KR102034538B1 - Jak inhibitor compounds, and method of preparing the same - Google Patents

Abstract

상기 식에서, R₁은 수소기, C₁-C₃ 알킬기, 또는 C₃-C₈ 시클로알킬기이고; R₂는 수소기, 또는 C₁-C₃ 알킬기이고; R₃는 수소기,

, 또는

이고; R₄, 및 R₅는, 각각 독립적으로, 수소기, C₁-C₃ 알킬기, C₁-C₃ 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다. 단, R₄, 및 R₅가 동시에 수소기인 경우, R₁은 수소기가 아니다.The present invention relates to a JAK inhibitor compound, and a method for preparing the same, and more particularly, to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention can modulate signal transduction at the level of JAK kinase, such as to exhibit therapeutic effects against inflammatory diseases, autoimmune diseases, myeloproliferative diseases, cancer of the human body, and the like.
[Formula I]

Wherein 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 is 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 0 or an integer of 1; However, when R <_4> and R <_5> are hydrogen groups at the same time, R <_1> is not a hydrogen group.

Description

JAK inhibitor compound, and a method for preparing the same {JAK INHIBITOR COMPOUNDS, AND METHOD OF PREPARING THE SAME}

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

Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, particularly cell growth, survival and differentiation, organ formation and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of proteins (or substrates), thereby modulating the cellular activity of the substrates in various biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in hosts of human disease, including cancer. Subpopulations of protein kinases (also referred to as tumor protein kinases), when unregulated, cause tumor formation and growth, and also contribute to tumor persistence and progression. Thus, tumor protein kinases are one of the largest and most interesting groups of protein targets for cancer modulation and drug development.

Janus Kinase (JAK) family plays an important role in cytokine dependent regulation of the proliferation and action of cells involved in immune responses. Currently, four mammalian JAK family members are known: JAK1 (Janus kinase-1), JAK-2 (Janus kinase-2), JAK3 (Janus kinase-3) and TYK2 (protein-tyrosine kinase 2) . JAK proteins range in size from 120 kDa to 140 kDa and contain seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other potentially regulatory and / or STAT. It is a pseudokinase domain that can function as a docking site for.

Blocking signal transduction at the level of JAK kinase has the potential for the development of treatments for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and human cancers, and skin immune diseases such as psoriasis and skin sensitization It will have a therapeutically beneficial effect in patients with the disease.

Thus, there are extensive searches for inhibitors of Janus kinase or related kinases, and several patent publications report a valid class of compounds. For example, it is disclosed in US Patent Application Publication US2007 / 0135461 A1 and the like that pyrrolopyridine and pyrrolopyrimidine can act as some JAK inhibitors (Patent Document 1). As a result, all of the contents disclosed in Patent Document 1 are cited and incorporated in the prior art described herein.

US 2007/0135461 A1 (2007.06.14.)

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

The present invention has been made to solve the above problems of the prior art,

There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[Formula I]

Where

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 is 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 0 or an integer of 1;

However, when R <_4> and R <_5> are hydrogen groups at the same time, 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 provides a compound or a pharmaceutically acceptable salt which is a hydrogen group or a methyl group.

In the present invention, each of R ₄ and R ₅ independently represents 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 use in the treatment or prevention of an autoimmune disease, inflammatory disease, or cancer comprising the 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, such as to exhibit therapeutic effects against inflammatory diseases, autoimmune diseases, myeloproliferative diseases, cancer of the human body, and the like.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

One aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[Formula I]

Where

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 is 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 0 or an integer of 1;

However, when R <_4> and R <_5> are hydrogen groups at the same time, 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 (enantiomers and diastereomers) and racemic forms of the compounds of the invention are included in the invention. In addition, many geometric isomers such as olefins, C═N double bonds, etc. may be present in the compound, and all of the stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and they can be isolated as a mixture of isomers or as isolated isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. Methods of preparing optically active forms (eg, by cleavage of racemic forms or by synthesis from optically active starting materials) are well known in the art. Unless specific stereochemical or isomeric forms are specifically indicated, all chiral (enantiomer and diastereomeric) and racemic forms of the structure, and all geometric isomeric forms, are intended.

