Patent Publication Number: US-2022220109-A1

Title: Jak inhibitor compound and pharmaceutical composition containing same

Description:
TECHNICAL FIELD 
     The present invention relates to a JAK inhibitor compound and a pharmaceutical composition including the same. 
     BACKGROUND ART 
     Protein kinases (PKs) are a group of enzymes that regulate diverse, important biological processes, including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases also play more specialized roles in a host of human diseases, including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression. Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development. 
     The Janus kinase (JAK) family plays a critical role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. At present, there are four known mammalian JAK family members: JAK1 (Janus kinase-1), JAK-2 (Janus kinase-2), JAK3 (Janus kinase-3) and TYK2 (protein-tyrosine kinase 2). The JAK proteins have a size ranging from 120 kDa to 140 kDa and comprise 7 conserved JAK homology (JH) domains. One of them is a functional catalytic kinase domain, and another is a pseudokinase domain which potentially exerts a regulatory function and/or acts as a docking site for STATs. 
     JAK1 is involved in most signal transduction pathways mediated by cytokines such as γc cytokines (IL-2, IL-4, IL-7, IL-9, IL-21), members of the gp130 cytokine family (IL-6, IL-11, LIF, OSM), members of the IRF family, and IL-10-like cytokines and regulates the functions of T-cells and B-cells (Non-Patent Document 1). Thus, JAK1 is being developed for the treatment of diseases such as rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, and psoriasis. 
     JAK2 is used for signal transduction in which cytokines such as βc cytokines, gp130 cytokine family members, EPO, IRF, IL-12, and IL-23 are involved. Particularly, when cytokines such as EPO, TPO, IL-3, and IL-5 bind to their receptors, JAK2 kinases tend to homodimerize and are ultimately involved in myeloid differentiation and haematopoiesis as well as T cell proliferation. Thus, selective JAK2 inhibitors are being developed for the treatment of myeloproliferative disorders such as myeloproliferative neoplasms (Non-Patent Document 2). 
     The expression of JAK3 is more restricted than that of other JAK kinases. When γc cytokines bind to their receptors, JAK3 is involved only in a single pathway through dimerization with JAK1. Thus, JAK3 inhibitors can be used to treat diseases such as rheumatoid arthritis and psoriasis (Non-Patent Document 3). JAK3 selective inhibitors are likely to cause fewer side effects than other inhibitors, but their efficacy may also be low compared to other inhibitors because they are involved only in a single pathway among various immune-related JAK/STAT pathways (Non-Patent Document 4). 
     Furthermore, blocking signal transduction at the level of JAK kinases also hold promise for developing treatments for various diseases, for example, inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and human cancers and may result in therapeutic benefits in patients suffering from immune disorders of the skin such as psoriasis and skin sensitization. 
     Accordingly, inhibitors of Janus kinases or related kinases are widely sought and several patent publications report effective classes of compounds. For example, certain JAK inhibitors, including pyrrolopyridine and pyrrolopyrimidine compounds, are disclosed in U.S. Patent Publication No. 2007/0135461 A1 (Patent Document 1). 
     The entire disclosure of all prior art documents cited above is incorporated herein by reference. 
     (Patent Document 1) US 2007/0135461 A1 (Jun. 14, 2007) 
     (Non-Patent Document 1) SCHWARTZ, Daniella M., et al. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.  Nature Reviews Rheumatology,  2016, 12.1: 25. 
     (Non-Patent Document 2) PURANDARE, A. V., et al. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2 . Leukemia,  2012, 26.2: 280. 
     (Non-Patent Document 3) VAINCHENKER, William, et al. JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders.  F 1000 Research,  2018, 7. 
     (Non-Patent Document 4) THOMA, Gebhard; DRUECKES, Peter; ZERWES, Hans-Guenter. Selective inhibitors of the Janus kinase Jak3—Are they effective?,  Bioorganic  &amp;  medicinal chemistry letters,  2014, 24.19: 4617-4621. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Problems to be Solved by the Invention 
     As described above, JAK kinases such as JAK1, JAK2, and JAK3 have their own characteristics. The present inventors have intended to develop a drug that selectively inhibits JAK1 so as to be more effective against most inflammation and autoimmune related diseases for better efficacy. 
     However, it is difficult to enhance the activities of ATP-binding kinase domains of all JAK family members for specific kinases because the structural differences of the kinase domains are not very significant. 
     The present inventors have referred to previously developed inhibitors whose structures are known to choose an initial structure, and as a result, succeeded in finding an inhibitor that not only exhibits high affinity for JAK1, but also acts more selectively on JAK1 than on other JAK kinases. The present invention has been accomplished based on this finding. An object of the present invention is to provide a novel compound that has high inhibitory activity against Janus kinases, particularly JAK1. 
     Means for Solving the Problems 
     The present invention has been made in an effort to solve the problems of the prior art and provides a compound represented by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is hydrogen, C 1 -C 3  alkyl or halogen, R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, a and b are each independently an integer from 0 to 2, c and d are each independently an integer of 0 or 1 and satisfy the relationship c+d≤1, e is an integer of 1 or 2 and satisfies the relationship e≤3−b, A is a secondary or tertiary amine structurally capable of forming chemical bonds, and Et is ethyl, provided that when c or d is 1, b and e are all 1 (b=e=1), or a pharmaceutically acceptable salt thereof. 
     In Formula I, b and e are all 1, c is 0, d is 1, R 1  is hydrogen, and R 2  is chlorine. 
     In Formula I, b and c are all 1, e is 0, d is 0, R 1  is methyl or fluorine, and R 2  is chlorine or methoxy. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula II: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula III: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula V: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula VI: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula VII: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula VIII: 
     
       
         
         
             
             
         
       
     
     wherein Ak is C 1 -C 3  alkyl and R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The compound represented by Formula I or pharmaceutically acceptable salt thereof is a compound represented by Formula IX: 
     
       
         
         
             
             
         
       
     
     wherein X is halogen and R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, or a pharmaceutically acceptable salt thereof. 
     The present invention also provides a pharmaceutical composition for treating or preventing an autoimmune disease or cancer including the compound represented by Formula I or pharmaceutically acceptable salt thereof. 
     Effects of the Invention 
     The compound of the present invention can exhibit therapeutic effects on a variety of diseases, for example, inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and human cancers due to its ability to regulate signal transduction at the level of JAK kinases. In particular, the compound of the present invention can exhibit better therapeutic effects on inflammatory diseases and autoimmune diseases at a low dose and with fewer side effects due to its high selectivity for JAK1. 
     BEST MODE FOR CARRYING OUT THE INVENTION 
     The present invention will now be described in detail. 
     One aspect of the present invention is directed to a compound represented by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is hydrogen, C 1 -C 3  alkyl or halogen, R 2  is hydrogen, halogen, cyan or C 1 -C 3  alkoxy, a and b are each independently an integer from 0 to 2, c and d are each independently an integer of 0 or 1 and satisfy the relationship c+d≤1, e is an integer of 1 or 2 and satisfies the relationship e≤3−b, A is a secondary or tertiary amine structurally capable of forming chemical bonds, and Et is ethyl, provided that when c or d is 1, b and e are all 1 (b=e=1), or a pharmaceutically acceptable salt thereof. 
     As will be understood with reference to Examples section that follows, it is preferrable that b and e are all 1, c is 0, d is 1, R 1  is hydrogen, and R 2  is chlorine orb and e are all 1, c is 0, d is 0, R 1  is methyl or fluorine, and R 2  is chlorine or methoxy. 
     The compound of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of the compound represented by Formulae I to IX are within the scope of the present invention. Many geometric isomers such as olefins, C═N double bonds, etc. may also exist in the compound and all stable isomers can be contemplated in the present invention. Cis and trans geometric isomers of the compound according to the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The compound of the present invention may be isolated in optically active or racemic forms. Methods for preparing optically active forms (for example, by resolution of racemic forms or by synthesis from optically active starting materials) are widely known in the art. All chiral (enantiomeric and diastereomeric), racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. 
     The compound represented by Formula I can regulate the activity of Janus kinases (JAKs). As used herein, the term “regulate” refers to the ability to increase or decrease the activity of one or more kinases of the JAK family. Due to this ability, the compound of the present invention or a composition including the compound can be brought into contact with JAKs to regulate the JAKs. Particularly, in some embodiments, the compound of the present invention may act as an inhibitor of one or more JAKs. 
     The compound of the present invention binds to and/or regulates JAKs, including any members 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 JAK1. In some embodiments, the JAK is JAK1 or JAK3. 
     Another aspect of the present invention is directed to a pharmaceutical composition for treating or preventing an autoimmune disease, an inflammatory disease or a cancer including the compound represented by Formula I or pharmaceutically acceptable salt thereof. 
     JAK-associated diseases include diseases, disorders, and conditions that are directly or indirectly associated with JAK expression or activity (for example, overexpression and/or aberrant activity). JAK-associated diseases may be, for example, diseases, disorders, and conditions that can be prevented, ameliorated or treated by regulation of JAK activity. 
     Examples of JAK-associated diseases include immune system-related diseases such as rejection reactions after organ transplantation (e.g., transplant rejection and graft versus host responses), multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn&#39;s disease, severe myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorders, asthma, food allergy, atopic dermatitis, psoriasis, and autoimmune bullous skin disorders such as pemphigus vulgaris (PV) and bullous pemphigoid (BP). 
     Other examples of JAK-associated diseases include inflammation and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis or related diseases), inflammatory diseases of the respiratory tract (e.g., rhinitis or sinusitis of the upper respiratory tract including the nose and sinuses and bronchitis and chronic obstructive pulmonary disease of the lower respiratory tract), inflammatory myopathy such as myocarditis, and other inflammatory diseases (e.g., systemic inflammatory response syndrome (SIRS) and septic shock. 
     Other examples of JAK-associated diseases include cancers characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi&#39;s sarcoma, Castleman&#39;s disease, and melanoma), hematologic cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides. 
     The JAK inhibitor of the present invention can be used to treat a disease or condition associated with ischemic reperfusion injury or an inflammatory ischemic event such as stroke or cardiac arrest. The JAK inhibitor of the present invention can also be used to treat stenosis, sclerodermatitis or fibrosis. 
     The JAK inhibitor of the present invention can also be used to treat a condition associated with hypoxia or astrocytosis, for example, diabetic retinopathy, cancer or neurodegeneration. See 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 inhibitor of the present invention can also be used to treat Alzheimer&#39;s disease. 
     The JAK inhibitor of the present invention can also be used to treat gout and increased prostate size, for example, due to benign prostatic hyperplasia or prostatic hyperplasia. 
     The pharmaceutical composition of the present invention may be formulated into tablets, capsules (including sustained release or timed release preparations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions for oral administration. These preparations may also be administered intravenously (by bolus injection or infusion), intraperitoneally, subcutaneously or intramuscularly. All available dosage forms are well known to those skilled in the pharmaceutical art. The dosage forms can be administered alone but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. 
     The pharmaceutical composition of the present invention may be administered intranasally through topical use of a suitable intranasal vehicle or via a transdermal route using a transdermal skin patch. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 
     The compounds that can be represented by Formula I are specifically exemplified in the following examples. The IC50 values of the compounds against JAK1, JAK2, and JAK3 were measured and the results are tabulated below. However, the specific examples of the compounds are given to provide complete disclosure of the invention and assist understanding of the invention by those skilled in the art and are not intended to limit the scope of the invention. 
     EXAMPLES 
     Tofacitinib—Reference Value 
     
       
         
           
               
               
               
            
               
                   
               
               
                   
                 
                   
                 
                 SELECTIVITY FOR JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 
                   
                 
                 0.0618 
                 0.00423 
                 0.00114 
                 0.0101 
                 2.34 
                 0.63 
                 5.61 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 1—Piperidin-4-ylmethanamine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK2/JAK1 
                 JAK3/JAK1 
                 TYK2/JAK1 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 14a 
                 H 
                 0.215 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 14b 
                 3-Cl 
                 0.343 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 14c 
                 4-Cl 
                 0.0722 
                 0.712 
                 0.420 
                 0.0489 
                 9.86 
                 9.91 
                 0.677 
               
               
                 14d 
                 3-OMe 
                 0.132 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 14e 
                 4-OMe 
                 0.0034 
                 1.08 
                 0.376 
                 0.200 
                 11.6 
                 0.16 
                 2.14 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 2—Aminopyrrolidine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 15a 
                 H 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15b 
                 3-Cl 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15c 
                 4-Cl 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15d 
                 3-OMe 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15e 
                 4-OMe 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15f 
                 3-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 15g 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 15h 
                 3-Cl 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 15i 
                 4-Cl 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 3—1,3-Cyclobutyldiamine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R1 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 16a 
                 H 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 16b 
                 3-Cl 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 16c 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 16d 
                 3-OMe 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 4—8-Azabicyclo[3.2.1]octan-3-amine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 17a 
                 H 
                 
                   
                 
                   
                   
                   
                   
                   
                   
               
               
                 17b 
                 3-Cl 
                 
                   
                 
                 
                   
                 
                   
                 
                   
                 
                 
                   
                 
                   
                 
                   
                 
               
               
                 17c 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 17d 
                 3-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 17e 
                 4-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 17f 
                 3-CN 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 17g 
                 4-CN 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 5—3-(S)-Aminopiperidine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 18a 
                 H 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 18b 
                 3-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 6—4-Aminoazepane Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 19a 
                 H 
                 
                   
                 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 19b 
                 3-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 19c 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 19d 
                 3-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 19e 
                 4-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 7—Trans-2-methylaminopiperidine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 20a 
                 H 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20b 
                 3-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20c 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20d 
                 3-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20e 
                 4-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 8—Cis-2-methylaminopiperidine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 20a 
                 H 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20b 
                 3-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20c 
                 4-Cl 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20d 
                 3-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 20e 
                 4-OMe 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Example 9—3-Fluoroaminopiperidine Derivatives 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
               
               
               
            
               
                   
               
               
                   
                   
                   
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 IC 50  (μM) 
                 JAK2/JAK 
                 JAK3/JAK 
                 TVK2/JAK 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 R 
                 JAK1 
                 JAK2 
                 JAK3 
                 TVK2 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 21a 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 0.0170 
                 0.0280 
                 
                   
                 
                 
                   
                 
                 1.65 
                 0.545 
                 
                   
                 
               
               
                   
               
               
                 21b 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                 
                 0.0109 
                 
                   
                 
                 0.116 
                 
                   
                 
                 
                   
                 
                 150 
               
               
                   
               
               
                     indicates data missing or illegible when filed 
               
            
           
         
       
     
     Experimental Examples—Results of Cell-Based Assays on Janus Kinase Inhibitors 
       
     
       
         
           
               
               
               
            
               
                   
               
               
                   
                 
                   
                 
                 Selectivity for JAK1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 JAK2/ 
                 JAK3/ 
                 TYK2/ 
               
               
                   
                 JAK1 
                 JAK2 
                 JAK3 
                 TYK2 
                 JAK1 
                 JAK1 
                 JAK1 
               
               
                   
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
                 
                   
                 
               
               
                   
               
               
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     The inventive compounds that can be represented by Formula I, including the compounds exemplified above, can be prepared by various methods, including methods specifically described in the general synthetic procedures that follow. Those skilled in the art can estimate and understand synthetic methods for specific exemplary compounds and the compounds of Examples 1-9 based on the description of the general synthetic procedures, and thus explanations of individual methods for preparing the compounds are omitted. 
     General Synthetic Procedures 
     
       
         
         
             
             
         
       
     
     As depicted in General Scheme I, an N-alkylated 1-H-pyrrolo[2,3-b]pyridine carboxamide 2 was synthesized by carbonyldiimidazole-mediated amide coupling of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. Compounds 5-8 were prepared from various Boc-protected amines by N-benzylation with K 2 CO 3  as a base. Microwaves assisted nucleophilic substitution of chlorine with various amines at the C4-position of compound 2. To obtain desired products 13, 14, 15, and 16a-c, the amines were prepared in situ by treatment of modified Boc-protected intermediates 5-8 with HCl/MeOH. Alternatively, compound 2 was reacted with various Boc-protected amines to provide intermediates 9-13. In situ Boc-deprotection of 9-13 with HCl/MeOH and subsequent reductive amination with various benzaldehydes gave final products 16-20 in high yields. 
     
