KR20190062081A - Jak inhibitor compounds, and method of preparing the same - Google Patents

Abstract

The present invention relates to a JAK inhibitor compound and a method for manufacturing the same. More particularly, the present invention relates to a compound of chemical formula I or a pharmaceutically acceptable salt thereof. The present invention can exhibit therapeutic effects on inflammatory diseases, autoimmune diseases, myeloproliferative diseases, cancer of human body and the like.

Description

JAK INHIBITOR COMPOUNDS, AND METHOD OF PREPARING THE SAME < RTI ID = 0.0 >

The present invention relates to JAK inhibitor compounds, and methods for their preparation.

Protein kinases (PKs) are a class of enzymes that regulate a variety of important biological processes, including cell growth, survival and differentiation, organogenesis and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of the protein (or substrate), thereby modulating the cellular activity of the substrate in a variety of biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in the host of human disease, including cancer. A subpopulation of protein kinases (also referred to as tumor protein kinase), when not regulated, induces tumor formation and growth, and also contributes to tumor progression and progression. Thus, tumor protein kinases are one of the largest and most interested groups of protein targets for cancer regulation and drug development.

The Janus Kinase (JAK) class plays an important role in the cytokine-dependent regulation of cell proliferation and action involved in the immune response. At present, the following four members of the mammalian JAK class are known: JAK1 (Janus kinase-1), JAK-2 (Janus kinase-2), JAK3 (Janus kinase-3) and TYK2 (Protein-Tyrosine Kinase 2) . The size of the JAK protein ranges from 120 kDa to 140 kDa and includes seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other is potentially regulatory and / or STAT Is a pseudokinase domain capable of functioning as a docking site for < Desc / Clms Page number 2 >

Blocking signal transduction at the level of JAK kinase has the potential for the development of therapies for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer of the human body, Will have a therapeutically beneficial effect on the patient suffering from.

Therefore, inhibitors against Janus kinase or related kinases are extensively sought, and several patent publications report effective classes of compounds. For example, pyrrolopyridines and pyrrolopyrimidines may act as some JAK inhibitors, as disclosed in US Patent Application Publication No. US2007 / 0135461 A1 (Patent Document 1). As a result, all of the contents disclosed in Patent Document 1 are cited by the prior art in this specification.

US 2007/0135461 A1 (Jun. 14, 2007)

It is an object of the present invention to provide a novel compound having Janus kinase inhibitory activity.

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems of the prior art,

Claims 1. A compound of formula (I): < EMI ID = 32.1 >

(I)

In this formula,

R ₁ is a hydrogen group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₈ cycloalkyl group;

R ₂ is a hydrogen group, or a C ₁ -C ₃ alkyl group;

, 또는

이고;R ₃ represents a hydrogen group,

, or

ego;

R ₄ and R ₅ are each independently a hydrogen group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;

Provided that when R ₄ and R ₅ are simultaneously a hydrogen group, R ₁ is not a hydrogen group.

In the present invention, R ₁ is a methyl group, or a pharmaceutically acceptable salt thereof.

In the present invention, R ₂ is a hydrogen group or a methyl group, or a pharmaceutically acceptable salt thereof.

In the present invention, R ₄ and R ₅ each independently represent a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group, or a pharmaceutically acceptable salt thereof.

Also provided is a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising a compound of any one of the present invention or a pharmaceutically acceptable salt thereof.

The present invention can modulate signal transduction at the level of JAK kinase, for example, to show therapeutic effects on inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer of the human body.

Hereinafter, the present invention will be described in detail.

An aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I)

In this formula,

R ₁ is a hydrogen group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₈ cycloalkyl group;

R ₂ is a hydrogen group, or a C ₁ -C ₃ alkyl group;

, 또는

이고;R ₃ represents a hydrogen group,

, or

ego;

R ₄ and R ₅ are each independently a hydrogen group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;

Provided that when R ₄ and R ₅ are simultaneously a hydrogen group, R ₁ is not a hydrogen group.

The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds of this invention are included in the present invention. Also, a number of geometric isomers such as olefins, C = N double bonds, etc., can be present in the compounds, and all the stable isomers thereof are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the invention are described, which can be isolated as a mixture of isomers or in isolated isomeric forms. The compounds of the present invention may be isolated in optically active form or in racemic form. Methods for preparing optically active forms (e. G., By resolution in racemic form or by synthesis from optically active starting materials) are well known in the art. Unless specific stereochemistry or isomeric forms are specifically indicated, all chiral (enantiomeric and diasteriomeric) and racemic forms of the structure, and all geometric isomeric forms are contemplated.

The compounds represented by the above formula (I) can control the activity of Janus kinase (JAK). As used herein, the term " modulate " refers to the ability to increase or decrease the activity of one or more of the JAK kinases. Thus, the compounds of the present invention can be used in a method of modulating JAK by contacting JAK with at least one compound or composition of the invention. In particular, in some embodiments, a compound of the invention may act as an inhibitor of one or more JAKs.