The compounds represented by Formula I may modulate the activity of Janus kinase (JAK). Here, the term "modulate" refers to the ability to increase or decrease the activity of one or more JAK classes of kinases. Thus, the compounds of the present invention can be used in a method of controlling JAK by contacting JAK with one or more compounds or compositions of the present invention. In particular, in some embodiments, the compounds of the present invention may act as inhibitors of one or more JAKs.

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

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

JAK-related diseases include diseases, diseases or symptoms that are directly or indirectly associated with the expression or activity of JAK, such as overexpression and / or abnormal activity. In addition, JAK-related diseases include diseases, diseases or symptoms that can be prevented, alleviated or cured by modulating JAK activity.

Examples of JAK related diseases include immune system related diseases, such as organ transplant rejection (eg, graft rejection and graft versus host reaction), multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis , Inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune bullous skin diseases such as vulgaris (PV) or a blistering bleb (BP) etc. are mentioned.

Other examples of JAK related diseases include inflammatory and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye (e.g. iris, uveitis, scleritis, conjunctivitis or related diseases), inflammatory diseases of the respiratory tract (e.g., upper respiratory tract including nasal and sinus, such as rhinitis or sinusitis, or bronchial, chronic Diseases of the lower respiratory tract, including obstructive pulmonary disease), and inflammatory myopathy 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 cancers characterized by solid tumors, such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, and Castleman. Diseases, melanoma), hematological cancers (eg, lymphomas, leukemias such as acute lymphocytic leukemia, acute myeloid leukemia (AML) or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Can be. Examples of cutaneous T-cell lymphomas include Sezary syndrome and myxosarcoma.

In addition, it can be used to treat diseases or symptoms associated with inflammatory ischemic events such as ischemia reperfusion injury or 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 can also be used to treat hypoxia or astrocytosis, such as diabetic retinopathy, cancer or symptoms associated with 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 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 an increase in prostate size due to, for example, benign or enlarged prostate.

The pharmaceutical compositions of the present invention may be administered in oral dosage forms such as tablets, capsules (each of which include sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Can be. They can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular forms and all used dosage forms are well known to those skilled in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

In addition, the pharmaceutical compositions of the present invention may be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the transdermal route using transdermal skin patches. When administered in the form of a transdermal delivery system, administration of the dose will of course be continuous rather than intermittent throughout the dosing regimen.

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

The compounds of the present invention represented by the formula (I), including the exemplified compounds of Tables 1 and 2 above, may be prepared including the methods specifically described in the general synthetic procedures described below. As a person skilled in the art can understand the synthesis method for specific exemplary compounds or example compounds through the description of the general synthetic procedure, the description of the individual preparation method for each compound will be omitted.

Scheme  1.1- benzylpiperidin General Procedure of Synthesis of 4-amine or Derivative Compounds thereof

General Reaction 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

To a solution (solvent DMF (5 ml), t -butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol)) was added K ₂ CO ₃ (0.83 g, 5.99 mmol) and aryl halide (ex.bromide) (2.75 mmol). Dropwise at room temperature. The reaction mixture was mixed at room temperature for about 8 hours. After reaction, the resultant was poured into Et ₂ O (40 ml) and washed with H ₂ O (40 ml), brine (40 ml), dry 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 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. Yield (yield-100%) was used without further purification.