       
         
         
             
             
         
       
     
     General Procedure A 
     A 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.05 g, 5.34 mmol) solution and CDI (0.963 g, 5.94 mmol) were added to DMF (20 ml) under a nitrogen atmosphere at room temperature. The mixture was stirred at the same temperature for 1 h. To the mixture was slowly added dropwise a 2.0 M methylamine (30.5 mmol) solution. The resulting mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and the DMF solvent was removed using a rotary evaporator. The resulting mixture was poured into ethyl acetate and the precipitate was collected by filtration. The precipitate was poured into water to remove the imidazole. Filtration afforded a product as a white solid. 
     4-Chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 2 
     The title compound was synthesized according to General procedure A. Yield: 86.5%.  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 8.37 (q, J=4.7 Hz, 1H), 8.24 (s, 1H), 7.65 (d, J=3.5 Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 2.80 (d, J=4.6 Hz, 3H).  13 C NMR (101 MHz, Methanol-d 4 ) δ 168.9, 149.4, 143.1, 134.3, 128.5, 124.5, 120.7, 100.6, 26.9. 
     General Procedure B 
     To a solution of Boc-protected amine 4 (1.3 mmol) in DMF solvent (5 ml) were added K 2 CO 3  (5.2 mmol) and benzyl bromide (2.6 mmol). The mixture was stirred at 40° C. for 1 h. The reaction mixture was poured into Et 2 O (40 ml), washed with H 2 O (40 ml), brine (40 ml), and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (30% ethyl acetate in n-hexane elution) to afford a desired Boc-protected product. 
     tert-Butyl ((1-benzylpiperidin-4-yl)methyl)carbamate 5a 
     The title compound was synthesized according to General procedure B. Yield: 52.9%.  1 H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J=4.4 Hz, 3H), 7.27-7.21 (m, 2H), 4.57 (s, 1H), 3.48 (s, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.88 (dt, J=11.5, 3.3 Hz, 2H), 1.94 (td, J=11.7, 2.5 Hz, 2H), 1.68-1.61 (m, 2H), 1.59 (s, 1H), 1.43 (s, 9H), 1.26 (qd, J=12.1, 3.9 Hz, 2H). 
     tert-Butyl ((1-(3-chlorobenzyl)piperidin-4-yl)methyl)carbamate 5b 
     The title compound was synthesized according to General procedure B. Yield: 78.8%.  1 H NMR (400 MHz, Chloroform-d) δ 7.32 (dt, J=2.2, 1.0 Hz, 1H), 7.26 (s, 1H), 7.24-7.16 (m, 3H), 4.57 (s, 1H), 3.45 (s, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.85 (d, J=11.3 Hz, 2H), 1.94 (td, J=11.6, 2.5 Hz, 2H), 1.65 (d, J=12.9 Hz, 2H), 1.57 (s, 1H), 1.44 (s, 9H), 1.32-1.21 (m, 2H). 
     tert-Butyl ((1-(3-4-chlorobenzyl)piperidin-4-yl)methyl)carbamate 5c 
     The title compound was synthesized according to General procedure B. Yield: 33.6%.  1 H NMR (400 MHz, Chloroform-d) δ 7.27 (d, J=6.1 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.57 (s, 1H), 3.44 (s, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.84 (d, J=11.3 Hz, 2H), 1.97-1.88 (m, 2H), 1.65 (d, J=12.5 Hz, 2H), 1.56 (s, 1H), 1.43 (s, 9H), 1.31-1.19 (m, 2H). 
     tert-Butyl ((1-(3-methoxybenzyl)piperidin-4-yl)methyl)carbamate 5d 
     The title compound was synthesized according to General procedure B. Yield: 76.9%.  1 H NMR (400 MHz, Chloroform-d) δ 7.21 (t, J=8.0 Hz, 1H), 6.91-6.87 (m, 2H), 6.80-6.77 (m, 1H), 4.57 (s, 1H), 3.81 (s, 3H), 3.46 (s, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.88 (d, J=11.4 Hz, 2H), 1.98-1.89 (m, 2H), 1.64 (d, J=12.8 Hz, 2H), 1.57 (s, 1H), 1.43 (s, 9H), 1.32-1.21 (m, 2H). 
     tert-Butyl ((1-(4-methoxybenzyl)piperidin-4-yl)methyl)carbamate 5e 
     The title compound was synthesized according to General procedure B. Yield: 58.2%.  1 H NMR (400 MHz, Chloroform-d) δ 7.23-7.18 (m, 2H), 6.87-6.82 (m, 2H), 4.56 (s, 1H), 3.80 (s, 3H), 3.42 (s, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.87 (d, J=11.0 Hz, 2H), 1.91 (dd, J=12.5, 10.0 Hz, 2H), 1.64 (d, J=12.8 Hz, 2H), 1.56 (s, 1H), 1.43 (s, 9H), 1.31-1.19 (m, 2H). 
     tert-Butyl (1-benzylpyrrolidin-3-yl)carbamate 6a 
     The title compound was synthesized according to General procedure B. Yield: 68.3%.  1 H NMR (400 MHz, Chloroform-d) δ 7.33-7.29 (m, 3H), 7.25-7.22 (m, 1H), 4.82 (s, 1H), 4.16 (s, 1H), 3.59 (s, 2H), 2.77 (s, 1H), 2.61 (t, J=8.1 Hz, 1H), 2.53 (s, 1H), 2.26 (dt, J=13.1, 7.9 Hz, 2H), 1.43 (s, 9H). 
     tert-Butyl (1-(3-chlorobenzyl)pyrrolidin-3-yl)carbamate 6b 
     The title compound was synthesized according to General procedure B. Yield: 95.5%.  1 H NMR (400 MHz, Chloroform-d) δ 7.32 (s, 1H), 7.25-7.20 (m, 2H), 7.18 (t, J=4.1 Hz, 1H), 4.80 (s, 1H), 4.17 (s, 1H), 3.62-3.50 (m, 2H), 2.77 (s, 1H), 2.61 (t, J=8.1 Hz, 1H), 2.53 (s, 1H), 2.27 (q, J=13.5, 11.1 Hz, 2H), 1.58 (d, J=9.1 Hz, 2H), 1.44 (s, 11H). 
     tert-Butyl (1-(4-chlorobenzyl)pyrrolidin-3-yl)carbamate 6c 
     The title compound was synthesized according to General procedure B. Yield: 31.8%.  1 H NMR (400 MHz, Chloroform-d) δ 7.30-7.28 (m, 1H), 7.27 (d, J=2.2 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.23-7.22 (m, 1H), 4.79 (s, 1H), 4.16 (s, 1H), 3.55 (s, 2H), 2.75 (s, 1H), 2.59 (dd, J=9.7, 6.4 Hz, 1H), 2.50 (d, J=9.6 Hz, 1H), 2.27 (td, J=15.2, 13.9, 6.3 Hz, 2H), 1.66-1.53 (m, 1H), 1.43 (s, 9H). 
     tert-Butyl (1-(3-methoxybenzyl)pyrrolidin-3-yl)carbamate 6d 
     The title compound was synthesized according to General procedure B. Yield: 62.9%.  1 H NMR (400 MHz, Chloroform-d) δ 7.25-7.19 (m, 1H), 6.91-6.86 (m, 2H), 6.81-6.77 (m, 1H), 4.82 (s, 1H), 4.15 (d, J=13.1 Hz, 1H), 3.81 (s, 3H), 3.57 (s, 2H), 2.78 (s, 1H), 2.60 (t, J=8.1 Hz, 1H), 2.52 (d, J=9.7 Hz, 1H), 2.37-2.18 (m, 2H), 1.67-1.53 (m, 2H), 1.43 (s, 9H). 
     tert-Butyl (1-(4-methoxybenzyl)pyrrolidin-3-yl)carbamate 6e 
     The title compound was synthesized according to General procedure B. Yield: 57.6%.  1 H NMR (400 MHz, Chloroform-d) δ 7.23-7.19 (m, 2H), 6.87-6.83 (m, 2H), 4.80 (s, 1H), 4.15 (s, 1H), 3.80 (s, 3H), 3.53 (s, 2H), 2.76 (d, J=11.3 Hz, 1H), 2.63-2.55 (m, 1H), 2.49 (d, J=9.7 Hz, 1H), 2.34-2.19 (m, 2H), 1.72-1.49 (m, 2H), 1.43 (s, 9H). 
     tert-Butyl (R)-(1-(3-chlorobenzyl)pyrrolidin-3-yl)carbamate 6f 
     The title compound was synthesized according to General procedure B. Yield: 85.2%.  1 H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J=2.0 Hz, 1H), 7.25-7.19 (m, 2H), 7.18 (ddd, J=6.2, 2.8, 1.6 Hz, 1H), 4.82 (s, 1H), 4.17 (s, 1H), 3.61-3.51 (m, 2H), 2.77 (s, 1H), 2.60 (t, J=8.1 Hz, 1H), 2.52 (d, J=9.6 Hz, 1H), 2.34-2.20 (m, 2H), 1.64-1.53 (m, 1H), 1.44 (s, 9H). 
     tert-Butyl (R)-(1-(4-chlorobenzyl)pyrrolidin-3-yl)carbamate 6g 
     The title compound was synthesized according to General procedure B. Yield: 66.4%.  1 H NMR (400 MHz, Chloroform-d) δ 7.30-7.26 (m, 2H), 7.26-7.22 (m, 2H), 4.81 (s, 1H), 4.16 (s, 1H), 3.55 (s, 2H), 2.76 (d, J=9.7 Hz, 1H), 2.59 (dd, J=9.7, 6.4 Hz, 1H), 2.50 (d, J=9.7 Hz, 1H), 2.33-2.20 (m, 2H), 1.61-1.54 (m, 1H), 1.43 (s, 9H). 
     tert-Butyl (S)-(1-(3-chlorobenzyl)pyrrolidin-3-yl)carbamate 6h 
     The title compound was synthesized according to General procedure B. Yield: 78.3%.  1 H NMR (400 MHz, Chloroform-d) δ 7.3 (s, 1H), 7.2-7.2 (m, 3H), 4.8 (s, 1H), 4.1 (dd, J=14.9, 7.7 Hz, 1H), 3.6-3.5 (m, 2H), 2.8 (s, 1H), 2.7-2.6 (m, 1H), 2.5 (d, J=8.1 Hz, 1H), 2.3-2.2 (m, 2H), 1.6 (d, J=2.5 Hz, 1H), 1.4 (s, 9H). 
     tert-Butyl (S)-(1-(4-chlorobenzyl)pyrrolidin-3-yl)carbamate 6i 
     The title compound was synthesized according to General procedure B. Yield: 78.9%.  1 H NMR (400 MHz, Chloroform-d) δ 7.3 (d, J=8.6 Hz, 2H), 7.3-7.2 (m, 2H), 4.8 (s, 1H), 4.2-4.1 (m, 1H), 3.5 (s, 2H), 2.8 (s, 1H), 2.6 (dd, J=9.6, 6.5 Hz, 1H), 2.5 (d, J=8.0 Hz, 1H), 2.3 (td, J=14.4, 13.8, 6.0 Hz, 2H), 1.6-1.5 (m, 1H), 1.4 (s, 9H). 
     tert-Butyl (3-(benzylamino)cyclobutyl)carbamate 7a 
     The title compound was synthesized according to General procedure B. Yield: 34.4% (trans:cis=2.5:1) 1 H NMR (400 MHz, Chloroform-d) δ 7.3-7.3 (m, 4H), 7.3-7.2 (m, 1H), 4.7 (s, 1H), 4.2 (s, 1H), 3.8 (d, J=2.6 Hz, 2H), 3.5-3.4 (m, 1H), 3.1-2.9 (m, 1H), 2.7-2.6 (m, 2H), 2.2-2.0 (m, 2H), 1.4 (s, 9H). 
     tert-Butyl (3-((3-chlorobenzyl)amino)cyclobutyl)carbamate 7b 
     The title compound was synthesized according to General procedure B. Yield: 44.3% (trans:cis=2.2:1) 1 H NMR (400 MHz, Chloroform-d) δ 7.3-7.2 (m, 4H), 4.7 (s, 1H), 4.2 (d, J=22.1 Hz, 1H), 3.7 (s, 2H), 3.4 (m, 1H), 2.7-2.6 (m, 2H), 2.2-2.0 (m, 2H), 1.4 (s, 14H). 
     tert-Butyl (3-((4-chlorobenzyl)amino)cyclobutyl)carbamate 7c 
     The title compound was synthesized according to General procedure B. Yield: 33.2% (trans:cis=2.5:1) 1 H NMR (400 MHz, Chloroform-d) δ 7.3-7.3 (m, 2H), 7.2 (t, J=0.9, 0.2 Hz, 2H), 4.7 (s, 1H) 4.2 (d, J=28.2 Hz, 1H), 3.7 (s, 2H), 3.7 (s, 2H), 3.4-3.3 (m, 1H), 2.7-2.6 (m, 2H), 2.1-2.0 (m, 2H), 1.4 (s, 9H). 
     tert-Butyl (3-((4-methoxybenzyl)amino)cyclobutyl)carbamate 7d 
     Yield: 34.4%.  1 H NMR (400 MHz, Chloroform-d) trans:cis=3:1 δ 7.24-7.18 (m, 8H), 6.87-6.82 (m, 8H), 4.70 (s, 1H), 4.66-4.57 (m, 3H), 4.17 (d, J=14.6 Hz, 1H), 3.82 (d, J=0.9 Hz, 3H), 3.80 (s, 12H), 3.63 (d, J=4.0 Hz, 8H), 3.44-3.37 (m, 1H), 2.98 (tt, J=8.4, 6.7 Hz, 3H), 2.71-2.62 (m, 6H), 2.20-2.04 (m, 1H), 1.59-1.45 (m, 16H), 1.43 (d, J=2.9 Hz, 36H). 
     tert-Butyl (8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)carbamate 8a 
     Commercial available 
     tert-Butyl (8-(3-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 8b 
     The title compound was synthesized according to General procedure B. Yield: 54.6%;  1 H NMR (400 MHz, Chloroform-d) δ 7.39 (dt, J=2.3, 1.1 Hz, 1H), 7.24-7.19 (m, 3H), 4.32 (s, 1H), 3.80 (s, 1H), 3.50 (s, 2H), 3.17 (p, J=3.0 Hz, 2H), 2.05-1.95 (m, 2H), 1.86-1.78 (m, 2H), 1.70 (d, J=8.1 Hz, 2H), 1.53-1.46 (m, 2H), 1.44 (s, 9H). 
     tert-Butyl (8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 8c 
     The title compound was synthesized according to General procedure B. Yield: 69.3%;  1 H NMR (400 MHz, Chloroform-d) δ 7.31-7.27 (m, 4H), 4.35-4.27 (m, 1H), 3.81 (d, J=14.8 Hz, 1H), 3.48 (s, 2H), 3.17 (q, J=3.7, 3.2 Hz, 2H), 2.00 (m, J=7.1, 2.9 Hz, 2H), 1.81 (m, J=12.1, 5.3, 2.7 Hz, 2H), 1.74-1.65 (m, 2H), 1.47 (dd, J=12.3, 2.7 Hz, 2H), 1.43 (s, 9H). 
     General Procedure C 
     DMA (2 eq) and 4-chloro-N-alkyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (1.0 mmol) were added to a solution of amine (2 eq) in NMP (2 ml). The mixture was stirred under microwave irradiation at 180° C. for 5 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to afford a title product 9-13. 
     tert-Butyl 3-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate 9 
     The title compound was synthesized according to General procedure C. Yield: 50.5% (endo exo 1:1)  1 H NMR (400 MHz, Chloroform-d) δ 9.8 (d, J=7.4 Hz, 1H), 9.0 (d, J=8.5 Hz, 1H), 8.2 (d, J=6.0 Hz, 2H), 7.1 (d, J=3.6 Hz, 1H), 7.0 (d, J=3.7 Hz, 1H), 6.6 (d, J=3.7 Hz, 1H), 6.5 (d, J=3.7 Hz, 1H), 6.2 (s, 2H), 4.6-4.4 (m, 1H), 4.4-4.3 (m, 1H), 4.3 (s, 4H), 3.0 (dd, J=6.2, 4.8 Hz, 6H), 2.4 (d, J=7.7 Hz, 2H), 2.2-2.1 (m, 8H), 1.9 (d, J=14.1 Hz, 3H), 1.8 (t, J=7.1 Hz, 3H), 1.5 (s, 9H), 1.5 (s, 9H). 
     tert-Butyl (R)-3-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 10 
     The title compound was synthesized according to General procedure C. Yield: 54.1%;  1 H NMR (400 MHz, Chloroform-d) δ 9.7 (s, 1H), 9.2 (d, J=6.6 Hz, 1H), 8.2 (s, 1H), 7.1 (d, J=3.7 Hz, 1H), 6.7 (s, 1H), 6.1 (s, 1H), 4.3 (dd, J=13.2, 3.8 Hz, 1H), 4.0 (s, 2H), 3.0 (d, J=4.8 Hz, 3H), 2.9 (d, J=9.2 Hz, 2H), 1.9-1.6 (m, 4H), 1.4 (s, 9H). 
     tert-Butyl 4-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azepane-1-carboxylate 11 
     The title compound was synthesized according to General procedure C. Yield: 38.1%.  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.19 (d, J=1.9 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.64 (t, J=4.1 Hz, 1H), 4.27-4.19 (m, 1H), 3.61-3.39 (m, 4H), 2.87 (d, J=1.1 Hz, 3H), 2.29-2.19 (m, 1H), 2.09 (d, J=12.5 Hz, 1H), 1.97-1.65 (m, 4H), 1.50 (s, 9H). 
     tert-Butyl trans-2-methyl-4-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 12a 
