Patent Publication Number: US-10329309-B2

Title: 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof

Description:
RELATED APPLICATIONS 
     This application is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2016/045311, having an International Filing Date of Aug. 3, 2016, which claims the benefit of U.S. Provisional Application Nos. 62/313,576, filed Mar. 25, 2016 and 62/200,329, filed Aug. 3, 2015, which are incorporated herein by reference in their entirety. 
    
    
     BACKGROUND 
     Technical Field 
     This disclosure relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a 4-azaindazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states. 
     Background 
     The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many short- and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression of genes including c-myc, c jun, fra-l, and cyclin Dl. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. The Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system. 
     SUMMARY 
     The present disclosure provides methods and reagents, involving contacting a cell with an agent, such as a 4-azaindazole compound, in a sufficient amount to antagonize a Wnt activity, e.g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components. 
     Some embodiments disclosed herein include Wnt inhibitors containing a 4-azaindazole core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds. 
     One embodiment disclosed herein includes a compound having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     as well as prodrugs and pharmaceutically acceptable salts thereof. 
     In some embodiments of Formula (I): 
     R 1  and R 2  are independently selected from the group consisting of H and halide; 
     R 3  is selected from the group consisting of -heteroaryl optionally substituted with 1-4 R 6  and -heterocyclyl optionally substituted with 1-10 R 7 ; 
     R 5  is selected from the group consisting of H, -heteroaryl optionally substituted with 1-4 R 8 , -heterocyclyl optionally substituted with 1-10 R 9 , and -aryl optionally substituted with 1-5 R 10 ; 
     each R 6  is independently selected from the group consisting of halide, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 R 13 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 R 13 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 R 13 , —NHC(═O)R 4 , —NR 15 R 16 , —(C 1-6  alkylene)NR 17 R 18 , —(C 2-6  alkenylene)NR 17 R 18 , —(C 2-6  alkynylene)NR 17 R 18 , and —(C 1-4  alkylene) p OR 24 ; 
     each R 7  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 8  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —OCH 3 , —CN, and —C(═O)R 19 ; 
     each R 9  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, and —OCH 3 ; 
     each R 10  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, —(C 1-6  alkylene) p NHSO 2 R 19 , —(C 2-6  alkenylene) p NHSO 2 R 19 , —(C 2-6  alkynylene) p NHSO 2 R 19 , —NR 15 (C 1-6  alkylene)NR 15 R 16 , —NR 15 (C 2-6  alkenylene)NR 15 R 16 , —NR 15 (C 2-6  alkynylene)NR 15 R 16 , —(C 1-6  alkylene) p NR 15 R 16 , —(C 2-6  alkenylene) p NR 15 R 16 , —(C 2-6  alkynylene) p NR 15 R 16 , and —OR 27 ; 
     each R 11  is independently selected from the group consisting of amino, —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 12  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 13  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 14  is independently selected from the group consisting of —(C 1-9  alkyl), —(C 1-4  haloalkyl), —(C 2-9  alkenyl), —(C 2-9  alkynyl), -heteroaryl optionally substituted with 1-4 R 20 , -aryl optionally substituted with 1-5 R 21 , —CH 2 aryl optionally substituted with 1-5 R 21 , -carbocyclyl optionally substituted with 1-12 R 22 , —CH 2 carbocyclyl optionally substituted with 1-12 R 22 , —(C 1-4  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , —(C 2-4  alkynylene) p NR 25 R 26 , -heterocyclyl optionally substituted with 1-10 R 23 , and —CH 2 heterocyclyl optionally substituted with 1-10 R 23 ; 
     each R 15  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 16  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 R 21 , and —CH 2 carbocyclyl optionally substituted with 1-12 R 22 ; 
     each R 17  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 18  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 R 21  and —CH 2 carbocyclyl optionally substituted with 1-12 R 22 ; 
     each R 19  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 20  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 21  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 22  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 23  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     R 24  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 R 21 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 R 21 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 R 21 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , and —(C 2-4  alkynylene) p NR 25 R 26 ; 
     each R 25  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 26  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     R 27  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-6  alkenylene) p NR 25 R 26 , and —(C 2-6  alkynylene) p NR 25 R 26 ; and 
     each p is independently an integer of 0 or 1. 
     In some embodiments of Formula (I): 
     R 1  and R 2  are independently selected from the group consisting of H and halide; 
     R 3  is selected from the group consisting of -heteroaryl optionally substituted with 1-4 R 6  and -heterocyclyl optionally substituted with 1-10 R 7 ; 
     R 5  is selected from the group consisting of H, -heteroaryl optionally substituted with 1-4 R 8 , -heterocyclyl optionally substituted with 1-10 R 9 , and -aryl optionally substituted with 1-5 R 10 ; 
     each R 6  is independently selected from the group consisting of halide, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 11 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 R 12 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 R 13 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 R 13 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 R 13 , —NHC(═O)R 14 , —NR 15 R 16 , —(C 1-6  alkylene)NR 17 R 18 , —(C 2-6  alkenylene)NR 17 R 18 , and —(C 2-6  alkynylene)NR 17 R 18 , —OR 24 ; 
     each R 7  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 8  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —OCH 3 , —CN, and —C(═O)R 19 ; 
     each R 9  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, and —OCH 3 ; 
     each R 10  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, —(C 1-6  alkylene) p NHSO 2 R 19 , —(C 2-6  alkenylene) p NHSO 2 R 19 , —(C 2-6  alkynylene) p NHSO 2 R 19 , —NR 15 (C 1-6  alkylene)NR 15 R 16 , —NR 15 (C 2-6  alkenylene)NR 15 R 16 , —NR 15 (C 2-6  alkynylene)NR 15 R 16 , —(C 1-6  alkylene) p NR 15 R 16 , —(C 2-6  alkenylene) p NR 15 R 16 , —(C 2-6  alkynylene) p NR 15 R 16 , and —OR 27 ; 
     each R 11  is independently selected from the group consisting of amino, —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 12  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 13  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 14  is independently selected from the group consisting of —(C 1-9  alkyl), —(C 2-9  alkenyl), —(C 2-9  alkynyl), -heteroaryl optionally substituted with 1-4 R 20 , -aryl optionally substituted with 1-5 R 21 , —CH 2 aryl optionally substituted with 1-5 R 21 , -carbocyclyl optionally substituted with 1-12 R 22 , —CH 2 carbocyclyl optionally substituted with 1-12 R 22 , —(C 1-4  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , —(C 2-4  alkynylene) p NR 25 R 26 , -heterocyclyl optionally substituted with 1-10 R 23 , and —CH 2 heterocyclyl optionally substituted with 1-10 R 23 ; 
     each R 15  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 16  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 R 21 , and —CH 2 carbocyclyl optionally substituted with 1-12 R 22 ; 
     each R 17  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 18  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 R 21  and —CH 2 carbocyclyl optionally substituted with 1-12 R 22 ; 
     each R 19  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 20  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 21  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 22  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     each R 23  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN; 
     R 24  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 R 22 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 R 21 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 R 21 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 R 21 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , and —(C 2-4  alkynylene) p NR 25 R 26 ; 
     each R 25  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     each R 26  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl); 
     R 27  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 R 23 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-6  alkenylene) p NR 25 R 26 , and —(C 2-6  alkynylene) p NR 25 R 26 ; and 
     each p is independently an integer of 0 or 1. 
     Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of Formula (I). 
     Some embodiments include pro-drugs of a compound of Formula (I). 
     Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. 
     Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a patient affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formula (I). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components. 
     Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer&#39;s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome. 
     Some embodiments of the present disclosure include methods to prepare compounds of Formula (I). 
     It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. 
    
    
     DETAILED DESCRIPTION 
     Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins. Other Wnt inhibitors and methods for using the same are disclosed in U.S. application Ser. Nos. 12/852,706; 12/968,505; 13/552,188; 13/800,963; 13/855,874; 13/887,177 13/938,691; 13/938,692; 14/019,103; 14/019,147; 14/019,940; 14/149,948; 14/178,749; 14/331,427; 14/334,005; and 14/664,517 and U.S. Provisional Application Ser. Nos. 61/232,603; 61/288,544; 61/305,459; 61/620,107; 61/642,915; 61/750,221; 61/968,350; 62/047,324; 62/047,371; 62/047,395; 62/047,401; 62/047,406; 62/047,438; 62/047,509; 62/047,575; 62/047,567, all of which are incorporated by reference in their entirety herein. 
     Some embodiments provided herein relate to a method for treating a disease or disorder including, but not limited to, cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer&#39;s disease, lung disease, osteoarthritis, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome. 
     In some embodiments, non-limiting examples of bone and cartilage diseases which can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, fibrodysplasia ossificans progressiva, fibrous dysplasia, giant cell tumor of bone, hip labral tear, meniscal tears, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), osteochondritis dissecans, osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis, and Salter-Harris fractures. 
     In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by the pathological activation or mutations of the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and a compound as described herein. 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. 
     As used herein, “alkyl” means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms). 
     As used herein, “alkenyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In various embodiments, alkenyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms). 
     “Exocyclic double bond” means a carbon-carbon double bond connected to and hence external to, a ring structure. 
     As used herein, “alkynyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like. In various embodiments, alkynyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms). 
     As used herein, “alkylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. Alkylene groups can be saturated or unsaturated (e.g., containing —C═C— or —C═C— subunits), at one or several positions. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms). 
     As used herein, “alkenylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, and the like. In various embodiments, alkenylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms). 
     As used herein, “alkynylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, and the like. In various embodiments, alkynylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms). 
     As used herein, “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms. 
     As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and others. In some embodiments, the aryl is phenyl. 
     As used herein, “arylalkylene” means an aryl-alkylene-group in which the aryl and alkylene moieties are as previously described. In some embodiments, arylalkylene groups contain a C 1-4 alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl. 
     As used herein, the term “heteroaryl” means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl. 
     As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, a halo is a chloro, bromo or fluoro. For example, a halide can be fluoro. 
     As used herein, “haloalkyl” means a hydrocarbon substituent, which is a linear or branched, alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. In some embodiments, haloalkyls are of 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or 1 carbon in length). The term “haloalkylene” means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group. 
     As used herein, “heterocyclyl” means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl. 
     As used herein, “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. 
     The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substituents can include, for example, —(C 1-9  alkyl) optionally substituted with one or more of hydroxyl, —NH 2 , —NH(C 1-3  alkyl), and —N(C 1-3  alkyl) 2 ; —(C 1-9  haloalkyl); a halide; a hydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [such as —C(S)OR, —C(O)SR, and —C(S)R]; —(C 1-9  alkoxyl) optionally substituted with one or more of halide, hydroxyl, —NH 2 , —NH(C 1-3  alkyl), and —N(C 1-3  alkyl) 2 ; —OPO(OH) 2 ; a phosphonate [such as —PO(OH) 2  and —PO(OR′) 2 ]; —OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro; an azido; —SH; —S—R; —OSO 2 (OR); a sulfonate [such as —SO 2 (OH) and —SO 2 (OR)]; —SO 2 NR′R″; and —SO 2 R; in which each occurrence of R, R′ and R″ are independently selected from H; —(C 1-9  alkyl); C 6-10  aryl optionally substituted with from 1-3R″′; 5-10 membered heteroaryl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R″′; C 3-7  carbocyclyl optionally substituted with from 1-3 R″′; and 3-8 membered heterocyclyl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R″′; wherein each R″′ is independently selected from —(C 1-6  alkyl), —(C 1-6  haloalkyl), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C 1-6  alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is independently selected from H and —(C 1-6  alkyl). In some embodiments, the substituent is selected from —(C 1-6  alkyl), —(C 1-6  haloalkyl), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C 1-6  alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is independently selected from H and —(C 1-6  alkyl). 
     As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring”, it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions. In some embodiments, such rings have from 3-7 members, for example, 5 or 6 members. 
     The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically, the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, though such resonance forms or tautomers are not represented herein. 
     The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. 
     The term “administration” or “administering” refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease. 
     A “diagnostic” as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art. 
     The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non-human primates, but also includes many other species. 
     The term “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck &amp; Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010);  Goodman and Gilman&#39;s: The Pharmacological Basis of Therapeutics,  12 th Ed ., The McGraw-Hill Companies. 
     The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87/05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. 
     “Solvate” refers to the compound formed by the interaction of a solvent and a compound as provided herein or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates. 
     “Patient” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human. 
     A “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula I in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay,  Advances in Enzyme Regulation  (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient&#39;s height, weight, sex, age and medical history. 
     A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease. 
     “Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop. 
     “Drug-eluting” and/or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue. 
     “Drug-eluting material” and/or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time. 
     “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body. 
     Compounds 
     The compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis. 
     Some embodiments of the present disclosure include compounds of Formula I: 
                         
or salts, pharmaceutically acceptable salts, or prodrugs thereof.
 
     In some embodiments, R 1  and R 2  are independently selected from the group consisting of H and halide (e.g., F, Cl, Br, I). 
     In some embodiments, R 1  is H, and R 2  is F. 
     In some embodiments, R 1  is F, and R 2  is H. 
     In some embodiments, R 1  and R 2  are both H. 
     In some embodiments, R 1  and R 2  are both F. 
     In some embodiments, R 3  is selected from the group consisting of -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 6  and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 7 . 
     In some embodiments, R 3  is selected from the group consisting of -heteroaryl optionally substituted with 1-2 (e.g., 1) R 6  and -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 7 . 
     In some embodiments, the heteroaryl of R 3  is selected from the group consisting of -pyridinyl, -pyrimidinyl, -pyrazolyl, -imidazolyl, -thiazolyl, and -oxazolyl. 
     In some embodiments, the heteroaryl of R 3  is selected from the group consisting of -pyridin-3-yl, -pyrimidin-5-yl, -pyrazol-4-yl, -imidazol-5-yl, -thiazol-2-yl, -thiazol-5-yl, -oxazol-2-yl, and -oxazol-5-yl. 
     In some embodiments, the -heterocyclyl of R 3  is selected from the group consisting of -tetrahydropyridinyl and -piperidinyl. 
     In some embodiments, the -heterocyclyl of R 3  is selected from the group consisting of -1,2,3,6-tetrahydropyridinyl and -piperidin-4-yl. 
     In some embodiments, R 3  is -pyridinyl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyridin-3-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrimidinyl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrimidin-5-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrazolyl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrazolyl substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrazolyl substituted with 1 methyl. 
     In some embodiments, R 3  is -pyrazolyl optionally substituted with 2 R 6 . 
     In some embodiments, R 3  is -pyrazolyl substituted with 2 R 6 . 
     In some embodiments, R 3  is -pyrazolyl substituted with 1 methyl and 1 —CH 2 OH. 
     In some embodiments, R 3  is -pyrazol-4-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrazol-4-yl substituted with 1 R 6 . 
     In some embodiments, R 3  is -pyrazol-4-yl substituted with 1 methyl. 
     In some embodiments, R 3  is -pyrazol-4-yl optionally substionally substituted with 2 R 6 . 
     In some embodiments, R 3  is -pyrazol-4-yl substituted with 2 R 6 . 
     In some embodiments, R 3  is -pyrazol-4-yl substituted with 1 methyl and 1 —CH 2 OH. 
     In some embodiments, R 3  is -imidazolyl optionally substituted with 1-2 R 6 . 
     In some embodiments, R 3  is -imidazolyl substituted with 1-2 R 6 . 
     In some embodiments, R 3  is -imidazolyl substituted with 1-2 methyls. 
     In some embodiments, R 3  is -imidazolyl substituted with 1 methyl. 
     In some embodiments, R 3  is -imidazolyl substituted with 2 methyls. 
     In some embodiments, R 3  is -imidazol-5-yl optionally substituted with 1-2 R 6 . 
     In some embodiments, R 3  is -imidazol-5-yl substituted with 1-2 R 6 . 
     In some embodiments, R 3  is -imidazol-5-yl substituted with 1-2 methyls. 
     In some embodiments, R 3  is -imidazol-5-yl substituted with 1 methyl. 
     In some embodiments, R 3  is -imidazol-5-yl substituted with 2 methyls. 
     In some embodiments, R 3  is -thiazolyl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -thiazol-2-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is thiazol-5-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -oxazolyl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -oxazol-2-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 3  is -oxazol-5-yl optionally substituted with 1 R 6 . 
     In some embodiments, R 5  is selected from the group consisting of H, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 8 , -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 9 , and -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 10 . 
     In some embodiments, R 5  is selected from the group consisting of H, -heteroaryl optionally substituted with 1-2 (e.g., 1) R 8 , -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 9 , and -phenyl optionally substituted with 1-2 (e.g., 1) R 10 . 
     In some embodiments, R 5  is H. 
     In some embodiments, R 5  is -heteroaryl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -piperidinyl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -piperazinyl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -aryl optionally substituted with 1-2 (e.g., 1) R 10 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 1-2 (e.g., 1) R 10 . 
     In some embodiments, R 5  is -pyridinyl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -pyridin-3-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -pyridin-4-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -pyridin-5-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -imidazolyl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -imidazolyl substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -imidazolyl substituted with 1 R 8 . 
     In some embodiments, R 5  is -imidazolyl substituted with 1 methyl. 
     In some embodiments, R 5  is -imidazol-1-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -imidazol-1-yl substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -imidazol-1-yl substituted with 1 R 8 . 
     In some embodiments, R 5  is -imidazol-1-yl substituted with 1 methyl. 
     In some embodiments, R 5  is -furanyl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -furan-2-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -furan-3-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -thiophenyl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R 8 , and each R 8  is independently halide. 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) F. 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) Cl. 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R 8 , and each R 8  is independently —(C 1-6  alkyl). 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) R 8 , and each R 8  is independently —(C 1-2  alkyl). 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) methyls. 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) —CF 3 . 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1-2 (e.g., 1) —CN. 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1 —C(═O)R 19 . 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-6  alkyl). 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-4  alkyl). 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-2  alkyl). 
     In some embodiments, R 5  is -thiophen-2-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is methyl. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R 8 . 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R 8  and each R 8  is independently halide. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) F. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) Cl. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R 8 , and each R 8  is independently —(C 1-6  alkyl). 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) R 8 , and each R 8  is independently —(C 1-2  alkyl). 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) methyls. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) —CF 3 . 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1-2 (e.g., 1) —CN. 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1 —C(═O)R 19 . 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-6  alkyl). 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-4  alkyl). 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is —(C 1-2  alkyl). 
     In some embodiments, R 5  is -thiophen-3-yl optionally substituted with 1 —C(═O)R 19 , and R 19  is methyl. 
     In some embodiments, R 5  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is -phenyl optionally substituted with 1-2 (e.g., 1) R 10 , and each R 10  is independently halide. 
     In some embodiments, R 5  is -phenyl optionally substituted with 1-2 (e.g., 1) F. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —(C 1-6  alkylene)NHSO 2 R 19 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —(C 1-4  alkylene)NHSO 2 R 19 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —(C 1-2  alkylene)NHSO 2 R 19 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —CH 2 NHSO 2 R 19 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —CH 2 NHSO 2 R 19 , R 19  is —(C 1-4  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —CH 2 NHSO 2 R 19 , R 19  is —(C 1-2  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —CH 2 NHSO 2 R 19 , R 19  is methyl. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —CH 2 NHSO 2 R 19 , R 19  is —(C 1-2  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —CH 2 NHSO 2 R 19 , R 19  is methyl. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NR 15 (C 1-6  alkylene)NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NR 15 (C 1-5  alkylene)NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NR 15 (C 1-4  alkylene)NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NR 15 (C 1-3  alkylene)NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NR 15 CH 2 CH 2 NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and R 15  and R 16  are independently selected from —(C 1-6  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and R 15  and R 16  are independently selected from —(C 1-4  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and R 15  and R 16  are independently selected from —(C 1-2  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and both R 15  and R 16  are methyls. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and R 15  and R 16  are independently selected from —(C 1-2  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —NHCH 2 CH 2 NR 15 R 16 , and both R 15  and R 16  are methyls. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OR 27 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OCH 2 CH 2 NR 25 R 26 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OCH 2 CH 2 NR 25 R 26 , and R 25  and R 26  are independently —(C 1-2  alkyl). 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OCH 2 CH 2 NR 25 R 26 , and R 25  and R 26  are both methyl. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —OCH 2 CH 2 NR 25 R 26 , and R 25  and R 26  are both methyl. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OCH 2 CH 2 heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is F and the other R 10  is —OCH 2 CH 2 heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OH. 
     In some embodiments, R 5  is -phenyl optionally substituted with 2 R 10 , one R 10  is halide and the other R 10  is —OMe. 
     In some embodiments, R 5  is -phenyl optionally substituted with 1 —OMe. 
     In some embodiments, R 5  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 5  is -piperidin-1-yl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -piperidin-1-yl optionally substituted with 1-2 (e.g., 1) R 9 , and each R 9  is independently halide. 
     In some embodiments, R 5  is -piperazin-1-yl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -piperazin-1-yl optionally substituted with 1 C 1-3  alkyl. 
     In some embodiments, R 5  is -piperazin-1-yl optionally substituted with 1 methyl. 
     In some embodiments, R 5  is -morpholinyl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is -morpholin-1-yl optionally substituted with 1-2 (e.g., 1) R 9 . 
     In some embodiments, R 5  is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     In some embodiments, each R 6  is independently selected from the group consisting of halide, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —NHC(═O)R 4 , —NR 15 R 16 , —(C 1-6  alkylene)NR 17 R 18 , —(C 2-6  alkenylene)NR 17 R 18 , —(C 2-6  alkynylene)NR 17 R 18 , and —OR 24 . 
     In some embodiments, each R 6  is independently selected from the group consisting of halide, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 12 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 13 , —NHC(═O)R 4 , —NR 15 R 16 , —(C 1-6  alkylene)NR 17 R 18 , —(C 2-6  alkenylene)NR 17 R 18 , —(C 2-6  alkynylene)NR 17 R 18 , and —(C 1-4  alkylene) p OR 24 . 
     In some embodiments, each R 6  is independently selected from the group consisting of F, Cl, —(C 1-3  alkyl), -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 11 , —CH 2 heterocyclyl optionally substituted with with 1-2 (e.g., 1) R 11 , -carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 , —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 , -aryl optionally substituted with 1-2 (e.g., 1) R 13 , —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 13 , —NHC(═O)R 14 , —NR 15 R 16 , —CH 2 NR 17 R 18 , and —OR 24 . 
     In some embodiments, each R 6  is independently selected from the group consisting of F, Cl, —(C 1-3  alkyl), -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 11 , —CH 2 heterocyclyl optionally substituted with with 1-2 (e.g., 1) R 11 , -carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 , —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 , -aryl optionally substituted with 1-2 (e.g., 1) R 13 , —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 13 , —NHC(═O)R 14 , —NR 15 R 16 , —CH 2 NR 17 R 18 , —CH 2 OR 24 , and —OR 24 . 
     In some embodiments, each R 6  is independently selected from the group consisting of F, -Me, -heterocyclyl optionally substituted with 1-2 (e.g., 1) halides, -heterocyclyl optionally substituted with 1-2 (e.g., 1) methyls, —CH 2 heterocyclyl optionally substituted with with 1-2 (e.g., 1) halides, —CH 2 heterocyclyl optionally substituted with with 1-2 (e.g., 1) methyls, -carbocyclyl optionally substituted with 1-2 (e.g., 1) halides, —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) halides, -aryl optionally substituted with 1-2 (e.g., 1) halides, —CH 2 aryl optionally substituted with 1-2 (e.g., 1) halides, —NHC(═O)R 14 , —NH 2 , —NHMe, —NHEt, —NHPr, —NMe 2 , —CH 2 NMe 2 , —CH 2 NHMe, —CH 2 NHEt, —CH 2 NHCH 2 phenyl, —CH 2 NHCH 2 carbocylyl, —CH 2 OH, and —OR 24 . 
     In some embodiments, R 6  is selected from the group consisting of —(C 1-3  alkyl), —CH 2 heterocyclyl optionally substituted with 1-2 R 11 , —NHC(═O)R 14 , —NR 15 R 16 , —CH 2 NR 17 R 18 , —CH 2 OH, and —OR 24 . 
     In some embodiments, at least one R 6  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is -Me. 
     In some embodiments, at least one R 6  is halide. 
     In some embodiments, at least one R 6  is F. 
     In some embodiments, at least one R 6  is —(C 1-4  alkylene)heterocyclyl optionally substituted with 1-2 R 11 . 
     In some embodiments, at least one R 6  is —(C 1-3  alkylene)heterocyclyl optionally substituted with 1-2 R 11 . 
     In some embodiments, at least one R 6  is —(C 1-2  alkylene)heterocyclyl optionally substituted with 1-2 R 11 . 
     In some embodiments, at least one R 6  is —CH 2 pyrrolidinyl optionally substituted with 1-2 R 11 . 
     In some embodiments, R 6  is —CH 2 pyrrolidinyl optionally substituted with 1-2 R 11 . 
     In some embodiments, R 6  is —CH 2 pyrrolidinyl optionally substituted with 1-2 R 11 , and each R 11  is independently halide. 
     In some embodiments, R 6  is —CH 2 pyrrolidinyl optionally substituted with 1-2 F. 
     In some embodiments, R 6  is —CH 2 pyrrolidinyl substituted with 1-2 F. 
     In some embodiments, R 6  is —CH 2 pyrrolidinyl substituted with 2 F. 
     In some embodiments, at least one R 6  is —CH 2 piperidinyl optionally substituted with 1-2 R 11 . 
     In some embodiments, R 6  is —CH 2 piperidinyl optionally substituted with 1-2 R 11 . 
     In some embodiments, R 6  is —CH 2 piperidinyl optionally substituted with 1-2 R 11 , and each R 11  is independently halide. 
     In some embodiments, R 6  is —CH 2 piperidinyl optionally substituted with 1-2 F. 
     In some embodiments, R 6  is 
     