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

Synthesized according to General Procedure A (yield: 78%); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.73 (br. S, 1 H), 7.68-7.63 (m, 1 H), 7.53 (t, J = 7.6 Hz, 1 H), 3.58 (s, 2 H), 3.40-3.32 (m, 1H), 2.87-2.80 (m, 2H), 2.19-2.10 (m, 2H), 1.89-1.91 (m, 2H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₅ N ₃ 0 ₂ [M + H] ⁺ 315.19, found 316.10.

tert - Butyl  (1- (3- methoxy ) piperidin -4- yl ) carbamate

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, 2H), 6.84 (dd, J = 2.4, 8.4 Hz, 1 H), 3.80 (S, 3H), 3.50 (s, 2H), 3.39-3.32 (m, 1H), 2.90-2.83 (m, 2H), 2.16-2.07 (m, 2H), 1.88-1.81 ( m, 2H), 1.55-1.46 (m, 2H), 1.45 (s, 9H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₈ N ₂ 0 ₃ [M + H] ⁺ 320.21, found 321.25.

tert - Butyl  (One-( pyridine -4- ylmethyl ) piperidin -4- yl ) carbamate

Synthesized according to General Procedure A (Yield 54%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (d, J = 6.0 Hz, 2H), 7.44 (d, J = 6.0 Hz, 2H), 3.58 (s, 2H), 3.41-3.31 ( m, 1H), 2.87-2.81 (m, 2H), 2.20-2.12 (m, 2H), 1.89-1.83 (m, 2H), 1.57-1.49 (m, 2H), 1.45 (s, 9 H). MS (ESI, m / z ) calculated for C ₁₆ H ₂₅ N ₃ 0 ₂ [M + H] ⁺ 291.19, found 292.30.

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

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 (m, 2H), 1.45-1.34 (m , 2H), 1.44 (s, 9H). MS (ESI, m / z ) calculated for C ₁₉ H ₃₀ N ₂ 0 ₄ [M + H] ⁺ 350.22, found 351.30.

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

Synthesized according to General Procedure A (yield: 93%); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.31-7.25 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 3.84 ( s, 3H), 3.59 (s, 2H), 3.33-3.27 (m, 1H), 2.95-2.88 (m, 2H), 2.23-2.13 (m, 2H), 1.87-.179 (m , 2H), 1.55-1.45 (m, 2H), 1.44 (s, 9H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₈ N ₂ 0 ₃ [M + H] ⁺ 320.21, found 321.10.

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

Synthesized according to General Procedure A (yield: 81%); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.47 (s, 2H), 3.38-3.28 (m, 1H), 2.90-2.82 (m, 2H), 2.14-2.05 (m, 2H), 1.88-1.80 (m, 2H), 1.53-1.44 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₈ N ₂ 0 ₃ [M + H] ⁺ 320.21, found 321.30.

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

Synthesized according to General Procedure A (yield: 87%); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.15 (t, J = 8.4 Hz, 1 H), 6.82-6.77 (m, 2H), 6.73-6.69 (m, 1H), 3.48 (s, 2 H), 3.40-3.33 (m, 1H), 2.93-2.85 (m, 2H), 2.19-2.09 (m, 2H), 1.89-1.81 (m, 2H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m / z ) calculated for C ₁₇ H ₂₆ N ₂ 0 ₃ [M + H] ⁺ 306.19, found 307.20.

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

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, 1H), 3.53-3.40 (m, 1H), 3.43 (s, 2H), 2.82-2.72 (m, 2H), 2.12-2.02 (m, 2H), 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- methylbenzyl ) piperidin -4- yl ) carbamate

Synthesized according to General Procedure A (Yield: 57%); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 (t, J = 7.6 Hz, 1 H), 7.16 (br. S, 1 H), 7.13-7.08 (m, 2H), 3.49 (s, 2 H), 3.39-3.31 (m, 1H), 2.90-2.82 (m, 2H), 2.35 (s, 3H), 2.16-2.06 (m, 2H), 1.88-1.80 (m, 2H) , 1.55-1.45 (m, 2H), 1.45 (s, 9H). MS (ESI, m / z ) calculated for C ₁₈ H ₂₈ N ₂ 0 ₂ [M + H] ⁺ 304.22, found 305.00.

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

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 ) piperidin -4- amine hydrochloride

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 ( d, J = 8.2 Hz, 1H), 4. 34 (s, 2H), 3.86 (s, 3H), 3.63-3.55 (m, 2H), 3.57-3.44 (m, 1H), 3.28 -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 0 [M + H] ⁺ 220.16, found 221.15.