     The title compound was synthesized according to General procedure C. Yield: 54.1%.  1 H NMR (400 MHz, Chloroform-d) δ 9.99 (s, 1H), 9.08 (d, J=7.9 Hz, 1H), 8.23 (s, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.7 Hz, 1H), 6.17 (s, 1H), 4.56 (s, 1H), 4.33-4.23 (m, 1H), 4.12 (d, J=13.8 Hz, 1H), 2.98 (d, J=4.7 Hz, 4H), 2.19-2.05 (m, 2H), 1.74-1.62 (m, 1H), 1.48 (s, 10H), 1.30 (d, J=7.0 Hz, 3H).  13 C NMR (101 MHz, Methanol-d 4 ) δ 172.5, 156.3, 150.7, 150.6, 144.9, 123.0, 106.6, 105.0, 103.1, 81.1, 47.5, 38.9, 34.6, 28.7, 26.6, 16.8. 
     tert-Butyl (2R,4R)-2-methyl-4-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 12b 
     The title compound was synthesized according to General procedure C. Yield: 46.8%;  1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.35 (s, 2H), 7.06 (d, J=3.7 Hz, 1H), 6.52 (d, J=3.7 Hz, 1H), 4.38 (p, J=4.5 Hz, 1H), 4.32-4.23 (m, 1H), 4.00-3.92 (m, 1H), 3.31 (dd, 1H), 2.94 (s, 3H), 2.10-1.98 (m, 2H), 1.96-1.84 (m, 2H), 1.48 (s, 9H), 1.27 (d, J=7.1 Hz, 3H). 
     tert-Butyl trans-3-fluoro-4-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 13a 
     The title compound was synthesized according to General procedure C. Yield: 30.5%,  1 H NMR (400 MHz, Chloroform-d) δ 9.99 (s, 1H), 9.08 (d, J=7.9 Hz, 1H), 8.23 (s, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.7 Hz, 1H), 6.17 (s, 1H), 4.56 (s, 1H), 4.33-4.23 (m, 1H), 4.12 (d, J=13.8 Hz, 1H), 2.98 (d, J=4.7 Hz, 4H), 2.19-2.05 (m, 2H), 1.74-1.62 (m, 1H), 1.48 (s, 10H), 1.30 (d, J=7.0 Hz, 3H). 
     tert-Butyl (3 S,4R)-3-fluoro-4-((5-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-carboxylate 13b 
     The title compound was synthesized according to General procedure C. Yield: 28.7%;  1 H NMR (400 MHz, Chloroform-d) δ 9.64 (s, 1H), 9.48 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.10 (d, J=3.7 Hz, 1H), 6.45 (d, J=3.7 Hz, 1H), 6.08 (s, 1H), 5.30 (d, J=0.4 Hz, 1H), 4.85 (d, J=48.3 Hz, 1H), 4.44 (s, 1H), 4.23 (dt, J=25.0, 8.1 Hz, 2H), 3.00 (d, J=4.8 Hz, 43H), 2.96 (s, 1H), 2.01 (q, J=7.5, 6.4 Hz, 2H), 1.48 (s, 9H). 
     General Procedure D 
     4 N HCl in dioxane (2 mL) was added to a solution of compound 5-8 in MeOH. The mixture was stirred at room temperature for 1 h for in situ Boc deprotection. After evaporation and further drying under high vacuum, the resulting product was used in the next step without further purification. 
     DMA (2 eq) and 4-chloro-N-alkyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (0.5 mmol) were added to a solution of the Boc-deprotected amine hydrochloride in NMP (2 ml). The mixture was stirred under microwave irradiation at 180° C. for 5 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to afford a title product 14a-e, 15a-i, 16a-d, 17a-c. 
     4-(((1-Benzylpiperidin-4-yl)methyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 14a 
     The title compound was synthesized according to General procedure D. Yield: 30.6%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.35-7.32 (m, 3H), 7.33-7.26 (m, 1H), 7.08 (d, J=3.7 Hz, 1H), 6.69 (d, J=3.7 Hz, 1H), 3.62 (d, J=5.6 Hz, 4H), 3.03 (d, J=11.7 Hz, 2H), 2.86 (s, 3H), 2.17 (t, J=11.9 Hz, 2H), 1.92 (d, J=13.2 Hz, 2H), 1.82-1.70 (m, 1H), 1.50-1.38 (m, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.7, 151.4, 149.7, 144.1, 136.1, 130.4, 128.8, 128.2, 121.6, 106.4, 103.9, 103.0, 63.4, 53.4, 50.7, 36.6, 29.7, 26.6; HRMS (ESI, m/z) calculated for C 22 H 28 N 5 O [M+H] +  378.2288 found 378.2293. 
     4-(((1-(3-Chlorobenzyl)piperidin-4-yl)methyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 14b 
     The title compound was synthesized according to General procedure D. Yield: 52.0%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 9.38 (t, J=5.4 Hz, 1H), 8.27 (s, 1H), 8.19 (d, J=4.7 Hz, 1H), 7.40-7.24 (m, 4H), 7.10 (dd, J=3.6, 2.4 Hz, 1H), 6.60 (dd, J=3.6, 1.9 Hz, 1H), 3.55-3.45 (m, 4H), 2.84 (d, J=11.1 Hz, 2H), 2.73 (d, J=4.4 Hz, 3H), 1.97 (s, 2H), 1.80-1.73 (m, 2H), 1.61 (s, 1H), 1.32 (q, J=10.8 Hz, 2H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 170.2, 150.2, 150.1, 144.4, 132.9, 130.0, 128.4, 127.4, 126.9, 121.3, 105.1, 102.5, 101.9, 61.3, 52.7, 49.7, 36.0, 29.4, 26.0; HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1901. 
     4-4(1-(4-Chlorobenzyl)piperidin-4-yl)methyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 14c 
     The title compound was synthesized according to General procedure D. Yield: 18.8%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.39 (s, 4H), 7.09 (d, J=3.6 Hz, 1H), 6.70 (d, J=3.7 Hz, 1H), 3.84-3.77 (m, 2H), 3.63 (d, J=6.7 Hz, 2H), 3.20-3.11 (m, 2H), 2.87 (s, 3H), 2.43 (s, 2H), 2.02-1.95 (m, 2H), 1.55-1.43 (m, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.1, 151.4, 148.3, 142.9, 134.6, 131.9, 129.1, 121.7, 106.4, 103.9, 103.0, 61.7, 53.0, 50.3, 35.9, 29.0, 26.5; HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1901. 
     4-(((1-(3-Methoxybenzyl)piperidin-4-yl)methyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 14d 
     The title compound was synthesized according to General procedure D. Yield: 17.3%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.25 (dd, J=8.2, 7.5 Hz, 1H), 7.08 (d, J=3.7 Hz, 1H), 6.96-6.85 (m, 3H), 6.69 (d, J=3.7 Hz, 1H), 3.80 (s, 3H), 3.64-3.58 (m, 4H), 3.05 (d, J=11.7 Hz, 2H), 2.86 (s, 3H), 2.22 (t, J=11.9 Hz, 2H), 1.93 (d, J=13.2 Hz, 2H), 1.84-1.72 (m, 1H), 1.45 (q, J=12.5, 3.8 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.5, 160.1, 151.3, 149.5, 143.9, 137.5, 129.7, 122.6, 121.6, 115.7, 113.7, 106.4, 103.9, 103.0, 63.2, 55.5, 53.4, 50.6, 36.4, 29.6, 26.5; HRMS (ESI, m/z) calculated for C 23 H 30 N 5 O 2  [M+H] +  408.2394 found 408.2392. 
     4-(((1-(4-Methoxybenzyl)piperidin-4-yl)methyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 14e 
     The title compound was synthesized according to General procedure D. Yield: 39.7%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.25-7.20 (m, 2H), 7.09 (d, J=3.6 Hz, 1H), 6.89-6.84 (m, 2H), 6.61 (d, J=3.7 Hz, 1H), 3.69 (s, 3H), 3.57 (s, 2H), 3.46 (d, J=6.5 Hz, 2H), 2.92 (d, J=11.3 Hz, 2H), 2.70 (s, 3H), 2.16 (s, 2H), 1.76 (d, J=13.1 Hz, 2H), 1.64 (s, 1H), 1.30 (q, J=12.3 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 172.0, 160.4, 151.5, 150.0, 144.4, 132.2, 122.0, 114.5, 106.6, 104.1, 103.0, 62.4, 55.6, 53.2, 50.6, 36.4, 29.4, 26.6; HRMS (ESI, m/z) calculated for C 23 H 30 N 5 O 2  [M+H] +  408.2394 found 408.2392. 
     4-((1-Benzylpyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15a 
     The title compound was synthesized according to General procedure D. Yield: 1.56%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.40-7.23 (m, 5H), 7.10 (d, J=3.7 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 4.77-4.70 (m, 1H), 3.74 (d, J=1.7 Hz, 2H), 3.05 (dd, J=10.1, 6.5 Hz, 1H), 2.88 (s, 3H), 2.86 (d, J=10.0 Hz, 1H), 2.72-2.63 (m, 2H), 2.51-2.41 (m, 1H), 1.90-1.79 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.9, 150.4, 149.9, 144.3, 138.1, 129.7, 129.0, 128.1, 122.3, 106.3, 104.5, 102.6, 62.3, 60.8, 53.4, 53.3, 49.7, 49.5, 49.3, 49.0, 48.8, 48.6, 48.4, 34.3, 26.6; HRMS (ESI, m/z) calculated for C 20 H 24 N 5 O [M+H] +  350.1975 found 350.1979. 
     4-((1-(3-Chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15b 
     The title compound was synthesized according to General procedure D. Yield: 11.7%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.19 (s, 1H), 7.43 (q, J=1.4 Hz, 1H), 7.32-7.29 (m, 2H), 7.28-7.24 (m, 1H), 7.10 (d, J=3.7 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.75-4.69 (m, 1H), 3.72 (s, 2H), 3.02-2.95 (m, 1H), 2.89 (s, 3H), 2.88-2.84 (m, 1H), 2.73-2.68 (m, 1H), 2.62 (td, J=8.8, 6.1 Hz, 1H), 2.50-2.41 (m, 1H), 1.90-1.80 (m, 1H); HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1588. 
     4-((1-(4-Chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15c 
     The title compound was synthesized according to General procedure D. Yield: 34.4%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.40-7.30 (m, 4H), 7.10 (d, J=3.7 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 4.75-4.69 (m, 1H), 3.71 (s, 2H), 2.99 (dd, J=10.0, 6.4 Hz, 1H), 2.89 (s, 4H), 2.69 (dd, J=10.0, 3.7 Hz, 1H), 2.62 (td, J=8.7, 6.0 Hz, 1H), 2.45 (m, J=13.8, 8.2, 5.8 Hz, 1H), 1.84 (m, J=13.6, 8.1, 6.0, 3.7 Hz, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.1, 150.0, 149.2, 143.6, 136.9, 133.1, 130.5, 128.6, 121.6, 105.8, 103.9, 102.4, 61.9, 59.6, 53.0, 52.9, 49.6, 49.4, 49.2, 49.0, 48.8, 48.6, 48.4, 34.0, 26.4; HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1588. 
     4-((1-(3-Methoxybenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15d 
     The title compound was synthesized according to General procedure D. Yield: 33.6%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.25-7.19 (m, 1H), 7.10 (d, J=3.6 Hz, 1H), 6.97 (dd, J=2.6, 1.4 Hz, 1H), 6.95-6.92 (m, 1H), 6.81 (m, J=8.2, 2.6, 1.0 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.73 (m, J=10.3, 7.8, 3.9 Hz, 1H), 3.78 (s, 3H), 3.75-3.65 (m, 2H), 3.01 (dd, J=10.1, 6.4 Hz, 1H), 2.88 (s, 4H), 2.67 (m, J=18.8, 9.4, 5.0 Hz, 2H), 2.51-2.41 (m, 1H), 1.89-1.81 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.0, 159.8, 150.0, 149.1, 143.4, 139.6, 129.5, 121.6, 121.5, 114.4, 113.1, 105.7, 103.9, 102.4, 61.8, 60.3, 55.3, 52.9, 33.9, 26.4; HRMS (ESI, m/z) calculated for C 21 H 26 N 5 O 2  [M+H] +  380.2081 found 380.2076. 
     4-((1-(4-Methoxybenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15e 
     The title compound was synthesized according to General procedure D. Yield: 18.6%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.19 (s, 1H), 7.33-7.26 (m, 2H), 7.11 (d, J=3.7 Hz, 1H), 6.91-6.86 (m, 2H), 6.64 (d, J=3.7 Hz, 1H), 4.76 (m, J=10.8, 8.0, 4.1 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 2H), 3.12 (dd, J=10.4, 6.5 Hz, 1H), 2.96-2.89 (m, 1H), 2.88 (s, 3H), 2.79-2.71 (m, 2H), 2.53-2.43 (m, 1H), 1.92-1.81 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.4, 159.5, 150.1, 149.4, 143.8, 130.8, 122.0, 114.2, 106.0, 104.2, 102.4, 61.6, 59.8, 55.5, 53.0, 52.9, 33.9, 26.5; HRMS (ESI, m/z) calculated for C 21 H 26 N 5 O 2  [M+H] +  380.2081 found 380.2079. 
     (R)-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15f 
     The title compound was synthesized according to General procedure D. Yield: 38.4%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.42 (m, J=1.4, 0.9 Hz, 1H), 7.31-7.29 (m, 2H), 7.28-7.23 (m, 1H), 7.10 (d, J=3.7 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.72 (m, J=10.2, 7.6, 3.8 Hz, 1H), 3.69 (s, 2H), 2.97 (dd, J=9.9, 6.4 Hz, 1H), 2.87-2.81 (m, 1H), 2.67 (dd, J=9.9, 3.7 Hz, 1H), 2.59 (m, J=8.7, 6.0 Hz, 1H), 2.45 (m, J=13.8, 8.2, 5.8 Hz, 1H), 1.88-1.79 (m, 1H).  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.3, 150.1, 149.3, 143.7, 140.7, 134.5, 130.0, 129.2, 127.7, 127.3, 121.8, 105.9, 104.1, 102.5, 62.0, 59.9, 53.0, 34.1, 26.5; HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1590. 
     (R)-4-((1-(4-Chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15g 
     The title compound was synthesized according to General procedure D. Yield: 57.6%;  1 H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 9.31 (d, J=7.5 Hz, 1H), 8.21 (s, 1H), 7.32-7.26 (m, 4H), 7.02 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.7 Hz, 1H), 6.16 (s, 1H), 4.64 (m, J=11.4, 3.9 Hz, 1H), 3.64 (d, J=1.0 Hz, 2H), 3.04-2.97 (m, 4H), 2.80-2.72 (m, 1H), 2.61 (ddd, J=13.3, 9.2, 4.8 Hz, 2H), 2.45-2.35 (m, 1H), 1.92-1.84 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.5, 150.2, 149.6, 144.0, 137.1, 133.4, 130.7, 128.9, 122.0, 106.0, 104.2, 102.5, 62.1, 59.8, 53.3, 53.1, 34.2, 26.5; HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1590. 
     (S)-4-((1-(3-Chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 15h 
     The title compound was synthesized according to General procedure D. Yield: 32.6%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (s, 1H), 7.43-7.41 (m, 1H), 7.32-7.29 (m, 2H), 7.28-7.23 (m, 1H), 7.10 (d, J=3.7 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.72 (m, J=10.2, 7.8, 3.9 Hz, 1H), 3.69 (s, 2H), 2.97 (dd, J=9.9, 6.3 Hz, 1H), 2.89 (s, 3H), 2.88-2.82 (m, 1H), 2.68 (dd, J=9.9, 3.7 Hz, 1H), 2.60 (m, J=8.7, 6.1 Hz, 1H), 2.45 (m, J=13.7, 8.1, 5.7 Hz, 1H), 1.89-1.79 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 170.5, 149.7, 148.8, 143.0, 140.4, 134.0, 129.5, 128.6, 127.1, 126.8, 121.2, 105.4, 103.6, 102.2, 61.6, 59.4, 52.7, 52.6, 33.7, 26.2; HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1590. 