JAKs that the compounds of the invention bind and / or modulate include any member of the JAK family. In some embodiments, the JAK is JAK1, JAK2, JAK3, or TYK2. In some embodiments, the JAK is JAK1 or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, JAK is JAK3.

Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising the compound represented by the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof.

JAK-related diseases include diseases or diseases or conditions that are directly or indirectly related to the expression or activity of JAK, such as hyperplasia and / or abnormal activity. In addition, JAK-related diseases include diseases, diseases or conditions that can be prevented, alleviated or cured by controlling JAK activity.

Examples of JAK-related diseases include, but are not limited to, immune system related diseases such as organ transplant rejection (e.g., transplant rejection and graft versus host response), multiple sclerosis, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis Inflammatory bowel disease, ulcerative colitis, Crohn's disease, severe myasthenia gravis, immunoglobulin nephritis, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune, (PV) or water-repellent oil pumice window (BP).

Other examples of JAK-related diseases include inflammatory and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye such as iritis, uveitis, scleritis, conjunctivitis or related diseases, inflammatory diseases of the respiratory tract such as upper respiratory tract including nose and sinus such as rhinitis or sinusitis, Obstructive pulmonary disease, and the like), inflammatory myopathies such as myocarditis and other inflammatory diseases. Other inflammatory diseases include, for example, systemic inflammatory response syndrome (SIRS) and sepsis shock, and may also be used to treat them.

Other examples of JAK-related diseases include cancer characterized by solid tumors such as prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, (AML) or multiple myeloma), and skin cancers such as skin T-cell lymphoma (CTCL) and skin B-cell lymphoma are administered to a mammal in need of such treatment, . Examples of skin T-cell lymphomas include Sezary syndrome and bacterial sarcoma.

In addition, it can be used to treat diseases or conditions related to ischemic reperfusion injury or inflammatory ischemic cases such as stroke or cardiac arrest, and can also be used to treat stenosis, percutaneous dermatitis or fibrosis.

In addition, the JAK inhibitors of the present invention may also be used to treat conditions associated with hypoxia or astrocytosis, such as diabetic retinopathy, cancer or neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390 (Pt 2): 427-36) and [Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Epub 2004 Mar 2]. The JAK inhibitors of the present invention can also be used to treat Alzheimer's disease.

Furthermore, the JAK inhibitors of the present invention can also be used to treat gout and prostatic enlargement due to, for example, benign prostatic hyperplasia or benign prostatic hyperplasia.

The pharmaceutical compositions of the present invention may be administered orally in dosage forms such as tablets, capsules (each of which includes a sustained release or time release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions . They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

In addition, the pharmaceutical composition of the present invention can be administered intranasally via topical use of suitable intranasal vehicles, or via the transdermal route using a transdermal patch. When administered in the form of a transdermal delivery system, administration of the dose will, of course, be continuous rather than intermittent throughout the course of the administration.

In various embodiments of the compounds represented by the above formula I, the compounds may specifically illustrate the compounds of Tables 1 and 2. The values of JAK1, JAK2, and JAK3 are shown by testing the IC50 concentration of each compound.

The compounds of the present invention represented by formula (I) including the exemplified compounds of Tables 1 and 2 above can be prepared by the methods specifically described in the general synthesis procedures described below. As a person skilled in the art, it will be understood from the description of this general synthesis procedure that the synthesis method for the specific exemplified compounds or the example compounds will also be understood from the description of the individual synthesis methods for each compound.

Scheme  1. 1- benzylpiperidine -4-amine < / RTI > or derivative compounds thereof

[General Scheme I]

Reagents and conditions: (a) t- butyl piperidin-4-yl carbamate, K ₂ CO ₃ , DMF, room temperature; (b) 10% HCl in MeOH, room temperature

General Procedure A

K ₂ CO ₃ (0.83 g, 5.99 mmol) and aryl halide (ex.bromide) (2.75 mmol) were added to a solution (solvent DMF (5 ml), t -butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol) Dropwise at room temperature. The reaction mixture was mixed at room temperature for about 8 hours. After the reaction, the resultant was poured into Et ₂ O (40 ml), washed with H ₂ O (40 ml), brine (40 ml), and dried MgSO ₄ . The crude compounds were purified by silica gel chromatography (30% Ethyl acetate in n-Hexane elution) (0.61 g, yield 78%).

