments containing the compounds of the invention can be safely administered alone or as a method for the preparation of pharmaceutical preparations according to methods known per se, mixed with pharmacologically acceptable carriers, and administered using the following forms: for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, and the like), pills, powders, granules, capsules (including soft capsules, microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled release formulations (e.g., immediate release formulations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosa-adherent films), injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous infusion, transdermal absorption formulations, creams, ointments, lotions, adhesives, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, and the like, oral or parenteral (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intratumoral, oral cavity tablets, and the like), oral or parenteral (e.g., intravenous, intramuscular, subcutaneous, intratumoral, intranasal, drop, intracerebral, intrarectal, intravaginal, intraperitoneal, and intratumoral administration, to the vicinity of tumors, and directly to lesions).

The amount of the compound of the present invention in the drug of the present invention is about 0.01 to 100% by weight of the total drug. The dose varies depending on the patient to be administered, the route of administration, the disease, and the like. For example, for oral administration to a patient suffering from psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus (approximately 60kg body weight), one to several servings per day of the active ingredient (compound (TM)) ranging from about 0.01mg/kg body weight to about 500mg/kg body weight, preferably from about 0.1mg/kg body weight to about 50mg/kg body weight, more preferably from about 1mg/kg body weight to about 30mg/kg body weight may be administered.

Pharmaceutically acceptable carriers which can be used for the preparation of the medicament of the present invention include various organic or inorganic carrier substances conventionally used as formulation substances, for solid preparations, for example, excipients, lubricants, binders and disintegrants; or, in the case of liquid drugs, solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, and the like. Further, if necessary, common additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like may also be used in appropriate amounts as appropriate.

Examples of the excipient include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like.

Examples of lubricants include: magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, and the like.

Examples of the binder include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethylcellulose, and the like.

Examples of disintegrants include starch, carboxymethylcellulose calcium, carboxymethyl starch sodium, 1-hydroxypropyl cellulose, and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and the like.

Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of suspending agents include: surfactants such as stearyl triethanolamine, sodium lauryl sulfonate, lauryl alanine, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.

Examples of isotonic agents include glucose, sorbitol, sodium chloride, glycerol, D-mannitol and the like.

Examples of buffers include: buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.

Examples of soothing agents include benzyl alcohol, and the like.

Examples of preservatives include: parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

Examples of antioxidants include sulfite, ascorbic acid, α -tocopherol, and the like.

The compounds of the present invention may also be used together with other drugs for the prevention or treatment of various diseases. Hereinafter, a drug when the compound of the present invention is used together with other drugs is referred to as "the combination drug of the present invention".

For example, when the compound of the present invention is used as a JAK-1 and/or JAK-3 inhibitor, it may be used in combination with the following drugs.

(1) Non-steroidal anti-inflammatory drugs (NSAIDs) including ① traditional NSAIDs, &lTtTtranslation = & "," &gTt & &lTt/T &gTt cyclooxygenase inhibitors (COX-1 selective inhibitors, COX-2 selective inhibitors, etc.), ③ nitric oxide-releasing NSAIDs, &lTtTtranslation = & "&gTt & &lTt/T &gTt JAK inhibitors, etc.;

(2) antirheumatic drugs (DMARDs) to ameliorate disease:

① penicillamine, ② aminosalicylic acid drug ③ pyrimidine synthesis inhibitors, and the like;

in addition to the above, other concomitant drugs include, for example, antibacterial agents, antifungal agents, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, hypotensive diuretics, anticoagulants, tranquilizers, antipsychotics, antitumor drugs, hypolipidemic drugs, muscle relaxants, antiepileptics, antidepressants, antiallergic drugs, cardiac stimulants, therapeutic drugs for arrhythmia, vasodilators, vasoconstrictors, therapeutic drugs for diabetes, antimycotics, vitamins, vitamin derivatives, antiasthmatics, therapeutic agents for pollakiuria/urinary incontinence, antipruritic drugs, therapeutic agents for atopic dermatitis, therapeutic agents for allergic rhinitis, blood pressure increasing agents, endotoxin-antagonists or-antibodies, signal transduction inhibitors, antitussives, and expectorants, Inhibitors of inflammatory mediator activity, antibodies that inhibit inflammatory mediator activity, inhibitors of anti-inflammatory mediator activity, antibodies that inhibit anti-inflammatory mediator activity, and the like.