     (S)-4-((1-(4-Chlorobenzyl)pyrrolidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 151 
     The title compound was synthesized according to General procedure D. Yield: 22.1%;  1 H NMR (400 MHz, Chloroform-d) δ 9.72 (s, 1H), 9.30 (d, J=7.5 Hz, 1H), 8.22 (s, 1H), 7.32-7.26 (m, 4H), 7.02 (d, J=3.7 Hz, 1H), 6.58 (d, J=3.7 Hz, 1H), 6.18 (s, 1H), 4.64 (m, J=11.7, 7.7, 3.9 Hz, 1H), 3.64 (d, J=0.9 Hz, 2H), 3.00 (d, J=4.8 Hz, 4H), 2.76 (m, J=8.5, 6.8 Hz, 1H), 2.60 (m, J=14.4, 9.3, 4.9 Hz, 2H), 2.45-2.35 (m, 1H), 1.93-1.85 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.0, 150.0, 149.2, 143.5, 136.9, 133.0, 130.4, 128.6, 121.6, 105.7, 103.9, 102.3, 61.8, 59.5, 52.9, 52.8, 33.9, 26.4; HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1590. 
     4-((3-(Benzylamino)cyclobutyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 16a 
     The title compound was synthesized according to General procedure D. Yield: 3.00%,  1 H NMR (400 MHz, Methanol-d 4 ) trans (85%), δ 8.18 (s, 1H), 7.42-7.30 (m, 5H), 7.11 (d, J=3.7 Hz, 1H), 6.68 (d, J=3.7 Hz, 1H), 4.37 (m, J=8.4, 7.1 Hz, 1H), 3.87 (s, 2H), 3.37-3.28 (m, 1H), 2.94-2.85 (m, 1H), 2.87 (s, 3H), 2.01-1.90 (m, 2H); HRMS (ESI, m/z) calculated for C 20 H 24 N 5 O [M+H] +  350.1975 found 350.1979. 
     4-((3-Chlorobenzyl)amino)cyclobutyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 16b 
     The title compound was synthesized according to General procedure D. Yield: 32.8%,  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.18 (d, J=6.7 Hz, 1H), 7.37-7.30 (m, 4H), 7.10 (d, J=3.7 Hz, 1H), 6.67 (d, J=3.7 Hz, 1H), 4.30 (tt, J=8.4, 7.0 Hz, 1H), 3.74 (s, 2H), 3.17 (tt, J=8.7, 7.1 Hz, 1H), 2.88 (s, 1H), 2.87 (s, 3H), 2.86-2.80 (m, 1H), 1.86 (tdd, J=11.7, 5.8, 2.7 Hz, 2H). HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1588. 
     4-((3-((4-Chlorobenzyl)amino)cyclobutyl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 16c 
     The title compound was synthesized according to General procedure D. Yield: 13.6% (trans:cis=2.5),  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.2 (s, 1H), 8.2 (s, 2H), 7.4-7.2 (m, 18H), 7.1 (d, J=3.6 Hz, 2H), 7.1 (d, J=3.6 Hz, 1H), 6.7 (d, J=3.7 Hz, 2H), 6.6 (d, J=3.7 Hz, 1H), 4.7-4.6 (m, 1H), 4.4-4.2 (m, 2H), 3.7 (s, 5H), 3.7 (s, 2H), 3.6-3.5 (m, 1H), 3.2-3.1 (m, 3H), 2.9 (s, 3H), 2.9 (s, 7H), 2.9-2.8 (m, 5H), 2.6 (d, J=11.7 Hz, 1H), 2.4-2.4 (m, 2H), 2.3-2.2 (m, 3H), 1.8 (qd, J=8.7, 2.8 Hz, 5H). HRMS (ESI, m/z) calculated for C 20 H 23 ClN 5 O [M+H] +  384.1586 found 384.1589. 
     4-((3-((3-Chlorobenzyl)amino)cyclobutyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 16d 
     The title compound was synthesized according to General procedure D. Yield: 35.0%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.3 (s, 1H), 7.4 (d, J=1.9 Hz, 1H), 7.3-7.3 (m, 3H), 7.1 (d, J=3.7 Hz, 1H), 6.7 (d, J=3.7 Hz, 1H), 4.4-4.3 (m, 1H), 3.8 (s, 2H), 3.5 (p, J=6.5 Hz, 1H), 2.9-2.8 (m, 2H), 1.9 (qd, J=8.8, 2.9 Hz, 2H); HRMS (ESI, m/z) calculated for C 19 H 20 ClN 5 O [M+H] +  370.1439 found 370.1431. 
     4-((8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17a 
     The title compound was synthesized according to General procedure D. Yield: 36.9%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.46-7.41 (m, 2H), 7.35 (tt, J=6.5, 1.0 Hz, 2H), 7.32-7.25 (m, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 4.42 (m, J=11.4, 5.8 Hz, 1H), 3.73 (s, 2H), 3.42 (s, 2H), 2.87 (s, 3H), 2.29-2.21 (m, 2H), 2.15-2.08 (m, 2H), 1.92 (t, J=7.2 Hz, 2H), 1.77 (t, J=11.7 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 170.8, 150.0, 149.1, 143.4, 139.1, 128.8, 128.4, 127.1, 121.4, 105.2, 103.9, 102.5, 58.6, 55.4, 45.5, 38.4, 26.9, 26.4; HRMS (ESI, m/z) calculated for C 23 H 28 N 5 O [M+H] +  390.2288 found 390.2293. 
     4-((8-(3-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17b 
     The title compound was synthesized according to General procedure D. Yield: 51.8%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.16 (s, 1H), 7.49 (dt, J=2.0, 1.0 Hz, 1H), 7.37-7.25 (m, 3H), 7.14 (d, J=3.6 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.39 (tt, J=11.3, 5.7 Hz, 1H), 3.66 (s, 2H), 3.37-3.32 (m, 2H), 2.87 (s, 3H), 2.25-2.18 (m, 2H), 2.13-2.05 (m, 2H), 1.89 (t, J=7.2 Hz, 2H), 1.75 (t, J=12.0 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.7, 150.3, 149.7, 144.2, 141.7, 134.6, 130.0, 129.2, 127.6, 127.4, 122.0, 105.7, 104.3, 102.6, 59.1, 55.4, 45.7, 38.9, 27.1, 26.5; HRMS (ESI, m/z) calculated for C 23 H 27 ClN 5 O [M+H] +  424.1899 found 424.1903. 
     4-((8-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17c 
     The title compound was synthesized according to General procedure D. Yield: 38.7%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.46-7.35 (m, 4H), 7.15 (d, J=3.6 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.42 (m, J=11.2, 5.8 Hz, 1H), 3.73 (s, 2H), 3.43 (s, 2H), 2.86 (s, 3H), 2.29-2.22 (m, 2H), 2.17-2.11 (m, 2H), 1.94 (d, J=7.8 Hz, 2H), 1.76 (t, J=12.1 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.6, 150.3, 149.6, 144.0, 137.5, 133.4, 130.7, 128.9, 122.1, 105.7, 104.3, 102.6, 59.1, 55.0, 45.7, 38.7, 27.0, 26.5; HRMS (ESI, m/z) calculated for C 23 H 27 ClN 5 O [M+H] +  424.1899 found 424.1903. 
     General Procedure E 
     4 N HCl in dioxane (2 mL) was added to a solution of compound 9-13 in MeOH. The mixture was stirred at room temperature for 1 h to remove the Boc group on the amine. The product was dried under vacuum and used without further purification. Triethylamine (2 eq) and sodium triacetoxyborohydride (2 eq) were added to an appropriate solution of the Boc deprotected intermediate (0.25 mmol) and benzaldehyde (0.5 mmol) in DCM (5 ml), followed by stirring at room temperature for 24 h. The resulting mixture was washed with a saturated aqueous solution of NaHCO 3 , diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to afford a title product. 
     4-((8-(3-Methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17d 
     The title compound was synthesized according to General procedure E. Yield: 59.4% (endo:exo=1:1);  1 H NMR (400 MHz, Chloroform-d) δ 9.6 (d, J=7.4 Hz, 1H), 9.4 (s, 1H), 9.3 (s, 1H), 9.0 (d, J=8.1 Hz, 1H), 8.2 (s, 1H), 8.2 (s, 1H), 7.3-7.2 (m, 2H), 7.1-6.9 (m, 6H), 6.8 (d, J=2.5 Hz, 1H), 6.8 (s, 1H), 6.6 (d, J=3.7 Hz, 1H), 6.5 (d, J=3.6 Hz, 1H), 6.0 (s, 2H), 4.3 (q, J=6.4 Hz, 2H), 3.8 (s, 3H), 3.8 (s, 3H), 3.6 (s, 2H), 3.6 (s, 2H), 3.3 (s, 2H), 3.2 (s, 2H), 3.0 (t, J=5.0 Hz, 6H), 2.3 (dd, J=8.0, 4.0 Hz, 2H), 2.1 (s, 4H), 2.1-2.0 (m, 2H), 1.9-1.7 (m, 8H); HRMS (ESI, m/z) calculated for C 24 H 29 N 5 O 2  [M+H] +  420.2394 found 420.2395. 
     4-((8-(4-Methoxybenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17e 
     The title compound was synthesized according to General procedure E. Yield: 70.7% (endo:exo=1:1);  1 H NMR (400 MHz, Chloroform-d) δ 9.6 (d, J=7.4 Hz, 1H), 9.6 (s, 1H), 9.5 (s, 1H), 9.0 (d, J=8.4 Hz, 1H), 8.2 (d, J=4.5 Hz, 2H), 7.3 (d, J=8.6 Hz, 4H), 7.1 (d, J=3.6 Hz, 1H), 7.0 (d, J=3.5 Hz, 1H), 6.9 (dd, J=8.6, 1.9 Hz, 4H), 6.6 (d, J=3.7 Hz, 1H), 6.5 (d, J=3.6 Hz, 1H), 6.0 (s, 1H), 4.3 (d, J=6.8 Hz, 2H), 3.8 (s, 6H), 3.6 (s, 2H), 3.5 (s, 2H), 3.3 (s, 2H), 3.2 (s, 2H), 3.0 (dd, J=6.5, 4.5 Hz, 6H), 2.3 (ddd, J=14.2, 6.3, 3.6 Hz, 2H), 2.1 (d, J=12.0 Hz, 6H), 2.0 (dd, J=7.9, 3.6 Hz, 2H), 1.9 (d, J=13.7 Hz, 2H), 1.9-1.7 (m, 6H). 
     4-((8-(3-Cyanobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17f 
     The title compound was synthesized according to General procedure E. Yield: 54.5% (endo:exo=1:1);  1 H NMR (400 MHz, Chloroform-d) δ 9.7 (d, J=7.2 Hz, 1H), 9.1 (d, J=8.6 Hz, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 8.2 (d, J=3.8 Hz, 2H), 8.2-8.0 (m, 2H), 7.8 (d, J=7.6 Hz, 1H), 7.7 (d, J=7.4 Hz, 1H), 7.5 (td, J=7.9, 5.5 Hz, 2H), 7.1 (d, J=3.7 Hz, 1H), 7.0 (d, J=3.7 Hz, 1H), 6.6 (d, J=3.7 Hz, 1H), 6.5 (d, J=3.7 Hz, 1H), 6.1 (s, 2H), 4.4 (q, J=6.8 Hz, 2H), 3.7 (s, 2H), 3.7 (s, 2H), 3.3 (s, 2H), 3.2 (s, 2H), 3.1-2.9 (m, 6H), 2.4-2.3 (m, 2H), 2.2-2.1 (m, 6H), 2.1-2.0 (m, 2H), 1.9 (d, J=13.8 Hz, 2H), 1.9-1.8 (m, 4H); HRMS (ESI, m/z) calculated for C 24 H 26 N 6 O [M+H] +  415.2241 found 415.2245. 
     4-((8-(4-Cyanobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 17g 
     The title compound was synthesized according to General procedure E. Yield: 67.6% (endo:exo=1:1);  1 H NMR (400 MHz, Chloroform-d) δ 9.7 (d, J=7.5 Hz, 1H), 9.1 (d, J=7.9 Hz, 1H), 8.2 (s, 1H), 8.2 (s, 1H), 7.6 (d, J=8.1 Hz, 4H), 7.5 (d, J=7.2 Hz, 4H), 7.0 (d, J=3.6 Hz, 1H), 7.0-7.0 (m, 1H), 6.6 (d, J=3.5 Hz, 1H), 6.5 (d, J=3.5 Hz, 1H), 6.2 (s, 2H), 4.3 (q, J=6.5 Hz, 2H), 3.7 (s, 2H), 3.6 (s, 2H), 3.2 (s, 2H), 3.2 (s, 2H), 3.0 (dd, J=4.8, 3.3 Hz, 5H), 2.4-2.3 (m, 2H), 2.2-2.1 (m, 7H), 2.1 (dd, J=7.9, 3.3 Hz, 2H), 1.9 (d, J=13.4 Hz, 2H), 1.8 (dd, J=15.6, 9.4 Hz, 5H). 
     (S)-4-((1-(3-Chlorobenzyl)piperidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 18a 
     The title compound was synthesized according to General procedure E. Yield: 43.3%;  1 H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 2H), 8.17 (s, 1H), 7.50 (s, 1H), 7.23 (d, J=0.7 Hz, 1H), 7.22-7.17 (m, 2H), 7.00 (d, J=3.7 Hz, 1H), 6.51 (d, J=3.7 Hz, 1H), 6.03 (s, 1H), 4.16 (d, J=9.3 Hz, 1H), 3.58-3.44 (m, 2H), 3.01 (d, J=4.8 Hz, 3H), 2.97-2.87 (m, 1H), 2.66-2.55 (m, 1H), 2.41-2.31 (m, 1H), 2.24 (s, 1H), 1.98 (d, J=6.0 Hz, 1H), 1.90-1.83 (m, 1H), 1.66 (s, 2H); HRMS (ESI, m/z) calculated for C 22 H 27 N 5 O 2  [M+H] +  394.2238 found 394.2235. 
     (S)-4-((1-(3-Methoxybenzyl)piperidin-3-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 18b 
     The title compound was synthesized according to General procedure E. Yield: 69.2%;  1 H NMR (400 MHz, Chloroform-d) δ 9.26 (d, J=7.9 Hz, 2H), 8.17 (s, 1H), 7.20 (dd, J=8.2, 7.5 Hz, 1H), 7.03 (s, 1H), 6.99-6.94 (m, 2H), 6.81-6.74 (m, 1H), 6.54 (d, J=3.7 Hz, 1H), 6.07 (s, 1H), 4.21-4.12 (m, 1H), 3.83 (s, 3H), 3.58-3.47 (m, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.97 (s, 1H), 2.60 (s, 1H), 2.39-2.31 (m, 1H), 2.27 (s, 1H), 1.98 (s, 1H), 1.85 (dd, J=6.3, 3.5 Hz, 1H), 1.64 (s, 2H); HRMS (ESI, m/z) calculated for C 21 H 25 ClN 5 O [M+H] +  398.1742 found 398.1747. 
     4-((1-Benzylazepan-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 19a 
     The title compound was synthesized according to General procedure E. Yield: 76.3%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.43-7.27 (m, 5H), 7.09 (d, J=3.7 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 4.44-4.36 (m, 1H), 3.86-3.75 (m, 2H), 2.87 (s, 7H), 2.26-2.16 (m, 2H), 1.95-1.75 (m, 4H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 163.2, 141.3, 141.1, 135.6, 121.3, 121.0, 120.7, 120.1, 119.4, 118.6, 113.4, 97.2, 95.5, 93.8, 53.9, 46.9, 44.0, 41.9, 26.3, 25.3, 17.2, 14.6; HRMS (ESI, m/z) calculated for C 22 H 28 N 5 O [M+H] +  378.2288 found 378.2292. 
     4-((1-(3-Chlorobenzyl)azepan-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 19b 
     The title compound was synthesized according to General procedure E. Yield: 55.9%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.44 (m, J=1.4, 0.8 Hz, 1H), 7.34-7.23 (m, 3H), 7.09 (d, J=3.7 Hz, 1H), 6.62 (d, J=3.7 Hz, 1H), 4.41 (m, J=8.2, 4.2 Hz, 1H), 3.72-3.62 (m, 2H), 2.88 (s, 3H), 2.84-2.67 (m, 4H), 2.17 (m, J=12.6, 9.4, 8.0, 4.2 Hz, 2H), 1.92-1.69 (m, 4H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.1, 149.7, 149.2, 143.6, 141.4, 134.2, 129.6, 129.0, 127.3, 127.2, 121.3, 105.4, 103.7, 102.7, 62.5, 55.8, 52.7, 50.9, 35.3, 34.8, 26.4, 24.5. HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1903. 
     4-((1-(4-Chlorobenzyl)azepan-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 19c 
     The title compound was synthesized according to General procedure E. Yield: 58.4%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.17 (s, 1H), 7.40-7.32 (m, 4H), 7.09 (d, J=3.6 Hz, 1H), 6.61 (d, J=3.7 Hz, 1H), 4.40 (m, J=8.1, 4.2 Hz, 1H), 3.69 (d, J=2.2 Hz, 2H), 2.88 (s, 3H), 2.85-2.69 (m, 4H), 2.24-2.13 (m, 3H), 1.95-1.70 (m, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.3, 149.9, 149.2, 143.7, 137.4, 133.1, 130.7, 128.7, 121.6, 105.7, 103.9, 102.8, 62.3, 55.9, 52.9, 50.8, 35.1, 34.9, 26.5, 24.3. HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1904. 
     4-((1-(4-Methoxybenzyl)azepan-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 19d 