General Procedure B

tert-butyl (1-aryl piperidin-4-yl) carbamate (2 mmol) was added to a 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. The yield (~ 100% yield) was used without further purification.

tert - Butyl  (1- (3- cyanobenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 78%); ¹ H NMR (400 MHz, CD ₃ OD)? 7.73 (br.s, 1H), 7.68-7.63 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H) 2 H), 1.89-1.91 (m, 2 H), 1.55-1.46 (m, 2 H), 3.40-3.32 H), 1.45 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 25 N 3 O 2 [M + H] + 315.19, found 316.10.

tert - Butyl  (1- (3- 메틸oxy ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 74%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.24 (t, J = 7.6 Hz, 1 H), 6.94-6.88 (m, 2 H), 6.84 (dd, J = 2.4, 8.4 Hz, 1 H), (M, 2H), 3.80-3.32 (m, 1H), 2.90-2.83 (m, 2H), 2.16-2.07 (m, 2H), 1.88-1.81 m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 3 [M + H] + 320.21, found 321.25.

tert - Butyl  (One-( 피리딘 -4- ylmethyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 54%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.49 (d, J = 6.0 Hz, 2 H), 7.44 (d, J = 6.0 Hz, 2 H), 3.58 (s, 2 H), 3.41-3.31 ( (m, 2H), 1.45 (s, 1H), 2.87-2.81 (m, 2H), 2.20-2.12 9 H). MS (ESI, m / z ) calculated for C ₁₆ H ₂₅ N ₃ O ₂ [M + H] ⁺ 291.19, found 292.30.

tert - Butyl  (1- (3,4- dimethoxybenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 55%); ^{1 H NMR (400 MHz, CDCl} 3) δ 6.87 (br. S, 1 H), 6.84-6.77 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.53-3.42 (m, 1H), 3.42 (s, 2H), 2.83-2.74 (m, 2H), 2.11-2.00 (m, 2H), 1.94-1.86 , 2 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 19 H 30 N 2 O 4 [M + H] + 350.22, found 351.30.

tert - Butyl  (1- (2- methoxybenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (yield: 93%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.31-7.25 (m, 2 H), 6.98 (d, J = 8.2 Hz, 1 H), 6.93 (t, J = 7.5 Hz, 1 H), 3.84 ( (m, 2H), 2.29-2.13 (m, 2H), 1.87-1.79 (m, 2H), 3.59 , 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 3 [M + H] + 320.21, found 321.10.

tert - Butyl  (1- (4- methoxybenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 81%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.24 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 3.80 (s, 3 H), 3.47 (s, (M, 2H), 1.38-1.80 (m, 2H), 1.53-1.44 (m, 2H), 2.38-2.22 2 H), 1.44 (s, 9 H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₈ N ₂ O ₃ [M + H] ⁺ 320.21, found 321.30.

tert - Butyl  (1- (3- hydroxybenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (yield: 87%); ¹ H NMR (400 MHz, CD ₃ OD)? 7.15 (t, J = 8.4 Hz, 1H), 6.82-6.77 (m, 2H), 6.73-6.69 2 H), 1.89-1.81 (m, 2 H), 1.55-1.45 (m, 2 H), 2.93-2.85 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 17 H 26 N 2 O 3 [M + H] + 306.19, found 307.20.

tert - Butyl  (1- (3- bromobenzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 81%); ^{1 H NMR (400 MHz, CDCl} 3) δ 7.47 (br. S, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.16 (t , J = 7.6 Hz, 1 H ), 3.53-3.40 (m, 1 H), 3.43 (s, 2 H), 2.82-2.72 (m, 2 H), 2.12-2.02 (m, 2 H), 1.94- 1.86 (m, 2H), 1.48-1.38 (m, 2H), 1.44 (s, 9H). MS (ESI, m / z ) calculated for C ₁₇ H ₂₅ BrN ₂ O ₂ [M + H] ⁺ 368.11, found 371.25.

tert - Butyl  (1- (3- 메틸benzyl ) piperidine -4- yl ) carbamate

Was synthesized according to general procedure A (Yield: 57%); ¹ H NMR (400 MHz, CD ₃ OD)? 7.21 (t, J = 7.6 Hz, 1H), 7.16 (br.s, 1H), 7.13-7.08 (M, 2H), 2.35 (s, 3H), 2.16-2.06 (m, 2H), 1.88-1.80 (m, 2H), 3.39-3.31 , 1.55-1.45 (m, 2H), 1.45 (s, 9H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 2 [M + H] + 304.22, found 305.00.

3 - ((4- aminopiperidine -One- yl ) methyl ) benzonitrile hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.07 (br. S, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.71 ( t, J = 7.8 Hz, 1 H), 4.47 (s, 2 H), 3.67-3.58 (m, 2 H), 3.58-3.48 (m, 1 H), 3.32-3.22 (m, 2 H), 2.35 -2.26 (m, 2H), 2.17-2.03 (m, 2H). MS (ESI, m / z) calculated for C 13 H 17 N 3 [M + H] + 215.14, found 216.10.

1- (3- Methoxybenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.42 (t, J = 7.9 Hz, 1 H), 7.23 (br. S, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 7.06 ( 3H), 3.63-3.55 (m, 2H), 3.57-3.44 (m, 1H), 3.28 (d, J = 8.2 Hz, 1H) -3.17 (m, 2H), 2.31-2.23 (m, 2H), 2.15-2.01 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.15.

One-( Pyridine -4- ylmethyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.86 (d, J = 6.3 Hz, 2 H), 8.32 (br. S, 2 H), 7.82 (d, J = 6.4 Hz, 2 H), 4.45 (m, 2H), 3.45 (d, J = 12.3 Hz, 2H), 3.37-3.25 (m, 1H), 3.20-3.00 1.94-1.68 (m, 2 H). MS (ESI, m / z) calculated for C 11 H 17 N 3 [M + H] + 191.14, found 192.10.