One-( Pyridin -4- ylmethyl ) piperidin -4- amine hydrochloride

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, 2H), 4.45 (s, 2H), 3.45 (d, J = 12.3 Hz, 2H), 3.37-3.25 (m, 1H), 3.20-3.00 (m, 2H), 2.17-1.99 (m, 2H), 1.94-1.68 (m, 2H). MS (ESI, m / z ) calculated for C ₁₁ H ₁₇ N ₃ [M + H] ⁺ 191.14, found 192.10.

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

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, 1H), 4.17 (d, J = 4.7 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 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 0 ₂ [M + H] ⁺ 250.17, found 251.15.

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

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 (s, 3H), 3.43-3.34 ( m, 2H), 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 0 [M + H] ⁺ 220.16, found 221.25.

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

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 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.92 (m, 2H). MS (ESI, m / z ) calculated for C ₁₃ H ₂₀ N ₂ 0 [M + H] ⁺ 220.16, found 221.25.

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

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 (br. s, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 4.14 (d, J = 4.8 Hz, 2 H), 3.40-3.30 (m, 2H), 3.27-3.17 (m , 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 ) piperidin -4- amine hydrochloride

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, 2H), 7.42 (t, J = 7.8 Hz, 1H), 4.27 (d, J = 4.6 Hz, 2H), 3.43-3.32 (m, 2H), 3.29-3.18 (m, 1H), 3.08-2.97 (m, 2H), 2.18 -2.08 (m, 2H), 2.06-1.95 (m, 2H). MS (ESI, m / z ) calculated for C ₁₂ H ₁₇ BrN ₂ [M + H] ⁺ 268.06, found 271.10.

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

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, 1 H), 4.19 (d, J = 4.8 Hz, 2 H), 3.39-3.31 (m, 2 H), 3.28-3.16 (m, 1 H), 3.05-2.94 (m, 2 H ), 2.33 (s, 3H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 2H). 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 Reaction Scheme II

Reagents and Conditions: (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ℃

General procedure C

To a solution of 4-chloro-1 H -pyrrolo [2,3- b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF (10 ml) was added dropwise CDI (1.07 g, 6.61 mmol) at room temperature. The reaction mixture was stirred at room temperature for about 1 hour. 30 mmol (solvent THF) 2.0 M of various amines were slowly added dropwise to the mixture, 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

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

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

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, 1 H), 2.80 (d, J = 4.6 Hz, 3 H). ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 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

Synthesized according to General Procedure C (yield 62%); 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) δ 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

Synthesized according to General Procedure C (yield 71%); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (s, 1 H), 7.49 (d, J = 3.4 Hz, 1 H), 6.47 (d, J = 3.4 Hz, 1 H). ^{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

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, 1 H), 4.27-4.17 (m, 1 H), 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) δ 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

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 (s, 2H), 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) δ 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

Synthesized according to General Procedure D (yield 27%); 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, 2H), 6.81 (d, J = 7.1 Hz, 1 H), 6.48 (br.s, 1 H), 4.02-3.92 (m., 1H), 3.75 (s, 3H), 3.47 (s, 2H), 2.78-2.66 (m, 2H), 2.74 (d, J = 4.3 Hz, 3 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, 29.58 25.36. MS (ESI, m / z ) calculated for C ₂₂ H ₂₇ N ₅ 0 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

Synthesized according to General Procedure D (yield 20%); ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.45 (d, J = 7.8 Hz, 1 H), 8.51 (d, J = 5.6 Hz, 2 H), 8.29 (s, 1 H), 8.23 (d , 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, 2H), 2.78-2.67 (m, 2H), 2.74 (d, J = 4.2 Hz, 2H), 2.35-2.26 (m, 2H), 2.06-1.98 (m, 2H), 1.60-1.49 (m, 2H). ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 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

Synthesized according to General Procedure D (yield 36%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (br. S, 1 H), 7.40-7.35 (m, 1 H), 7.19-7.05 (m, 4 H), 6.99-6.92 (m, 1 H ), 4.58-4.47 (m, 1H), 4.33 (br. S, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69-3.61 (m, 2H), 3.38- 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, 50 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