     The title compound was synthesized according to General procedure E. Yield: 73.5%;  1 H NMR (400 MHz, Chloroform-d) δ 9.89 (s, 1H), 9.38 (d, J=8.0 Hz, 1H), 8.28 (s, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.93 (d, J=3.5 Hz, 1H), 6.90-6.86 (m, 2H), 6.46 (d, J=3.7 Hz, 1H), 4.30 (s, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 3.00 (d, J=4.7 Hz, 3H), 2.88 (d, J=0.6 Hz, 1H), 2.84 (s, 2H), 2.80-2.69 (m, 2H), 2.32-2.16 (m, 2H), 1.99-1.85 (m, 2H), 1.85-1.76 (m, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 170.6, 159.3, 149.6, 149.4, 148.5, 142.8, 131.0, 121.4, 113.9, 105.3, 103.5, 102.4, 61.5, 55.1, 55.0, 51.9, 34.4, 32.9, 26.4, 26.2, 22.6; HRMS (ESI, m/z) calculated for C 23 H 30 N 5 O 2  [M+H] +  408.23941 found 408.2390. 
     4-((1-(4-Cyanobenzyl)azepan-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 19e 
     The title compound was synthesized according to General procedure E. Yield: 65.0%;  1 H NMR (400 MHz, Chloroform-d) δ 10.10 (s, 1H), 9.32 (d, J=8.1 Hz, 1H), 8.24 (s, 1H), 7.64-7.59 (m, 2H), 7.53-7.49 (m, 2H), 7.00 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.7 Hz, 1H), 6.34 (s, 1H), 4.38-4.28 (m, 1H), 3.71 (s, 2H), 2.99 (d, J=4.7 Hz, 3H), 2.79-2.61 (m, 4H), 2.21-2.09 (m, 3H), 1.95-1.82 (m, 3H), 1.76-1.64 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 170.7, 149.6, 148.6, 145.4, 143.0, 132.1, 129.3, 121.1, 118.9, 110.4, 105.3, 103.5, 102.5, 62.5, 55.7, 52.6, 51.0, 35.4, 34.3, 26.3, 24.5; HRMS (ESI, m/z) calculated for C 23 H 27 N 6 O [M+H] +  403.2241 found 403.2246. 
     4-((trans-1-Benzyl-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20a 
     The title compound was synthesized according to General procedure E. Yield: 49.3%;  1 H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 9.47 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 7.41-7.29 (m, 4H), 7.25-7.23 (m, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.54-6.50 (m, 1H), 6.41 (s, 1H), 4.33 (s, 1H), 4.02 (d, J=13.3 Hz, 1H), 3.35 (d, J=13.3 Hz, 1H), 3.01 (d, J=4.7 Hz, 3H), 2.96-2.88 (m, 1H), 2.73-2.67 (m, 1H), 2.50-2.42 (m, 1H), 1.94 (d, J=5.7 Hz, 3H), 1.84-1.75 (m, 1H), 1.23 (d, J=6.3 Hz, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.8, 150.2, 149.7, 144.2, 137.2, 130.2, 128.9, 128.1, 122.1, 106.0, 104.1, 102.9, 58.7, 53.4, 46.7, 39.1, 31.1, 26.6, 17.8; HRMS (ESI, m/z) calculated for C 22 H 28 N 5 O [M+H] +  378.2288 found 378.2295. 
     4-((trans-1-(3-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20b 
     The title compound was synthesized according to General procedure E. Yield: 45.4%;  1 H NMR (400 MHz, Chloroform-d) δ 9.42 (d, J=7.8 Hz, 2H), 8.22 (s, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.24-7.18 (m, 3H), 7.03 (d, J=3.6 Hz, 1H), 6.55 (d, J=3.7 Hz, 1H), 6.22 (s, 1H), 4.34 (s, 1H), 3.94 (d, J=13.7 Hz, 1H), 3.31 (d, J=13.8 Hz, 1H), 3.01 (d, J=4.8 Hz, 3H), 2.92-2.85 (m, 1H), 2.71-2.63 (m, 1H), 2.48-2.40 (m, 1H), 1.87-1.77 (m, 4H), 1.19 (d, J=6.3 Hz, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 172.2, 150.5, 150.0, 144.5, 141.3, 135.0, 130.4, 130.1, 128.3, 128.1, 122.4, 106.3, 104.4, 103.3, 58.7, 53.3, 47.3, 47.1, 39.9, 32.0, 26.9, 18.0; HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1903. 
     4-((trans-1-(4-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20c 
     The title compound was synthesized according to General procedure E. Yield: 57.3%;  1 H NMR (400 MHz, Chloroform-d) δ 9.80 (s, 1H), 9.44 (d, J=7.8 Hz, 1H), 8.22 (s, 1H), 7.32-7.27 (m, 4H), 7.03 (d, J=3.6 Hz, 1H), 6.54 (d, J=3.7 Hz, 1H), 6.25 (s, 1H), 4.33 (s, 1H), 3.94 (d, J=13.6 Hz, 1H), 3.31 (d, J=13.6 Hz, 1H), 3.00 (d, J=4.7 Hz, 3H), 2.92-2.84 (m, 1H), 2.69-2.62 (m, 1H), 2.46-2.38 (m, 1H), 1.95 (dd, J=12.6, 3.9 Hz, 3H), 1.80 (d, J=11.2 Hz, 1H), 1.19 (d, J=6.3 Hz, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.5, 150.1, 149.4, 143.9, 136.8, 133.3, 131.2, 128.8, 121.9, 105.8, 103.9, 102.9, 57.9, 52.8, 46.8, 39.3, 31.4, 26.6, 17.6; HRMS (ESI, m/z) calculated for C 22 H 27 ClN 5 O [M+H] +  412.1899 found 412.1903. 
     4-((trans-1-(3-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20d 
     The title compound was synthesized according to General procedure E. Yield: 55.6%;  1 H NMR (400 MHz, Chloroform-d) δ 9.98 (s, 1H), 9.47 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.01 (d, J=3.7 Hz, 1H), 6.99-6.92 (m, 2H), 6.81-6.77 (m, 1H), 6.53 (d, J=3.7 Hz, 1H), 6.34 (s, 1H), 4.33 (s, 1H), 3.99 (d, J=13.5 Hz, 1H), 3.82 (s, 3H), 3.35 (d, J=13.4 Hz, 1H), 3.00 (d, J=4.7 Hz, 3H), 2.97-2.91 (m, 1H), 2.76-2.69 (m, 1H), 2.52-2.44 (m, 1H), 2.05-2.00 (m, 1H), 1.95 (t, J=5.3 Hz, 2H), 1.84-1.75 (m, 1H), 1.22 (d, J=6.4 Hz, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.6, 160.1, 150.1, 149.4, 143.9, 138.9, 129.7, 122.4, 121.9, 115.4, 113.5, 105.9, 104.0, 102.9, 58.6, 55.5, 53.3, 46.6, 39.0, 31.1, 26.6, 17.6; HRMS (ESI, m/z) calculated for C 23 H 30 N 5 O 2  [M+H] +  408.2394 found 408.2399. 
     4-((trans-1-(4-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20e 
     The title compound was synthesized according to General procedure E. Yield: 48.5%;  1 H NMR (400 MHz, Chloroform-d) δ 10.20 (s, 1H), 9.54 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.01 (d, J=3.6 Hz, 1H), 6.89-6.85 (m, 2H), 6.50 (d, J=3.7 Hz, 2H), 4.34 (s, 1H), 4.05 (d, J=13.1 Hz, 1H), 3.81 (s, 3H), 3.36 (d, J=13.1 Hz, 1H), 3.02-2.95 (m, 4H), 2.77 (d, J=12.3 Hz, 1H), 2.49 (t, J=10.9 Hz, 1H), 2.00 (dd, J=28.9, 10.6 Hz, 3H), 1.83 (d, J=13.3 Hz, 1H), 1.29 (d, J=6.3 Hz, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.5, 159.9, 150.0, 149.4, 143.8, 131.8, 127.1, 122.2, 114.4, 105.9, 104.0, 102.7, 57.6, 55.5, 53.7, 49.9, 46.3, 38.5, 30.3, 26.6, 17.6; HRMS (ESI, m/z) calculated for C 23 H 30 N 5 O 2  [M+H] +  408.2394 found 408.2401. 
     4-((cis-1-(3-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20f 
     The title compound was synthesized according to General procedure E. Yield: 65.1%;  1 H NMR (400 MHz, Chloroform-d) δ 9.50 (s, 1H), 9.10-9.04 (m, 1H), 8.18 (s, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.20 (tt, J=5.3, 3.4 Hz, 2H), 7.02 (d, J=3.7 Hz, 1H), 6.52 (d, J=3.7 Hz, 1H), 6.05 (s, 1H), 4.08 (d, J=13.7 Hz, 1H), 3.98-3.87 (m, 1H), 3.11 (d, J=13.8 Hz, 1H), 2.96 (d, J=4.8 Hz, 3H), 2.91-2.83 (m, 1H), 2.48-2.37 (m, 1H), 2.19-2.11 (m, 1H), 2.10-2.02 (m, 2H), 1.50 (dt, J=12.7, 11.3 Hz, 2H), 1.21 (d, J=6.1 Hz, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 170.9, 149.8, 149.3, 143.6, 140.9, 134.2, 129.5, 129.1, 127.3, 127.2, 121.3, 105.2, 103.6, 102.6, 57.7, 57.7, 57.1, 56.0, 51.5, 51.0, 42.0, 33.2, 26.3, 20.9; HRMS (ESI, m/z) calculated for C 22 H 26 ClN 5 O [M+H] +  412.1899 found 412.1904. 
     4-((cis-1-(4-Chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20g 
     The title compound was synthesized according to General procedure E. Yield: 62.6%;  1 H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 9.12-9.05 (m, 1H), 8.20 (s, 1H), 7.31-7.27 (m, 4H), 7.03 (d, J=3.7 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 6.05 (s, 1H), 4.08 (d, J=13.7 Hz, 1H), 4.00-3.87 (m, 1H), 3.12 (d, J=13.7 Hz, 1H), 2.98 (d, J=4.8 Hz, 3H), 2.89-2.83 (m, 1H), 2.48-2.39 (m, 1H), 2.19-2.13 (m, 1H), 2.12-2.03 (m, 2H), 1.61-1.45 (m, 2H), 1.23 (d, J=6.1 Hz, 3H).  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.7, 150.1, 149.9, 144.3, 137.1, 133.3, 131.2, 128.8, 122.0, 105.8, 104.1, 102.8, 57.3, 56.5, 51.8, 51.4, 42.5, 33.7, 26.5, 21.1; HRMS (ESI, m/z) calculated for C 22 H 26 ClN 5 O [M+H] +  412.1903 found 412.1899. 
     4-((cis-1-(3-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20h 
     The title compound was synthesized according to General procedure E. Yield: 66.2%;  1 H NMR (400 MHz, Chloroform-d) δ 9.66 (s, 1H), 9.09 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.03 (d, J=3.6 Hz, 1H), 6.93-6.90 (m, 2H), 6.82-6.77 (m, 1H), 6.53 (d, J=3.7 Hz, 1H), 6.09 (s, 1H), 4.11 (d, J=13.5 Hz, 1H), 3.99-3.88 (m, 1H), 3.82 (s, 3H), 3.15 (d, J=13.6 Hz, 1H), 2.98 (d, J=4.8 Hz, 3H), 2.92 (dt, J=11.9, 3.4 Hz, 1H), 2.47-2.40 (m, 1H), 2.20-2.05 (m, 3H), 1.64-1.47 (m, 2H), 1.24 (d, J=6.1 Hz, 4H);  13 C NMR (101 MHz, Chloroform-d) δ 170.9, 158.7, 149.7, 149.3, 143.5, 130.7, 129.7, 121.2, 113.6, 105.2, 103.6, 102.6, 56.7, 55.7, 55.2, 51.0, 41.9, 33.1, 26.3, 20.8; HRMS (ESI, m/z) calculated for C 23 H 29 N 5 O 2  [M+H] +  408.2394 found 408.2403. 
     4-((cis-1-(4-Methoxybenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20i 
     The title compound was synthesized according to General procedure E. Yield: 90.5%;  1 H NMR (400 MHz, Chloroform-d) δ 9.66 (s, 1H), 9.07 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 7.26-7.22 (m, 2H), 7.03 (d, J=3.6 Hz, 1H), 6.88-6.84 (m, 2H), 6.52 (d, J=3.7 Hz, 1H), 6.06 (s, 1H), 4.06 (d, J=13.3 Hz, 1H), 3.97-3.86 (m, 1H), 3.81 (s, 3H), 3.15 (d, J=13.3 Hz, 1H), 2.97 (d, J=4.8 Hz, 3H), 2.94-2.87 (m, 1H), 2.45-2.36 (m, 1H), 2.15 (dd, J=12.9, 2.7 Hz, 1H), 2.11-2.02 (m, 2H), 1.63-1.46 (m, 2H), 1.26 (d, J=6.1 Hz, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.9, 159.6, 149.7, 149.3, 143.5, 139.9, 129.2, 121.7, 121.2, 114.9, 112.4, 105.2, 103.6, 102.6, 57.5, 55.9, 55.2, 51.4, 51.0, 42.0, 33.2, 26.3, 20.9; HRMS (ESI, m/z) calculated for C 23 H 29 N 5 O 2  [M+H] +  408.2394 found 408.2394. 
     4-((cis-1-(4-Cyanobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 20j 
     The title compound was synthesized according to General procedure E. Yield: 91.4%;  1 H NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H), 9.12 (d, J=7.9 Hz, 1H), 8.21 (s, 1H), 7.63-7.44 (m, 4H), 7.04 (d, J=3.7 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 6.09 (s, 1H), 4.16 (d, J=14.3 Hz, 1H), 4.01-3.91 (m, 1H), 3.19 (d, J=14.4 Hz, 1H), 2.98 (d, J=4.8 Hz, 3H), 2.82 (dt, J=12.4, 3.5 Hz, 1H), 2.51-2.42 (m, 1H), 2.22-2.04 (m, 3H), 1.49 (d, J=11.8 Hz, 2H), 1.20 (d, J=6.1 Hz, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.8, 149.8, 149.3, 145.5, 143.5, 132.1, 129.4, 121.3, 119.0, 110.5, 105.2, 103.6, 102.5, 57.3, 56.2, 51.9, 51.0, 42.1, 33.3, 26.4, 21.1; HRMS (ESI, m/z) calculated for C 23 H 26 N 6 O [M+H] +  403.2241 found 403.2247. 
     4-((trans-1-(3-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 21a 
     The title compound was synthesized according to General procedure E. Yield: 24.6%;  1 H NMR (400 MHz, Chloroform-d) δ 10.7 (s, 1H), 9.5 (d, J=8.0 Hz, 1H), 8.3 (s, 1H), 7.4 (s, 1H), 7.3-7.2 (m, 3H), 7.0 (d, J=3.5 Hz, 1H), 6.5 (d, J=3.5 Hz, 1H), 6.0 (s, 1H), 4.4-4.3 (m, 1H), 3.7-3.6 (m, 2H), 2.8-2.6 (m, 4H), 2.2-2.1 (m, 2H), 1.9 (ddt, J=23.9, 12.9, 5.9 Hz, 3H), 1.8-1.6 (m, 1H); HRMS (ESI, m/z) calculated for C 21 H 23 ClFN 5 O [M+H] +  416.1648 found 416.1648. 
     4-((cis-3-Fluoro-1-(3-methoxybenzyl)piperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 21b 
     The title compound was synthesized according to General procedure E. Yield: 39.6%;  1 H NMR (400 MHz, Chloroform-d) δ 9.90 (s, 1H), 9.51 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.06 (d, J=3.7 Hz, 1H), 6.96-6.90 (m, 2H), 6.84-6.79 (m, 1H), 6.46 (d, J=3.7 Hz, 1H), 6.10 (s, 1H), 4.87 (d, J=48.7 Hz, 1H), 4.18 (d, J=24.4 Hz, 1H), 3.82 (s, 3H), 3.62-3.60 (m, 2H), 3.21 (s, 1H), 3.00 (d, J=4.7 Hz, 3H), 2.96-2.87 (m, 1H), 2.52-2.28 (m, 2H), 2.18-2.06 (m, 2H); HRMS (ESI, m/z) calculated for C 22 H 27 FN 5 O 2  [M+H] +  412.2143 found 412.2145. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     As depicted in General Scheme III, an N-alkylated 1-H-pyrrolo[2,3-b]pyridine carboxamides 2 was synthesized by carbonyldiimidazole-mediated amide coupling of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid. Compound 2 was reacted with various Boc-protected amines to provide intermediates. In situ deprotection of the Boc protecting groups from the intermediates by treatment with HCl/MeOH and subsequent reductive amination with various benzaldehydes gave final product 21″-24″ in high yields. 2-Dimethylpiperidine derivatives were synthesized by carrying out the reactions in the reverse order. Benzyl group-introduced amine intermediates 18″-20″ were synthesized by the introduction of a benzyl group into the starting material 11″ and subsequent amination of the ketone. Compound 2 was allowed to react with the amines 18″-20″ to give desired products 21″-25″. 
     