For the combined use, there is no limitation on the administration time of the compound of the present invention and the concomitant drug, and the compound of the present invention or the concomitant drug may be administered to the patient at the same time, or may be administered to the patient at different times. The dosage of "concomitant drug" can be determined in accordance with the clinically used dosage, and the dosage can be appropriately selected depending on the administration patient, the administration route, the disease, the concomitant drug, and the like.

The administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug can be used in combination. Examples of such modes of administration include the following:

(1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two preparations of the compound of the present invention and the concomitant drug, which are separately prepared, by the same administration route, (3) administration of two preparations of the compound of the present invention and the concomitant drug, which are separately prepared, by the same administration route in an interleaved manner, (4) simultaneous administration of two preparations of the compound of the present invention and the concomitant drug, which are separately prepared, by different administration routes, (5) administration of two preparations of the compound of the present invention and the concomitant drug, which are separately prepared, by different administration routes in an interleaved manner (for example, administration in the order of the compound of the present invention and the concomitant drug, or administration in the reverse order), and the like.

In the combination drug of the present invention, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, the administration route, the disease and the like.

For example, although the content of the compound of the present invention in the combination drug of the present invention varies depending on the form of the preparation, it is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight of the whole preparation.

In the combination drug of the present invention, the content of the concomitant drug varies depending on the form of the preparation, and is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight of the whole preparation.

Meanwhile, the content of additives (e.g., carriers, etc.) in the combined preparation of the present invention varies depending on the form of the preparation, and is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the preparation.

When the compound of the present invention is prepared separately and the drug is used in combination, the same content may be used. The dosage of the combination drug varies depending on the kind of the compound of the present invention, the administration route, the symptoms, the age of the patient, and the like. For example, for oral administration to a patient suffering from rheumatoid arthritis (body weight about 60kg), the dose of compound (TM) is from about 0.1mg/kg body weight to about 30mg/kg body weight, preferably from about 1mg/kg body weight to 20mg/kg body weight, and may be administered once to several times per day.

Any number of drugs used in combination may be used as long as side effects do not cause problems. When the combination drug of the present invention is administered, the compound of the present invention and the concomitant drug may be administered simultaneously, or may be administered in a staggered manner. When administered at intervals, the interval varies depending on the active ingredient, the dosage form and the administration method, and for example, when the drug is first administered in combination, the following administration methods are one example: following administration of the combination drug, the compounds of the present invention are administered within a time range of 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hour. When the compound of the present invention is administered first, the following administration method is an example: the administration of the compound of the present invention is followed by administration of the combination drug over a period ranging from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour.

Examples

Hereinafter, the present invention is explained in more detail with reference to reference examples, experimental examples and formulation examples, but these examples do not limit the present invention and may be changed within the scope of the present invention.

In the examples below, "room temperature" generally means about 10 ℃ to about 35 ℃. The proportions indicated by the mixed solvents are volume mixing proportions unless otherwise specified. Unless otherwise specified,% means wt%.

In silica gel column chromatography, basic silica gel refers to silica gel bound with aminopropylsilane. In high performance liquid chromatography (HPlC), C18 refers to the use of octadecyl bonded silica gel. The ratio of elution solvents is a volume mixing ratio unless otherwise specified.

In the following examples and experimental examples, the following abbreviations are used.

THF: the reaction mixture of tetrahydrofuran and water is taken as a reaction mixture,

HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate,

DIEA: n, N-diisopropylethylamine

M: molar concentration.

Determination by Fourier transform type NMR¹H-NMR (proton nuclear magnetic resonance spectrum). For the analysis, ACD/SpecMarager, etc. were used. The peaks of very light protons (e.g. hydroxyl, amino, etc.) are not described.

MS (Mass Spectrometry) was determined by 1C/MS (liquid chromatography Mass Spectrometry). As the ionization method, an ESI (electrospray ionization) method or the like is used. The data represent those measured values. Typically, molecular ion peaks are observed. In the case of salts, a molecular ion peak or fragment ion peak is usually observed in free form.

Reference example 1

N-methyl-4-aminoimidazole

4-nitroimidazole (1.41g), potassium carbonate (2.5g), methyl iodide (1.9g) and 20mL of acetonitrile were reacted under reflux for 12 h. Spin-drying under reduced pressure, adding 50mL water, extracting with 50mL ethyl acetate for 3 times, mixing organic layers, washing with saturated saline, adding anhydrous Na into organic phase₂SO₄Drying, drying under reduced pressure to obtain 1-methyl-4-nitroimidazole (1.5 g).

1-methyl-4-nitroimidazole (1g), Pd/C (0.1g) and 20ml ethanol were reacted at room temperature for about 24 hours while replacing the air with a hydrogen balloon. Suction filtration over celite was carried out under reduced pressure and the filtrate was dried under reduced pressure to give the title product (0.75 g).