Synthesized according to General Procedure D (yield 20%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (s, 1 H), 7.38-7.28 (m, 2H), 7.13 (d, J = 3.4 Hz, 1H), 7.04-6.93 (m, 2 H), 6.61 (d, J = 3.6 Hz, 1 H), 4.20-4.08 (m, 1 H), 3.87 (s, 3 H), 3.75 (s, 2 H), 3.05-2.94 (m, 2 H ), 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, 31.35 25.23. MS (ESI, m / z ) calculated for C ₂₂ H ₂₇ N ₅ 0 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

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, 3H), 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 ) δ 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 0 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

Synthesized according to General Procedure D (yield 30%); 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 (s, 3H), 2.32-2.24 (m, 2H), 1.88-1.77 (m, 2H) . ¹³ C NMR (100 MHz, CD ₃ OD) δ 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

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 , 4 H), 4.48-4.30 (m, 1 H), 4.21 (br. S, 2 H), 3.58-3.43 (m, 2 H), 2.80 (s, 3 H), 2.40-2.35 (m, 2 H), 1.90-1.73 (m, 2H), 1.29-1.15 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) δ 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 0 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

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, 1 H), 3.53 (s, 2 H), 2.95 (s, 3 H), 2.88-2.78 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.71 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) δ 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

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, 2H), 7.10 (d, J = 7.4 Hz , 1 H), 7.04 (d, J = 3.6 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.57 (s, 2 H), 2.94 (s, 3H), 2.92-2.82 (m, 2H), 2.43-2.32 (m, 2H), 2.36 (s, 3H), 2.20-2.10 (m, 2H), 1.83-1.72 (m , 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

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, 2H), 7.39 (d, J = 4.0 Hz, 1 H) , 6.98 (d, J = 4.0 Hz, 1 H), 4.63-4.53 (m, 1 H), 4.51 (s, 2 H), 3.71-3.55 (m, 2 H), 3.51-3.39 (m, 2 H ), 2.93-2.81 (m, 1H), 2.54-2.38 (m, 2H), 2.10-1.97 (m, 2H), 0.89-0.82 (m, 2H), 0.71-0.64 (m, 2H) ). 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 ) piperidin -4- yl ) amino) -1H-pyrrolo [2,3-b] pyridine -5-carboxamide

Synthesized according to General Procedure D (yield 20%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (br. S, 1 H), 7.37-7.29 (m, 1 H), 7.05-6.93 (m, 3 H), 6.82 (br. S, 1 H ), 4.48-4.31 (m, 1 H), 4.25 (br. S, 2 H), 3.60-3.48 (m, 2 H), 3.30-3.20 (m, 2 H), 2.84-2.70 (m, 1 H ), 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 0 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

Synthesized according to General Procedure D (yield 14%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (br. S, 1 H), 7.50-7.42 (m, 1 H), 7.37 (br. S, 1 H), 7.18-7.09 (m, 3 H ), 6.95 (br. S, 1 H), 4.59-4.43 (m, 1 H), 4.37 (br. S, 2 H), 3.70-3.59 (m, 2 H), 3.42-3.32 (m, 2 H ), 2.57-2.49 (m, 2H), 1.99-1.84 (m, 2H); MS (ESI, m / z ) calculated for C ₂₁ H ₂₅ N ₅ 0 ₂ [M + H] ⁺ 379.20, found 380.15.