       
         
         
             
             
         
       
     
     General Procedure F 
     4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1 eq) and CDI (1.05 eq) were added dropwise to a DMF (20 ml) solution at room temperature under a N 2  gas atmosphere. The mixture was stirred at the same temperature for 1 h. To the reaction mixture was slowly added dropwise methylamine (5 eq). The resulting mixture was stirred at room temperature for 1 h. The completion of the reaction was confirmed by TLC monitoring and the DMF solvent was removed using a rotary evaporator. Ethyl acetate was poured into the resulting mixture and the precipitate was collected by filtration. Water was poured into the precipitate to remove the imidazole. Filtration afforded a product as a white solid. 
     4-Chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 2 
     The title compound was synthesized according to General procedure F. Yield: 86.5%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 8.37 (q, J=4.7 Hz, 1H), 8.24 (s, 1H), 7.65 (d, J=3.5 Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 2.80 (d, J=4.6 Hz, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 168.85, 149.42, 143.10, 134.32, 128.48, 124.54, 120.69, 100.59, 26.93; MS (ESI, m/z) calculated for C 9 H 8 ClN 3 O [M+H] +  209.04, found 210.00. 
     General Procedure G 
     DIEA (2 eq) and 4-chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (1.0 mmol) were added dropwise to a solution of amine 3″-6″ (2 eq) in NMP (2 ml). The mixture was stirred at 180° C. overnight. The resulting mixture was cooled to room temperature, diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to obtain a mixture of protected and unprotected products. To the mixture was added dropwise 4 N HCl in dioxane (2 mL). The resulting mixture was stirred at room temperature for 1 h for in situ Boc deprotection. After evaporation and further drying under high vacuum, the resulting product 7″-10″ was used in the next step without further purification. 
     N-Methyl-4-((cis-2-methylpiperidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride 7″ 
     The title compound was synthesized according to General procedure G. Yield: 37.6%;  1 H NMR (400 MHz, Deuterium Oxide) δ 8.10 (d, J=0.9 Hz, 1H), 7.19 (dd, J=3.7, 0.8 Hz, 1H), 6.51 (dd, J=3.8, 0.9 Hz, 1H), 4.43-4.37 (m, 1H), 3.51-3.41 (m, 1H), 3.42-3.35 (m, 1H), 3.23-3.11 (m, 1H), 2.90 (d, J=0.8 Hz, 3H), 2.15-2.00 (m, 2H), 1.99-1.88 (m, 1H), 1.48-1.43 (m, 1H), 1.35 (d, J=6.5 Hz, 3H);  13 C NMR (101 MHz, Deuterium Oxide) δ 171.4, 148.6, 148.5, 143.5, 122.4, 104.9, 103.1, 101.7, 47.6, 44.2, 39.0, 34.6, 27.5, 26.7, 26.0; HRMS (ESI, m/z) calculated for C 15 H 21 N 5 O [M+H] +  288.1819 found 288.1821. 
     4-((trans-3-Fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride 8″ 
     The title compound was synthesized according to General procedure G. Yield: 71%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.46 (s, 1H), 7.40 (d, J=3.7 Hz, 1H), 7.01 (d, J=3.7 Hz, 1H), 5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 3.63-3.57 (m, 2H), 2.93 (s, 3H), 2.61-2.49 (m, 2H), 2.17-2.06 (m, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 169.32, 154.26, 139.88, 135.89, 125.50, 108.37, 106.48, 105.19, 87.31 (d, J C-F =181.0 Hz), 51.81 (d, J C-F =23.8 Hz), 44.84 (d, J C-F =26.3 Hz), 41.59, 26.80, 26.24; MS (ESI, m/z) calculated for C 14 H 18 FN 5 O [M+H] +  292.16 found 292.10. 
     4-((ci s-3-Fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride 9″ 
     The title compound was synthesized according to General procedure G. Yield: 79%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.59 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=4.4 Hz, 1H), 7.16 (d, J=3.5 Hz, 1H), 6.53 (d, J=3.6 Hz, 1H), 4.71 (d, J=50.5 Hz, 1H), 4.34-4.14 (m, 1H), 3.12 (t, J=11.4 Hz, 1H), 2.90 (d, J=14.9 Hz, 1H), 2.84-2.76 (m, 1H), 2.74 (d, J=4.4 Hz, 3H), 2.65 (t, J=12.0 Hz, 1H), 1.86-1.75 (m, 1H), 1.67-1.51 (m, 2H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 170.02, 150.34, 148.53, 144.51, 122.04, 104.62, 103.13, 101.54, 88.88 (d, J C-F =173.6 Hz), 51.71 (d, J C-F =18.1 Hz), 48.23 (d, J C-F =20.5 Hz), 29.62, 28.05, 26.09; MS (ESI, m/z) calculated for C 14 H 18 FN 5 O [M+H] +  292.16 found 292.10. 
     4-((3,3-Difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride 10″ 
     The title compound was synthesized according to General procedure G. Yield: 89%;  1 H NMR (400 MHz, Chloroform-d) δ 12.09 (s, 1H), 8.93 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 7.38 (d, J=3.6 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H), 3.92-3.82 (m, 1H), 3.59-3.51 (m, 1H), 3.49 (s, 3H), 3.31 (t, J=11.0 Hz, 1H), 3.27-3.16 (m, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.20-2.10 (m, 1H), 1.78-1.69 (m, 1H), 1.46 (d, J=6.5 Hz, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 167.37, 151.57, 149.10, 146.45, 125.61, 122.48 (t, J C-F =244.4 Hz), 116.47, 114.41, 100.57, 55.10 (dd, J C-F =31.5, 26.4 Hz), 52.38 (t, J C-F =22.8 Hz), 51.17, 31.20, 26.33; MS (ESI, m/z) calculated for C 14 H 17 F 2 N 5 O [M+H] +  310.15 found 310.10. 
     General Procedure H 
     K 2 CO 3  (5.2 mmol) and benzyl bromide (2.6 mmol) were added dropwise to a solution of 2,2-dimethylpiperidin-4-one (1.3 mmol) in DMF (5 ml). The mixture was stirred at 80° C. overnight. The resulting mixture was poured into DCM (40 ml), washed with H 2 O (40 ml) and brine (40 ml), and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (30% ethyl acetate in n-hexane elution) to obtain a desired product 15″-17″. For the conversion of the carbonyl group of the intermediate 15″-17″, ammonium acetate (10 eq) and 4 Å molecular sieves were added dropwise to the intermediate 15″-17″ (1 eq) in methanol (10 ml). The mixture was stirred for 1 h. To the mixture was added dropwise sodium cyanoborohydride (2 eq). The resulting mixture was stirred at room temperature overnight. The reaction solution was poured into DCM (40 ml), washed with H 2 O (40 ml), and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:methanol=10:1) to afford an amine compound 18″-20″. 
     1-Benzyl-2,2-dimethylpiperidin-4-one 15″ 
     The title compound was synthesized according to General procedure H. Yield: 41.4%;  1 H NMR (400 MHz, Chloroform-d) δ 7.39 (d, J=7.1 Hz, 2H), 7.33 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 3.63 (s, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.39 (s, 2H), 2.36-2.28 (m, 2H), 1.19 (s, 6H);  13 C NMR (101 MHz, Chloroform-d) δ 210.35, 140.46, 128.43, 128.40, 127.01, 57.79, 55.61, 52.92, 46.29, 41.62, 24.07; MS (ESI, m/z) calculated for C 14 H 19 NO [M+H] +  218.15 found 218.10. 
     1-(3-Chlorobenzyl)-2,2-dimethylpiperidin-4-one 16″ 
     The title compound was synthesized according to General procedure H. Yield: 45.6%;  1 H NMR (400 MHz, Chloroform-d) δ 7.43-7.40 (m, 1H), 7.27-7.21 (m, 3H), 3.61 (s, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.39 (s, 2H), 2.34 (dd, J=6.4, 1.4 Hz, 2H), 1.18 (s, 6H);  13 C NMR (101 MHz, Chloroform-d) δ 210.02, 142.80, 134.45, 129.68, 128.32, 127.23, 126.47, 57.84, 55.55, 52.58, 46.51, 41.59, 24.09; MS (ESI, m/z) calculated for C 14 H 18 ClNO [M+H] +  252.12 found 252.05. 
     1-(4-Chlorobenzyl)-2,2-dimethylpiperidin-4-one 17″ 
     The title compound was synthesized according to General procedure H. Yield: 54.5%;  1 H NMR (400 MHz, Chloroform-d) δ 7.35-7.27 (m, 4H), 3.59 (s, 2H), 2.73 (t, J=6.3 Hz, 2H), 2.38 (s, 2H), 2.36-2.29 (m, 2H), 1.18 (s, 6H);  13 C NMR (101 MHz, Chloroform-d) δ 210.03, 139.02, 132.63, 129.67, 128.57, 57.81, 55.56, 52.33, 46.34, 41.58, 24.08; MS (ESI, m/z) calculated for C 14 H 18 ClNO [M+H] +  252.12 found 252.05. 
     1-Benzyl-2,2-dimethylpiperidin-4-amine 18″ 
     The title compound was synthesized according to General procedure H. Yield: 85.8%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 7.33-7.22 (m, 4H), 7.19 (t, J=7.1 Hz, 1H), 3.49 (dd, J=435.5, 13.5 Hz, 2H), 2.88-2.77 (m, 1H), 2.61-2.50 (m, 1H), 2.35-2.23 (m, 1H), 1.74-1.59 (m, 2H), 1.33 (t, J=12.2 Hz, 1H), 1.27 (d, J=3.6 Hz, 3H), 1.23-1.11 (m, 1H), 1.06 (s, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 141.75, 129.97, 129.13, 127.74, 55.37, 54.73, 50.65, 47.02, 46.60, 36.70, 31.21, 16.36; MS (ESI, m/z) calculated for C 14 H 22 N 2  [M+H] +  219.19 found 219.15. 
     1-(3-Chlorobenzyl)-2,2-dimethylpiperidin-4-amine 19″ 
     The title compound was synthesized according to General procedure H. Yield: 98.0%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 7.37 (s, 1H), 7.28-7.23 (m, 2H), 7.23-7.19 (m, 1H), 3.51 (dd, J=422.1, 14.1 Hz, 2H), 2.90-2.81 (m, 1H), 2.58-2.49 (m, 1H), 2.40-2.30 (m, 1H), 1.78-1.71 (m, 1H), 1.71-1.65 (m, 1H), 1.35 (t, J=12.2 Hz, 1H), 1.26 (d, J=2.9 Hz, 3H), 1.23-1.16 (m, 1H), 1.07 (s, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 144.78, 135.13, 130.61, 129.45, 128.00, 127.75, 55.30, 54.17, 50.67, 47.23, 46.61, 36.81, 31.26, 16.44; MS (ESI, m/z) calculated for C 14 H 21 ClN 2  [M+H] +  253.15 found 253.10. 
     1-(4-Chlorobenzyl)-2,2-dimethylpiperidin-4-amine 20″ 
     The title compound was synthesized according to General procedure H. Yield: 93.9%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 7.28 (q, J=8.7 Hz, 4H), 3.47 (dd, J=418.1, 13.9 Hz, 2H), 2.89-2.78 (m, 1H), 2.56-2.43 (m, 1H), 2.33-2.24 (m, 1H), 1.76-1.61 (m, 2H), 1.36-1.27 (m, 1H), 1.24 (s, 3H), 1.21-1.10 (m, 1H), 1.05 (s, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 140.91, 133.26, 131.22, 129.16, 55.29, 53.92, 50.62, 47.08, 46.59, 36.74, 31.25, 16.39; MS (ESI, m/z) calculated for C 14 H 21 ClN 2  [M+H] +  253.15 found 253.10. 
     General Procedure I 
     Triethylamine (1.1 eq), acetic acid (1.5 eq), and sodium triacetoxyborohydride (2 eq) were added dropwise to an appropriate solution of the deprotected intermediate 7″-10″ (0.25 mmol) and benzaldehyde (0.5 mmol) in DCM (5 ml) with stirring at 60° C. for 24 h. The resulting mixture was washed with a saturated aqueous solution of NaHCO 3 , diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to afford a title compound 21″a-b, 22″a-g, 23″a-g, 24″a-g. 
     4-((cis-1-((5-Chloropyridin-2-yl)methyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 21″a 
     The title compound was synthesized according to General procedure I. Yield: 40.5%;  1 H NMR (400 MHz, Chloroform-d) δ 9.16 (d, J=7.9 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.23 (s, 1H), 7.65 (dd, J=8.4, 2.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.02 (d, J=3.6 Hz, 1H), 6.51 (s, 1H), 6.49 (d, J=3.7 Hz, 1H), 4.01-3.89 (m, 1H), 3.77 (dd, J=296.5, 14.7 Hz, 2H), 2.96 (d, J=4.7 Hz, 3H), 2.91-2.84 (m, 1H), 2.55-2.43 (m, 1H), 2.32-2.23 (m, 1H), 2.21-2.06 (m, 2H), 1.70-1.44 (m, 2H), 1.19 (d, J=6.1 Hz, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.60, 158.42, 149.99, 149.33, 147.74, 142.87, 136.24, 130.16, 123.77, 121.27, 105.20, 103.59, 102.71, 58.88, 56.20, 52.44, 51.19, 42.31, 33.58, 26.60, 21.19; HRMS (ESI, m/z) calculated for C 21 H 25 ClN 6 O [M+H] +  413.1851 found 413.1853. 
     4-((cis-1-((6-Chloropyridin-3-yl)methyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 21″b 