MS(ESI⁺)：[M+H]⁺98.0。

Reference example 2

1- (2-methoxyethyl) -1H-pyrazol-4-amine

The title compound was obtained from 4-nitropyrazole, 2-bromomethylethyl ether, Pd/C using the same method as in reference example 1.

MS(ESI⁺)：[M+H]⁺142.0。

Reference example 3

2- (4-amino-1H-pyrazol-1-yl) ethanol

The title compound was obtained from 4-nitropyrazole, 2-bromoethanol, Pd/C using the same method as in reference example 1.

MS(ESI⁺)：[M+H]⁺128.0。

Reference example 4

1-Ethyl-3-pyrazole boronic acid pinacol ester

The title compound was obtained from 4-nitropyrazole, methyl iodide, Pd/C using the same method as in reference example 1.

MS(ESI⁺)：[M+H]⁺97.0。

Reference example 5

4- (4-morpholinyl) aniline

4-Fluoronitrobenzene (1g), K₂CO₃(1.1g) and 5ml DMSO, stirring at room temperature for 30min, adding morpholine (0.6g) dropwise, heating at 120 deg.C, stirring for 2h, pouring the mixture into mixture of alcohol and water (1: 1)2In 0mL, the yellow precipitate was filtered to give 1.4g of 4- (4-nitrophenyl) morpholine. 4- (4-Nitrophenyl) morpholine (1g), Pd/C (0.1g) and 20ml ethanol were reacted at room temperature for about 24 hours while replacing the air with a hydrogen balloon. Suction filtration was performed on celite under reduced pressure, and the filtrate was dried under reduced pressure to give the title product (0.85 g).

MS(ESI⁺)：[M+H]⁺179.1。

Reference example 6

4- (4-methylpiperazine) aniline

Using the same method as in reference example 5, from 4-fluoronitrobenzene, K₂CO₃N-methylpiperazine, Pd/C gave the title product.

MS(ESI⁺)：[M+H]⁺192.1。

Example 1

N- (3- (((6- (4-morpholinylphenylamino) -4-pyrimidinyl) amino) methyl) phenyl) acrylamide

A) N- (3-nitrobenzyl) -6-chloro-4-pyrimidinamine

To 4, 6-dichloropyrimidine (1.7g) and 25mL of isopropanol were added 3-nitrobenzylamine (2g) and DIEA3.8g at room temperature, and the mixture was stirred at room temperature for 1 hour, then reacted at reflux for 6 hours, cooled to room temperature, and a precipitate was precipitated, which was filtered off with suction and washed to give the title compound (2.4 g).

MS(ESI⁺)：[M+H]⁺265.0

B) N-4- (4-Morpholphenyl) -N-6- (3-nitrobenzyl) -4, 6-pyrimidinediamine

To N- (3-nitrobenzyl) -6-chloro-4-pyrimidinamine (2g) and N-butanol (25 mL) at room temperature were added 4- (4-morpholinyl) aniline (1.48g) and TFA (2g), and the mixture was stirred at room temperature for 1 hour, followed by reflux for 6 hours, cooled to room temperature, precipitated, filtered, and washed to give the title compound.

MS(ESI⁺)：[M+H]⁺407.2

C) N-4- (3-aminobenzyl) -N-6- (4-morpholinylphenyl) -4, 6-pyrimidinediamine

To a reaction flask were added N-4- (4-morpholinophenyl) -N-6- (3-nitrobenzyl) -4, 6-pyrimidinediamine (0.2g), 0.02g Pd/C, and 20ml EtOH, N₂Heating to reflux under protection, slowly dropwise adding 85% hydrazine hydrate (0.32g) within 30min, reacting after dropwise adding, filtering, and drying the filtrate under reduced pressure to obtain the title compound.

MS(ESI⁺)：[M+H]⁺377.2

D) N- (3- (((6- (4-morpholinophenylamino) pyrimidin-4-yl) amino) methyl) phenyl) acrylamide

The title compound was obtained by adding N-4- (3-aminobenzyl) -N-6- (4-morpholinophenyl) -4, 6-pyrimidinediamine (0.04g) to a reaction flask, 10mL of dried DCM, 1mL of acryloyl chloride diluted with dried DCM was added dropwise at 0 deg.C, stirring for 30min, and suction filtration.