1- (3,4- diMethoxybenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.51 (br. S, 3 H), 7.41 (d, J = 1.6 Hz, 1 H), 7.06 (dd, J = 1.5, 8.2 Hz, 1 H) , 6.99 (d, J = 8.3 Hz, 1 H), 4.17 (d, J = 4.7 Hz, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.38-3.30 (m, 2 H), 3.31-3.14 (m, 1H), 3.06-2.94 (m, 2H), 2.18-2.09 (m, 2H), 2.09-1.96 (m, 2H). MS (ESI, m / z) calculated for C 14 H 22 N 2 O 2 [M + H] + 250.17, found 251.15.

1- (2- Methoxybenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.61 (br. S, 3 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.19 (d, J = 4.6 Hz, 2H), 3.85 m, 2 H), 3.33-3.19 (m, 1H), 3.10-2.98 (m, 2H), 2.17-2.09 (m, 2H), 2.08-1.95 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.25.

1- (4- Methoxybenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.50 (br. S, 3 H), 7.53 (d, J = 8.6 Hz, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 4.17 (d, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.39-3.31 (m, 2H), 3.28-3.13 (m, 1H), 3.03-2.92 2.16-2.07 (m, 2H), 2.04-1.92 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.25.

3 - ((4- Aminopiperidine -One- yl ) methyl ) phenol hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.34 (br. S, 3 H), 7.24 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 6.96 (m, 2H), 3.27-3.17 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.14 (d, J = 4.8 Hz, 2H) , 1H), 3.03-2.91 (m, 2H), 2.14-2.04 (m, 2H), 2.01-1.89 (m, 2H). MS (ESI, m / z ) calculated for C ₁₂ H ₁₈ N ₂ O [M + H] ⁺ 206.14, found 207.25.

1- (3- Bromobenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.50 (br. S, 3 H), 7.92 (br. S, 1 H), 7.68-7.62 (m, 2 H), 7.42 (t, J = 7.8 Hz), 4.27 (d, J = 4.6 Hz, 2H), 3.43-3.32 (m, 2H), 3.29-3.18 (m, 1H), 3.08-2.97 -2.08 (m, 2 H), 2.06-1.95 (m, 2 H). MS (ESI, m / z ) calculated for C ₁₂ H ₁₇ BrN ₂ [M + H] ⁺ 268.06, found 271.10.

1- (3- Methylbenzyl ) piperidine -4- amine hydrochloride

Was synthesized according to general procedure B; ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.44 (br. S, 3 H), 7.43-7.38 (m, 2 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1H), 4.19 (d, J = 4.8 Hz, 2H), 3.39-3.31 (m, 2H), 3.28-3.16 (m, 1H), 3.05-2.94 ), 2.33 (s, 3 H), 2.15-2.06 (m, 2 H), 2.04-1.93 (m, 2 H). MS (ESI, m / z) calculated for C 13 H 20 N 2 [M + H] + 204.16, found 205.25.

Scheme  2. Synthesis of Compound

[General Scheme II]

Reagents and conditions: (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ° C

General procedure C

CDI (1.07 g, 6.61 mmol) was added dropwise to a solution of 4-chloro- 1H- pyrrolo [2,3- b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF , And the reaction mixture was stirred at room temperature for about 1 hour. To this mixture was slowly added dropwise 2.0 mmol of various amines (30 mmol, solvent THF), followed by stirring at room temperature for about 1 hour. The resulting mixture was poured into ethyl acetate and a white solid was obtained as a precipitate.

General procedure D

NMP (2 ml) of 1- (benzyl) piperidin-4- amine hydrogen chloride salt (0.36 g, 1.43 mmol) in TEA (0.40 ml, 2.86 mmol) and 4-chloro- N -alkyl-1 H -pyrrolo solution [ 2,3- b ] pyridine-5-carboxamide (0.286 mmol) was added dropwise thereto, followed by stirring at about 180 ° C for about 3 hours under microwave irradiation. The resultant was cooled to room temperature, distilled with ethyl acetate and then washed with H ₂ O, brine, dried MgSO ₄ . The crude compounds were purified by silica gel property chromatography (20% Methaol in dichloromethane elution) to give the title product.

4-Chloro-N-methyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure C (Yield 76%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.19 (br. S, 1 H), 8.45-8.38 (m, 1 H), 7.66 (d, J = 3.5 Hz, 1 H), 6.57 (d, J = 3.5 Hz, 1H), 2.80 (d, J = 4.6 Hz, 3 H). ¹³ C NMR (100 MHz, DMSO- d ₆ ) 隆 166.24, 148.98, 142.77, 132.01, 128.82, 124.87, 118.97, 99.31, 26.66. MS (ESI, m / z ) calculated for C ₉ H ₈ ClN ₃ O [M + H] ⁺ 209.04, found 210.00.