       
         
         
             
             
         
       
     
     In some embodiments, at least one R 6  is —(C 1-4  alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 . 
     In some embodiments, at least one R 6  is —(C 1-3  alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 . 
     In some embodiments, at least one R 6  is —(C 1-2  alkylene)carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 . 
     In some embodiments, at least one R 6  is —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 . 
     In some embodiments, R 6  is —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 12 . 
     In some embodiments, at least one R 6  is —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 13 , 
     In some embodiments, at least one R 6  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 13 , 
     In some embodiments, R 6  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 13 , 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 . 
     In some embodiments, R 6  is —NHC(═O)R 4 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-9  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-8  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-7  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-6  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-5  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —(C 1-5  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-4  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-3  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 1-2  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —(C 1-2  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —CF 3 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 2-5  alkyl). 
     In some embodiments, R 6  is —NHC(═O)R 14  and R 14  is —(C 2-5  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14  and R 14  is —(C 3-4  alkyl). 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -aryl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -phenyl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -heteroaryl optionally substituted with 1-2 (e.g., 1) R 20 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -cyclopropyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -cyclobutyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -cyclopentyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is -cyclohexyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHC(═O)R 14 , R 14  is —CH 2 cyclopropyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NR 15 R 16 . 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and —(C 1-6  alkyl). 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and —(C 1-5  alkyl). 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —NR 15 R 16 , and R 15  and R 16  are independently selected from the group consisting of H and methyl. 
     In some embodiments, at least one R 6  is —NH 2 . 
     In some embodiments, R 6  is —NH 2 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —(C 1-2  alkyl). 
     In some embodiments, R 6  is —NHR 16  and R 16  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 cyclopropyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 cyclobutyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 cyclopentyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —NHR 16  and R 16  is —CH 2 cyclohexyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —(C 1-6  alkylene)NR 17 R 18 . 
     In some embodiments, at least one R 6  is —(C 1-5  alkylene)NR 17 R 18 . 
     In some embodiments, at least one R 6  is —(C 1-4  alkylene)NR 17 R 18 . 
     In some embodiments, at least one R 6  is —(C 1-3  alkylene)NR 17 R 18 . 
     In some embodiments, at least one R 6  is —(C 1-2  alkylene)NR 17 R 18 . 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 . 
     In some embodiments, R 6  is —CH 2 NR 17 R 18 . 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and —(C 1-6  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and —(C 1-5  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and methyl. 
     In some embodiments, R 6  is —CH 2 NR 17 R 18 , and R 17  and R 18  are independently selected from the group consisting of H and methyl. 
     In some embodiments, at least one R 6  is —CH 2 NH 2 . 
     In some embodiments, R 6  is —CH 2 NH 2 . 
     In some embodiments, at least one R 6  is —CH 2 NMe 2 . 
     In some embodiments, R 6  is —CH 2 NMe 2 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —(C 1-2  alkyl). 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 aryl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —CH 2 phenyl optionally substituted with 1-2 (e.g., 1) R 21 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclopropyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclopropyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclobutyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclobutyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclopentyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclopentyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclohexyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, R 6  is —CH 2 NHR 18  and R 18  is —CH 2 cyclohexyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —OR 24 . 
     In some embodiments, at least one R 6  is —OH. 
     In some embodiments, R 6  is —OH. 
     In some embodiments, at least one R 6  is —(C 1-4  alkylene)OR 24 . 
     In some embodiments, R 6  is —(C 1-4  alkylene)OR 24 . 
     In some embodiments, R 6  is —(C 1-3  alkylene)OR 24 . 
     In some embodiments, R 6  is —(C 1-2  alkylene)OR 24 . 
     In some embodiments, R 6  is —CH 2 OR 24 . 
     In some embodiments, R 6  is —CH 2 OH. 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —OMe. 
     In some embodiments, R 6  is —OMe. 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, R 6  is —OR 24  and R 24  is -heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, R 6  is —OR 24  and R 24  is -carbocyclyl optionally substituted with 1-2 (e.g., 1) R 22 . 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(C 1-4  alkylene)heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )heterocyclyl optionally substituted with 1-2 (e.g., 1) R 23 . 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(C 1-4  alkylene)NR 25 R 26  and R 25  and R 26  are independently —(C 1-4  alkyl). 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )NR 25 R 26  and R 25  and R 26  are independently —(C 1-2  alkyl). 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )NMe 2 . 
     In some embodiments, R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )NMe 2 . 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(C 1-4  alkylene)aryl optionally substituted with 1-2 (e.g., 1) R 21 , and each R 21  is independently halide. 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )phenyl optionally substituted with 1-2 (e.g., 1) R 21 , and each R 21  is independently halide. 
     In some embodiments, R 6  is —OR 24  and R 24  is —(CH 2 CH 2 )phenyl optionally substituted with 1-2 (e.g., 1) R 21 , and each R 21  is independently halide. 
     In some embodiments, at least one R 6  is —OR 24  and R 24  is —(CH 2 )phenyl optionally substituted with 1-2 (e.g., 1) R 21 , and each R 21  is independently halide. 
     In some embodiments, R 6  is —OR 24  and R 24  is —(CH 2 )phenyl optionally substituted with 1-2 (e.g., 1) R 21 , and each R 21  is independently halide. 
     In some embodiments, each R 7  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 7  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, at least one R 7  is —(C 1-4  alkyl). 
     In some embodiments, at least one R 7  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 7  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 7  is methyl. 
     In some embodiments, at least one R 7  is halide. 
     In some embodiments, at least one R 7  is F. 
     In some embodiments, each R 8  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —OCH 3 , —CN, and —C(═O)R 19 . 
     In some embodiments, each R 8  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , —OCH 3 , —CN, and —C(═O)Me. 
     In some embodiments, at least one R 8  is halide. 
     In some embodiments, at least one R 8  is F. 
     In some embodiments, at least one R 8  is —(C 1-4  alkyl). 
     In some embodiments, at least one R 8  is —(C 1-3  alkyl). 
     In some embodiments, at least one R 8  is —(C 1-2  alkyl). 
     In some embodiments, at least one R 8  is methyl. 
     In some embodiments, R 8  is methyl. 
     In some embodiments, at least one R 8  is —C(═O)(C 1-3  alkyl). 
     In some embodiments, at least one R 8  is —C(═O)Me. 
     In some embodiments, R 8  is —C(═O)Me. 
     In some embodiments, each R 9  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, and —OCH 3 . 
     In some embodiments, each R 9  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , —CN, and —OCH 3 . 
     In some embodiments, each R 10  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), halide, —CF 3 , —CN, —(C 1-6  alkylene) p NHSO 2 R 19 , —(C 2-6  alkenylene) p NHSO 2 R 19 , —(C 2-6  alkynylene) p NHSO 2 R 19 , —NR 15 (C 1-6  alkylene)NR 15 R 16 , —NR 15 (C 2-6  alkenylene)NR 15 R 16 , —NR 15 (C 2-6  alkynylene)NR 15 R 16 , —(C 1-6  alkylene) p NR 15 R 16 , —(C 2-6  alkenylene) p NR 15 R 16 , —(C 2-6  alkynylene) p NR 15 R 16 , and —OR 27 . 
     In some embodiments, each R 11  is independently selected from the group consisting of amino, —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 11  is independently selected from the group consisting of amino, methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 12  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 12  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 13  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 13  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 14  is independently selected from the group consisting of —(C 1-9  alkyl), —(C 1-4  haloalkyl), —(C 2-9  alkenyl), —(C 2-9  alkynyl), -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 20 , -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , —CH 2 aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 , —CH 2 carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 , —(C 1-4  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , —(C 2-4  alkynylene) p NR 25 R 26 , -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , and —CH 2 heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 . 
     In some embodiments, each R 15  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl). 
     In some embodiments, each R 16  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , and —CH 2 carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 . 
     In some embodiments, each R 17  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl). 
     In some embodiments, each R 18  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —CH 2 aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21  and —CH 2 carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 . 
     In some embodiments, each R 19  is independently selected from the group consisting of —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl). 
     In some embodiments, each R 20  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 20  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 21  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 21  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 22  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 22  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, each R 23  is independently selected from the group consisting of —(C 1-4  alkyl), —(C 2-4  alkenyl), —(C 2-4  alkynyl), halide, —CF 3 , and —CN. 
     In some embodiments, each R 23  is independently selected from the group consisting of methyl, F, Cl, —CF 3 , and —CN. 
     In some embodiments, R 24  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 1-4  alkylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 , —(C 2-4  alkenylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 , —(C 2-4  alkynylene) p carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 22 , —(C 1-4  alkylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , —(C 2-4  alkenylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , —(C 2-4  alkynylene) p aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-4  alkenylene) p NR 25 R 26 , and —(C 2-4  alkynylene) p NR 25 R 26 . 
     In some embodiments, each R 25  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl). 
     In some embodiments, each R 26  is independently selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), and —(C 2-6  alkynyl). 
     In some embodiments, R 27  is selected from the group consisting of H, —(C 1-6  alkyl), —(C 2-6  alkenyl), —(C 2-6  alkynyl), —(C 1-4  alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 2-4  alkenylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 2-4  alkynylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 23 , —(C 1-6  alkylene) p NR 25 R 26 , —(C 2-6  alkenylene) p NR 25 R 26 , and —(C 2-6  alkynylene)NR 25 R 26 . 
     In some embodiments, each p is independently an integer of 0 or 1. 
     In some embodiments, p is 0. 
     In some embodiments, p is 1. 
     Illustrative compounds of Formula (I) are shown in Table 1. 
                         TABLE 1                                        1                                      2                                      3                                      4                                      5                                      6                                      7                                      8                                      9                                      10                                      11                                      12                                      13                                      14                                      15                                      16                                      17                                      18                                      19                                      20                                      21                                      22                                      23                                      24                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Administration and Pharmaceutical Compositions
 
     Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier. 
     The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents. 
     Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, diabetic retinopathy, idiopathic pulmonary fibrosis/pulmonary fibrosis, and osteoarthritis. 
     In some embodiments, colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment). 
     In some embodiments, ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®), Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide (IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine (XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed (ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin). 
     In some embodiments, a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®), tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA® or RITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k) radiation therapy. 
     In some embodiments, diabetic retinopathy can be treated with a combination of a compound of Formula (I) and one or more of the following natural supplements: Bilberry, Butcher&#39;s broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark). 
     In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently being studied in patients with IPF, [ The American Journal of Respiratory and Critical Care Medicine  (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [ British Journal of Pharmacology  (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids. 
     In some embodiments, a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery. 
     In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class. 
     In some embodiments, macular degeneration can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc. 
     In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the  Argus ® II retinal implant; and (b) with stem cell and/or gene therapy. 
     Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracistemally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. In some embodiments, the administration method includes oral or parenteral administration. 
     Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. 
     The compounds can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient or the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington:  The Science and Practice of Pharmacy,  22 nd  Edition (Pharmaceutical Press, London, UK. 2012). 
     In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG&#39;s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. 
     Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans. 
     In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans. 
     In some embodiments, the compositions are provided in unit dosage forms suitable for single administration. 
     In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration. 
     In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration. 
     Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of a compound provided herein contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages. 
     In some embodiments, the composition will comprise about 0.1-10% of the active agent in solution. 
     In some embodiments, the composition will comprise about 0.1-5% of the active agent in solution. 
     In some embodiments, the composition will comprise about 0.1-4% of the active agent in solution. 
     In some embodiments, the composition will comprise about 0.15-3% of the active agent in solution. 
     In some embodiments, the composition will comprise about 0.2-2% of the active agent in solution. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-96 hours. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-72 hours. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-48 hours. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-24 hours. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-12 hours. 
     In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-6 hours. 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2  to about 300 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2  to about 200 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2  to about 100 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m 2  to about 50 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m 2  to about 200 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m 2  to about 175 mg/m 2 . 
     In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m 2  to about 150 mg/m 2 . 
     It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. 
     In one embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique. 
     In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 μm are useful (e.g., about 1 to about 10 microns). Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles. 
     In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERx® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device. 
     In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used. 
     Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559). 
     If desired, formulations of the invention can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211). 
     In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea. 
     Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal implanted pumping system. 
     Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815). 
     Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae. 
     In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like. 
     Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted. 
     Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent. 
     Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In one embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound. 
     On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound. 
     Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions. 
     Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer&#39;s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome. 
     Methods of Treatment 
     The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer&#39;s disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, multiple sclerosis or autism, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome. 
     The compounds and compositions described herein can be used to treat tendinopathy includes all tendon pathologies (tendinitis, tendinosis and paratenonitis) localized in and around the tendons and is characterized by pain, swelling and impaired performance due to the degeneration of the tendon&#39;s collagen in response tendon overuse, often referred to as tendinosis. Tendinopathy may be categorized into two histopathologic entities—tendonitis, which results from acute injury to the tendon accompanied by intratendinous inflammation, and more commonly, tendinosis, which is a degenerative response to repetitive microtrauma resulting from overuse. Tendinosis may be accompanied by paratenonitis, an inflammatory condition of the lining of the tendon. 
     With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer. 
     Other cancers can also be treated with the compounds and compositions described herein. 
     More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following: 
     1) Breast cancers, including, for example ER +  breast cancer, ER −  breast cancer, her2 −  breast cancer, her2 +  breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget&#39;s disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER − ), progesterone receptor negative, and her2 negative (her2 − ). In some embodiments, the breast cancer may have a high risk Oncotype score. 
     2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma. 
     3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma. 
     4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi&#39;s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma. 
     5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm&#39;s tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma. 
     6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma. 
     7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing&#39;s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors. 
     8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma. 
     9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma. 
     10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma (malignant lymphoma) and Waldenström&#39;s macroglobulinemia. 
     11) Skin cancers and skin disorders, including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi&#39;s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma. 
     12) Adrenal gland cancers, including, for example, neuroblastoma. 
     Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders. 
     A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment. 
     The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. For example, the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition. 
     In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells. 
     Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:
         a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi&#39;s sarcoma.   a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; fatty liver disease (FLD); adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative disorders such as Alzheimer&#39;s Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.   defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neuro-degenerative disorders (including but not limited to Alzheimer&#39;s disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson&#39;s disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), tendinopathies such as tendinitis and tendinosis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.   genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.       