Example  14

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

Synthesized according to General Procedure D (yield 11%); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (br. S, 1 H), 7.49-7.40 (m, 1 H), 7.38 (d, J = 4.0 Hz, 1 H), 7.18-7.09 (m , 3 H), 6.95 (br. S, 1 H), 4.58-4.45 (m, 1 H), 4.37 (s, 2 H), 4.34-4.26 (m, 1 H), 3.70-3.60 (m, 2 H), 3.40-3.30 (m, 2H), 2.57-2.41 (m, 2H), 2.11-2.00 (m, 4H), 2.00-1.88 (m, 2H), 1.74-1.56 (m, 4 H). MS (ESI, m / z ) calculated for C ₂₆ H ₃₃ N ₅ 0 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

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, 1H), 6.96 (d, J = 4.0 Hz, 1H), 4.61-4.53 (m, 1H), 4.32 (s, 2H), 4.40-4.29 (m, 1H ), 3.72-3.54 (m, 2H), 3.54-3.38 (m, 2H), 2.55-2.40 (m, 2H), 2.12-2.00 (m, 4H), 1.88-1.75 (m, 2H) ), 1.75-1.57 (m, 4H). 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

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, 5H), 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, 3H), 2.91-2.80 (m, 2H), 2.35-2.22 (m, 2H), 2.17-2.08 (m, 2H), 1.82-1.73 (m, 2H); 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

Synthesized according to General Procedure D (yield 12%); ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.50 (s, 1 H), 9.36 (d, J = 4.6 Hz, 1 H), 9.05 (s, 1 H), 7.38-7.21 (m, 5 H), 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, 2H), 1.78-1.70 (m, 2H). MS (ESI, m / z ) calculated for C ₂₂ H ₂₇ N ₅ O [M + H] ⁺ 377.22, found 378.00.

Example  18

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

Synthesized according to General Procedure D (yield 12%); 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 H), 6.74 (s, 1H), 4.39 (s, 2H), 4.19-4.02 (m, 1H), 3.73-3.56 (m, 2H), 3.29-3.15 (m, 2H), 2.41 -2.23 (m, 2H), 2.10-1.91 (m, 2H). 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

Synthesized according to General Procedure D (yield 11%); ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (br.s, 1 H), 9.28 (d, J = 7.8 Hz, 1 H), 8.12 (s, 1 H), 7.38-7.30 (m, 4 H ), 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, 1H), 3.56 (s, 2H), 2.94-2.77 (m, 2H), 2.34-2.20 (m, 2H), 2.16-2.06 (m, 2H), 2.08-1.97 (m, 1H), 1.81-1.71 (m, 2H), 0.92-0.85 (m, 2H), 0.67-0.59 (m, 2H). 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

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, 5H), 7.40 (d, J = 4.0 Hz, 1H), 6.97 (d, J = 4.0 Hz, 1H), 4.57-4.48 (m, 1H), 4.34 (s, 2H), 4.34-4.26 (m, 1H), 3.72-3.62 (m, 2H), 3.50-3.40 (m, 2H), 2.56-2.44 (m, 2H), 2.11-2.02 (m, 2H), 1.99-1.89 (m, 2H), 1.88-1.76 (m, 2H), 1.76-1.54 (m, 4 H). MS (ESI, m / z ) calculated for C ₂₅ H ₂₉ N ₅ 0 ₂ [M + H] ⁺ 417.25, found 418.15.

Claims (8)

A compound of formula (I) or a pharmaceutically acceptable salt thereof.
[Formula I]

Where
R ₁ is a methyl group;
R ₂ is a hydrogen group;
R ₃ is

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 1.
Provided that at least one of R ₄ and R ₅ is a hydrogen group. delete delete The compound according to claim 1, or a pharmaceutically acceptable salt thereof, each of R ₄ and R ₅ is 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 prevention of an autoimmune disease or cancer comprising the compound of claim 1 or 4 or a pharmaceutically acceptable salt thereof. The method of claim 5, wherein the autoimmune disease is a skin disease, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis or autologous Pharmaceutical composition which is an immune thyroid disease. The pharmaceutical composition according to claim 6, wherein the skin disease is atopic dermatitis, psoriasis, skin rash, or contact dermatitis. The method according to claim 5, wherein the cancer is pancreatic cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, colon cancer, ovarian cancer, gastric cancer, liver cancer, Castleman's disease, multiple myeloma, lymphoma, melanoma, neuroblastoma, glioblastoma, systemic mastocytosis, Or leukemia.