     The title compound was synthesized according to General procedure I. Yield: 62.1%;  1 H NMR (400 MHz, Chloroform-d) δ 9.16 (d, J=7.7 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.68 (dd, J=8.2, 2.3 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.52 (s, 1H), 6.48 (d, J=3.7 Hz, 1H), 4.01-3.85 (m, 1H), 3.61 (dd, J=365.0, 14.0 Hz, 2H), 2.96 (d, J=4.7 Hz, 3H), 2.81 (dd, J=8.8, 3.2 Hz, 1H), 2.44 (dd, J=8.4, 6.0 Hz, 1H), 2.18-2.05 (m, 3H), 1.62-1.44 (m, 2H), 1.22 (d, J=6.0 Hz, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.59, 150.03, 149.96, 149.76, 149.32, 142.96, 139.39, 133.94, 124.07, 121.28, 105.18, 103.62, 102.68, 56.05, 54.02, 51.59, 51.10, 42.22, 33.37, 26.59, 21.19; HRMS (ESI, m/z) calculated for C 21 H 25 ClN 6 O [M+H] +  413.1851 found 413.1853. 
     4-((trans-1-Benzyl-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″a 
     The title compound was synthesized according to General procedure I. Yield: 55.8%;  1 H NMR (400 MHz, Chloroform-d) δ 11.20 (s, 1H), 9.36 (d, J=8.2 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 7.34 (s, 1H), 7.33 (s, 2H), 7.32-7.23 (m, 2H), 7.05 (d, J=3.6 Hz, 1H), 6.59 (d, J=3.5 Hz, 1H), 6.31-6.17 (m, 1H), 4.78-4.54 (m, 1H), 4.32-4.17 (m, 1H), 3.60 (s, 2H), 3.11-3.04 (m, 1H), 2.98 (d, J=4.7 Hz, 3H), 2.80-2.71 (m, 1H), 2.54-2.42 (m, 1H), 2.37 (t, J=9.5 Hz, 1H), 2.31-2.22 (m, 1H), 1.80-1.67 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.82, 150.67, 150.25, 143.38, 137.82, 128.98, 128.36, 127.27, 121.42, 105.41, 103.95, 102.48, 90.63 (d, J C-F =180.1 Hz), 62.42, 55.43 (d, J C-F =23.6 Hz), 53.96 (d, J C-F =23.0 Hz), 50.46, 30.17, 26.66; HRMS (ESI, m/z) calculated C 21 H 24  FN 5 O [M+H] +  382.2038 found 382.2041. 
     4-((trans-1-(3-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″b 
     The title compound was synthesized according to General procedure I. Yield: 24.6%;  1 H NMR (400 MHz, Chloroform-d) δ 10.7 (s, 1H), 9.5 (d, J=8.0 Hz, 1H), 8.3 (s, 1H), 7.4 (s, 1H), 7.3-7.2 (m, 3H), 7.0 (d, J=3.5 Hz, 1H), 6.5 (d, J=3.5 Hz, 1H), 6.0 (s, 1H), 4.4-4.3 (m, 1H), 3.7-3.6 (m, 2H), 2.8-2.6 (m, 4H), 2.2-2.1 (m, 2H), 2.04-1.99 (m, 1H), 1.8-1.6 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.83, 150.22, 149.30, 143.33, 139.77, 134.27, 129.65, 128.97, 127.50, 127.11, 121.59, 105.51, 104.02, 102.34, 90.21 (d, J C-F =182.0 Hz), 61.76, 55.13 (d, J C-F =23.9 Hz), 53.48 (d, J C-F =23.7 Hz), 50.22, 29.75, 26.36; HRMS (ESI, m/z) calculated for C 21 H 23 ClFN 5 O [M+H] +  416.1648 found 416.1648. 
     4-((trans-1-(4-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″c 
     The title compound was synthesized according to General procedure I. Yield: 65.6%;  1 H NMR (400 MHz, Chloroform-d) δ 11.37 (s, 1H), 9.38 (d, J=8.2 Hz, 1H), 8.25 (d, J=4.1 Hz, 1H), 7.34-7.21 (m, 4H), 7.04 (d, J=3.1 Hz, 1H), 6.57 (d, J=3.4 Hz, 1H), 6.30 (s, 1H), 4.74-4.55 (m, 1H), 4.32-4.19 (m, 1H), 3.55 (s, 2H), 3.02 (d, J=14.5 Hz, 1H), 2.98 (d, J=4.7 Hz, 3H), 2.75-2.67 (m, 1H), 2.56-2.43 (m, 1H), 2.37 (t, J=9.0 Hz, 1H), 2.33-2.21 (m, 1H), 1.81-1.67 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.78, 150.23, 143.23, 143.16, 136.40, 132.97, 130.19, 128.52, 121.54, 105.43, 103.91, 102.37, 90.37 (d, J C-F =179.6 Hz), 61.59, 55.22 (d, J C-F =23.8 Hz), 53.61 (d, J C-F =24.1 Hz), 50.23, 29.95, 26.66; HRMS (ESI, m/z) calculated for C 21 H 23 ClFN 5 O 2  [M+H] +  416.1648 found 416.1651. 
     4-((trans-1-(3-Methoxybenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″d 
     The title compound was synthesized according to General procedure I. Yield: 61.3%;  1 H NMR (400 MHz, Chloroform-d) δ 11.40 (s, 1H), 9.36 (d, J=8.2 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.28-7.17 (m, 1H), 7.08-6.96 (m, 1H), 6.94-6.87 (m, 2H), 6.81 (dd, J=8.9, 1.8 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 6.30 (s, 1H), 4.77-4.55 (m, 1H), 4.34-4.15 (m, 1H), 3.81 (s, 3H), 3.57 (s, 2H), 3.10 (td, J=15.5, 13.4, 6.8 Hz, 1H), 2.97 (d, J=4.7 Hz, 3H), 2.82-2.75 (m, 1H), 2.47 (q, J=7.1 Hz, 1H), 2.35 (t, J=9.5 Hz, 1H), 2.26 (d, J=5.3 Hz, 1H), 1.85-1.68 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.79, 159.75, 150.30, 143.17, 143.02, 139.55, 129.31, 121.50, 121.23, 114.21, 112.85, 105.42, 103.94, 102.41, 90.68 (d, J C-F =180.1 Hz), 62.31, 55.50 (d, J C-F =24.1 Hz), 55.23, 54.16 (d, J C-F =22.8 Hz), 50.53, 30.27, 26.65; HRMS (ESI, m/z) calculated for C 22 H 26 FN 5 O 2  [M+H] +  412.2143 found 412.2139. 
     4-((trans-1-(4-Methoxybenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″e 
     The title compound was synthesized according to General procedure I. Yield: 69.2%;  1 H NMR (400 MHz, Chloroform-d) δ 11.23 (s, 1H), 9.35 (d, J=8.2 Hz, 1H), 8.24 (d, J=4.1 Hz, 1H), 7.23 (d, J=8.5 Hz), 2H), 7.06-6.97 (m, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.56 (d, J=3.2 Hz, 1H), 6.34 (s, 1H), 4.74-4.54 (m, 1H), 4.26-4.08 (m, 1H), 3.80 (s, 3H), 3.53 (s, 2H), 3.07 (d, J=5.1 Hz, 1H), 2.97 (d, J=4.7 Hz, 3H), 2.79-2.69 (m, 1H), 2.44 (d, J=10.5 Hz, 1H), 2.33 (t, J=9.4 Hz, 1H), 2.29-2.19 (m, 1H), 1.79-1.66 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.78, 150.23, 143.23, 143.16, 136.40, 132.97, 130.19, 128.52, 121.54, 105.43, 103.91, 102.37, 90.37 (d, J C-F =178.4 Hz), 61.59, 60.43, 55.22 (d, J C-F =23.1 Hz), 53.61 (d, J C-F =17.6 Hz), 50.23, 29.95, 26.66; HRMS (ESI, m/z) calculated for C 22 H 26 FN 5 O [M+H] +  412.2143 found 412.2146. 
     4-((trans-1-(3-Cyanobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″f 
     The title compound was synthesized according to General procedure I. Yield: 59.1%;  1 H NMR (400 MHz, Chloroform-d) δ 11.19 (s, 1H), 9.42 (d, J=8.2 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.62-7.52 (m, 2H), 7.44 (t, J=7.7 Hz, 1H), 7.09 (d, J=3.6 Hz, 1H), 6.60 (d, J=3.7 Hz, 1H), 6.28 (d, J=4.7 Hz, 1H), 4.78-4.55 (m, 1H), 4.34-4.25 (m, 1H), 3.61 (s, 2H), 2.99 (d, J=4.7 Hz, 3H), 3.03-2.90 (m, 1H), 2.71 (s, 1H), 2.61-2.50 (m, 1H), 2.43 (t, J=8.7 Hz, 1H), 2.36-2.25 (m, 1H), 1.84-1.73 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.91, 150.79, 150.25, 143.52, 139.82, 133.28, 132.32, 131.17, 129.34, 121.68, 119.00, 112.60, 105.55, 104.04, 102.48, 90.09 (d, J C-F =180.0 Hz), 60.53, 55.14 (d, J C-F =22.5 Hz), 53.19 (d, J C-F =18.6 Hz), 50.16, 29.81, 26.78; HRMS (ESI, m/z) calculated for C 22 H 23 FN 6 O [M+H] +  407.1990 found 407.1995. 
     4-((trans-1-(4-Cyanobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 22″g 
     The title compound was synthesized according to General procedure I. Yield: 55.8%;  1 H NMR (400 MHz, Chloroform-d) δ 11.40 (s, 1H), 9.43 (d, J=8.2 Hz, 1H), 8.27 (s, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.58 (d, J=3.4 Hz, 1H), 6.32 (s, 1H), 4.79-4.54 (m, 1H), 4.28 (d, J=4.8 Hz, 1H), 3.63 (s, 2H), 3.10-2.91 (m, 1H), 2.99 (d, J=4.7 Hz, 3H), 2.70 (s, 1H), 2.61-2.49 (m, 1H), 2.42 (t, J=8.7 Hz, 1H), 2.37-2.23 (m, 1H), 1.84-1.70 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.88, 150.61, 150.28, 143.88, 143.33, 132.35, 129.37, 121.75, 119.02, 111.19, 105.56, 103.99, 102.40, 90.12 (d, J C-F =179.6 Hz), 61.86 Hz, 55.19 (d, J C-F =23.6 Hz), 53.17 (d, J C-F =25.0 Hz), 50.24, 29.80, 26.77; HRMS (ESI, m/z) calculated for C 22 H 23 FN 6 O [M+H] +  407.1990 found 407.1996. 
     4-((cis-1-Benzyl-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″a 
     The title compound was synthesized according to General procedure I. Yield: 26.0%;  1 H NMR (400 MHz, Chloroform-d) δ 10.99 (s, 1H), 9.45 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.37-7.31 (m, 4H), 7.29-7.26 (m, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.44 (d, J=3.7 Hz, 1H), 6.15 (d, J=4.6 Hz, 1H), 4.87 (d, J=48.3 Hz, 1H), 4.33-4.05 (m, 1H), 3.63 (s, 2H), 3.20 (s, 1H), 2.99 (d, J=4.8 Hz, 3H), 2.91 (d, J=10.0 Hz, 1H), 2.54-2.37 (m, 1H), 2.32 (t, J=10.6 Hz, 1H), 2.16-2.05 (m, 1H), 2.05-1.98 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 170.82, 150.67, 150.25, 143.38, 137.82, 128.98, 128.36, 127.27, 121.42, 105.41, 103.95, 102.48, 88.25 (d, J C-F =180.1 Hz), 62.42, 55.13 (d, J C-F =22.2 Hz), 52.53 (d, J C-F =19.8 Hz), 50.46, 30.17, 26.66; HRMS (ESI, m/z) calculated C 21 H 24 FN 5 O [M+H] +  382.2038 found 382.2040. 
     4-((cis-1-(3-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″b 
     The title compound was synthesized according to General procedure I. Yield: 35.1%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 10.42 (d, J=8.6 Hz, 1H), 9.11 (s, 1H), 9.04 (d, J=4.5 Hz, 1H), 8.22-8.14 (m, 2H), 8.14-8.04 (m, 2H), 7.96 (d, J=2.1 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 5.64 (d, J=49.5 Hz), 1H), 5.10-4.88 (m, 1H), 4.37 (s, 2H), 3.86 (s, 1H), 3.58 (s, 1H), 3.54 (d, J=4.3 Hz, 3H), 3.23 (d, J=12.6 Hz, 1H), 3.12 (t, J=10.7 Hz, 1H), 2.60 (t, J=10.7 Hz, 2H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 169.97, 150.33, 148.69, 144.47, 140.85, 133.00, 130.12, 128.36, 127.36, 126.98, 122.14, 104.65, 103.23, 101.42, 88.59 (d, J C-F =177.1 Hz), 60.36, 54.58 (d, J C-F =17.6 Hz), 51.33 (d, J C-F =17.9 Hz), 50.14, 27.95, 26.09; HRMS (ESI, m/z) calculated for C 21 H 23 ClFN 5 O [M+H] +  416.1648 found 416.1648. 
     4-((cis-1-(4-Chlorobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″c 
     The title compound was synthesized according to General procedure I. Yield: 35.1%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.63 (d, J=8.7 Hz, 1H), 8.32 (s, 1H), 8.27-8.17 (m, 1H), 7.44-7.30 (m, 4H), 7.17 (dd, J=3.4, 2.4 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 4.85 (d, J=49.4 Hz, 1H), 4.29-4.14 (m, 1H), 3.55 (s, 2H), 3.05 (d, J=9.3 Hz, 1H), 2.81-2.77 (m, 1H), 2.75 (d, J=4.4 Hz, 3H), 2.43 (d, J=12.7 Hz, 1H), 2.31 (t, J=11.1 Hz, 1H), 1.90 (d, J=9.1 Hz, 1H), 1.79 (q, J=10.7 Hz, 1H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 170.42, 150.78, 149.15, 144.92, 137.59, 131.97, 131.00, 128.64, 122.56, 105.08, 103.66, 101.86, 89.03 (d, J C-F =177.2 Hz), 60.77, 55.03 (d, J C-F =20.5 Hz), 51.82 (d, J C-F =17.6 Hz), 33.91, 28.37, 26.5; HRMS (ESI, m/z) calculated for C 21 H 23  ClFN 5 O [M+H] +  416.1648 found 416.1648. 
     4-((cis-1-(3-Methoxybenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″d 
     The title compound was synthesized according to General procedure I. Yield: 39.6%;  1 H NMR (400 MHz, Chloroform-d) δ 9.90 (s, 1H), 9.51 (d, J=8.5 Hz, 1H), 8.21 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.06 (d, J=3.7 Hz, 1H), 6.96-6.90 (m, 2H), 6.84-6.79 (m, 1H), 6.46 (d, J=3.7 Hz, 1H), 6.10 (s, 1H), 4.87 (d, J=48.7 Hz, 1H), 4.18 (d, J=24.4 Hz, 1H), 3.82 (s, 3H), 3.62-3.60 (m, 2H), 3.21 (s, 1H), 3.00 (d, J=4.7 Hz, 3H), 2.96-2.87 (m, 1H), 2.52-2.28 (m, 2H), 2.18-2.06 (m, 2H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.69, 160.36, 150.11, 149.89, 144.22, 138.98, 129.85, 122.61, 122.29, 115.30, 113.55, 106.10, 104.87, 102.29, 88.89 (d, J C-F =179.0 Hz), 62.71, 55.54 (d, J C-F =18.4 Hz), 52.95 (d, J C-F =19.3 Hz), 51.56, 30.15, 28.33, 26.62; HRMS (ESI, m/z) calculated for C 22 H 26 FN 5 O 2  [M+H] +  412.2143 found 412.2148. 
     4-((cis-1-(4-Methoxybenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″e 
     The title compound was synthesized according to General procedure I. Yield: 50.3%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.62 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.27-8.19 (m, 1H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (dd, J=3.3, 2.2 Hz, 1H), 6.95-6.83 (m, 2H), 6.49 (d, J=2.5 Hz, 1H), 4.83 (d, J=49.6 Hz, 1H), 4.26-4.09 (m, 1H), 3.74 (s, 3H), 3.48 (s, 2H), 3.04 (s, 1H), 2.82-2.77 (m, 1H), 2.74 (d, J=4.4 Hz, 3H), 2.48-2.31 (m, 1H), 2.26 (t, J=10.8 Hz, 1H), 1.89 (d, J=9.9 Hz, 1H), 1.76 (q, J=10.9 Hz, 1H);  13 C NMR (101 MHz, DMF-d 7 ) δ 169.97, 158.33, 150.32, 148.71, 144.47, 130.06, 129.74, 122.11, 113.59, 104.62, 103.19, 101.41, 88.62 (d, J C-F =177.0 Hz), 60.73, 54.99, 54.53 (d, J C-F =14.5 Hz), 51.48 (d, J C-F =17.5 Hz), 50.05, 27.95, 26.0; HRMS (ESI, m/z) calculated for C 22 H 26 FN 5 O 2  [M+H] +  412.2143 found 412.2148. 