     The compounds and compositions described herein can be used to treat neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer&#39;s disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell&#39;s palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing&#39;s syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, de Morsier&#39;s syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb&#39;s palsy, erythromelalgia, essential tremor, Fabry&#39;s disease, Fahr&#39;s syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich&#39;s ataxia, fibromyalgia, Foville&#39;s syndrome, Gaucher&#39;s disease, Gerstmann&#39;s syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington&#39;s disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh&#39;s disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig&#39;s disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere&#39;s disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O&#39;Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson&#39;s disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick&#39;s disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen&#39;s encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye&#39;s syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder&#39;s disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren&#39;s syndrome, snatiation, Sotos syndrome, spasticity, spina  bifida , spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham&#39;s chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd&#39;s paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, tryl)anosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg&#39;s syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson&#39;s disease and Zellweger syndrome. 
     The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis. 
     In some embodiments, the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent. 
     In some embodiments, the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim  1 , or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the disorder or disease is cancer. 
     In some embodiments, the disorder or disease is systemic inflammation. 
     In some embodiments, the disorder or disease is metastatic melanoma. 
     In some embodiments, the disorder or disease is fatty liver disease. 
     In some embodiments, the disorder or disease is liver fibrosis. 
     In some embodiments, the disorder or disease is tendon regeneration. 
     In some embodiments, the disorder or disease is diabetes. 
     In some embodiments, the disorder or disease is degenerative disc disease. 
     In some embodiments, the disorder or disease is osteoarthritis. 
     In some embodiments, the disorder or disease is diabetic retinopathy. 
     In some embodiments, the disorder or disease is pulmonary fibrosis. 
     In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis (IPF). 
     In some embodiments, the disorder or disease is degenerative disc disease. 
     In some embodiments, the disorder or disease is rheumatoid arthritis. 
     In some embodiments, the disorder or disease is scleroderma. 
     In some embodiments, the disorder or disease is a mycotic or viral infection. 
     In some embodiments, the disorder or disease is a bone or cartilage disease. 
     In some embodiments, the disorder or disease is Alzheimer&#39;s disease. 
     In some embodiments, the disorder or disease is osteoarthritis. 
     In some embodiments, the disorder or disease is lung disease. 
     In some embodiments, the disorder or disease is tendinitis. 
     In some embodiments, the disorder or disease is tendinosis. 
     In some embodiments, the disorder or disease is paratenonitis. 
     In some embodiments, the disorder or disease is degeneration of the tendon&#39;s collagen. 
     In some embodiments, the disorder or disease is tendinopathy. 
     In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome. 
     In some embodiments, the patient is a human. 
     In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer. 
     In some embodiments, the cancer is chosen from: lung cancer—non-small cell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer—basal and squamous cell, skin cancer—melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer. 
     In some embodiments, the cancer is hepatocellular carcinoma. 
     In some embodiments, the cancer is colon cancer. 
     In some embodiments, the cancer is colorectal cancer. 
     In some embodiments, the cancer is breast cancer. 
     In some embodiments, the cancer is pancreatic cancer. 
     In some embodiments, the cancer is chronic myeloid leukemia (CML). 
     In some embodiments, the cancer is chronic myelomonocytic leukemia. 
     In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). 
     In some embodiments, the cancer is acute myeloid leukemia. 
     In some embodiments, the cancer is acute lymphocytic leukemia. 
     In some embodiments, the cancer is Hodgkin lymphoma. 
     In some embodiments, the cancer is lymphoma. 
     In some embodiments, the cancer is sarcoma. 
     In some embodiments, the cancer is ovarian cancer. 
     In some embodiments, the cancer is lung cancer—non-small cell. 
     In some embodiments, the cancer is lung cancer—small cell. 
     In some embodiments, the cancer is multiple myeloma. 
     In some embodiments, the cancer is nasopharyngeal cancer. 
     In some embodiments, the cancer is neuroblastoma. 
     In some embodiments, the cancer is osteosarcoma. 
     In some embodiments, the cancer is penile cancer. 
     In some embodiments, the cancer is pituitary tumors. 
     In some embodiments, the cancer is prostate cancer. 
     In some embodiments, the cancer is retinoblastoma. 
     In some embodiments, the cancer is rhabdomyosarcoma. 
     In some embodiments, the cancer is salivary gland cancer. 
     In some embodiments, the cancer is skin cancer—basal and squamous cell. 
     In some embodiments, the cancer is skin cancer—melanoma. 
     In some embodiments, the cancer is small intestine cancer. 
     In some embodiments, the cancer is stomach (gastric) cancers. 
     In some embodiments, the cancer is testicular cancer. 
     In some embodiments, the cancer is thymus cancer. 
     In some embodiments, the cancer is thyroid cancer. 
     In some embodiments, the cancer is uterine sarcoma. 
     In some embodiments, the cancer is vaginal cancer. 
     In some embodiments, the cancer is vulvar cancer. 
     In some embodiments, the cancer is Wilms tumor. 
     In some embodiments, the cancer is laryngeal or hypopharyngeal cancer. 
     In some embodiments, the cancer is kidney cancer. 
     In some embodiments, the cancer is Kaposi sarcoma. 
     In some embodiments, the cancer is gestational trophoblastic disease. 
     In some embodiments, the cancer is gastrointestinal stromal tumor. 
     In some embodiments, the cancer is gastrointestinal carcinoid tumor. 
     In some embodiments, the cancer is gallbladder cancer. 
     In some embodiments, the cancer is eye cancer (melanoma and lymphoma). 
     In some embodiments, the cancer is Ewing tumor. 
     In some embodiments, the cancer is esophagus cancer. 
     In some embodiments, the cancer is endometrial cancer. 
     In some embodiments, the cancer is colorectal cancer. 
     In some embodiments, the cancer is cervical cancer. 
     In some embodiments, the cancer is brain or spinal cord tumor. 
     In some embodiments, the cancer is bone metastasis. 
     In some embodiments, the cancer is bone cancer. 
     In some embodiments, the cancer is bladder cancer. 
     In some embodiments, the cancer is bile duct cancer. 
     In some embodiments, the cancer is anal cancer. 
     In some embodiments, the cancer is adrenal cortical cancer. 
     In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer&#39;s disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson&#39;s disease, Huntington&#39;s disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease. 
     In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway. 
     In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins. 
     In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16. 
     In some embodiments, the compound of Formula (I) inhibits a kinase activity. 
     In some embodiments, the method treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins. 
     In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis. 
     In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 
     In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim  1  in combination with a pharmaceutically acceptable carrier and one or more other agents. 
     Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like. 
     Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G 0 . or G. 1  stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes. 
     Evaluation of Biological Activity 
     The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, see, e.g., WO 2001/053268 and WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below. 
     In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above. 
     In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a candidate inhibitor with cells containing constitutively active Wnt/β-catenin signaling. The cells are cultured for a period of time sufficient to stabilize β-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin. 
     In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al.  Cell  (1997), 88(6), 747-756). 
     To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. 
     EXAMPLES 
     Compound Preparation 
     The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds. 
     It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as  March&#39;s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure  7 th  Ed., John Wiley &amp; Sons (2013), Carey and Sundberg,  Advanced Organic Chemistry  5 th  Ed., Springer (2007),  Comprehensive Organic Transformations: A Guide to Functional Group Transformations,  2nd Ed., John Wiley &amp; Sons (1999) (incorporated herein by reference in its entirety) and the like. 
     The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts  Protective Groups  in  Organic Synthesis,  4th Ed., John Wiley &amp; Sons (2007), incorporated herein by reference in its entirety. 
     Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention. 
     ( 1 H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for  1 H or Avance TM DRX500, 500 MHz for  1 H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for  1 H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet. 
     The following abbreviations have the indicated meanings: 
     Ac 2 O=acetic anhydride 
     BH 3 -Me 2 S=borane dimethyl sulfide complex 
     B(iPrO) 3 =triisopropyl borate 
     (Boc) 2 O=di-tert-butyl dicarbonate 
     nBuLi=n-butyl lithium 
     brine=saturated aqueous sodium chloride 
     CDCl 3 =deuterated chloroform 
     CD 3 OD=deuterated methanol 
     DCAD=di-(4-chlorobenzyl)azodicarboxylate 
     DCE=dichloroethane 
     DCM=dichloromethane 
     DEAD=diethyl azodicarboxylate 
     DHP=dihydropyran 
     DIPEA=N,N-diisopropylethylamine 
     DMA=dimethylacetamide 
     DMAP=4-dimethylaminopyridine 
     DME=dimethoxyethane 
     DMF=N,N-dimethylformamide 
     DMSO-d 6 =deuterated dimethylsulfoxide 
     ESIMS=electron spray mass spectrometry 
     EtOAc=ethyl acetate 
     EtOH=ethanol 
     HCl=hydrochloric acid 
     HOAc=acetic acid 
     K 2 CO 3 =potassium carbonate 
     KOAc=potassium acetate 
     LC/MS=liquid chromatography-mass spectrometry 
     MeOH=methanol 
     MgSO 4 =magnesium sulfate 
     MsCl=methanesulfonyl chloride or mesyl chloride 
     MW=microwave 
     NaBH 4 =sodium borohydride 
     NaBH(OAc) 3 =sodium triacetoxyborohydride 
     NaCNBH 3 =sodium cyanoborohydride 
     NaHCO 3 =sodium bicarbonate 
     NaIO 4 =sodium periodate 
     NaOH=sodium hydroxide 
     NMR=nuclear magnetic resonance 
     ON=overnight 
     Pd/C=palladium(0) on carbon 
     Pd(dppf)Cl 2 =1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 
     Pd(PPh 3 ) 4 =tetrakis(triphenylphosphine)palladium(0) 
     PE=petroleum ether 
     PPh 3 =triphenylphosphine 
     r.t=room temperature 
     TBDMS-Cl=tert-butylchlorodimethylsilane 
     TEA=triethylamine 
     TFA=trifluoroacetic acid 
     THF=tetrahydrofuran 
     THP=tetrahydropyran 
     TLC=thin layer chromatography 
     p-TsOH=p-toluenesulfonic acid 
     The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above. 
     General Procedure 
     Compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 1a. 
     
       
         
         
             
             
         
       
     
     The 1H-pyrazolo[4,3-b]pyridine (II) is first protected, for example, with a Boc or THP (III) followed by Suzuki coupling with various boronic acids (IV). The 1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde (V) is then reacted with a 1,2-diamine (VI) to produce (VII). Final deprotection of the pyrazole nitrogen yields the desired 1H-pyrazolo[4,3-b]pyridine derivatives (VIII). 
     Compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 1. 
     
       
         
         
             
             
         
       
     
     Scheme 1 describes a method for preparation of 3-(3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine (XII) by iodination of the 5-chloro-1H-pyrazolo[4,3-b]pyridine (II) with iodine and sodium periodate to produce the 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (III). The pyrazolopyridine (III) is then protected with THP followed by Suzuki coupling with styrylboronic acid to form a 3-styrylpyrazolopyridine (VI). The double bond is oxidatively cleaved with osmium tetroxide to yield the aldehyde (VII). The pyrazolopyridine (VII) reacted with various boronic acids (VIII) using Suzuki coupling. The pyrazolopyridine aldehyde (IX) is reacted with various 1,2-diamines (X) to produce (XI). Final deprotection of the pyrazole nitrogen yields the desired substituted 3-(3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine (XII). 
     Illustrative Compound Examples 
     Preparation of intermediate (XVI) is depicted below in Scheme 2. 
                         
Step 1
 
     To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (XIII) (13 g, 84.7 mmol) in DMF (100 mL) was added iodine (43.0 g, 169 mmol) followed by potassium hydroxide powder (23.75 g, 423 mmol) portion wise under ice water cooling. The reaction mixture was stirred at 25° C. overnight. The solid KOH was filtered off, washed with EtOAc, most of the DMF was removed under vacuum and the residue was diluted with water (200 mL) and extracted with EtOAc (5×200 mL), washed with brine (500 mL), dried over Na 2 SO 4  and concentrated to give 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (XIV) as an orange solid (23.5 g, 84.1 mmol, 99.3% yield). ESIMS found for C 6 H 3 ClIN 3  m/z 279.9 (M+H). 
     Step 2 
     A mixture 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (XIV) (23.5 g, 84.1 mmol) and p-toluenesulfonic acid (3.20 g, 16.82 mmol) in THF (200 mL) was heated to 60° C. for 12 h. The solvents were concentrated and the residue taken in EtOAc (300 mL), washed with sat. NaHCO 3  (200 mL), and brine solution (200 mL). The organic layer was dried over anhydrous Na 2 SO 4 , and concentrated to give crude 5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (XV) as yellow gummy syrup (30.2 g, 83.1 mmol, 98.8% yield), which was used without further purification for the Suzuki coupling. ESIMS found for C 11 H 11 ClIN 3 O m/z 364.0 (M+H). 
     Step 3 
     A slurry of 5-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (XV) (30.2 g, 83.1 mmol), (E)-styrylboronic acid (V) (14.75 g, 100 mmol) and 2 M aqueous potassium carbonate (83 mL, 166 mmol) in toluene (240.0 mL) and EtOH (80.0 mL) was purged with argon for 5 minutes before and after adding PdCl 2 (dppf)-CH 2 Cl 2  adduct (3.39 g, 4.15 mmol). The reaction was heated at refluxed at 110° C. for 6 h. The reaction mixture was cooled and diluted with water (200 mL), extracted with EtOAc (2×300 mL), dried and evaporated, the residue was purified by column chromatography (0-30% EtOAc/hexanes), to obtain (E)-5-chloro-3-styryl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (XVI) as a white solid (21.1 g, 62.1 mmol, 74.8% yield). ESIMS found for C 19 H 18 ClN 3 O m/z 340.1 (M+H). 
     Step 4 
     To a solution of (E)-5-chloro-3-styryl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (XVI) (5.745 g, 16.91 mmol) and trimethylamine oxide (2.54 g, 33.8 mmol) in DCM (70.0 mL) under an atmosphere of dry argon was added osmium (VIII) oxide (0.215 g, 0.845 mmol). The reaction mixture was stirred for 3 h at room temperature. After complete conversion of olefin to diol (by LCMS), sodium periodate (5.42 g, 25.4 mmol) in water (50.0 mL) was added and the mixture was stirred for another 2 h at room temperature. Reaction mixture was diluted with DCM, washed water (100 mL), brine (100 mL), dried over Na 2 SO 4  and evaporated. The crude residue was purified by chromatography (0-70% EtOAc/hexanes) to obtain 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde (XVII) as a white solid (3.641 g, 13.7 mmol, 81.0% yield).  1 H NMR (CDCL 3 , 500 MHz) δ ppm 1.71-1.79 (m, 2H), 1.79-1.88 (m, 1H), 2.11-2.25 (m, 2H), 2.43-2.52 (m, 1H), 3.76-3.83 (m, 1H), 3.91-3.98 (m, 1H), 5.87 (dd, J=8.23, 3.02 Hz, 1H), 7.40 (d, J=8.78 Hz, 1H), 8.08 (d, J=9.06 Hz, 1H), 10.38 (s, 1H); ESIMS found for C 12 H 12 ClN 3 O 2  m/z 266.0 (M+H). 
     Preparation of intermediate N-(5-bromopyridin-3-yl)pivalamide (XX) is depicted below in Scheme 3. 
                         
Step 1
 
     To a solution of 3-amino-5-bromo pyridine (XVIII) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XIX) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO 3  mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XX) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.23 (s, 9H), 8.37 (d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs, 1H); ESIMS found C 10 H 13 BrN 2 O m/z 258.9 (Br 81 M+H). 
     The following intermediates were prepared in accordance with the procedure described in the above Scheme 3. 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)isobutyramide (XXI): Off-white solid, (71% yield).  1 H NMR (CDCl 3 ) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C 9 H 11 BrN 2 O m/z 242.9 (Br 79 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)propionamide (XXII): Off white solid (92% yield).  1 H NMR (DMSO-d 6 ) δ ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 2H), 8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS found C 8 H 9 BrN 2 O m/z 231.1 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)butyramide (XXIII): Yellow solid (2.1 g, 8.64 mmol, 88.8% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 1.02 (t, J=7.2 Hz, 3H), 1.74 (sxt, J=7.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 8.35 (d, J=2 Hz, 1H), 8.46 (t, J=2 Hz, 1H), 8.63 (d, J=2 Hz, 1H); ESIMS found C 9 H 11 BrN 2 O m/z 243.1 (Br 79 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)pentanamide (XXIV): Yellow solid (2.0 g, 7.78 mmol, 85.3% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 0.98 (t, J=7.4 Hz, 3H), 1.43 (sxt, J=7.4 Hz, 2H), 1.70 (quin, J=7.4 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 8.35 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H); ESIMS found C 10 H 13 BrN 2 O m/z 256.9 (Br 79 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XXV): Off white solid, (67% yield),  1 H NMR (CDCl 3 , 500 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J=6 Hz, 6H); ESIMS found C 10 H 13 BrN 2 O m/z 258.9 (Br 18 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XXVI): Yellow solid (1.7 g, 6.27 mmol, 78.6% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 1.10 (s, 9H), 2.29 (s, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C 11 H 15 BrN 2 O m/z 273.1 ((Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XXVII): White solid (2.5 g, 8.59 mmol, 77.9% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.76 (s, 2H), 7.26-7.45 (m, 5H), 7.57 (brs, 1H), 8.33 (s, 1H), 8.37 (s, 2H); ESIMS found C 13 H 11 BrN 2 O m/z 292.8 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)benzamide (XXIVIII): White solid (2.7 g, 9.74 mmol, 60% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 7.40-7.52 (m, 2H), 7.52-7.62 (m, 1H), 7.86 (d, J=7.2 Hz, 2H), 8.39 (d, J=1.6 Hz, 1H), 8.46 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H); ESIMS found C 12 H 9 BrN 2 O m/z 278.8 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XXIX): Off-white solid, (83% yield),  1 H NMR (CDCl 3 , 500 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found for C 9 H 9 BrN 2 O m/z 240.9 (Br 79 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XXX): Yellow solid (2.1 g, 6.27 mmol, 86.6% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 1.80-1.99 (m, 1H), 1.99-2.15 (m, 1H), 2.16-2.30 (m, 2H), 2.30-2.45 (m, 2H), 3.25-3.35 (m, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C 10 H 11 BrN 2 O m/z 257.1 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XXXI): Yellow solid (1.9 g, 7.06 mmol, 80.2% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 1.57-1.74 (m, 2H), 1.74-1.91 (m, 4H), 1.91-2.07 (m, 2H), 2.77-2.92 (m, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.65 (d, J=2.0 Hz, 1H); ESIMS found C 11 H 13 BrN 2 O m/z 271.1 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XXXII): Yellow solid (2.0 g, 7.06 mmol, 84.3% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 1.19-1.46 (m, 3H), 1.46-1.63 (m, 2H), 1.74 (d, J=11.6 Hz, 1H), 1.88 (t, J=14.0 Hz, 4H), 2.40 (tt, J=11.6 Hz, J=3.6 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.44 (t, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H); ESIMS found C 12 H 15 BrN 2 O m/z 285.1 (Br 81 M+H). 
     
       
         
         
             
             
         
       
     
     N-(5-bromopyridin-3-yl)-2-cyclohexylacetamide (XXXIII): Yellow solid (261 mg, 0.878 mmol, 84.4% yield). ESIMS found C 13 H 17 BrN 2 O m/z 297.1 (Br 81 M+H). 
     Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (XXXV) is depicted below in Scheme 4. 
                         
Step 1
 
     To a solution of 3,5-dibromopyridine (XXXIV) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K 2 CO 3  (4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200° C. in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO 4 , and concentrated to afford 5-bromo-N,N-dimethylpyridin-3-amine (XXXV) as an off-white solid (1.78 g, 8.85 mmol, 88% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.94 (s, 6H), 7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMS found C 7 H 9 BrN 2  m/z 201.1 (M+H). 
     Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (XXXVI) is depicted below in Scheme 5. 
                         
Steps 1
 
     To a solution of 5-bromopyridin-3-amine (XVIII) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH 3  (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic layer was dried over MgSO 4  and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane→90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XXXVI) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C 8 H 11 BrN 2  m/z 215.1 (M+H). 
     Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXXVIII) is depicted below in Scheme 6. 
                         
Steps 1
 
     Preparation of 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXXVIII) was performed following the procedure listed in Scheme 5, Step 1. Brown oil (1.20 g, 5.59 mmol, 45% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H); ESIMS found C 8 H 11 BrN 2  m/z 215 (M Br79 +H) and 217 (M Br81 +H). 
     Preparation of intermediate 3-bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (XXXIX) is depicted below in Scheme 7. 
                         
Steps 1
 
     To a mixture of 5-bromopyridine-3-carbaldehyde (XXXVII) (6.00 g, 32.26 mmol, 1.0 eq), 3,3-difluoropyrrolidine (5.56 g, 38.71 mmol, 1.20 eq) and TEA (5.39 mL, 38.71 mmol, 1.2 eq) in DCE (200 mL) was stirred at room temperature for 30 min, then added sodium triacetoxyborohydride (10.25 g, 48.38 mmol, 1.50 eq) in one portion at room temperature under N 2 . The mixture was stirred at room temperature for 6 hours. TLC showed the reaction was complete. The reaction was quenched with 1N NaOH (100 mL), extracted with DCE (100 mL×2). The combined organic layers were washed with brine (100 mL), dried and concentrated. The residue was purified by silica gel chromatography (column height: 50 mm, diameter: 50 mm, 300-400mesh silica gel, DCM/MeOH=30/1→20/1) to give 3-bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl) pyridine (XXXIX): Yellow oil (8.00 g, 28.9 mmol, 89.5% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 2.30 (spt, J=7.2 Hz. 2H), 2.75 (t, J=6.8 Hz, 2H), 2.91 (t, J=13.2 Hz, 2H), 7.85 (s, 1H), 8.45 (s, 1H), 8.59 (d, J=2 Hz, 1H); ESIMS found for C 10 H 11 BrF 2 N 2  m/z 277.0 (M+H). 
     The following intermediates were prepared in accordance with the procedure described in the above Schemes 5-7. 
     
       
         
         
             
             
         
       
     
     3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XL): Golden liquid (1.35 g, 97% yield).  1 H NMR (DMSO-d 6 ) δ ppm 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H); ESIMS found for C 10 H 13 BrN 2  m/z 242.2 (M+H). 
     
       
         
         
             
             
         
       
     
     3-Bromo-5-(piperidin-1-ylmethyl)pyridine (XLI): Brown liquid (13.1 g, 94% yield).  1 H NMR (DMSO-d 6 ) δ ppm 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H), 2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H); ESIMS found for C 11 H 15 BrN 2  m/z 257.0 (M+H). 
     
       
         
         
             
             
         
       
     
     N-((5-Bromopyridin-3-yl)methyl)ethanamine (XLII): Golden liquid (1.29 g, 6.00 mmol, 60% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 1.14 (t, J=7.2 Hz, 3H), 2.67 (q, J=7.2 Hz, 2H), 3.79 (s, 2H), 7.85 (t, J=2 Hz, 1H), 8.46 (d, J=1.6 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H); ESIMS found for C 8 H 11 BrN 2  m/z 215.1 (M+H). 
     