4-Chloro-N-cyclopropyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure C (62% yield); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.18 (s, 1 H), 8.53 (d, J = 4.4 Hz, 1 H), 8.21 (s, 1 H), 7.65 (d, J = 3.5 Hz , 1H), 6.56 (d, J = 3.5 Hz, 1H), 2.91-2.80 (m, 1H), 0.76-0.66 (m, 2H), 0.60-0.51 (m, 2H). ¹³ C NMR (100 MHz, DMSO- d ₆ )? 167.01, 148.94, 142.63, 132.06, 128.81, 124.79, 118.93, 99.29, 23.39, 6.25. MS (ESI, m / z ) calculated for C ₁₁ H ₁₀ ClN ₃ O [M + H] ⁺ 235.05, found 235.95.

4-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure C (71% yield); ¹ H NMR (400 MHz, DMSO- d ₆ )? 8.44 (s, 1H), 7.49 (d, J = 3.4 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1H). ^{13 C NMR (100 MHz, DMSO-} d 6) δ 168.76, 148.24, 145.29, 132.33, 128.10, 127.23, 119.13, 99.24. MS (ESI, m / z ) calculated for C ₈ H ₆ ClN ₃ O [M + H] ⁺ 195.02, found 196.90.

4-Chloro-N-cyclopentyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure C (yield 32%); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.44 (d, J = 7.2 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d, J = 3.4 Hz, 1 H), 6.56 (d , J = 3.4 Hz, 1H), 4.27-4.17 (m, 1H), 1.96-1.82 (m, 2H), 1.78-1.61 (m, 3H), 1.59-1.42 (m, 5H). ¹³ C NMR (100 MHz, DMSO- d ₆ )? 165.27, 148.90, 142.64, 131.96, 128.74, 125.29, 118.89, 99.19, 51.43, 32.64, 24.03. MS (ESI, m / z) calculated for C 13 H 14 ClN 3 O [M + H] + 263.08, found 263.95.

Example  One

4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield 17%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.38 (s, 1 H), 7.99 (br. S, 1 H), 7.93-7.89 (m, 8.1 Hz, 2 H), 7.73 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 4.0 Hz, 1H), 4.62-4.52 (m, 1H), 4.50 3.67-3.50 (m, 2H), 3.50-3.38 (m, 2H), 2.93 (s, 3H), 2.52-2.40 (m, 2H), 2.18-1.90 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD)? 168.08, 152.04, 138.93, 135.68, 135.68, 134.79, 134.68, 133.53, 130.63, 123.83, 117.49, 113.22, 106.50, 104.86, 103.67, 58.85, 48.44, 29.26, 25.37. MS (ESI, m / z) calculated for C 22 H 24 N 6 O [M + H] + 388.20, found 389.10.

Example  2

4 - ((1- (3-Methoxybenzyl) piperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (27% yield); ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.44 (d, J = 7.9 Hz, 1 H), 8.28 (s, 1 H), 8.22 (d, J = 4.4 Hz, 1 H), 7.23 (t , J = 8.0 Hz, 1 H ), 7.15-7.12 (m, 1 H), 6.92-6.87 (m, 2 H), 6.81 (d, J = 7.1 Hz, 1 H), 6.48 (br. s, 1 2 H), 2.74 (d, J = 4.3 Hz, 3 H), 4.02-3.92 (m, 1H), 3.75 H), 2.30-2.22 (m, 2H), 2.05-1.97 (m, 2H), 1.58-1.47 (m, 2H). ^{13 C NMR (100 MHz, CD} 3 OD) δ 167.96, 160.40, 152.11, 138.61, 134.49, 130.17, 130.14, 130.09, 123.85, 122.87, 121.45, 116.21, 115.47, 104.88, 103.74, 60.26, 54.46, 50.67, 29.58, 25.36. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.10.

Example  3

N -Methyl-4 - ((1- (pyridin-4-ylmethyl) piperidin-4- yl) amino) -1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (20% yield); ¹ H NMR (400 MHz, DMSO- d ₆ )? 9.45 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 5.6 Hz, 2H), 8.29 , J = 4.3 Hz, 1 H ), 7.35 (d, J = 5.5 Hz, 2 H), 7.14 (br. s, 1 H), 6.49 (br. s, 1 H), 4.04-3.95 (m, 1 H), 3.54 (s, 2 H), 2.78-2.67 (m, 2 H), 2.74 (d, J = 4.2 Hz, 2 H), 2.35-2.26 (m, 2 H), 2.06-1.98 (m, 2 H), 1.60-1.49 (m, 2 H). ¹³ C NMR (100 MHz, DMSO- d ₆ )? 170.61, 150.71, 150.00, 149.31, 148.21, 144.98, 124.15, 122.29, 104.97, 103.09, 102.18, 61.16, 51.51, 49.29, 33.19, 26.54. MS (ESI, m / z) calculated for C 20 H 24 N 6 O [M + H] + 364.20, found 365.20.