¹H NMR(300MHz，HCl salt，DMSO-d₆)δ10.67(s)，10.04(s，1H)，8.70(s，1H)，8.28(s，1H)，7.81(d，J＝9Hz，1H)，7.68(s，1H)，7.30(t，J＝9Hz，1H)，7.19(d，J＝9Hz，2H)，6.93(d，J＝6Hz，2H)，6.80(d，J＝9Hz，1H)，6.61(dd，J＝15，9Hz，1H)，6.22(d，J＝15Hz，1H)，5.82(s，1H)，5.71(d，J＝9Hz，1H)，4.40(s，2H)，3.71(s，4H)，3.07(s，4H).

MS(ESI⁺)：[M+H]⁺430.2。

Examples 2 to 7

In examples 2 to 27, the title compound was obtained in the same manner as in example 1. The MS in the table is an observed value.

TABLE 1

Example 28

N- (3- (((6- (4-morpholinylphenylamino) -4-pyrimidinyl) amino) methyl) phenyl) cyanamide

Experimental Steps A), B), C) Using the same procedure as in example 1, N-4- (3-aminobenzyl) -N-6- (4-morpholinophenyl) -4, 6-pyrimidinediamine was obtained

D) N- (3- (((6- (4-morpholinylphenylamino) -4-pyrimidinyl) amino) methyl) phenyl) cyanamide

N-4- (3-aminobenzyl) -N-6- (4-morpholinophenyl) -4, 6-pyrimidinediamine (0.094g), AcOK (0.057g) and 10ml of anhydrous methanol were added with bromocyanogen (0.037g) at 0 ℃ and reacted at room temperature overnight. After the reaction, water was added and the reaction mixture was quenched, dried under reduced pressure, and purified by silica gel column chromatography using 10mL of DCM system sand to obtain the title compound.

MS(ESI⁺)：[M+H]⁺401.2。

Examples 29 to 34

In examples 29 to 34, the title compound was obtained in the same manner as in example 28. The MS in the table is an observed value.

TABLE 2

Example 35

2-cyano-N- (3- (((6- (4-morpholinylphenylamino) -4-pyrimidinyl) amino) methyl) phenyl) acetamide

Experimental steps a), B), C) N-4- (3-aminobenzyl) -N-6- (4-morpholinophenyl) -4, 6-pyrimidinediamine was obtained in the same manner as in example 1.

D) 2-cyano-N- (3- (((6- (4-morpholinylphenylamino) -4-pyrimidinyl) amino) methyl) phenyl) acetamide

N-4- (3-aminobenzyl) -N-6- (4-morpholinophenyl) -4, 6-pyrimidinediamine (0.08 g), cyanoacetic acid (0.02g), DIEA (0.07g) and 15mL of dried DCM were added to HATU (0.2g) with stirring at 0 ℃ and reacted for 30min, followed by stirring at room temperature. After the reaction was complete, 20ml of DCM were added and saturated NaHCO was added₃The title compound was obtained by washing twice with aqueous solution, mixing the samples with organic phase, and separating and purifying by silica gel column chromatography.

MS(ESI⁺)：[M+H]⁺443.2。

Examples 36 to 41

In examples 36 to 42, the title compound was obtained in the same manner as in example 35. The MS in the table is an observed value.

TABLE 3

Experimental example (JAK1, JAK-2 and JAK-3 enzyme inhibition assay)

Purpose of the experiment:

compounds were evaluated for their inhibitory effects on JAK1, JAK-2 and JAK-3 kinases.

The experimental principle is as follows:

proteolytic effects of fluorescence resonance energy transfer technology (FRET) -based coupled proteolytic enzymes on specific phosphorylated versus non-phosphorylated polypeptide substrates. Two ends of the polypeptide substrate are respectively marked as FRET energy donor coumarin and energy acceptor fluorescein, and then the donor and the acceptor can be excited to transfer energy when being close to each other.

In the Kinase Reaction (Kinase Reaction), JAK1, JAK-2 or JAK-3 can transfer gamma-phosphate in ATP to a single tyrosine residue of a polypeptide substrate, and if an inhibitor of JAK1, JAK-2 or JAK-3 exists in the system, the gamma-phosphate group on ATP is not transferred to the substrate polypeptide, so that phosphorylation Reaction cannot occur. An evaluation experiment of a kinase inhibitor is designed based on the principle, a substrate polypeptide is provided with a kinase phosphorylation site and a protein enzyme cutting site, two ends of the substrate polypeptide are respectively connected with 2 fluorescent groups which are respectively a donor and an acceptor, if the activity of the kinase is kept in a reaction system, a gamma-phosphate group is transferred to the enzyme cutting site of a substrate, so that the substrate polypeptide cannot be cut by protease and is separated into two sections, and under the excitation of laser with specific wavelength, the energy of one section of fluorescence can be transferred to the fluorescent group at the other end to emit energy. Otherwise, after the enzyme activity is inhibited, the phosphate group can not be transferred, the enzyme cutting site of the substrate can be cut by enzyme in the system, and the substrate is separated into two sections, so that the energy transfer of fluorescence can not occur. Based on this, the activity of the kinase was evaluated.