       
         
         
             
             
         
       
     
     N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (XLIII): Yellow oil (8.0 g, 28.9 mmol, 89.5% yield).  1 H NMR (DMSO-d 6 , 400 MHz) δ ppm 3.71 (s, 2H), 3.74 (s, 2H), 7.18-7.28 (m, 1H), 7.28-7.40 (m, 4H), 8.04 (s, 1H), 8.52 (s, 1H), 8.58 (s, 1H); ESIMS found for C 13 H 13 BrN 2  m/z 277.1 (M+H). 
     Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (XLVIII) is depicted below in Scheme 8. 
                         
Step 1
 
     To a solution of 5-bromonicotinaldehyde (XXXVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH 4  (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL×3). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (XLIV) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil.  1 H NMR (CDCl 3 , 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C 6 H 6 BrNO m/z 188.0 (M+H). 
     Step 2 
     To a stirred solution of (5-bromopyridin-3-yl)methanol (XLIV) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh 3  (3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0° C. under N 2 . Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO 3  solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO 4 , concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc=4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (XLV) (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C 1-4 H 9 BrN 2 O 2  m/z 317.1 (M+H). 
     Step 3 
     A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (XLV) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL×3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (XLVI) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid.  1 H NMR (D 2 O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found for C 6 H 7 BrN 2  m/z 187.0 (M+H). 
     Step 4 
     A solution of (5-bromopyridin-3-yl)methanamine (XLVI) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH 3 CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO 4  and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil.  1 H NMR (CDCl 3 , 400 MHz) δ ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C 12 H 17 BrN 2  m/z 269.1 (M+H). 
     Step 5 
     To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVII) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5 eq) in DCM (20 mL) was added portion wise Boc 2 O (0.85 g, 4.0 mmol, 1.1 eq) at 0° C., the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with water (10 mL), brine (10 mL), the organic layer was separated, dried over MgSO 4  and concentrated in vacuo to give tert-butyl (5-bromopyridin-3-yl)methyl(cyclopentylmethyl) carbamate (XLVIII) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found for C 17 H 25 BrN 2 O 2  m/z 369.1 (M+H). 
     Preparation of intermediate 3-bromo-5-(cyclohexyloxy)pyridine (LI) is depicted below in Scheme 9. 
                         
Step 1
 
     To a solution of 5-bromopyridin-3-ol (XLIX) (523 mg, 3.01 mmol) in THF (30 mL) cooled to 0° C. were added triphenylphosphine (867 mg, 3.31 mmol) and cyclohexanol (L) (331 mg, 3.31 mmol) followed by (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (1.21 g, 3.31 mmol), added portion wise. The reaction mixture was then stirred at 25° C. overnight. The reaction was worked-up with an EtOAc-NaHCO 3  extraction and the solid filtered off. The solvent was removed and the residue was purified by ISCO (20% EtOAc-hexanes) to give 3-bromo-5-(cyclohexyloxy)pyridine (LI) (209 mg, 0.82 mmol, 27.2% yield) as a yellow oil.  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.21-1.31 (m, 1H) 1.34-1.48 (m, 4H) 1.49-1.57 (m, 1H) 1.70 (br dd, J=9.74, 4.25 Hz, 2H) 1.88-1.96 (m, 2H) 2.50 (dt, J=3.70, 1.72 Hz, 5H) 4.46-4.54 (m, 1H) 7.72 (t, J=2.20 Hz, 1H) 8.24 (d, J=1.92 Hz, 1H) 8.27 (d, J=2.47 Hz, 1H). 
     The following intermediate was prepared in accordance with the procedure described in the above Scheme 9. 
     
       
         
         
             
             
         
       
     
     tert-Butyl 4-((5-bromopyridin-3-yl)oxy)piperidine-1-carboxylate (LII): Yellow oil (244 mg, 0.683 mmol, 23.2% yield). ESIMS found for C 15 H 21 BrN 2 O 3  m/z 358.3 (M+H). 
     Preparation of intermediate 3-(benzyloxy)-5-bromopyridine (LIV) is depicted below in Scheme 10. 
                         
Step 1
 
     To a solution of 5-bromopyridin-3-ol (XLIX) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 h and then cooled to 25° C. The (bromomethyl)benzene (LIII) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100% EtOAc-hexanes). The 3-(benzyloxy)-5-bromopyridine (LIV) (105 mg, 0.398 mmol, 39.8% yield) was obtained as yellow oil. ESIMS found for C 12 H 10 BrNO m/z 266.1 (M+H). 
     The following intermediates were prepared in accordance with the procedure described in the above Scheme 10. 
     
       
         
         
             
             
         
       
     
     3-Bomo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine (LV): Yellow oil (97 mg, 0.358 mmol, 15.56% yield). ESIMS found for C 11 H 15 BrN 2 O m/z 272.2 (M+H). 
     
       
         
         
             
             
         
       
     
     2-((5-bromopyridin-3-yl)oxy)-N,N-dimethylethan-1-amine (LVI): Yellow oil (97 mg, 0.396 mmol, 28.9% yield). ESIMS found for C 9 H 13 BrN 2 O m/z 245.1 (M+H). 
     
       
         
         
             
             
         
       
     
     1-(2-(3-bromo-5-fluorophenoxy)ethyl)pyrrolidine (LVII): Yellow oil (370 mg, 1.284 mmol, 85.8% yield). ESIMS found for C 12 H 15 BrFNO m/z 289.0 (M+H). 
     
       
         
         
             
             
         
       
     
     2-(3-bromo-5-fluorophenoxy)-N,N-dimethylethan-1-amine (LVIII): Yellow oil (364 mg, 1.389 mmol, 50.2% yield). ESIMS found for C 10 H 13 BrFNO m/z 263.9 (M+H). 
     Preparation of intermediate tert-butyl 4-(2-((5-bromopyridin-3-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (LX) is depicted below in Scheme 11. 
                         
Step 1
 
     To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (LIX) (3.4 g, 13.97 mmol) in DCM (10 mL) was added DMF (1 mL). The solution was cooled in ice-water to 0° C. Oxalyl chloride (1.835 mL, 20.96 mmol) was then added dropwise. The mixture was stirred for 1 h at 25° C. The organic volatile was then removed under vacuum. The residue was dissolved in DCM (10 mL). DMAP (0.171 g, 1.397 mmol) and 5-bromopyridin-3-amine (XVIII) (2.418 g, 13.97 mmol) were added to the solution and cooled to 0° C. DIEA (4.88 ml, 27.9 mmol) was then added dropwise and the mixture was stirred for 2 hours at 25° C. The reaction was worked-up with DCM and saturated NaHCO 3 . The product was purified by ISCO (0-100% EtOAc-hexanes). The tert-butyl 4-(2-((5-bromopyridin-3-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (LX) (2.82 g, 7.08 mmol, 50.7% yield) was obtained as a yellow oil. ESIMS found for C 17 H 24 BrN 3 O 3  m/z 343.1 (M−56). 
     The following intermediate was prepared in accordance with the procedure described in the above Scheme 11. 
     
       
         
         
             
             
         
       
     
     N-(5-Bromopyridin-3-yl)-2-(dimethylamino)acetamide (LXI): Yellow oil (528 mg, 2.05 mmol, 19.0% yield). ESIMS found for C 9 H 12 BrN 3 O m/z 259.3 (M+H). 
     Preparation of tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXIV) is depicted below in Scheme 12. 
                         
Step 1
 
     To a solution of tert-butyl azetidin-3-ylcarbamate hydrochloride (LXII) (2 g, 9.58 mmol) in dry DMF (19.2 mL) was added DIPEA (8.37 ml, 47.9 mmol). To this mixture was added 2,6-dichloropyrazine (LXIII) (1.428 g, 9.58 mmol) and the reaction was stirred at 95° C. for 3 h. The reaction was quenched with water (20 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (40 g) (100% hexanes-*hexanes:EtOAc 1:1) to yield tert-butyl (1-(6-chloropyrazin-2-yl)azetidin-3-yl)carbamate (LXIV) (2.2882 g, 8.04 mmol, 84% yield) as a white solid. ESIMS found for C 12 H 17 ClN 4 O 2  m/z 285.1 (M+H). 
     Preparation of intermediate (3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid (LXVII) is depicted below in Scheme 13. 
                         
Step 1
 
     To a solution of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (LXV) (1.0 g, 5.23 mmol, 1.o eq) and DMAP (64.0 mg, 0.524 mmol, 0.1 eq) in DCM (20 mL) was added tert-butylchlorodimethylsilane (789.0 mg, 5.23 mmol, 1 eq), and imidazole (712.8 mg, 10.47 mmol, 2.0 eq) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction was filtered to remove a white precipitate and the filtrate was concentrated and purified on a silica gel column (EtOAc/hexanes) to produce 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole (LXVI) (1.11 g, 3.64 mmol, 69.6% yield) as a white solid. ESIMS found for C 11 H 21 BrN 2 OSi m/z 305.1 (M+H). 
     Step 2 
     To a solution of nBuLi (256.2 mg, 4.0 mmol) and triisopropyl borate (1.01 mL, 4.36 mmol) dissolved in BuOH (0.5 mL) was added 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole (LXVI) (1.11 g, 3.64 mmol). The mixture was heated at 120° C. for 3 h before the solvent was removed under high vacuum. The residue was purified on a silica gel column (DCM: 0-10% MeOH) to give (3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid (LXVII) (813 mg, 3.01 mmol, 82.8% yield) as a white solid. ESIMS found for C 11 H 23 BN 2 O 3 Si m/z 271.1 (M+H). 
     Preparation of intermediate 4-(2-fluorophenyl)-3-nitropyridin-2-amine (LXXI) is depicted below in Scheme 14. 
                         
Step 1
 
     A solution of 4-bromo-3-nitropyridin-2-amine (LXVIII) (5.00 g, 22.9 mmol, 1.00 eq), (2-fluorophenyl)boronic acid (LXIX) (3.82 g, 27.5 mmol, 1.20 eq), Pd(PPh 3 ) 4  (1.32 g, 1.14 mmol, 0.05 eq), and Na 2 CO 3  (4.85 g, 45.8 mmol, 2 eq) in a mixture of toluene (25 mL), H 2 O (9 mL) and EtOH (6 mL) was stirred at 75° C. for 15 h under nitrogen atmosphere. The reaction mixture was the washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=3:1) to give 4-(2-fluorophenyl)-3-nitropyridin-2-amine (LXX) (4.0 g, 17.15 mmol, 74.9%) as a yellow solid.  1 H NMR (CDCl 3 , 400 MHz) δ ppm 6.29 (brs, 2H), 6.68 (d, J=4.8 Hz, 1H), 7.14 (t, J=5.2 Hz, 1H), 7.23-7.50 (m, 3H), 8.32 (d, J=4.8 Hz, 1H); ESIMS found C 11 H 8 FN 3 O 2  m/z 234.2 (M+H). 
     Step 2 
     A mixture of 4-(2-fluorophenyl)-3-nitropyridin-2-amine (LXX) (2.8 g, 12.0 mmol, 1 eq) and Pd/C (0.2 g) in MeOH (200 mL) was stirred under 50 psi of H 2  at room temperature overnight. The reaction was monitored by TLC. The mixture was filtered and the filtrate was concentrated in vacuo to produce 4-(2-fluorophenyl)pyridine-2,3-diamine (LXXI) (1.55 g, 7.63 mmol, 63.6% yield) as a black solid.  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.38 (brs, 2H), 4.40 (brs, 2H), 6.64 (d, J=4.8 Hz, 1H), 7.11-7.53 (m, 4H), 7.72 (d, J=4.8 Hz, 1H); ESIMS found C 11 H 10 FN 3  m/z 204.2 (M+H). 
     The following intermediates were prepared in accordance with the procedure described in the above Scheme 14. 
     
       
         
         
             
             
         
       
     
     4-(3-Fluorophenyl)pyridine-2,3-diamine (LXXII): Grey solid, (1.55 g, 7.63 mmol, 86.0% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.50 (brs, 2H), 4.36 (brs, 2H), 6.63 (d, J=3.6 Hz, 1H), 7.3-7.37 (m, 3H), 7.47 (d, J=6 Hz, 1H), 7.72 (d, J=3.6 Hz, 1H); ESIMS found C 11 H 10 FN 3  m/z 204.2 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(4-Fluorophenyl)pyridine-2,3-diamine (LXXIII): Grey solid, (1.55 g, 7.63 mmol, 60.0% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.46 (brs, 2H), 4.36 (brs, 2H), 6.62 (s, 1H), 7.19 (s, 2H), 7.43 (s, 2H), 7.70 (d, J=3.2 Hz, 1H); ESIMS found C 11 H 10 FN 3  m/z 204.1 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(4-Fluorophenyl)pyridine-2,3-diamine (LXXIV): Grey solid, (1.55 g, 7.63 mmol, 60.0% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.46 (brs, 2H), 4.36 (brs, 2H), 6.62 (s, 1H), 7.19 (s, 2H), 7.43 (s, 2H), 7.70 (d, J=3.2 Hz, 1H); ESIMS found C 11 H 10 FN 3  m/z 204.1 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(Thiophen-3-yl)pyridine-2,3-diamine (LXXV): Yellow solid, (1.9 g, 9.94 mmol, 84.9% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.80 (brs, 2H), 4.34 (brs, 2H), 6.77 (s, 1H), 7.18 (s, 1H), 7.27 (s, 2H), 7.44 (s, 1H), 7.68 (s, 1H); ESIMS found C 9 H 9 N 3 S m/z 192.2 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(Furan-3-yl)pyridine-2,3-diamine (LXXVI): Black solid, (1.9 g, 10.84 mmol, 89.0% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.64 (brs, 2H), 4.32 (brs, 2H), 6.65 (s, 1H), 6.69 (d, J=4.8 Hz, 1H), 7.58 (s, 1H), 7.67 (d, J=4.8 Hz, 1H), 7.71 (s, 1H); ESIMS found C 9 H 9 N 3 O m/z 176.3 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(Thiophen-2-yl)pyridine-2,3-diamine (LXXVII): Yellow solid, (0.90 g, 4.71 mmol, 96.5% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 3.63 (brs, 2H), 4.35 (brs, 2H), 6.71 (s, 1H), 7.27 (s, 1H), 7.45 (s, 1H), 7.49 (s, 1H), 7.69 (s, 1H); ESIMS found C 9 H 9 N 3 S m/z 192.1 (M+H). 
     
       
         
         
             
             
         
       
     
     3-(2,3-Diaminopyridin-4-yl)-5-fluorophenol (LXXVIII): White solid (303 mg, 1.38 mmol, 84.4% yield). ESIMS found for C 11 H 10 FN 3 O m/z 220.1 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(3-Fluoro-5-methoxyphenyl)pyridine-2,3-diamine (LXXIX): White solid (404 mg, 1.73 mmol, 75.1% yield). ESIMS found for C 12 H 12 FN 3 O m/z 234.1 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(3-Fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridine-2,3-diamine (LXXX): Black oil (368 mg, 1.163 mmol, 95.0% yield). ESIMS found for C 17 H 21 FN 4 O m/z 317.1 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(3-(2-(Dimethylamino)ethoxy)-5-fluorophenyl)pyridine-2,3-diamine (LXXXI): Black oil (352 mg, 1.212 mmol, 83.6% yield). ESIMS found for C 15 H 19 FN 4 O m/z 291.1 (M+H). 
     Preparation of intermediate 3-nitro-[4,4′-bipyridin]-2-amine (LXXXV) is depicted below in Scheme 15. 
                         
Step 1
 
     To a solution of 4-chloro-3-nitropyridin-2-amine (LXXXII) (5.00 g, 28.9 mmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXXXIII) (7.1 g, 34.6 mmol, 1.20 eq) in a mixture of toluene (30 mL), H 2 O (18 mL) and EtOH (6 mL) was added Pd(PPh 3 ) 4  (1.0 g, 0.87 mmol, 0.03 eq) and Na 2 CO 3  (6.1 g, 57.6 mmol, 2 eq). The mixture was stirred at 75° C. for 15 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (100 mL) and extracted with EtOAc (30 mL×3), the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1→1:1) to afford 3-nitro-[4,4′-bipyridin]-2-amine (LXXXIV) (1.80 g, 8.33 mmol, 28.8% yield) as a yellow solid. ESIMS found C 10 H 8 N 4 O 2  m/z 217.1 (M+H). 
     Step 2 
     To a solution of 3-nitro-[4,4′-bipyridin]-2-amine (LXXXIV) (1.80 g, 8.33 mol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g) under a nitrogen atmosphere. The mixture was stirred under 50 psi of H 2  for 6 h at room temperature. Then the mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to afford [4,4′-bipyridine]-2,3-diamine (LXXXV) (1.4 g, 7.52 mmol, 90.4% yield) as a black solid. ESIMS found C 10 H 10 N 4  m/z 186.0 (M+H). 
     Preparation of intermediate 3-nitro-[4,4′-bipyridin]-2-amine (LXXXVIII) is depicted below in Scheme 16. 
                         
Step 1
 
     A solution of 4-chloro-3-nitropyridin-2-amine (LXXXII) (5.00 g, 28.9 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (LXXXVI) (15.9 g, 43.4 mmol, 1.50 eq), and Pd(PPh 3 ) 2 Cl 2  (1.05 g, 1.44 mmol, 0.05 eq) in a mixture of toluene (25 mL) and H 2 O (9 mL) was stirred at 75° C. for 16 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (80 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1→1:1) to afford 3′-nitro-[2,4′-bipyridin]-2′-amine (LXXXVII) (1.6 g, 7.40 mmol, 25.6% yield) as a yellow solid. ESIMS found C 10 H 8 N 4 O 2  m/z 217.1 (M+H). 
     Step 2 
     To a solution of compound 3′-nitro-[2,4′-bipyridin]-2′-amine (LXXXVII) (1.6 g, 7.4 mmol, 1.0 eq) in MeOH (50 mL) was added Pd/C (0.5 g) under a nitrogen atmosphere. The mixture was stirred under 50 psi of H 2  for 6 h at room temperature. The mixture was then filtered and concentrated in vacuo to afford [2,4′-bipyridine]-2′,3′-diamine (LXXXVIII) (1.1 g, 5.91 mmol, 79.8%) as a black solid. ESIMS found C 10 H 10 N 4  m/z 186.1 (M+H). 
     Preparation of intermediate 4-(4-methylpiperazin-1-yl)pyridine-2,3-diamine (XCI) is depicted below in Scheme 17. 
                         
Step 1
 
     A solution of 4-bromo-3-nitropyridin-2-amine (LXXXIX) (2.50 g, 11.47 mmol) in 1-methylpiperazine (4 mL, 34.5 mmol) was heated at 140° C. overnight. The reaction was poured into an EtOAc/H 2 O mixture; the organic layer was separated, dried over MgSO 4  and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl 3 →3:97 MeOH(7N NH 3 ):CHCl 3 ) to give 4-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (XC) as a yellow solid (1.80 g, 7.59 mmol, 66.1% yield).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 2.36 (s, 3H), 2.54 (t, J=4.8 Hz, 4H), 3.25 (t, J=5 Hz, 4H), 6.18 (s, 2H), 6.22 (d, J=6 Hz, 1H), 7.85 (d, J=6 Hz, 1H); ESIMS found C 10 H 15 N 5 O 2  m/z 238.0 (M+H). 
     Step 2 
     To a solution of 4-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (XC) (1.80 g, 7.59 mmol) in MeOH (52 mL) was added 10% Pd/C (0.5 g). The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 4-(4-methylpiperazin-1-yl) pyridine-2,3-diamine (XCI) as black solid (1.4 g, 6.75 mmol, 89.0% yield).  1 H NMR (CDCl 3 , 400 MHz): δ ppm 2.38 (s, 3H), 2.60 (brs, 4H), 2.99 (s, 4H), 3.49 (brs, 2H), 4.12 (brs, 2H), 6.52 (d, J=5.6 Hz, 1H), 7.64 (d, J=5.6 Hz, 1H); ESIMS found C 10 H 17 N 5  m/z 208.1 (M+H). 
     The following intermediate was prepared in accordance with the procedure described in the above Scheme 17. 
     
       
         
         
             
             
         
       
     
     4-(Piperidin-1-yl)pyridine-2,3-diamine (XCII): Black solid, (2.40 g, 12.48 mmol, 92.5% yield).  1 H NMR (CDCl 3 , 400 MHz): δ ppm 1.61 (brs, 2H), 1.73 (s, 4H), 2.88 (s, 4H), 3.48 (brs, 2H), 4.13 (brs, 2H), 6.50 (d, J=5.2 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H); ESIMS found C 10 H 6 N 4  m/z 193.1 (M+H). 
     Preparation of intermediate 4-(2-fluorophenyl)-3-nitropyridin-2-amine (XCV) is depicted below in Scheme 18. 
                         