     4-((cis-1-(3-Cyanobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″f 
     The title compound was synthesized according to General procedure I. Yield: 49.1%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.63 (d, J=8.7 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=4.5 Hz, 1H), 7.78-7.72 (m, 2H), 7.69 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.17 (dd, J=3.2, 2.2 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.86 (d, J=49.4 Hz, 1H), 4.30-4.14 (m, 1H), 3.63 (s, 2H), 3.06 (t, J=9.3 Hz, 1H), 2.81-2.77 (m, 1H), 2.75 (d, J=4.4 Hz, 3H), 2.51 (dd, J=35.7, 12.9 Hz, 1H), 2.34 (t, J=10.6 Hz, 1H), 1.90 (d, J=9.7 Hz, 1H), 1.80 (q, J=10.7 Hz, 1H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 169.96, 150.32, 148.69, 144.46, 139.93, 133.64, 132.09, 130.90, 129.53, 122.13, 118.93, 111.24, 104.65, 103.24, 101.43, 88.58 (d, J C-F =176.9 Hz), 60.02, 54.50 (d, J C-F =18.4 Hz), 51.28 (d, J C-F =17.9 Hz), 50.04, 27.91, 26.08; HRMS (ESI, m/z) calculated for C 22 H 23 FN 6 O [M+H] +  407.1990 found 407.1991. 
     4-((cis-1-(4-Cyanobenzyl)-3-fluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 23″g 
     The title compound was synthesized according to General procedure I. Yield: 31.9%;  1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.62 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=4.6 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.17 (dd, J=3.3, 2.4 Hz, 1H), 6.52-6.49 (m, 1H), 4.85 (d, J=49.5 Hz, 1H), 4.29-4.14 (m, 1H), 3.66 (s, 2H), 3.06 (t, J=9.3 Hz, 1H), 2.82-2.76 (m, 1H), 2.74 (d, J=4.4 Hz, 3H), 2.60-2.42 (m, 1H), 2.35 (t, J=10.4 Hz, 1H), 1.90 (d, J=9.8 Hz, 1H), 1.85-1.71 (m, 1H);  13 C NMR (101 MHz, DMSO-d 6 ) δ 169.96, 150.32, 148.68, 144.46, 144.34, 132.23, 129.48, 122.15, 118.95, 109.77, 104.64, 103.23, 101.41, 88.57 (d, J C-F =177.1 Hz) 60.50, 54.65 (d, J C-F =19.7 Hz), 51.27 (d, J C-F =18.0 Hz), 50.17, 27.92, 26.08; HRMS (ESI, m/z) calculated for C 22 H 23 FN 6 O [M+H] +  407.1990 found 407.1991. 
     4-((1-Benzyl-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″a 
     The title compound was synthesized according to General procedure I. Yield: 36.5%;  1 H NMR (400 MHz, Chloroform-d) δ 12.07 (s, 1H), 8.98 (s, 1H), 8.63 (d, J=4.5 Hz, 1H), 7.41-7.33 (m, 5H), 7.33-7.28 (m, 1H), 6.64 (d, J=3.4 Hz, 1H), 4.01 (s, 2H), 3.94-3.84 (m, 1H), 3.58-3.45 (m, 2H), 3.24-3.08 (m, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.13 (dd, J=8.5, 3.9 Hz, 1H), 1.88-1.76 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 167.24, 151.70, 149.17, 146.66, 139.73, 128.60, 128.08, 127.32, 125.47, 120.7 (t, J C-F =247.02 Hz), 116.52, 114.42, 100.67, 56.42 (t, J C-F =21.4 Hz), 55.01 (t, J C-F =29.4 Hz), 51.59, 30.95, 29.41, 26.29; HRMS (ESI, m/z) calculated for C 21 H 23 F 2 N 5 O [M+H] +  400.1943 found 400.1946. 
     4-((1-(3-Chlorobenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″b 
     The title compound was synthesized according to General procedure I. Yield: 60.6%;  1 H NMR (400 MHz, Chloroform-d) δ 12.30 (s, 1H), 8.96 (s, 1H), 8.66-8.51 (m, 1H), 7.41 (s, 1H), 7.38 (d, J=3.0 Hz, 1H), 7.30-7.24 (m, 4H), 6.63 (d, J=3.3 Hz, 1H), 4.00 (d, J=7.1 Hz, 2H), 3.93-3.82 (m, 1H), 3.59-3.44 (m, 2H), 3.22 (t, J=10.0 Hz, 1H), 3.17-3.06 (m, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.13 (dd, J=9.0, 4.5 Hz, 1H), 1.88-1.77 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 167.38, 151.80, 149.20, 146.61, 142.09, 134.54, 129.94, 128.24, 127.56, 126.25, 125.70, 120.74 (t, J C-F =246.2 Hz), 116.56, 114.54, 100.69, 56.73 (t, J C-F =21.5 Hz), 55.25 (t, J C-F =29.0 Hz), 51.21, 31.07, 29.80, 26.42; HRMS (ESI, m/z) calculated for C 21 H 22 ClF 2 N 5 O [M+H] +  434.1554 found 434.1559. 
     4-((1-(4-Chlorobenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″c 
     The title compound was synthesized according to General procedure I. Yield: 60.6%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 9.84 (s, 1H), 8.91 (dd, J=23.9, 8.5 Hz, 4H), 8.86 (s, 1H), 8.23 (d, J=3.7 Hz, 1H), 5.50 (s, 2H), 5.46-5.35 (m, 2H), 5.25-5.15 (m, 1H), 5.11-4.98 (m, 1H), 4.69-4.57 (m, 1H), 4.50 (s, 3H), 3.72-3.63 (m, 1H), 3.47-3.34 (m, 1H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 171.48, 151.58, 150.61, 145.66, 140.08, 133.83, 130.96, 129.50, 125.90, 121.8 (t, J C-F =247.3 Hz), 117.01, 114.62, 101.72, 58.0 (t, J C-F =20.8 Hz), 56.2 (t, J C-F =29.7 Hz), 51.58, 50.14, 30.46, 26.85; HRMS (ESI, m/z) calculated for C 21 H 22 ClF 2 N 5 O [M+H] +  434.1554 found 434.11557. 
     4-((1-(3-Methoxybenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″d 
     The title compound was synthesized according to General procedure I. Yield: 60.6%;  1 H NMR (400 MHz, Chloroform-d) δ 11.72 (s, 1H), 8.98 (s, 1H), 8.60 (s, 1H), 7.38 (s, 1H), 7.28 (d, J=10.4 Hz, 1H), 6.97 (d, J=6.7 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 3.99 (s, 2H), 3.95-3.87 (m, 1H), 3.84 (s, 3H), 3.51 (t, J=14.6 Hz, 2H), 3.21 (t, J=10.7 Hz, 1H), 3.14 (d, J=5.7 Hz, 1H), 3.03 (d, J=4.3 Hz, 3H), 2.12 (s, 1H), 1.95-1.79 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 167.20, 159.85, 151.63, 149.15, 146.77, 141.38, 129.61, 125.35, 120.63 (t, J C-F =246.2 Hz), 120.31, 116.58, 114.36, 113.67, 100.75, 56.32 (t, J C-F =21.5 Hz), 55.24, 55.03 (t, J C-F =29.0 Hz), 50.39, 29.41, 26.29; HRMS (ESI, m/z) calculated for C 22 H 25 F 2 N 5 O [M+H] +  430.2049 found 430.2057. 
     4-((1-(4-Methoxybenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″e 
     The title compound was synthesized according to General procedure I. Yield: 62.3%;  1 H NMR (400 MHz, Chloroform-d) δ 11.83 (s, 1H), 8.98 (s, 1H), 8.61 (d, J=4.7 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 6.95-6.87 (m, 2H), 6.64 (d, J=3.4 Hz, 1H), 3.94 (s, 2H), 3.91-3.84 (m, 1H), 3.82 (s, 3H), 3.55-3.49 (m, 2H), 3.20 (t, J=10.0 Hz, 1H), 3.16-3.06 (m, 1H), 3.02 (d, J=4.8 Hz, 3H), 2.11 (dd, J=8.2, 4.2 Hz, 1H), 1.88-1.78 (m, 1H);  13 C NMR (101 MHz, Chloroform-d) δ 167.24, 158.90, 151.73, 149.19, 146.80, 131.81, 129.31, 125.38, 120.68 (t, J C-F =247.0 Hz), 116.63, 114.41, 113.99, 100.75, 56.30 (t, J C-F =21.5 Hz), 55.32, 55.04 (t, J C-F =28.9 Hz), 51.02, 50.35, 29.46, 26.28; HRMS (ESI, m/z) calculated for C 22 H 25 F 2 N 5 O [M+H] +  430.2049 found 430.2052. 
     4-((1-(3-Cyanobenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″f 
     The title compound was synthesized according to General procedure I. Yield: 30.3%;  1 H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H), 8.96 (s, 1H), 8.45 (s, 1H), 8.17 (t, J=1.4 Hz, 1H), 8.08-8.00 (m, 1H), 7.82-7.75 (m, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.36 (dd, J=3.6, 2.5 Hz, 1H), 6.75 (dd, J=3.7, 2.0 Hz, 1H), 4.07 (d, J=11.2 Hz, 1H), 3.88 (d, J=10.1 Hz, 2H), 3.69-3.59 (m, 1H), 3.55-3.47 (m, 1H), 3.35-3.27 (m, 1H), 3.07 (d, J=4.0 Hz, 3H), 2.03 (d, J=11.0 Hz, 1H), 1.36-1.26 (m, 4H); HRMS (ESI, m/z) calculated for C 22 H 22 F 2 N 6 O [M+H] +  425.1896 found 425.1898. 
     4-((1-(4-Cyanobenzyl)-3,3-difluoropiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 24″g 
     The title compound was synthesized according to General procedure I. Yield: 58.6%;  1 H NMR (400 MHz, Chloroform-d) δ 11.64 (s, 1H), 8.94 (s, 1H), 8.43 (d, J=4.5 Hz, 1H), 7.68-7.65 (m, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.38 (d, J=3.2 Hz, 1H), 6.63 (d, J=3.4 Hz, 1H), 4.18-4.05 (m, 2H), 3.94-3.84 (m, 1H), 3.55-3.47 (m, 2H), 3.25 (t, J=10.4 Hz, 1H), 3.11-3.05 (m, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.17-2.12 (m, 1H), 1.88-1.78 (m, 1H); HRMS (ESI, m/z) calculated for C 22 H 22 F 2 N 6 O [M+H] +  425.1896 found 425.1897. 
     General Procedure J 
     DIEA (10 eq) and 4-chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (0.5 mmol) were added dropwise to a solution of the amine 18″-20″ (4 eq) in NMP (2 ml). The mixture was stirred at 180° C. overnight. The resulting mixture was cooled to room temperature, diluted with ethyl acetate, washed with H 2 O and brine, and dried over MgSO 4 . The crude mixture was purified by silica gel flash chromatography (dichloromethane:MeOH=10:1 elution) to afford a title product 25″a-c. 
     4-((1-Benzyl-2,2-dimethylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 25″a 
     The title compound was synthesized according to General procedure J. Yield: 62.3%;  1 H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J=7.8 Hz, 1H), 8.25 (s, 1H), 7.37 (d, J=7.1 Hz, 2H), 7.31 (t, J=7.4 Hz), 2H), 7.23 (t, J=7.2 Hz, 1H), 6.99 (d, J=3.1 Hz, 1H), 6.56 (s, 1H), 6.53 (d, J=3.3 Hz, 1H), 4.19-4.09 (m, 1H), 3.56 (dd, J=397.7, 14.1 Hz, 2H), 2.98 (d, J=4.7 Hz, 3H), 2.72-2.61 (m, 1H), 2.47-2.34 (m, 1H), 2.11-1.97 (m, 2H), 1.67 (t, J=12.1 Hz, 1H), 1.61-1.49 (m, 1H), 1.27 (s, 3H), 1.18 (s, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.5, 150.1, 142.8, 142.7, 141.1, 128.2, 128.2, 126.6, 121.0, 105.2, 103.7, 102.8, 54.2, 53.3, 48.4, 47.4, 45.5, 34.3, 30.4, 26.6, 16.5; HRMS (ESI, m/z) calculated for C 23 H 29 N 5 O [M+H] +  392.2445 found 392.2447. 
     4-((1-(3-Chlorobenzyl)-2,2-dimethylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 25″b 
     The title compound was synthesized according to General procedure J. Yield: 11.0%;  1 H NMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 9.10 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 7.38 (s, 1H), 7.24-7.14 (m, 3H), 7.04 (d, J=3.5 Hz, 1H), 6.57 (d, J=3.5 Hz, 1H), 6.21 (s, 1H), 4.26-4.09 (m, 1H), 3.54 (dd, J=384.1), 14.3 Hz, 2H), 2.98 (d, J=4.7 Hz, 3H), 2.67-2.58 (m, 1H), 2.48-2.40 (m, 1H), 2.12-2.05 (m, 1H), 2.05-1.99 (m, 1H), 1.67 (t, J=12.1 Hz, 1H), 1.63-1.50 (m, 1H), 1.25 (s, 3H), 1.18 (s, 3H);  13 C NMR (101 MHz, Chloroform-d) δ 170.6, 150.0, 143.5, 143.4, 143.3, 134.2, 129.4, 128.2, 126.8, 126.3, 120.9, 105.2, 103.7, 102.8, 54.2, 52.9, 48.3, 47.4, 45.7, 34.2, 30.4, 26.6, 16.6; HRMS (ESI, m/z) calculated for C 23 H 28 ClN 5 O [M+H] +  426.2055 found 426.2059. 
     4-((1-(4-Chlorobenzyl)-2,2-dimethylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 25″c 
     The title compound was synthesized according to General procedure J. Yield: 10.4%;  1 H NMR (400 MHz, Methanol-d 4 ) δ 8.36 (s, 1H), 7.63-7.50 (m, 4H), 7.40 (d, J=3.5 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 4.68-4.58 (m, 1H), 4.40 (dd, J=318.5, 13.2 Hz, 2H), 3.76-3.58 (m, 1H), 3.59-3.50 (m, 1H), 3.43 (d, J=10.4 Hz, 1H), 2.88 (s, 3H), 2.42 (d, J=11.6 Hz, 1H), 2.09 (t, J=13.0 Hz, 1H), 1.89-1.78 (m, 1H), 1.75 (s, 3H), 1.73 (s, 3H);  13 C NMR (101 MHz, Methanol-d 4 ) δ 169.2, 139.7, 137.5, 135.8, 134.5, 134.4, 130.5, 129.6, 125.4, 106.5, 105.2, 104.2, 65.3, 54.4, 47.5, 47.4, 44.5, 31.2, 27.3, 26.7, 18.5; HRMS (ESI, m/z) calculated for C 23 H 28 ClN 5 O [M+H] +  426.2055 found 426.2058. 
     INDUSTRIAL APPLICABILITY 
     The compound of the present invention can exhibit therapeutic effects on a variety of diseases, for example, inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and human cancers due to its ability to regulate signal transduction at the level of JAK kinases. Therefore, the present invention is applicable to a wide variety of fields, including medicine, nursing, pharmacology, pharmaceutics, hygienics, and public health.