Example  4

4 - ((1- (3,4-Dimethoxybenzyl) piperidin-4-yl) amino) N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield 36%); ¹ H NMR (400 MHz, CD ₃ OD)? 8.36 (br.s, 1H), 7.40-7.35 (m, 1H), 7.19-7.05 (m, 4H), 6.99-6.92 3H), 3.87 (s, 3H), 3.69-3.61 (m, 2H), 3.38 (s, 3.27 (m, 2H), 2.91 (s, 3H), 2.53-2.44 (m, 2H), 2.02-1.87 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) δ 167.90, 150.68, 149.54, 138.54, 134.44, 124.08, 123.85, 121.05, 117.91, 115.01, 113.88, 111.50, 106.41, 104.90, 103.74, 60.22, 55.07, 55.02, 50.39, 29.61, 25.35. MS (ESI, m / z ) calculated for C ₂₃ H ₂₉ N ₅ O ₃ [M + H] ⁺ 423.23, found 424.20.

Example  5

4 - ((1- (2-Methoxybenzyl) piperidin-4-yl) amino) N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (20% yield); ¹ H NMR (400 MHz, CD ₃ OD)? 8.21 (s, 1H), 7.38-7.28 (m, 2H), 7.13 (d, J = 3.4 Hz, 1H), 7.04-6.93 3H), 3.75 (s, 2H), 3.05-2.94 (m, 2H), 6.61 (d, J = 3.6 Hz, 1H), 4.20-4.08 ), 2.89 (s, 3H), 2.62-2.50 (m, 2H), 2.22-2.12 ( m , 2H), 1.80-1.69 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) δ 171.29, 158.20, 149.39, 149.35, 143.63, 131.39, 129.02, 123.65, 121.60, 119.96, 110.36, 105.24, 103.49, 101.85, 55.63, 54.44, 50.95, 31.78, 31.35, 25.23. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.00.

Example  6

4 - ((1- (4-Methoxybenzyl) piperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (Yield 21%); ^{1 H NMR (400 MHz, CDCl} 3) δ 8.23 (s, 1 H), 7.27-7.23 (m, 3 H), 7.03 (d, J = 3.5 Hz, 1 H), 6.87 (d, J = 8.6 Hz , 2 H), 6.53 (d , J = 3.5 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.81 (s, 3 H), 3.50 (s, 2 H), 2.98 (s, 3 H ), 2.89-2.77 (m, 2H), 2.32-2.22 (m, 2H), 2.15-2.08 (m, 2H), 1.83-1.68 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) 隆 170.66, 158.71, 149.89, 149.76, 143.37, 130.33, 120.96, 113.59, 105.12, 103.51, 102.75, 62.44, 55.27, 51.63, 32.83, 32.10, 26.65, 26.51. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.05.

Example  7

N -Methyl-4 - ((1-phenylpiperidin-4-yl) amino) -1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (30% yield); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.28 (s, 1 H), 7.26 (t, J = 8.7 Hz, 2 H), 7.15 (d, J = 3.7 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 4.30-4.21 (m, 1H), 3.67-3.58 (M, 2H), 3.37 (s, 2H), 3.13-3.05 (m, 2H), 2.89 . ¹³ C NMR (100 MHz, CD ₃ OD)? 171.33, 151.51, 149.46, 149.38, 143.64, 128.65, 121.56, 119.74, 116.82, 105.30, 103.51, 102.01, 60.14, 49.48, 32.44, 25.24. MS (ESI, m / z) calculated for C 20 H 23 N 5 O [M + H] + 349.19, found 350.05.

Example  8

4 - ((1- (3-Hydroxybenzyl) piperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield: 22%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.24 (br. S, 1 H), 7.23 (br. S, 1 H), 7.21 (d, J = 7.8 Hz, 1 H), 6.90-6.78 (m , 4H), 4.48-4.30 (m, 1H), 4.21 (br.s, 2H), 3.58-3.43 (m, 2H), 2.80 H), 1.90-1.73 (m, 2H), 1.29-1.15 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD)? 167.99, 158.13, 152.07, 138.70, 134.56, 130.12, 130.07, 123.84, 121.61, 117.60, 116.72, 116.69, 104.86, 103.72, 65.50, 50.64, 41.49, 29.58, 25.37. MS (ESI, m / z ) calculated for C ₂₁ H ₂₅ N ₅ O ₂ [M + H] ⁺ 379.20, found 379.80.

Example  9

4 - ((1- (3-Bromobenzyl) piperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield 36%); ^{1 H NMR (400 MHz, CDCl} 3) δ 8.13 (s, 1 H), 7.51 (br. S, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.6 Hz , 1 H), 7.21 (t , J = 7.6 Hz, 1 H), 7.04 (d, J = 3.7 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 4.09-3.99 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 3.52 (s, 1.82-1.71 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD)? 170.78, 149.75, 149.24, 143.47, 140.42, 132.08, 130.24, 129.84, 127.77, 122.38, 121.13, 77.28, 62.38, 51.53, 32.51, 26.38. MS (ESI, m / z ) calculated for C ₂₁ H ₂₄ BrN ₅ O [M + H] ⁺ 441.12, found 443.50.