Step 1
 
     4-Chloro-3-nitro-pyridin-2-amine (LXXXII) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (XCIII) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130° C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH 4 Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCIV) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid.  1 H NMR (CDCl 3 , 400 MHz) δ ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C 9 H 9 N 5 O 2  m/z 219.1 (M+H). 
     Step 2 
     To a solution of 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCIV) (900.0 mg, 4.11 mmol, 1.0 eq) in MeOH (50 mL) was added Pd/C (100.0 mg, 4.11 mmol, 1.0 eq) at room temperature. The mixture was stirred at 20° C. under H 2  for 2 h. TLC (DCM:MeOH=20:1) showed that starting the material was consumed completely. The mixture was filtered and concentrated to afford 4-(4-methyl-1H-imidazol-1-yl)pyridine-2,3-diamine (XCV) (750.0 mg, 3.96 mmol, 96.4% yield) as a brown solid.  1 H NMR (CDCl 3 , 400 MHz) δ ppm 2.17 (s, 3H), 4.58 (brs, 2H), 5.85 (brs, 2H), 6.36 (d, J=5.4 Hz, 1H), 7.06 (s, 1H), 7.34 (s, 1H), 7.34 (s, 1H), 7.69 (d, J=0.88 Hz, 1H); ESIMS found C 9 H 11 N 5  m/z 190.1 (M+H). 
     Preparation of intermediate 4-(5-fluorothiophen-2-yl)pyridine-2,3-diamine (XCVIII) is depicted below in Scheme 19. 
                         
Step 1
 
     A solution of 2-chloro-3-nitro-pyridin-4-amine (LXXXII) (1.5 g, 8.64 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XCVI) (2.96 g, 12.96 mmol), Pd(dppf)Cl 2  (632 mg, 0.86 mmol) and Cs 2 CO 3  (5.63 g, 17.29 mmol) in dioxane (30 mL) and H 2 O (5 mL) was de-gassed and then heated to 100° C. under N 2  for 3 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography to afford 4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine (XCVII) (800 mg, 3.34 mmol, 38.7% yield). ESIMS found C 9 H 6 FN 3 O 2 S m/z 240.1 (M+H). 
     Step 2 
     A solution of 4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine (XCVII) (700 mg, 2.93 mmol), Fe (817 mg, 14.63 mmol) and NH 4 Cl (939 mg, 17.56 mmol) in EtOH (18 mL) and H 2 O (6 mL) was heated to 80° C. for 2 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was filtered, washed with HCl/EtOH, concentrated, basified to pH=7-8, extracted with EtOAc and H 2 O, the organic layer was concentrated to give 4-(5-fluorothiophen-2-yl)pyridine-2,3-diamine (XCVIII) (550 mg, 2.63 mmol, 89.7% yield). ESIMS found C 9 H 8 FN 3 S m/z 210.0 (M+H). 
     The following intermediates were prepared in accordance with the procedure described in the above Scheme 19. 
     
       
         
         
             
             
         
       
     
     4-(5-Methylthiophen-2-yl)pyridine-2,3-diamine (XCIX): Brown solid, (1.20 g, 5.85 mmol, 86.0% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 2.54 (s, 3H), 6.63 (d, J=4.8 Hz, 1H), 6.85 (s, 1H), 7.12 (s, 1H), 7.38 (d, J=5.2 Hz, 1H); ESIMS found C 10 H 11 N 3 S m/z 206.2 (M+H). 
     
       
         
         
             
             
         
       
     
     1-(5-(2,3-Diaminopyridin-4-yl)thiophen-2-yl)ethan-1-one (C): Brown solid, (500 mg, 2.14 mmol, 56.4% yield).  1 H NMR (DMSO-d 6 , 400 MHz) δ ppm 2.55 (s, 3H), 4.89 (brs, 2H), 5.80 (brs, 2H), 6.52 (d, J=5.2 Hz, 1H), 7.33 (d, J=5.2 Hz, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.96 (d, J=4.0 Hz, 1H); ESIMS found C 11 H 11 N 3 OS m/z 234 (M+H). 
     Preparation of intermediate 5-(3-methoxyphenyl)pyridine-3,4-diamine (CIV) is depicted below in Scheme 20. 
                         
Step 1
 
     A solution of 4-bromo-3-nitropyridin-2-amine (CI) (2 g, 9.17 mmol) and (3-methoxyphenyl)boronic acid (CII) (1.394 g, 9.17 mmol) in 1,4-dioxane (20 mL) was added sodium carbonate (2.92 g, 27.5 mmol) in water (2 mL). The slurry was purged with argon for 1 minute before adding Pd(Ph 3 P) 4  (0.530 g, 0.459 mmol). The reaction was heated at 90° C. for 4 h. The reaction was extracted with a mixture of saturated NaHCO 3 -EtOAc. The product was purified by ISCO (0-50% EtOAc-hexanes) to yield 4-(3-methoxyphenyl)-3-nitropyridin-2-amine (CIII) as an orange oil (2.06 g, 8.40 mmol, 92.6% yield). ESIMS found for C 12 H 11 N 3 O 3  m/z 246.1 (M+H). 
     Step 2 
     To a solution of 4-(3-methoxyphenyl)-3-nitropyridin-2-amine (CIII) (2.3 g, 9.38 mmol) in EtOH (100 mL) was added Na 2 S (3 g, 38.4 mmol). The slurry was heated under reflux for 2 h at 90° C. The mixture was solid loaded onto a ISCO column for purification (10% MeOH—CHCl 3 ) to afford the 4-(3-methoxyphenyl)pyridine-2,3-diamine (CIV) as a black oil (1.18 g, 5.48 mmol, 58.5% yield). ESIMS found for C 12 H 13 N 3 O m/z 216.1 (M+H). 
     The following intermediate was prepared in accordance with the procedure described in the above Scheme 19. 
     
       
         
         
             
             
         
       
     
     4-(5-Chlorothiophen-2-yl)-3-nitropyridin-2-amine (CV): Yellow solid (1.42 g, 67.29 mmol, 64.3% yield). ESIMS found for C 9 H 8 ClN 3 S m/z 226.0 (M+H). 
     
       
         
         
             
             
         
       
     
     4-(Benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (CVI): Reddish-brown solid (615.5 mg, 2.69 mmol, 51.2% yield).  1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 4.32 (s, 2H), 5.49 (s, 2H), 6.05 (s, 2H), 6.29 (d, J=4.94 Hz, 1H), 6.87 (dd, J=7.96, 1.65 Hz, 1H), 6.94 (d, J=1.65 Hz, 1H), 7.00 (d, J=7.96 Hz, 1H), 7.32 (d, J=4.94 Hz, 1H); ESIMS found for C 12 H 11 N 3 O 2  m/z 230.1 (M+H). 
     Preparation of intermediate 4-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)pyridine-2,3-diamine (CXI) is depicted below in Scheme 20. 
                         
Step 1
 
     A solution of 3-bromo-5-fluorobenzaldehyde (CVII) (20.0 g, 98.2 mmol, 1.0 eq) in MeOH (1.8 L) was added N 1 ,N 1 -dimethylethane-1,2-diamine (21.5 mL, 196.4 mmol, 2.0 eq). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH 3  (8.6 g, 137.5 mmol, 1.4 eq) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl 3  and saturated aqueous NaHCO 3 . The organic layer was dried over MgSO 4  and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl 3 →3:97 MeOH[7N NH 3 ]:CHCl 3 ) to produce N 1 -(3-bromo-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CVIII) as a yellow oil (13.0 g, 49.9 mmol, 51% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.28 (s, 6H), 2.39 (t, J=4 Hz, 2H), 3.07 (q, J=6 Hz, 2H), 6.10 (t, J=5 Hz, 1H), 6.38 (td, J=12 Hz, J=2 Hz, 1H), 6.51 (td, J=8.6 Hz, J=2 Hz, 1H), 6.61 (t, J=2 Hz, 1H); ESIMS found C 10 H 14 BrFN 2  m/z 261.0 (M+H). 
     Step 2 
     A solution of N 1 -(3-bromo-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CVIII) (13.0 g, 49.9 mmol, 1.0 eq), bis(pinacolato)diboron (12.6 g, 59.9 mmol, 1.2 eq), KOAc (12.1 g, 124.3 mmol, 2.5 eq) and dioxane (600 mL) was purged with argon. Pd(dppf)Cl 2  (2.0 g, 2.47 mmol, 0.05 eq) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CVIII), the solution was cooled to room temperature and then concentrated under reduced pressure to produce crude N 1 -(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CIX) (7.4 g, 24.0 mmol, 48.2% yield). 
     Step 3 
     To a solution of N 1 -(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CIX) (5.0 g, 16.22 mmol, 1.2 eq) in water (25 mL) was added K 2 CO 3  (448 mg, 3.24 mmol, 2.0 eq), 4-bromo-3-nitropyridin-2-amine (LXVIII) (3.5 g, 16.22 mmol, 1.0 eq) and Pd(dppf)Cl 2  (1.0 g, 81.0 μmol, 0.05 eq). The solution was purged with argon and heated at 100° C. for 48 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified on a silica gel column (100% CHCl 3 →2:98 MeOH[7N NH 3 ]:CHCl 3 ) to give N 1 -(3-(3-amino-2-nitropyridin-4-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CX) as a yellow amorphous solid (4.5 g, 14.1 mmol, 86.9% yield). ESIMS found for C 15 H 15 FN 5 O 2  m/z 220.1 (M+H). 
     Step 4 
     To a solution of N 1 -(3-(3-amino-2-nitropyridin-4-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine (CX) (4.50 g, 10.43 mmol, 1.0 eq) in MeOH (15 mL) was added 10% Pd/C (540 mg, 15% by wt). The solution was purged with hydrogen and stirred for 48 h at room temperature under hydrogen (15 psi). The suspension was filtered through Celite® and concentrated under vacuum and purified by silica gel chromatography (MeOH:DCM=10:1) to produce 4-(3-((2-(dimethylamino)ethyl) amino)-5-fluorophenyl) pyridine-2,3-diamine (CXI) as a tan solid (750.0 mg, 2.59 mmol, 24.9% yield).  1 H NMR (CD 3 OD, 400 MHz) δ ppm 2.32 (s, 6H), 2.60 (t, J=6.8 Hz, 2H), 3.26 (t, J=6.8 Hz, 2H), 6.34-6.43 (m, 2H), 6.47 (d, J=5.6 Hz, 1H), 7.58 (s, 1H), 7.75 (s, 1H); ESIMS found C 15 H 20 FN 5  m/z 290.1 (M+H). 
     Preparation of intermediate N-(3-(2,3-diaminopyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CXVII) is depicted below in Scheme 21. 
                         
Step 1
 
     A solution of 3-bromo-5-fluorobenzonitrile (CXII) (44.0 g, 220.0 mmol, 1.0 eq) was dissolved in THF (30 mL). BH 3 -Me 2 S (33.43 g, 440.0 mmol, 2.0 eq) was added to the solution at 20° C. Then it was stirred at 80° C. for 2 h, HCl (6 N, 100 mL) was added to the mixture slowly at 20° C. The mixture was stirred at 80° C. for 1 h, then it was washed with EtOAc (300 mL). The water phase was basified with 50% aqueous NaOH and it was extracted with EtOAc (300 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated in vacuo to produce (3-bromo-5-fluoro-phenyl)methanamine (CXIII) (24.0 g, 117.62 mmol, 53.5% yield).  1 H NMR (CDCl 3 , 300 MHz) ppm 3.86 (s, 2H), 7.01 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.28 (s, 1H); ESIMS found C 7 H 7 BrFN m/z 203.9 (Br 79 M+H). 
     Step 2 
     A solution of (3-bromo-5-fluoro-phenyl)methanamine (CXIII) (23.0 g, 112.7 mmol, 1.0 eq) was dissolved in DCM (15 mL), TEA (34.22 g, 338.2 mmol, 3.0 eq) was added to the mixture. Then MsCl (13.44 g, 117.3 mmol, 1.04 eq) was added slowly to the solution at 0° C. It was stirred at 0-30° C. for 2 h. The reaction was washed with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4  and concentrated to give N-(3-bromo-5-fluorobenzyl)methanesulfonamide (CXIV) (34.0 g, 102.44 mmol, 90.9% yield, 85% purity) as an oil.  1 H NMR (CDCl 3 , 300 MHz) ppm 2.88 (s, 3H), 4.24 (d, J=4.5 Hz, 2H), 6.99 (d, J=9 Hz, 1H), 7.13 (dt, J=8.1 Hz, J=2 Hz, 1H), 7.25 (s, 1H); ESIMS found C 8 H 9 BrFNO 2 S m/z 282.0 (Br 79 M+H). 
     Step 3 
     A solution of N-(3-bromo-5-fluorobenzyl)methanesulfonamide (CXIV) (34.0 g, 102.4 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (52.02 g, 204.9 mmol, 2.0 eq), KOAc (20.11 g, 204.9 mmol, 2.0 eq) was dissolved in dioxane (20 mL). Then Pd(dppf)Cl 2  (7.60 g, 10.2 mmol, 0.1 eq) was added to the mixture. It was stirred at 90° C. for 2 h. Then the solvent was removed to get the residue which was purified by silica gel column (PE:EtOAc=10:1→100% EtOAc) to get N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CXV) (30.0 g, crude).  1 H NMR (CDCl 3 , 400 MHz) δ ppm 1.37 (s, 12H), 2.92 (s, 3H), 4.34 (d, J=6.3 Hz, 2H), 7.19 (dt, J=9.3 Hz, J=2.1 Hz, 1H), 7.44 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 7.54 (s, 1H); ESIMS found C 1-4 H 21 BFNO 4 S m/z 330.1 (M+H). 
     Step 4 
     A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)methanesulfonamide (CXV) (6.83 g, 20.75 mmol, 1.2 eq), 4-chloro-3-nitropyridin-2-amine (LXXXII) (3.0 g, 17.29 mmol, 1.0 eq), Na 2 CO 3  (6.41 g, 60.52 mmol) and Pd(dppf)Cl 2  (641.27 mg, 864.50 μmol) in dioxane (40 mL) and H 2 O (8 mL) was de-gassed and then heated to 80° C. overnight under N 2 . TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H 2 O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with brine (300 mL), dried over anhydrous NaSO 4 , concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CXVI) (2.2 g, 6.46 mmol, 37.4% yield) as brown solid. ESIMS found Cl 3 H 13 FN 4 O 4 S m/z 341.1 (M+H). 
     Step 5 
     A solution of N-[[3-(4-amino-3-nitro-2-pyridyl)-5-fluoro-phenyl]methyl]methanesulfonamide (CXVI) (2.2 g, 6.46 mmol, 1.0 eq), Fe (1.44 g, 25.84 mmol, 4.0 eq) and NH 4 Cl (2.8 g, 51.68 mmol, 8.0 eq) was dissolved in MeOH (30 mL). The mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature and concentrated in reduced pressure at 60° C. The combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to get crude N-(3-(3,4-diaminopyridin-2-yl)-5-fluorobenzyl) methanesulfonamide (CXVII) (1.60 g, 5.16 mmol, 79.8% yield) as brown solid.  1 H NMR (CD 3 OD, 400 MHz) δ ppm 2.96 (s, 3H), 3.37 (s, 2H), 6.53 (d, J=4 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.31 (s, 1H), 7.44 (d, J=4 Hz, 1H); ESIMS found Cl 3 H 15 FN 4 O 2 S m/z 311.1 (M+H). 
     Example 1 
     Preparation of 1-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (13) is depicted below in Scheme 22. 
                         
Steps 1-2
 
     To a solution of 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXXVIII) (1.238 g, 5.76 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.827 g, 7.20 mmol) and potassium acetate (1.413 g, 14.39 mmol) in 1,4-dioxane (10 mL) was purged with argon for 5 minutes before and after adding PdCl 2 (dppf) (0.351 g, 0.480 mmol). The reaction was heated overnight at 85° C. To this mixture was added 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde (XVII) (1.27 g, 4.80 mmol) followed by potassium phosphate (6.00 mL, 11.99 mmol) and Pd(PPh 3 ) 4  (0.277 g, 0.240 mmol). The mixture was heated again at 100° C. for about 2 h. The reaction was cooled down to room temperature and extracted into EtOAc, purified on a silica gel column (DCM/MeOH: 0-10%) to give 5-(5-((dimethylamino)methyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde (CXIX) as an off-white solid (1.122 g, 3.07 mmol, 64.0% yield). ESIMS found for C 20 H 23 N 5 O 2  m/z 366.2 (M+H). 
     Step 3 
     A mixture of 5-(5-((dimethylamino)methyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde (CXIX) (40 mg, 0.1095 mmol), 4-(3-fluorophenyl) pyridine-2,3-diamine (LXXII) (22.2 mg, 0.1095 mmol) and sulfur (4.1 mg, 0.1204 mmol) in n-BuOH (0.50 mL) was heated at 120° C. for 3 h. LC-MS showed complete disappearance of the aldehyde. 
     Step 4 
     To the above n-BuOH solution was added TFA (1.0 mL) was heated at 45° C. overnight. The TFA was evaporated by nitrogen flushing, the resulting residue was diluted with a 1:1 mixture of MeOH/DMSO, filtered and purified by prep-HPLC using 0.1% formic acid-acetonitrile/water. Pure fractions were speed vacuumed to obtain 1-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (13) (12.5 mg, 0.027 mmol, 24.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.37 (s, 6H), 3.81 (br s, 2H), 7.38 (td, J=8.37, 2.20 Hz, 1H), 7.66-7.75 (m, 2H), 8.20 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.45 (d, J=5.21 Hz, 1H), 8.48 (br d, J=7.96 Hz, 1H), 8.54 (br d, J=10.98 Hz, 1H), 8.58 (br s, 1H), 8.65 (d, J=1.92 Hz, 1H), 9.56 (s, 1H), 13.68 (br s, 1H), 14.17 (br s, 1H); ESIMS found for C 26 H 21 FN 8  m/z 465.2 (M+1). 
     The following compounds were prepared in accordance with the procedures described herein. See, for example, Schemes 1a and 1-22. 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)propionamide 1 
     Yellow solid (55.8 mg, 0.117 mmol, 88.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.11 (t, J=7.55 Hz, 3H), 2.41 (q, J=7.59 Hz, 2H), 7.34 (td, J=8.58, 2.33 Hz, 1H), 7.60-7.69 (m, 1H), 7.69-7.74 (m, 1H), 8.08 (d, J=9.06 Hz, 1H), 8.32 (d, J=9.06 Hz, 1H), 8.39-8.59 (m, 2H), 8.45 (d, J=4.94 Hz, 1H), 8.80 (s, 1H), 8.87 (d, J=2.20 Hz, 1H), 9.25 (s, 1H), 10.25 (s, 1H), 13.72 (br s, 1H), 13.99 (br s, 1H); ESIMS found for C 26 H 19 FN 8 O m/z 479.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)-3-methylbutanamide 2 
     Off-white solid (17.1 mg, 0.034 mmol, 33.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.96 (d, J=6.59 Hz, 6H), 2.12 (tt, J=13.52, 6.66 Hz, 1H), 2.27 (d, J=7.14 Hz, 2H), 7.33 (td, J=8.30, 2.61 Hz, 1H), 7.62-7.70 (m, 2H), 7.95 (br d, J=8.51 Hz, 1H), 8.26 (d, J=8.78 Hz, 1H), 8.40 (d, J=5.21 Hz, 1H), 8.42-8.46 (m, 1H), 8.46-8.54 (m, 1H), 8.76 (s, 1H), 8.88 (d, J=2.20 Hz, 1H), 9.24 (d, J=1.65 Hz, 1H), 10.26 (s, 1H); ESIMS found for C 28 H 23 FN 8 O m/z 507.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-N,N-dimethylpyridin-3-amine 7 
     Yellow solid (19.5 mg, 0.043 mmol, 42.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.03 (s, 6H), 7.36 (td, J=8.37, 2.20 Hz, 1H), 7.62-7.71 (m, 2H), 7.87 (br s, 1H), 8.17 (d, J=9.06 Hz, 1H), 8.23 (d, J=2.74 Hz, 1H), 8.26 (d, J=8.78 Hz, 1H), 8.35-8.52 (m, 2H), 8.44 (d, J=4.94 Hz, 1H), 8.87 (s, 1H), 13.78 (br s, 1H); ESIMS found for C 25 H 19 FN 8  m/z 451.1 (M+1). 
     