The experimental steps are as follows:

in this experiment, 10. mu.l of a kinase reaction system was selected, and 2.5. mu.l of kinase (concentration: 1nM), 2.5. mu.l of a polypeptide substrate (concentration: 2. mu.M), 2.5. mu.l of ATP (concentration: 10. mu.M) and 2.5. mu.l of a compound were added to each system, and reacted at room temperature for 1 hour, then 5. mu.l of a test solution was added, reacted at room temperature for 1 hour, and 5. mu.l of a stop buffer was added thereto. Fluorescence intensity (detection of coumarin emission at 445nm and fluorescein emission at 520nm under 400nm excitation) was measured using a microplate reader (Synergy H1, BioTek, USA). The inhibitory activity of each compound was calculated, wherein the fluorescence intensity of wells without enzyme was considered to be 100% inhibition.

TABLE 11

TABLE 12 IC inhibition of kinase phosphorylation levels by active compounds₅₀Results

Formulation example 1 (preparation of tablets)

The total amount of 1), 2), 3) and 4) (30g) were stirred with water, dried under vacuum and sieved. The sieved powder was mixed with 4) (14g) and 5) (1g) and the mixture was pressed with a tablet press, whereby 1000 tablets each containing 30mg of the compound of example 1 were obtained.

Formulation example 2 (preparation of capsules)

Mixing 1), 2), 3) and 4) and filling into capsules.

The compound of the present invention has an excellent JAK-1 and/or JAK-3 inhibitory action and is useful as a medicament for preventing, treating or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.) and the like.

Claims (9)

1. A compound represented by the formula (TM):

wherein

X₁Is a nitrogen atom or-CH-;

X₂is a nitrogen atom or-CH-;

w isSubstituted or unsubstituted C_3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;

y is independently selected from substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8A 4-, 5-or 6-membered heteroaryl group substituted or unsubstituted with a heterocycloalkyl group;

R₁is independently selected from hydrogen atom, halogen, cyano, hydroxyl, Wherein,

z is independently selected from hydrogen atom, halogen, cyano, hydroxyl;

R₇、R₈、R₉and R₁₀Independently selected from hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6Heterohydrocarbyl or substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted C_3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;

R₂is a hydrogen atom, unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6Heterohydrocarbyl or substituted or unsubstituted C_3-8A cyclic hydrocarbon group;

R₃is a hydrogen atom, a halogen atom, a cyano group, an amino group, an optionally substituted C_1-6A hydrocarbyl group;

R₄is a hydrogen atom, a halogen atom, a substituted or unsubstituted 4-, 5-, 6-, 7-or 8-membered heterocyclic ring;

R₅is optional and when present is a bond, optionally substituted or unsubstituted C_1-6A hydrocarbyl group;

R₆is optional and when present is a bond, optionally substituted or unsubstituted C_1-6Hydrocarbyl or substituted or unsubstituted C_1-6A heterohydrocarbyl group.

2. A compound or salt thereof according to claim 1, wherein the compound has the formula (I), (II),

3. a compound according to any one of claims 1-2, wherein R₁Is a cyano group,

4. A compound according to any one of claims 1 to 3, wherein R₄Is a hydrogen atom, a fluorine atom, a substituted or unsubstituted 4-, 5-or 6-membered nitrogen-containing heterocyclic ring.

5. A compound according to any one of claims 1 to 4 wherein Y is a nitrogen-containing five-membered heteroaromatic ring.

6. A compound according to any one of claims 1 to 5, wherein R₆Is that

(1) Methyl radical

(2) C optionally substituted with 1 to 3 substituents selected from the group consisting of_1-6Alkyl groups: (a) halogen atom, (b) hydroxyl group, (C) C_1-6Alkoxy group, (d) C_3-8Cycloalkyl, (e) C_1-6Alkyl-carbonyl mono-or di-substituted amino.

7. The compound of any one of claims 1-6, which is a JAK-1 and/or JAK-3 inhibitor.

8. The compound or a salt thereof according to claim 7, which is a drug for preventing, treating and/or ameliorating an autoimmune disease.

9. The medicament of claim 8, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, or systemic lupus erythematosus.