Example  10

N-Methyl-4 - ((1- (3-methylbenzyl) piperidin-4-yl) amino) -1H-pyrrolo [2,3- b] pyridine-5-carboxamide

Was synthesized according to general procedure D (Yield 21%); ^{1 H NMR (400 MHz, CDCl} 3) δ 8.14 (s, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.19-7.13 (m, 2 H), 7.10 (d, J = 7.4 Hz (M, 1H), 7.07 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H) (s, 3H), 2.92-2.82 (m, 2H), 2.43-2.32 (m, 2H), 2.36 , 2 H). ^{13 C NMR (100 MHz, CD} 3 OD) δ 170.75, 149.77, 148.93, 143.23, 137.92, 136.87, 130.26, 128.16, 128.10, 126.58, 121.23, 105.23, 103.56, 102.64, 77.29, 35.94, 51.34, 32.19, 26.35, 21.28. MS (ESI, m / z) calculated for C 22 H 27 N 5 O [M + H] + 377.22, found 378.60.

Example  11

4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - N -cyclopropyl-1 H pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield 16%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.37 (s, 1 H), 8.01 (s, 1 H), 7.95-7.89 (m, 2 H), 7.39 (d, J = 4.0 Hz, 1 H) , 6.98 (d, J = 4.0 Hz, 1H), 4.63-4.53 (m, 1H), 4.51 (s, 2H), 3.71-3.55 ), 2.93-2.81 (m, 1H), 2.54-2.38 (m, 2H), 2.10-1.97 (m, 2H), 0.89-0.82 ). MS (ESI, m / z ) calculated for C ₂₄ H ₂₆ N ₆ O [M + H] ⁺ 414.22, found 415.15.

Example  12

N- cyclopropyl -4 - ((1- (3- methoxybenzyl ) piperidine -4- yl ) amino) -1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (20% yield); ¹ H NMR (400 MHz, CD ₃ OD)? 8.23 (br.s, 1H), 7.37-7.29 (m, 1H), 7.05-6.93 ), 4.48-4.31 (m, 1H), 4.25 (br.s, 2H), 3.60-3.48 (m, 2H), 3.30-3.20 (m, 2H), 2.84-2.70 ), 2.43-2.31 (m, 2H), 1.90-1.73 (m, 2H), 0.80-0.69 (m, 2H), 0.60-0.49 (m, 2H). MS (ESI, m / z ) calculated for C ₂₄ H ₂₉ N ₅ O ₂ [M + H] ⁺ 419.23, found 420.15.

Example  13

4 - ((1- (3-Methoxybenzyl) piperidin-4-yl) amino) -1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (14% yield); ¹ H NMR (400 MHz, CD ₃ OD)? 8.49 (br.s, 1H), 7.50-7.42 (m, 1H), 7.37 (br.s, 1H), 7.18-7.09 ), 6.95 (br.s, 1H), 4.59-4.43 (m, 1H), 4.37 (br.s, 2H), 3.70-3.59 (m, 2H), 3.42-3.32 ), 2.57-2.49 (m, 2H), 1.99-1.84 (m, 2H); MS (ESI, m / z) calculated for C 21 H 25 N 5 O 2 [M + H] + 379.20, found 380.15.

Example  14

N- cyclopentyl -4 - ((1- (3- methoxybenzyl ) piperidine -4- yl ) amino) -1H-pyrrolo [2,3-b] pyridine-5-carboxamide

Was synthesized according to general procedure D (11% yield); ¹ H NMR (400 MHz, CD ₃ OD)? 8.40 (br s, 1H), 7.49-7.40 (m, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.18-7.09 , 3 H), 6.95 (br s, 1H), 4.58-4.45 (m, 1H), 4.37 (s, 2H), 4.34-4.26 (m, 1H), 3.70-3.60 (M, 2H), 3.40-3.30 (m, 2H), 2.57-2.41 (m, 2H), 2.11-2.00 H). MS (ESI, m / z ) calculated for C ₂₆ H ₃₃ N ₅ O ₂ [M + H] ⁺ 447.26, found 448.20.

Example  15

4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - N -cyclopentyl-1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield: 22%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.41 (s, 1 H), 7.98 (s, 1 H), 7.96-7.88 (m, 2 H), 7.78-7.70 (m, 1 H), 7.39 ( d, J = 4.0 Hz, 1 H), 6.96 (d, J = 4.0 Hz, 1 H), 4.61-4.53 (m, 1 H), 4.32 (s, 2 H), 4.40-4.29 (m, 1 H ), 3.72-3.54 (m, 2H), 3.54-3.38 (m, 2H), 2.55-2.40 (m, 2H), 2.12-2.00 ), 1.75-1.57 (m, 4 H). MS (ESI, m / z ) calculated for C ₂₆ H ₃₀ N ₆ O [M + H] ⁺ 442.25, found 443.15.