       
         
         
             
             
         
       
     
     1-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 13 
     White solid (12.5 mg, 0.027 mmol, 24.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.37 (s, 6H), 3.81 (br s, 2H), 7.38 (td, J=8.37, 2.20 Hz, 1H), 7.66-7.75 (m, 2H), 8.20 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.45 (d, J=5.21 Hz, 1H), 8.48 (br d, J=7.96 Hz, 1H), 8.54 (br d, J=10.98 Hz, 1H), 8.58 (br s, 1H), 8.65 (d, J=1.92 Hz, 1H), 9.56 (s, 1H), 13.68 (br s, 1H), 14.17 (br s, 1H); ESIMS found for C 26 H 21 FN 8  m/z 465.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine 18 
     Brown solid (10.0 mg, 0.025 mmol, 19.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.41 (td, J=8.44, 2.33 Hz, 1H), 7.64-7.71 (m, 1H), 7.73 (br s, 1H), 8.27-8.31 (m, 1H), 8.36 (br dd, J=5.49, 3.84 Hz, 1H), 8.31-8.35 (m, 1H), 8.39 (br d, J=3.84 Hz, 2H), 8.46 (d, J=5.21 Hz, 1H), 8.76-8.79 (m, 2H), 8.82 (br s, 1H), 13.80 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 23 H 14 FN 7  m/z 408.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 20 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.82-0.89 (m, 4H), 1.81-1.90 (m, 1H), 7.31-7.39 (m, 1H), 7.62-7.69 (m, 1H), 7.71 (br d, J=4.39 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.49 (br s, 2H), 8.46 (d, J=4.94 Hz, 1H), 8.81 (s, 1H), 8.86 (d, J=1.92 Hz, 1H), 9.25 (s, 1H), 10.58 (s, 1H), 13.67 (br s, 1H), 14.14 (s, 1H); ESIMS found for C 27 H 19 FN 8 O m/z 491.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 26 
     Brown solid (10.0 mg, 0.019 mmol, 16.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.21-2.33 (m, 2H), 2.78 (br s, 2H), 2.97 (br s, 2H), 3.83 (br s, 2H), 7.38 (td, J=8.44, 2.06 Hz, 1H), 7.65-7.74 (m, 2H), 8.22 (d, J=9.06 Hz, 1H), 8.31 (d, J=9.06 Hz, 1H), 8.43-8.59 (m, 2H), 8.46 (d, J=5.21 Hz, 1H), 8.56 (br s, 1H), 8.65 (d, J=1.37 Hz, 1H), 9.53 (br s, 1H), 13.68 (br s, 1H), 14.13 (s, 1H); ESIMS found for C 28 H 21 F 3 N 8  m/z 527.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)pivalamide 36 
     Off-white solid (14.5 mg, 0.029 mmol, 23.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.28 (s, 9H), 7.43 (t, J=8.92 Hz, 2H), 7.66 (d, J=4.94 Hz, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.43 (d, J=4.94 Hz, 1H), 8.76 (dd, J=8.78, 5.76 Hz, 2H), 8.85 (t, J=2.06 Hz, 1H), 8.96 (d, J=2.20 Hz, 1H), 9.30 (d, J=1.92 Hz, 1H), 9.62 (s, 1H), 13.65 (s, 1H), 14.11 (s, 1H); ESIMS found for C 28 H 23 FN 8 O m/z 507.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 42 
     Light brown solid (15.7 mg, 0.029 mmol, 21.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.72 (br s, 4H), 2.51-2.56 (m, 4H), 3.78 (s, 2H), 7.48 (br t, J=8.78 Hz, 2H), 7.65 (d, J=5.21 Hz, 1H), 8.20-8.25 (m, 1H), 8.26-8.32 (m, 1H), 8.43 (d, J=4.94 Hz, 1H), 8.56 (s, 1H), 8.64 (d, J=1.37 Hz, 1H), 8.73 (br dd, J=8.51, 5.49 Hz, 2H), 9.53 (d, J=1.37 Hz, 1H), 13.65 (br s, 1H), 14.11 (br s, 1H); ESIMS found for C 28 H 23 FN 8  m/z 491.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 49 
     White solid (2.2 mg, 0.004 mmol, 4.4% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.77-1.88 (m, 1H), 1.92-2.05 (m, 1H), 2.11-2.20 (m, 2H), 2.22-2.33 (m, 2H), 3.23-3.32 (m, 1H), 7.39-7.46 (m, 2H), 7.65 (br d, J=4.39 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.44 (d, J=5.21 Hz, 1H), 8.73 (br s, 2H), 8.87 (s, 2H), 9.27 (s, 1H), 10.16 (s, 1H), 13.64 (br s, 1H), 14.12 (s, 1H); ESIMS found for C 28 H 21 FN 8 O m/z 505.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine 55 
     Brown solid (4.9 mg, 0.012 mmol, 11.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.48 (br t, J=8.37 Hz, 2H), 7.65 (br d, J=3.57 Hz, 1H), 8.26-8.32 (m, 1H), 8.32-8.38 (m, 1H), 8.43 (br d, J=4.94 Hz, 1H), 8.74 (br s, 2H), 9.34 (s, 1H), 9.82 (s, 2H), 13.80 (br s, 1H); ESIMS found for C 22 H 13 FN 8  m/z 409.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-amine 59 
     Yellow solid (11.3 mg, 0.027 mmol, 26.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 5.45 (br s, 2H), 7.38-7.51 (m, 3H), 7.55-7.63 (m, 1H), 7.70 (br s, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.06 (br s, 1H), 8.21-8.35 (m, 2H), 8.41-8.50 (m, 1H), 8.68 (br s, 1H), 13.48 (br s, 1H), 14.09 (br s, 1H); ESIMS found for C 23 H 15 FN 8  m/z 423.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)isobutyramide 65 
     Yellow solid (18.1 mg, 0.037 mmol, 36.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.16 (d, J=6.59 Hz, 6H), 2.68 (dt, J=13.65, 6.76 Hz, 1H), 7.39 (br d, J=4.39 Hz, 1H), 7.41-7.49 (m, 2H), 7.53-7.61 (m, 1H), 7.88 (br d, J=8.78 Hz, 1H), 8.11-8.20 (m, 1H), 8.24 (d, J=8.78 Hz, 1H), 8.41 (d, J=4.94 Hz, 1H), 8.71 (s, 1H), 8.90 (d, J=1.92 Hz, 1H), 9.17 (s, 1H), 10.22 (s, 1H); ESIMS found for C 27 H 21 FN 8 O m/z 493.2 (M+1 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide 72 
     Light brown solid (28.7 mg, 0.055 mmol, 41.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.06 (s, 9H), 2.28 (s, 2H), 7.37-7.51 (m, 3H), 7.54-7.66 (m, 1H), 8.06 (br d, J=8.78 Hz, 1H), 8.27-8.35 (m, 2H), 8.45 (br d, J=4.67 Hz, 1H), 8.75 (br s, 1H), 8.85 (br s, 1H), 9.24 (br s, 1H), 10.19 (br s, 1H), 13.56 (br s, 1H), 14.11 (br s, 1H); ESIMS found for C 29 H 25 FN 8 O m/z 521.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopentanecarboxamide 78 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.55-1.63 (m, 2H), 1.64-1.73 (m, 2H), 1.73-1.82 (m, 2H), 1.86-1.95 (m, 2H), 2.86 (quin, J=7.96 Hz, 1H), 7.40-7.49 (m, 3H), 7.54-7.62 (m, 1H), 8.05 (d, J=8.78 Hz, 1H), 8.33 (br s, 1H), 8.30 (d, J=9.06 Hz, 1H), 8.47 (br s, 1H), 8.76 (br s, 1H), 8.88 (br s, 1H), 9.20 (br s, 1H), 10.26 (br s, 1H), 13.58 (br s, 1H), 14.04 (br s, 1H); ESIMS found for C 29 H 23 FN 8 O m/z 519.2 (M+1). 
     
       
         
         
             
             
         
       
     
     1-Cyclopentyl-N-((5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 81 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.16-1.25 (m, 2H), 1.43-1.60 (m, 4H), 1.69-1.78 (m, 2H), 2.00-2.11 (m, 1H), 2.64 (br d, J=6.59 Hz, 2H), 4.01 (s, 2H), 7.40-7.54 (m, 3H), 7.56-7.65 (m, 1H), 8.17 (d, J=8.78 Hz, 1H), 8.32 (br d, J=8.23 Hz, 2H), 8.46 (br d, J=1.10 Hz, 1H), 8.60 (br s, 1H), 8.69 (br s, 1H), 9.51 (br s, 1H), 12.91 (br s, 1H), 13.56 (br s, 1H); ESIMS found for C 30 H 27 FN 8  m/z 519.25 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 84 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.43-7.57 (m, 4H), 7.60-7.65 (m, 1H), 8.07 (br t, J=7.41 Hz, 1H), 8.25-8.34 (m, 2H), 8.46 (br d, J=3.57 Hz, 1H), 8.60 (br d, J=8.51 Hz, 1H), 8.73 (br d, J=3.02 Hz, 1H), 8.78 (br d, J=7.68 Hz, 1H), 13.60 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 23 H 14 FN 7  m/z 408.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(pyridin-3-yl)-3-(7-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridine 88 
     Beige solid (10.0 mg, 0.026 mmol, 20.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.79 (d, J=5.21 Hz, 1H), 7.81-7.87 (m, 2H), 8.25-8.30 (m, 1H), 8.33-8.39 (m, 1H), 8.52 (d, J=5.21 Hz, 1H), 8.78-8.85 (m, 2H), 8.98 (br d, J=7.96 Hz, 1H), 9.17 (br d, J=8.23 Hz, 1H), 9.68 (d, J=1.92 Hz, 1H), 9.74 (s, 1H), 14.22 (br s, 1H); ESIMS found for C 22 H 14 N 8  m/z 391.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)isobutyramide 93 
     Yellow solid (11.4 mg, 0.024 mmol, 23.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.16 (d, J=6.86 Hz, 6H), 2.70 (quin, J=6.86 Hz, 1H), 7.67 (dd, J=8.10, 4.80 Hz, 1H), 7.72-7.80 (m, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.49 (d, J=4.94 Hz, 1H), 8.72 (dd, J=4.80, 1.51 Hz, 1H), 8.83 (t, J=1.92 Hz, 1H), 8.97 (d, J=2.20 Hz, 1H), 9.04 (br s, 1H), 9.25 (s, 1H), 9.73 (br s, 1H), 10.29 (s, 1H), 13.72 (br s, 1H), 14.14 (s, 1H); ESIMS found for C 26 H 21 N 9 O m/z 476.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-isopropyl-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-amine 96 
     Brown solid (27.0 mg, 0.060 mmol, 41.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.23 (d, J=6.31 Hz, 6H), 3.75-3.85 (m, 1H), 7.67 (dd, J=7.82, 4.53 Hz, 1H), 7.75 (br d, J=3.84 Hz, 1H), 7.96 (br s, 1H), 8.09 (d, J=2.47 Hz, 1H), 8.12-8.19 (m, 1H), 8.27 (d, J=8.78 Hz, 1H), 8.48 (br d, J=4.94 Hz, 1H), 8.68-8.76 (m, 2H), 8.90 (br d, J=6.31 Hz, 1H), 9.97 (br s, 1H), 13.70 (br s, 1H), 14.09 (s, 1H); ESIMS found for C 25 H 21 N 9  m/z 448.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-Benzyl-1-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methanamine 108 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.78 (s, 2H), 3.91 (s, 2H), 7.18-7.25 (m, 1H), 7.30 (t, J=7.55 Hz, 2H), 7.38 (d, J=7.41 Hz, 2H), 7.63-7.69 (m, 1H), 7.75 (br d, J=4.39 Hz, 1H), 8.21 (d, J=8.78 Hz, 1H), 8.31 (d, J=9.06 Hz, 1H), 8.48 (br d, J=4.94 Hz, 1H), 8.62-8.71 (m, 3H), 9.00 (br d, J=7.14 Hz, 1H), 9.47 (s, 1H), 9.75 (br s, 1H), 13.69 (br s, 1H), 14.14 (br s, 1H); ESIMS found for C 30 H 23 N 9  m/z 510.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(4-methylpyridin-3-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 117 
     Yellow solid (14.2 mg, 0.035 mmol, 34.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.64 (s, 3H), 7.47 (br d, J=4.67 Hz, 1H), 7.73 (br d, J=4.94 Hz, 1H), 7.77 (br d, J=8.78 Hz, 1H), 8.28 (d, J=8.78 Hz, 1H), 8.45 (d, J=4.94 Hz, 1H), 8.50 (br s, 2H), 8.53 (br d, J=4.94 Hz, 1H), 8.76 (br d, J=5.49 Hz, 2H), 8.82 (s, 1H); ESIMS found for C 23 H 16 N 8  m/z 405.1 (M+1). 
     
       
         
         
             
             
         
       
     