Example  16

4 - ((1-Benzylpiperidin-4-yl) amino) - N -methyl-1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield 6%); ^{1 H NMR (400 MHz, CDCl} 3) δ 9.21 (d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 7.38-7.23 (m, 5 H), 7.04 (d, J = 3.7 Hz , 1 H), 6.56 (d , J = 3.7 Hz, 1 H), 6.04 (s, 1 H), 4.07-3.96 (m, 1 H), 3.56 (s, 2 H), 2.99 (d, J = 4.8 Hz, 3 H), 2.91-2.80 (m, 2 H), 2.35-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.73 (m, 2 H); MS (ESI, m / z) calculated for C 21 H 25 N 5 O [M + H] + 363.21, found 363.90.

Example  17

4 - ((1-Benzylpiperidin-4-yl) (methyl) amino) - N -methyl-1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (12% yield); ¹ H NMR (400 MHz, CDCl ₃ )? 10.50 (s, 1H), 9.36 (d, J = 4.6 Hz, 1H), 9.05 (s, 1H), 7.38-7.21 6.61 (d, J = 3.3 Hz , 1 H), 3.48 (s, 2 H), 3.32-3.27 (m, 1 H), 3.10-2.95 (m, 8 H), 2.90-2.82 (m, 2 H) , 2.00-1.91 (m, 2 H), 1.78-1.70 (m, 2 H). MS (ESI, m / z) calculated for C 22 H 27 N 5 O [M + H] + 377.22, found 378.00.

Example  18

4 - ((1- Benzylpiperidine -4- yl ) amino) -1 H - pyrrolo [2,3- b ] pyridine -5-carboxylic acid

Was synthesized according to general procedure D (12% yield); ^{1 H NMR (400 MHz, CD} 3 OD) δ 7.96 (s, 1 H), 7.67-7.44 (m, 5 H), 7.35-7.23 (m, 1 H), 6.90 (d, J = 3.6 Hz, 1 (M, 2H), 3.27-3.15 (m, 2H), 2.41 (s, 2H) -2.23 (m, 2 H), 2.10-1.91 (m, 2 H). MS (ESI, m / z) calculated for C 20 H 22 N 4 O 2 [M + H] + 350.17, found 348.15.

Example  19

4 - ((1-Benzylpiperidin-4-yl) amino) - N -cyclopropyl-1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (11% yield); ¹ H NMR (400 MHz, CDCl ₃ )? 9.34 (br.s, 1H), 9.28 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.38-7.30 ), 7.30-7.27 (m, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.7 Hz, 1H), 6.18 (s, 1H), 4.08-3.91 (m, 2H), 2.16-2.06 (m, 2H), 2.08-1.97 (m, 2H) 1 H), 1.81-1.71 (m, 2 H), 0.92-0.85 (m, 2 H), 0.67-0.59 (m, 2 H). MS (ESI, m / z ) calculated for C ₂₃ H ₂₇ N ₅ O [M + H] ⁺ 389.22, found 389.75.

Example  20

4 - ((1-Benzylpiperidin-4-yl) amino) - N -cyclopentyl-1 H pyrrolo [2,3- b ] pyridine-5-carboxamide

Was synthesized according to general procedure D (yield: 23%); ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.39 (s, 1 H), 7.61-7.52 (m, 5 H), 7.40 (d, J = 4.0 Hz, 1 H), 6.97 (d, J = 4.0 (M, 2H), 3.50-3.40 (m, 2H), 4.34-4.26 (m, 1H) (M, 2 H), 1.76-1.46 (m, 2 H), 2.16-2.44 (m, 4 H). MS (ESI, m / z ) calculated for C ₂₅ H ₂₉ N ₅ O ₂ [M + H] ⁺ 417.25, found 418.15.

Claims (8)

Claims 1. Compounds of the general formula < RTI ID = 0.0 > (I) < / RTI >
(I)

In this formula,
R ₁ is a hydrogen group, a C ₁ -C ₃ alkyl group, or a C ₃ -C ₈ cycloalkyl group;
R ₂ is a hydrogen group, or a C ₁ -C ₃ alkyl group;
R ₃ represents a hydrogen group,

, or

ego;
R ₄ and R ₅ are each independently a hydrogen group, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
Provided that when R ₄ and R ₅ are simultaneously a hydrogen group, R ₁ is not a hydrogen group. 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R < _{1 >} is a methyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ is a hydrogen group or a methyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₄ and R ₅ are each independently a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group. A pharmaceutical composition for use in the treatment or prophylaxis of an autoimmune disease, inflammatory disease, or cancer comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. The method of claim 5, wherein the autoimmune disease is selected from the group consisting of skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, A pharmaceutical composition which is an immune thyroid disease. [Claim 7] The pharmaceutical composition according to claim 6, wherein the skin disease is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. 6. The method of claim 5, wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, colon cancer, ovarian cancer, gastric cancer, hepatoma, castellae, multiple myeloma, lymphoma, melanoma, neuroblastoma, ≪ / RTI >