     2-phenyl-N-(5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 122 
     Yellow solid (28.0 mg, 0.054 mmol, 47.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.76 (s, 2H), 7.21-7.28 (m, 1H), 7.29-7.40 (m, 4H), 7.90 (d, J=5.21 Hz, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.34 (d, J=8.78 Hz, 1H), 8.57 (d, J=5.21 Hz, 1H), 8.89-8.99 (m, 6H), 9.34 (d, J=1.65 Hz, 1H), 10.67 (s, 1H), 14.24 (br s, 1H); ESIMS found for C 30 H 21 N 9 O m/z 524.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)butyramide 129 
     White solid (4.2 mg, 0.009 mmol, 8.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.94 (t, J=7.27 Hz, 3H), 1.65 (sxt, J=7.35 Hz, 2H), 2.39 (t, J=7.27 Hz, 2H), 7.80 (br s, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.50 (d, J=5.21 Hz, 1H), 8.65 (br s, 2H), 8.79-8.83 (m, 2H), 8.84 (d, J=2.20 Hz, 1H), 8.88 (s, 1H), 9.29 (s, 1H), 10.30 (s, 1H), 13.80 (br s, 1H), 14.19 (br s, 1H); ESIMS found for C 26 H 21 N 9 O m/z 476.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(pyridin-4-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridine 130 
     Yellow solid (21.0 mg, 0.054 mmol, 28.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.75-7.86 (m, 1H), 8.26-8.30 (m, 1H), 8.32-8.36 (m, 1H), 8.37 (br d, J=4.67 Hz, 2H), 8.52 (d, J=4.94 Hz, 1H), 8.62 (br dd, J=4.39, 1.65 Hz, 2H), 8.79-8.82 (m, 2H), 8.82-8.87 (m, 2H), 13.81 (br s, 1H), 14.19 (br s, 1H); ESIMS found for C 22 H 14 N 8  m/z 391.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 135 
     Yellow solid (22.7 mg, 0.044 mmol, 43.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.15-1.25 (m, 1H), 1.25-1.37 (m, 2H), 1.44 (qd, J=12.26, 2.47 Hz, 2H), 1.67 (br d, J=11.80 Hz, 1H), 1.74-1.81 (m, 2H), 1.84-1.90 (m, 2H), 2.38-2.46 (m, 1H), 7.75-7.83 (m, 1H), 8.08 (d, J=8.78 Hz, 1H), 8.31 (d, J=9.06 Hz, 1H), 8.50 (d, J=4.94 Hz, 1H), 8.63 (br s, 2H), 8.81 (d, J=6.04 Hz, 2H), 8.85 (d, J=1.92 Hz, 1H), 8.89 (s, 1H), 9.28 (s, 1H), 10.22 (s, 1H), 13.97 (br s, 1H); ESIMS found for C 29 H 25 N 9 O m/z 516.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-((5-(3-(7-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methyl)ethanamine 146 
     Off-white solid (12.0 mg, 0.027 mmol, 23.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.24 (t, J=7.27 Hz, 3H), 3.04-3.15 (m, 2H), 4.36 (br s, 2H), 7.59 (br d, J=6.04 Hz, 1H), 8.06 (br s, 1H), 8.09-8.15 (m, 1H), 8.18 (d, J=9.06 Hz, 1H), 8.39-8.50 (m, 1H), 8.55-8.63 (m, 1H), 8.73 (br s, 1H), 8.81-8.89 (m, 1H), 8.89-9.09 (m, 3H), 9.80 (s, 1H), 13.09 (br s, 1H), 14.31 (br s, 1H); ESIMS found for C 25 H 21 N 9  m/z 448.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(Pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)benzamide 151 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.36 (br s, 1H), 7.54-7.60 (m, 2H), 7.62-7.69 (m, 1H), 7.95-8.07 (m, 5H), 8.35 (d, J=8.51 Hz, 1H), 8.52 (br d, J=4.12 Hz, 1H), 8.83-8.92 (m, 1H), 8.97 (br s, 1H), 9.13 (br s, 1H), 9.41 (d, J=1.10 Hz, 1H), 10.66 (s, 1H), 13.15 (br s, 1H); ESIMS found for C 29 H 19 N 9 O m/z 510.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)pentanamide 159 
     White solid (5.5 mg, 0.011 mmol, 11.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.90 (t, J=7.41 Hz, 3H), 1.34 (dq, J=14.89, 7.39 Hz, 2H), 1.55-1.63 (m, 2H), 2.38 (t, J=7.55 Hz, 2H), 7.54 (ddd, J=7.48, 4.73, 0.96 Hz, 1H), 8.07-8.15 (m, 3H), 8.40 (d, J=9.06 Hz, 1H), 8.62 (d, J=5.21 Hz, 1H), 8.74-8.88 (m, 1H), 8.83-8.89 (m, 2H), 8.95 (d, J=2.20 Hz, 1H), 9.33 (d, J=2.20 Hz, 1H), 10.35 (s, 1H), 14.33 (br s, 2H); ESIMS found for C 27 H 23 N 9 O m/z 490.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)propionamide 169 
     Yellow solid (16.8 mg, 0.036 mmol, 27.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.13 (t, J=7.41 Hz, 3H), 1.69 (br s, 6H), 2.41 (q, J=7.41 Hz, 2H), 4.00-4.08 (m, 4H), 6.52 (d, J=5.76 Hz, 1H), 7.96 (d, J=6.04 Hz, 1H), 8.05 (d, J=8.78 Hz, 1H), 8.26 (d, J=8.78 Hz, 1H), 8.79 (s, 2H), 9.17 (s, 1H), 10.22 (s, 1H), 13.05 (br s, 1H), 13.89 (br s, 1H); ESIMS found for C 25 H 25 N 9 O m/z 468.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-dimethyl-5-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-amine 175 
     Yellow solid (5.2 mg, 0.012 mmol, 11.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.69 (br s, 6H), 3.05 (s, 6H), 4.04 (br s, 4H), 6.52 (d, J=5.76 Hz, 1H), 7.84 (br s, 1H), 7.96 (d, J=5.76 Hz, 1H), 8.12-8.18 (m, 1H), 8.18-8.26 (m, 2H), 8.82 (s, 1H), 12.99 (br s, 1H), 13.84 (br s, 1H); ESIMS found for C 24 H 25 N 9  m/z 440.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-dimethyl-1-(5-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methanamine 181 
     White solid (13.5 mg, 0.030 mmol, 27.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.83 (s, 6H), 4.44 (s, 2H), 6.78 (br s, 1H), 8.00 (br s, 1H), 8.15 (d, J=9.06 Hz, 1H), 8.37 (br d, J=8.51 Hz, 1H), 8.68 (s, 1H), 8.77 (d, J=1.92 Hz, 1H), 9.65 (br s, 1H), 14.14 (br s, 1H); ESIMS found for C 25 H 27 N 9  m/z 454.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 188 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.84-0.90 (m, 4H), 1.71 (br s, 6H), 1.85 (quin, J=6.24 Hz, 1H), 4.10 (br s, 4H), 6.59-6.70 (m, 1H), 7.97 (br d, J=6.04 Hz, 1H), 8.06 (d, J=8.78 Hz, 1H), 8.27 (d, J=8.78 Hz, 1H), 8.77 (d, J=2.47 Hz, 1H), 8.81 (t, J=2.06 Hz, 1H), 9.15 (d, J=1.65 Hz, 1H), 10.56 (s, 1H), 13.25 (br s, 1H), 13.97 (br s, 1H); ESIMS found for C 26 H 25 N 9 O m/z 480.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 194 
     Beige solid (14.0 mg, 0.027 mmol, 23.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.75 (br s, 6H), 2.23-2.35 (m, 2H), 2.77 (t, J=7.00 Hz, 2H), 2.95 (t, J=13.31 Hz, 2H), 3.79 (s, 2H), 4.09-4.27 (m, 4H), 6.72 (br d, J=2.20 Hz, 1H), 7.99 (br d, J=4.94 Hz, 1H), 8.18-8.23 (m, 1H), 8.26-8.32 (m, 1H), 8.53 (s, 1H), 8.61 (d, J=1.92 Hz, 1H), 9.44 (d, J=1.92 Hz, 1H), 14.03 (br s, 1H); ESIMS found for C 27 H 27 F 2 N 9  m/z 516.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-methyl-N-(5-(3-(7-(4-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)butanamide 198 
     Brown solid (7.0 mg, 0.014 mmol, 11.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.97 (d, J=6.59 Hz, 6H), 2.13 (tt, J=13.48, 6.69 Hz, 2H), 2.29 (s, 3H), 2.34 (d, J=7.14 Hz, 2H), 7.64 (d, J=5.49 Hz, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.27-8.35 (m, 2H), 8.41 (d, J=5.49 Hz, 1H), 8.79 (t, J=2.06 Hz, 1H), 8.96 (d, J=2.47 Hz, 1H), 9.24 (d, J=1.92 Hz, 1H), 9.30 (s, 1H), 10.26 (s, 1H); ESIMS found for C 26 H 24 N 10 O m/z 493.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)pivalamide 204 
     Beige solid (6.0 mg, 0.012 mmol, 9.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.28 (s, 9H), 2.27 (s, 3H), 7.65 (d, J=5.49 Hz, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.30-8.34 (m, 2H), 8.41 (d, J=5.21 Hz, 1H), 8.81 (t, J=2.06 Hz, 1H), 8.96 (d, J=2.20 Hz, 1H), 9.19 (s, 1H), 9.26 (s, 1H), 9.57 (s, 1H), 13.86 (br s, 1H), 14.17 (s, 1H); ESIMS found for C 26 H 24 N 10 O m/z 493.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 210 
     Brown solid (14.5 mg, 0.029 mmol, 22.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.92 (br d, J=1.65 Hz, 4H), 2.31 (s, 3H), 3.10-3.28 (m, 4H), 4.55 (br s, 2H), 7.63 (d, J=5.49 Hz, 1H), 8.18 (s, 1H), 8.28-8.32 (m, 1H), 8.32-8.37 (m, 1H), 8.42 (d, J=5.49 Hz, 1H), 8.80 (br s, 1H), 8.92 (br s, 1H), 9.58 (br s, 2H), 13.97 (br s, 1H), 14.22 (br s, 1H); ESIMS found for C 26 H 24 N 10  m/z 477.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 217 
     White solid (1.3 mg, 0.003 mmol, 2.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.80-1.91 (m, 1H), 1.93-2.03 (m, 1H), 2.11-2.21 (m, 2H), 2.24-2.34 (m, 5H), 3.36-3.44 (m, 1H), 7.61 (d, J=5.49 Hz, 1H), 8.07 (d, J=8.78 Hz, 1H), 8.30 (d, J=8.78 Hz, 1H), 8.38 (d, J=5.21 Hz, 1H), 8.48 (s, 1H), 8.77-8.82 (m, 1H), 8.98 (d, J=2.20 Hz, 1H), 9.22 (d, J=1.92 Hz, 1H), 9.28 (s, 1H), 10.13 (s, 1H); ESIMS found for C 26 H 22 N 10 O m/z 491.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-amine 227 
     Yellow solid (3.6 mg, 0.008 mmol, 8.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.89 (s, 3H), 3.18-3.33 (m, 4H), 3.52-3.70 (m, 4H), 5.18 (br s, 2H), 6.73 (br d, J=5.21 Hz, 1H), 7.96 (br s, 1H), 8.05 (d, J=9.06 Hz, 1H), 8.08 (d, J=2.47 Hz, 1H), 8.11 (br d, J=5.76 Hz, 1H), 8.29 (d, J=8.78 Hz, 1H), 8.73 (s, 1H), 13.36 (br s, 1H), 14.04 (br s, 1H); ESIMS found for C 22 H 22 N 10  m/z 427.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)isobutyramide 233 
     Yellow solid (11.1 mg, 0.022 mmol, 22.0% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.16 (d, J=6.86 Hz, 6H), 2.24 (s, 3H), 2.51-2.56 (m, 4H), 2.65-2.72 (m, 1H), 4.04 (br s, 4H), 6.54 (d, J=6.04 Hz, 1H), 7.99 (d, J=5.76 Hz, 1H), 8.05 (d, J=8.78 Hz, 1H), 8.26 (d, J=8.78 Hz, 1H), 8.79-8.86 (m, 2H), 9.16 (d, J=1.92 Hz, 1H), 10.20 (s, 1H), 13.10 (br s, 1H), 13.91 (br s, 1H); ESIMS found for C 26 H 28 N 10 O m/z 497.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopentanecarboxamide 246 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.52-1.63 (m, 2H), 1.65-1.72 (m, 2H), 1.75-1.83 (m, 2H), 1.86-1.94 (m, 2H), 2.25 (s, 3H), 2.51-2.54 (m, 4H), 2.87 (quin, J=7.96 Hz, 1H), 3.97-4.04 (m, 4H), 6.53 (d, J=5.76 Hz, 1H), 7.94 (d, J=9.06 Hz, 1H), 7.97 (d, J=5.76 Hz, 1H), 8.22 (d, J=8.78 Hz, 1H), 8.77 (t, J=2.06 Hz, 1H), 8.83 (d, J=2.20 Hz, 1H), 9.14 (d, J=1.65 Hz, 1H), 10.25 (s, 1H); ESIMS found for C 28 H 30 N 10 O m/z 523.25 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine 251 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.28 (s, 3H), 2.57 (br s, 4H), 4.04 (br s, 4H), 6.55 (br d, J=5.21 Hz, 1H), 8.00 (br d, J=5.21 Hz, 1H), 8.20-8.26 (m, 1H), 8.26-8.33 (m, 1H), 9.28 (s, 1H), 9.71 (br s, 2H), 13.19 (br s, 1H); ESIMS found for C 21 H 20 N 10  m/z 413.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 256 
     Gray solid (5.2 mg, 0.017 mmol, 10.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.37 (dd, J=7.96, 4.94 Hz, 1H), 7.66 (dd, J=7.96, 4.94 Hz, 1H), 8.18 (dd, J=7.96, 1.37 Hz, 1H), 8.22 (d, J=8.78 Hz, 1H), 8.34 (d, J=8.78 Hz, 1H), 8.47 (dd, J=4.80, 1.23 Hz, 1H), 8.73 (dd, J=4.94, 1.65 Hz, 1H), 8.75 (dd, J=7.96, 1.92 Hz, 1H), 9.56 (d, J=1.65 Hz, 1H), 14.23 (br s, 1H); ESIMS found for C 17 H 11 N 7  m/z 314.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-2-phenylacetamide 262 
     Brown solid (4.5 mg, 0.010 mmol, 12.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.75 (s, 2H), 7.23-7.30 (m, 1H), 7.33-7.42 (m, 5H), 8.10 (d, J=9.06 Hz, 1H), 8.12-8.18 (m, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.46 (d, J=3.84 Hz, 1H), 8.76 (t, J=1.92 Hz, 1H), 8.96 (d, J=2.20 Hz, 1H), 9.18 (d, J=1.65 Hz, 1H), 10.66 (s, 1H), 14.22 (br s, 1H); ESIMS found for C 25 H 18 N 8 O m/z 447.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(3H-Imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl) pyridin-3-yl)-3,3-dimethylbutanamide 268 
     White solid (17.6 mg, 0.041 mmol, 32.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.07 (s, 9H), 2.29 (s, 2H), 7.30 (dd, J=7.96, 4.94 Hz, 1H), 7.98-8.17 (m, 1H), 8.08 (br d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.37-8.48 (m, 1H), 8.73 (br s, 1H), 8.94 (d, J=2.20 Hz, 1H), 9.14 (br s, 1H), 10.25 (s, 1H), 13.43 (br s, 1H), 14.13 (br s, 1H); ESIMS found for C 23 H 22 N 8 O m/z 427.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(3H-Imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl) pyridin-3-yl)cyclohexanecarboxamide 275 
     Yellow solid (12.7 mg, 0.029 mmol, 28.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.19-1.36 (m, 3H), 1.46 (qd, J=12.26, 2.74 Hz, 2H), 1.67 (br d, J=12.35 Hz, 1H), 1.75-1.82 (m, 2H), 1.85-1.91 (m, 2H), 2.42 (tt, J=11.56, 3.40 Hz, 1H), 7.29 (dd, J=7.96, 4.67 Hz, 1H), 8.05 (d, J=8.78 Hz, 1H), 8.08 (br d, J=6.04 Hz, 1H), 8.29 (d, J=8.78 Hz, 1H), 8.40 (br d, J=3.84 Hz, 1H), 8.73 (s, 1H), 8.95 (d, J=2.20 Hz, 1H), 9.13 (d, J=1.65 Hz, 1H), 10.26 (s, 1H); ESIMS found for C 24 H 22 N 8 O m/z 439.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(3H-Imidazo[4,5-b]pyridin-2-yl)-5-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 280 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.30 (dd, J=7.96, 4.67 Hz, 1H), 7.48-7.54 (m, 1H), 8.06 (td, J=7.68, 1.65 Hz, 1H), 8.10 (br s, 1H), 8.30 (d, J=9.06 Hz, 1H), 8.42 (br s, 1H), 8.60 (d, J=9.06 Hz, 1H), 8.74 (d, J=4.67 Hz, 1H), 8.79 (br s, 1H), 13.42 (br s, 1H), 14.13 (br s, 1H); ESIMS found for C 17 H 11 N 7  m/z 314.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)propionamide 281 
     Yellow solid (34.9 mg, 0.075 mmol, 56.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.13 (t, J=7.55 Hz, 3H), 2.42 (q, J=7.68 Hz, 2H), 7.31 (dd, J=5.08, 3.70 Hz, 1H), 7.58 (d, J=5.21 Hz, 1H), 7.80 (dd, J=5.08, 0.96 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.36 (d, J=5.21 Hz, 1H), 8.61 (br s, 1H), 8.85 (s, 2H), 9.27 (s, 1H), 10.25 (s, 1H), 13.57 (br s, 1H), 14.12 (s, 1H); ESIMS found for C 24 H 18 N 8 OS m/z 467.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(4-methylpyridin-3-yl)-3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 285 
     Yellow solid (23.9 mg, 0.058 mmol, 57.4% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.65 (s, 3H), 7.45 (d, J=4.94 Hz, 1H), 7.67 (br d, J=4.94 Hz, 1H), 7.74 (dd, J=5.08, 2.88 Hz, 1H), 7.82 (d, J=8.78 Hz, 1H), 8.25-8.32 (m, 2H), 8.36 (d, J=4.94 Hz, 1H), 8.53 (d, J=4.94 Hz, 1H), 8.82 (s, 1H), 9.00 (br s, 1H), 13.52 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 22 H 15 N 7 S m/z 410.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(Thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)benzamide 291 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.55-7.62 (m, 2H), 7.63-7.67 (m, 2H), 7.69 (d, J=5.21 Hz, 1H), 8.02-8.08 (m, 2H), 8.18 (d, J=9.06 Hz, 1H), 8.26 (d, J=4.94 Hz, 1H), 8.37 (d, J=8.78 Hz, 1H), 8.40 (d, J=5.21 Hz, 1H), 9.05 (br s, 1H), 9.10-9.13 (m, 1H), 9.13 (d, J=1.92 Hz, 1H), 9.35 (d, J=1.65 Hz, 1H), 10.75 (s, 1H), 14.19 (br s, 1H); ESIMS found for C 28 H 18 N 8 OS m/z 515.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)butyramide 297 
     White solid (7.4 mg, 0.015 mmol, 15.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.95 (t, J=7.27 Hz, 3H), 1.67 (sxt, J=7.35 Hz, 2H), 2.40 (t, J=7.27 Hz, 2H), 7.68 (d, J=5.21 Hz, 1H), 7.74 (dd, J=4.94, 3.02 Hz, 1H), 8.09 (d, J=9.06 Hz, 1H), 8.28 (br s, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.36-8.41 (m, 1H), 8.85 (d, J=2.20 Hz, 1H), 8.89 (s, 1H), 9.10 (br s, 1H), 9.22 (d, J=1.37 Hz, 1H), 10.29 (s, 1H), 13.58 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 25 H 20 N 8 OS m/z 481.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-Benzyl-1-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methanamine 304 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.80 (s, 2H), 3.92 (s, 2H), 7.18-7.26 (m, 1H), 7.31 (t, J=7.55 Hz, 2H), 7.38 (d, J=7.14 Hz, 2H), 7.70 (d, J=5.21 Hz, 1H), 7.75 (dd, J=4.94, 3.02 Hz, 1H), 8.21 (d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.33-8.36 (m, 1H), 8.38 (d, J=5.21 Hz, 1H), 8.65 (s, 1H), 8.68 (d, J=1.65 Hz, 1H), 9.11 (d, J=2.20 Hz, 1H), 9.48 (d, J=1.92 Hz, 1H), 13.57 (br s, 1H), 14.11 (br s, 1H); ESIMS found for C 29 H 22 N 8 S m/z 515.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 306 
     Beige solid (8.0 mg, 0.014 mmol, 12.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.21-2.33 (m, 2H), 2.78 (br t, J=7.00 Hz, 2H), 2.97 (br t, J=13.31 Hz, 2H), 3.85 (s, 2H), 7.70 (d, J=4.94 Hz, 1H), 7.78 (dd, J=4.94, 3.02 Hz, 1H), 8.21-8.26 (m, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.33 (br d, J=4.94 Hz, 1H), 8.38 (d, J=5.21 Hz, 1H), 8.60 (s, 1H), 8.65 (d, J=1.92 Hz, 1H), 9.12 (d, J=1.92 Hz, 1H), 9.51 (s, 1H), 13.58 (br s, 1H), 14.10 (s, 1H); ESIMS found for C 26 H 20 F 2 N 8 S m/z 515.2 (M+1) 
     
       
         
         
             
             
         
       
     
     N-((5-(3-(7-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methyl)ethanamine 314 
     Beige solid (10.0 mg, 0.023 mmol, 15.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.10 (t, J=7.14 Hz, 3H), 2.72 (q, J=7.14 Hz, 2H), 4.00 (s, 2H), 7.50 (s, 1H), 7.58 (d, J=5.21 Hz, 1H), 7.92 (t, J=1.65 Hz, 1H), 8.22 (d, J=8.78 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.36 (d, J=4.94 Hz, 1H), 8.68 (d, J=1.92 Hz, 1H), 8.73 (s, 1H), 9.11 (br s, 1H), 9.47 (d, J=1.65 Hz, 1H); ESIMS found for C 24 H 20 N 8 O m/z 437.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-isopropylpyridin-3-amine 320 
     Brown solid (27.5 mg, 0.063 mmol, 33.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.20 (d, J=6.31 Hz, 6H), 3.73-3.82 (m, 1H), 5.83 (br d, J=8.23 Hz, 1H), 7.47 (d, J=1.10 Hz, 1H), 7.57 (d, J=4.94 Hz, 1H), 7.74 (s, 1H), 7.90 (t, J=1.51 Hz, 1H), 8.07 (d, J=2.47 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.25 (d, J=8.78 Hz, 1H), 8.35 (d, J=4.94 Hz, 1H), 8.64 (s, 1H), 9.06 (s, 1H), 13.49 (br s, 1H), 14.05 (br s, 1H); ESIMS found for C 24 H 20 N 8 O m/z 437.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)pentanamide 327 
     White solid (39.0 mg, 0.082 mmol, 83.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.91 (t, J=7.41 Hz, 3H), 1.36 (dq, J=14.82, 7.41 Hz, 2H), 1.62 (quin, J=7.48 Hz, 2H), 2.42 (t, J=7.41 Hz, 2H), 7.47 (d, J=1.37 Hz, 1H), 7.59 (d, J=4.94 Hz, 1H), 7.88 (t, J=1.65 Hz, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.34 (d, J=8.78 Hz, 1H), 8.38 (d, J=5.21 Hz, 1H), 8.91 (d, J=2.20 Hz, 1H), 8.95-8.98 (m, 1H), 9.03 (s, 1H), 9.25 (d, J=1.65 Hz, 1H), 10.38 (s, 1H), 14.17 (br s, 1H); ESIMS found for C 26 H 22 NO 2  m/z 479.2 (M+1). 
     
       
         
         
             
             
         
       
     
     1-Cyclopentyl-N-((5-(3-(7-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 333 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.13-1.22 (m, 2H), 1.42-1.49 (m, 2H), 1.49-1.56 (m, 2H), 1.67-1.75 (m, 2H), 2.03 (dt, J=15.03, 7.44 Hz, 1H), 2.61 (d, J=7.41 Hz, 2H), 4.01 (s, 2H), 7.50 (s, 1H), 7.58 (d, J=4.94 Hz, 1H), 7.91 (t, J=1.51 Hz, 1H), 8.22 (d, J=9.06 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.36 (d, J=4.94 Hz, 1H), 8.69 (d, J=1.65 Hz, 1H), 8.72 (br s, 1H), 9.11 (s, 1H), 9.46 (s, 1H), 13.54 (br s, 1H); ESIMS found for C 28 H 26 N 8 O m/z 491.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-dimethyl-5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-amine 343 
     Yellow solid (8.3 mg, 0.019 mmol, 18.6% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.07 (s, 6H), 7.28-7.33 (m, 1H), 7.59 (d, J=5.21 Hz, 1H), 7.79-7.83 (m, 1H), 7.97 (br s, 1H), 8.18-8.22 (m, 1H), 8.23-8.29 (m, 2H), 8.35 (d, J=5.21 Hz, 1H), 8.56 (d, J=3.29 Hz, 1H), 8.87 (s, 1H), 13.57 (br s, 1H), 14.08 (br s, 1H); ESIMS found for C 23 H 18 N 8 S m/z 439.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-dimethyl-1-(5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)methanamine 349 
     White solid (5.1 mg, 0.011 mmol, 10.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.25 (s, 6H), 3.65 (s, 2H), 7.35 (dd, J=4.94, 3.57 Hz, 1H), 7.60 (d, J=5.21 Hz, 1H), 7.84 (dd, J=5.08, 0.96 Hz, 1H), 8.21-8.26 (m, 1H), 8.28-8.32 (m, 1H), 8.36 (d, J=4.94 Hz, 1H), 8.56-8.60 (m, 1H), 8.62 (d, J=1.65 Hz, 1H), 8.65 (s, 1H), 9.53 (d, J=1.92 Hz, 1H), 13.62 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 24 H 20 N 8 S m/z 453.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(Pyridin-4-yl)-3-(7-(thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 354 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.38 (dd, J=4.94, 3.84 Hz, 1H), 7.60 (d, J=5.21 Hz, 1H), 7.92 (d, J=4.67 Hz, 1H), 8.26-8.31 (m, 1H), 8.31-8.35 (m, 1H), 8.36 (d, J=5.21 Hz, 1H), 8.43 (d, J=6.04 Hz, 2H), 8.59 (br s, 1H), 8.79-8.85 (m, 2H), 13.26 (br s, 1H); ESIMS found for C 21 H 13 N 7 S m/z 396.05 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(Thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 356 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.84-0.90 (m, 4H), 1.86 (quin, J=6.11 Hz, 1H), 7.31 (dd, J=4.94, 3.84 Hz, 1H), 7.58 (d, J=4.94 Hz, 1H), 7.80 (dd, J=5.08, 0.96 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.31 (d, J=8.78 Hz, 1H), 8.35 (d, J=5.21 Hz, 1H), 8.61 (br s, 1H), 8.83 (d, J=1.92 Hz, 1H), 8.85 (d, J=2.20 Hz, 1H), 9.27 (d, J=1.37 Hz, 1H), 10.59 (s, 1H), 13.59 (br s, 1H), 14.09 (br s, 1H); ESIMS found for C 25 H 18 N 8 OS m/z 479.15 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(5-methylthiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-amine 395 
     Yellow solid (16.7 mg, 0.039 mmol, 38.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.60 (s, 3H), 5.44 (s, 2H), 7.01 (br d, J=2.47 Hz, 1H), 7.49 (d, J=5.21 Hz, 1H), 7.76 (br s, 1H), 8.01 (d, J=9.06 Hz, 1H), 8.05 (d, J=2.47 Hz, 1H), 8.26 (d, J=8.78 Hz, 1H), 8.31 (d, J=5.21 Hz, 1H), 8.36 (br d, J=3.29 Hz, 1H), 8.80 (s, 1H), 13.46 (br s, 1H), 14.06 (br s, 1H); ESIMS found for C 22 H 16 N 8 S m/z 425.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(5-methylthiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)isobutyramide 401 
     Yellow solid (19.5 mg, 0.039 mmol, 38.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.15 (d, J=6.86 Hz, 6H), 2.59 (s, 3H), 2.67 (quin, J=6.86 Hz, 1H), 6.99 (dd, J=3.57, 1.10 Hz, 1H), 7.48 (d, J=5.21 Hz, 1H), 8.08 (d, J=9.06 Hz, 1H), 8.29-8.34 (m, 2H), 8.39 (d, J=3.57 Hz, 1H), 8.81 (t, J=2.06 Hz, 1H), 8.88 (d, J=2.20 Hz, 1H), 9.35 (d, J=1.92 Hz, 1H), 10.22 (s, 1H), 13.55 (s, 1H), 14.10 (s, 1H); ESIMS found for C 26 H 22 N 8 OS m/z 495.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(5-Methylthiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)cyclopentanecarboxamide 414 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.53-1.62 (m, 2H), 1.66-1.74 (m, 2H), 1.74-1.83 (m, 2H), 1.86-1.94 (m, 2H), 2.87 (dt, J=15.85, 7.86 Hz, 1H), 6.98 (br d, J=2.47 Hz, 1H), 7.39 (d, J=4.94 Hz, 1H), 7.82 (br d, J=8.51 Hz, 1H), 8.17-8.25 (m, 2H), 8.34 (br d, J=1.10 Hz, 1H), 8.75 (s, 1H), 8.87 (d, J=1.92 Hz, 1H), 9.27 (s, 1H), 10.23 (s, 1H); ESIMS found for C 28 H 24 N 8 OS m/z 521.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-(2-(5-(5-((ethylamino)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 454 
     Dark brown solid (10.0 mg, 0.018 mmol, 17.0% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.22 (t, J=7.27 Hz, 3H), 2.60 (s, 6H), 2.96-3.09 (m, 4H), 3.40 (br s, 2H), 4.29 (s, 2H), 6.19 (br s, 1H), 6.52-6.65 (m, 1H), 7.43 (br d, J=0.82 Hz, 1H), 7.58 (br s, 1H), 7.68-7.77 (m, 1H), 8.17 (d, J=8.78 Hz, 1H), 8.38 (d, J=8.78 Hz, 1H), 8.44 (br d, J=5.21 Hz, 1H), 8.71 (s, 1H), 8.77 (d, J=1.65 Hz, 1H), 9.63 (br s, 1H), 13.56 (br s, 1H); ESIMS found for C 30 H 31 FN 10  m/z 551.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-fluoro-5-(2-(5-(5-(isopropylamino)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 460 
     Golden yellow solid (14.8 mg, 0.027 mmol, 17.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.17 (d, J=6.31 Hz, 6H), 2.21 (s, 6H), 2.51 (br s, 2H), 3.21 (br d, J=5.21 Hz, 2H), 3.66-3.77 (m, 1H), 5.72-5.81 (m, 1H), 5.91 (br s, 1H), 6.46-6.57 (m, 1H), 7.46 (br s, 1H), 7.56 (br d, J=3.02 Hz, 2H), 7.65 (br s, 1H), 8.02-8.10 (m, 2H), 8.26 (d, J=9.06 Hz, 1H), 8.42 (br d, J=4.39 Hz, 1H), 8.63 (br s, 1H), 13.42 (br s, 1H), 14.04 (br s, 1H); ESIMS found for C 30 H 31 FN 10  m/z 551.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-((2-(dimethylamino)ethyl)amino)-5-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)pentanamide 467 
     White solid (3.9 mg, 0.007 mmol, 6.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.91 (t, J=7.27 Hz, 3H), 1.35 (dq, J=14.92, 7.38 Hz, 2H), 1.61 (quin, J=7.48 Hz, 2H), 2.38 (t, J=7.41 Hz, 2H), 2.45 (br s, 6H), 2.80 (br s, 2H), 3.32 (br s, 2H), 6.04 (br s, 1H), 6.54 (dt, J=11.66, 2.13 Hz, 1H), 7.48 (br s, 1H), 7.57 (br s, 1H), 7.60-7.69 (m, 1H), 8.07 (d, J=9.06 Hz, 1H), 8.32 (d, J=9.06 Hz, 1H), 8.43 (br d, J=4.67 Hz, 1H), 8.72 (br s, 1H), 8.89 (d, J=1.65 Hz, 1H), 9.21 (br s, 1H), 10.23 (s, 1H), 13.52 (br s, 1H), 14.13 (br s, 1H); ESIMS found for C 32 H 33 FN 10 O m/z 593.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-(2-(5-(5-(((Cyclopentylmethyl)amino)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamin 473 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.13-1.22 (m, 2H), 1.42-1.50 (m, 2H), 1.50-1.58 (m, 2H), 1.68-1.76 (m, 2H), 2.04 (dt, J=15.03, 7.44 Hz, 1H), 2.26 (s, 6H), 2.57 (br s, 2H), 2.64 (d, J=7.14 Hz, 2H), 3.24 (br s, 2H), 4.01 (s, 2H), 5.96 (br s, 1H), 6.54 (br d, J=11.80 Hz, 1H), 7.44 (br s, 1H), 7.57 (br d, J=1.92 Hz, 1H), 7.63-7.73 (m, 1H), 8.18 (d, J=9.06 Hz, 1H), 8.33 (d, J=8.78 Hz, 1H), 8.43 (br d, J=4.67 Hz, 1H), 8.62 (br s, 1H), 8.69 (d, J=1.65 Hz, 1H), 9.47 (br d, J=0.82 Hz, 1H), 13.53 (br s, 1H); ESIMS found for C 34 H 37 FN 10  m/z 605.35 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-Fluoro-5-(2-(5-(pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 476 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.17 (s, 6H), 2.45 (t, J=6.59 Hz, 2H), 3.17-3.23 (m, 2H), 5.92 (br t, J=4.80 Hz, 1H), 6.58 (br d, J=11.80 Hz, 1H), 7.31 (br s, 1H), 7.45-7.51 (m, 1H), 7.52 (br d, J=4.94 Hz, 1H), 7.84 (br s, 1H), 7.96 (td, J=7.68, 1.65 Hz, 1H), 8.25 (d, J=8.78 Hz, 1H), 8.38 (d, J=5.21 Hz, 1H), 8.53 (d, J=8.78 Hz, 1H), 8.70-8.75 (m, 1H), 8.77 (br d, J=6.59 Hz, 1H); ESIMS found for C 27 H 24 FN 9  m/z 494.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(3-fluoro-5-(2-(5-(4-methylpyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)methanesulfonamide 481 
     Yellow solid (32.4 mg, 0.061 mmol, 60.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.57 (s, 3H), 2.94 (s, 3H), 4.30 (d, J=6.31 Hz, 2H), 7.32 (br d, J=9.33 Hz, 1H), 7.41 (d, J=4.94 Hz, 1H), 7.65 (d, J=4.94 Hz, 1H), 7.73 (t, J=6.31 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 8.12 (s, 1H), 8.30 (d, J=8.51 Hz, 1H), 8.44 (d, J=5.21 Hz, 1H), 8.49-8.56 (m, 2H), 8.79 (s, 1H), 13.64 (s, 1H), 14.14 (s, 1H); ESIMS found for C 26 H 21 FN 8 O 2 S m/z 529.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-Fluoro-5-(methylsulfonamidomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)benzamide 487 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.94 (s, 3H), 4.32 (d, J=6.31 Hz, 2H), 7.18 (br d, J=9.06 Hz, 1H), 7.55-7.61 (m, 2H), 7.62-7.67 (m, 1H), 7.68 (d, J=5.21 Hz, 1H), 7.74 (t, J=6.17 Hz, 1H), 8.03 (d, J=7.14 Hz, 2H), 8.16 (br d, J=9.06 Hz, 2H), 8.37 (d, J=9.06 Hz, 1H), 8.49 (d, J=5.21 Hz, 1H), 8.55 (br s, 1H), 9.03 (s, 1H), 9.13 (d, J=2.20 Hz, 1H), 9.35 (d, J=1.37 Hz, 1H), 10.69 (s, 1H), 14.20 (br s, 1H); ESIMS found for C 32 H 24 FN 9 O 3 S m/z 634.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-fluoro-5-(methylsulfonamidomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)butyramide 493 
     White solid (11.7 mg, 0.020 mmol, 19.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.94 (t, J=7.41 Hz, 3H), 1.64 (sxt, J=7.35 Hz, 2H), 2.36 (t, J=7.41 Hz, 2H), 2.94 (s, 3H), 4.35 (d, J=6.31 Hz, 2H), 7.32 (br d, J=9.33 Hz, 1H), 7.68 (br d, J=2.47 Hz, 1H), 7.76 (t, J=6.45 Hz, 1H), 8.08 (d, J=8.78 Hz, 1H), 8.19 (br s, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.48 (d, J=5.21 Hz, 1H), 8.56 (br s, 1H), 8.78 (t, J=2.06 Hz, 1H), 8.88 (d, J=2.20 Hz, 1H), 9.24 (br s, 1H), 10.25 (s, 1H), 13.65 (br s, 1H), 14.15 (s, 1H); ESIMS found for C 29 H 26 FN 9 O 3 S m/z 600.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(3-(2-(5-(5-((Benzylamino)methyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-5-fluorobenzyl)methanesulfonamide 500 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.96 (s, 3H), 3.79 (s, 2H), 3.90 (s, 2H), 4.36 (d, J=6.31 Hz, 2H), 7.20-7.26 (m, 1H), 7.28-7.35 (m, 3H), 7.37-7.41 (m, 2H), 7.69 (d, J=5.21 Hz, 1H), 7.78 (t, J=6.31 Hz, 1H), 8.17-8.22 (m, 2H), 8.32 (d, J=8.78 Hz, 1H), 8.48 (d, J=5.21 Hz, 1H), 8.54-8.59 (m, 2H), 8.65 (d, J=1.65 Hz, 1H), 9.49 (d, J=1.92 Hz, 1H), 13.64 (br s, 1H), 14.15 (br s, 1H); ESIMS found for C 33 H 28 FN 9 O 2 S m/z 634.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(3-Fluoro-5-(2-(5-(pyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)methanesulfonamide 503 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.97 (br s, 3H), 4.37 (br s, 2H), 7.36 (br d, J=8.23 Hz, 1H), 7.68 (br s, 1H), 7.75 (br s, 1H), 8.18 (br s, 1H), 8.28 (br d, J=8.78 Hz, 1H), 8.36 (br d, J=8.51 Hz, 1H), 8.44-8.50 (m, 1H), 8.60 (br s, 1H), 9.30 (br s, 1H), 9.77 (br s, 2H), 13.88 (br s, 1H); ESIMS found for C 24 H 18 FN 9 O 2 S m/z 516.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridine 505 
     Beige solid (14.0 mg, 0.034 mmol, 94.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.06-2.17 (m, 2H), 2.25-2.31 (m, 2H), 3.07-3.16 (m, 2H), 3.26-3.32 (m, 1H), 3.44 (br d, J=12.62 Hz, 2H), 7.36 (td, J=8.51, 2.47 Hz, 1H), 7.48 (d, J=8.78 Hz, 1H), 7.61-7.68 (m, 1H), 7.72 (d, J=5.21 Hz, 1H), 8.15 (d, J=8.78 Hz, 1H), 8.36 (d, J=7.96 Hz, 1H), 8.43 (d, J=5.21 Hz, 1H), 8.67 (br d, J=10.98 Hz, 1H), 13.47 (br s, 1H), 14.01 (br s, 1H); ESIMS found for C 23 H 20 FN 7  m/z 414.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine 506 
     Beige solid (20.0 mg, 0.049 mmol, 45.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.12 (br s, 2H), 3.42 (br t, J=5.76 Hz, 2H), 3.89 (br s, 2H), 6.88 (br s, 1H), 7.33-7.41 (m, 1H), 7.59-7.67 (m, 1H), 7.73 (d, J=5.21 Hz, 1H), 7.89 (d, J=9.06 Hz, 1H), 8.18 (d, J=8.78 Hz, 1H), 8.33 (br d, J=7.96 Hz, 1H), 8.43 (d, J=5.21 Hz, 1H), 8.82 (br d, J=11.25 Hz, 1H); ESIMS found for C 23 H 18 FN 7  m/z 412.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine 507 
     Beige solid (316.0 mg, 0.040 mmol, 42.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.38 (td, J=8.23, 2.20 Hz, 1H), 7.61-7.69 (m, 1H), 7.72 (d, J=5.21 Hz, 1H), 7.87 (d, J=8.78 Hz, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.30-8.39 (m, 2H), 8.44 (d, J=5.21 Hz, 1H), 8.58 (br s, 1H), 8.75 (br d, J=10.70 Hz, 1H), 13.16 (br s, 1H); ESIMS found for C 21 H 13 FN 8  m/z 397.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine 508 
     Beige solid (29.0 mg, 0.071 mmol, 77.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.96 (s, 3H), 7.39 (td, J=8.16, 1.78 Hz, 1H), 7.61-7.68 (m, 1H), 7.72 (d, J=4.94 Hz, 1H), 7.82 (d, J=8.78 Hz, 1H), 8.14 (d, J=8.78 Hz, 1H), 8.26 (s, 1H), 8.31 (br d, J=7.96 Hz, 1H), 8.44 (d, J=4.94 Hz, 1H), 8.49 (s, 1H), 8.79 (br d, J=10.98 Hz, 1H); ESIMS found for C 22 H 15 FN 8  m/z 411.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(1,2-dimethyl-1H-imidazol-5-yl)-3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 509 
     Beige solid (19.0 mg, 0.045 mmol, 73.4% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.41 (s, 3H), 4.19 (br s, 3H), 7.35-7.42 (m, 1H), 7.54 (s, 1H), 7.62-7.70 (m, 2H), 7.84 (br d, J=9.06 Hz, 1H), 8.14 (br d, J=9.06 Hz, 1H), 8.23-8.30 (m, 1H), 8.39-8.48 (m, 2H); ESIMS found for C 23 H 17 FN 8  m/z 425.1 (M+1). 
     
       
         
         
             
             
         
       
     
     1-(6-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyrazin-2-yl)azetidin-3-amine 510 
     Yellow solid (10.1 mg, 0.021 mmol, 27.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 4.16 (dd, J=9.33, 4.67 Hz, 2H), 4.26 (br s, 1H), 4.46 (dd, J=8.92, 7.55 Hz, 2H), 7.39 (td, J=8.30, 2.33 Hz, 1H), 7.65-7.72 (m, 1H), 7.74 (br d, J=4.67 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.42 (br s, 2H), 8.46 (d, J=4.94 Hz, 1H), 8.48 (d, J=8.78 Hz, 1H), 8.53 (br s, 1H), 8.64 (br s, 1H), 9.37 (br s, 1H), 13.74 (br s, 1H), 14.19 (s, 1H); ESIMS found for C 25 H 19 FN 10  m/z 479.0 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy) pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 512 
     Cream colored solid (25.0 mg, 0.049 mmol, 48.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.87-1.97 (m, 2H), 2.17-2.25 (m, 2H), 3.10-3.17 (m, 2H), 3.29-3.33 (m, 2H), 4.92 (dq, J=7.55, 3.80 Hz, 1H), 7.39 (td, J=8.37, 2.20 Hz, 1H), 7.67-7.77 (m, 2H), 8.22-8.27 (m, 1H), 8.28-8.33 (m, 1H), 8.34 (br s, 1H), 8.46 (d, J=5.21 Hz, 1H), 8.47-8.54 (m, 3H), 8.60 (br d, J=7.68 Hz, 1H), 9.23 (d, J=1.37 Hz, 1H), 13.67 (br s, 1H), 14.16 (br s, 1H); ESIMS found for C 27 H 23 FN 8 O m/z 507.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 514 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68 (dt, J=6.86, 3.16 Hz, 4H), 2.54-2.58 (m, 4H), 2.87 (t, J=5.90 Hz, 2H), 4.29 (t, J=5.76 Hz, 2H), 7.36 (td, J=8.23, 2.20 Hz, 1H), 7.67-7.76 (m, 2H), 8.22-8.32 (m, 4H), 8.42 (d, J=2.74 Hz, 1H), 8.45 (br d, J=5.21 Hz, 1H), 8.48 (br d, J=11.25 Hz, 1H), 8.56 (br d, J=7.41 Hz, 1H), 9.20 (s, 1H), 13.67 (br s, 1H), 14.16 (br s, 1H); ESIMS found for C 29 H 25 FN 8 O m/z 521.3 (M+1). 
     
       
         
         
             
             
         
       
     
     2-((5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)oxy)-N,N-dimethylethan-1-amine 515 
     Off-white solid (8.2 mg, 0.017 mmol, 20.0% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.90 (s, 6H), 3.58-3.64 (m, 2H), 4.58 (t, J=4.94 Hz, 2H), 7.39 (td, J=8.71, 2.33 Hz, 1H), 7.65-7.78 (m, 2H), 8.25 (d, J=8.78 Hz, 1H), 8.29 (br s, 1H), 8.31-8.36 (m, 1H), 8.46 (d, J=4.94 Hz, 1H), 8.50 (d, J=2.74 Hz, 1H), 8.53 (br s, 1H), 9.30 (br s, 1H), 9.83 (br s, 1H), 13.68 (br s, 1H), 14.18 (s, 1H); ESIMS found for C 27 H 23 FN 8 O m/z 495.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 516 
     Yellow solid (31.4 mg, 0.072 mmol, 43.0% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.96 (s, 3H), 7.33-7.42 (m, 1H), 7.64-7.74 (m, 2H), 8.15 (br d, J=8.78 Hz, 1H), 8.21-8.29 (m, 2H), 8.38-8.46 (m, 3H), 8.48 (br d, J=7.41 Hz, 1H), 9.18 (s, 1H); ESIMS found for C 24 H 16 FN 7 O m/z 438.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-ol 517 
     Brown solid (12.6 mg, 0.030 mmol, 29.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.36 (td, J=8.44, 2.33 Hz, 1H), 7.69-7.76 (m, 2H), 8.08 (t, J=2.20 Hz, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.25-8.31 (m, 2H), 8.42-8.49 (m, 2H), 8.59 (d, J=7.96 Hz, 1H), 9.05 (d, J=1.65 Hz, 1H), 10.12 (s, 1H), 13.62 (s, 1H), 14.10 (s, 1H); ESIMS found for C 23 H 14 FN 7 O m/z 424.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-pyrazolo[4,3-b]pyridine 520 
     Brown solid (35.0 mg, 0.085 mmol, 47.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.40 (td, J=8.37, 2.47 Hz, 1H), 7.65-7.72 (m, 1H), 7.73 (d, J=5.21 Hz, 1H), 8.36 (d, J=8.78 Hz, 1H), 8.47 (d, J=5.21 Hz, 1H), 8.51 (br s, 1H), 8.55 (d, J=9.06 Hz, 1H), 8.61 (br s, 1H), 8.74-8.82 (m, 2H), 10.07 (s, 1H), 13.76 (br s, 1H), 14.22 (s, 1H); ESIMS found for C 22 H 13 FN 8  m/z 409.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Cyclohexyloxy)pyridin-3-yl)-3-(7-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 559 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.26-1.35 (m, 1H), 1.36-1.45 (m, 2H), 1.49-1.59 (m, 3H), 1.74 (br dd, J=9.33, 3.84 Hz, 2H), 1.98-2.04 (m, 2H), 4.61-4.68 (m, 1H), 7.70 (dd, J=7.82, 4.80 Hz, 1H), 7.75 (br d, J=3.29 Hz, 1H), 8.21-8.25 (m, 1H), 8.26 (br s, 1H), 8.27-8.31 (m, 1H), 8.41 (d, J=2.74 Hz, 1H), 8.48 (d, J=4.94 Hz, 1H), 8.71 (dd, J=4.67, 1.65 Hz, 1H), 9.10 (br s, 1H), 9.14 (s, 1H), 9.63 (br s, 1H); ESIMS found for C 28 H 24 N 8 O m/z 489.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(Pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-ol 565 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.72-7.79 (m, 2H), 8.16 (d, J=9.06 Hz, 1H), 8.24-8.29 (m, 2H), 8.35 (br s, 1H), 8.46-8.50 (m, 2H), 8.73 (dd, J=4.80, 1.51 Hz, 1H), 9.02 (br s, 1H), 9.01 (d, J=1.65 Hz, 1H), 9.98 (br s, 1H); ESIMS found for C 22 H 14 N 8 O m/z 407.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Piperidin-4-yloxy)pyridin-3-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 576 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.92-2.00 (m, 2H), 2.22 (ddd, J=10.15, 6.59, 3.29 Hz, 2H), 3.11-3.18 (m, 2H), 3.34 (br d, J=2.47 Hz, 2H), 4.91-4.98 (m, 1H), 7.86 (d, J=5.21 Hz, 1H), 8.25-8.29 (m, 1H), 8.31-8.35 (m, 1H), 8.38-8.41 (m, 1H), 8.51 (br s, 1H), 8.53-8.55 (m, 2H), 8.79 (br s, 2H), 8.90-8.95 (m, 2H), 9.29 (d, J=1.65 Hz, 1H), 13.84 (br s, 1H), 14.21 (br s, 1H); ESIMS found for C 27 H 23 N 9 O m/z 490.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Benzyloxy)pyridin-3-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 582 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 5.38 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H), 7.53-7.57 (m, 2H), 7.89 (d, J=5.21 Hz, 1H), 8.25-8.30 (m, 1H), 8.30-8.35 (m, 1H), 8.45-8.49 (m, 1H), 8.54 (d, J=2.74 Hz, 1H), 8.56 (d, J=5.21 Hz, 1H), 8.90 (br s, 2H), 8.94-8.98 (m, 2H), 9.31 (d, J=1.65 Hz, 1H), 13.87 (br s, 1H), 14.21 (br s, 1H); ESIMS found for C 29 H 20 N 8 O m/z 497.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(Pyrazin-2-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 584 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.88 (d, J=5.21 Hz, 1H), 8.36 (d, J=8.78 Hz, 1H), 8.53 (d, J=8.78 Hz, 1H), 8.56 (d, J=5.21 Hz, 1H), 8.77-8.83 (m, 2H), 8.88 (br s, 2H), 8.91-8.97 (m, 2H), 10.11 (d, J=1.10 Hz, 1H), 13.91 (br s, 1H), 14.26 (br s, 1H); ESIMS found for C 21 H 13 N 9  m/z 391.9 (M+1). 
     
       
         
         
             
             
         
       
     
     2-(Piperidin-4-yl)-N-(5-(3-(7-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 593 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.32-1.43 (m, 2H), 1.81 (br d, J=12.90 Hz, 2H), 2.00-2.11 (m, 1H), 2.35 (br d, J=6.59 Hz, 2H), 2.83 (td, J=12.56, 2.33 Hz, 2H), 3.21 (br d, J=12.62 Hz, 2H), 7.52-7.57 (m, 1H), 8.06-8.13 (m, 3H), 8.40 (br s, 1H), 8.48 (br s, 1H), 8.60 (br s, 1H), 8.82 (br s, 1H), 8.87 (br s, 1H), 8.94 (br s, 1H), 9.36 (s, 1H), 10.44 (br s, 1H), 13.19 (br s, 1H); ESIMS found for C 29 H 26 N 10 O m/z 531.25 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 610 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67-1.76 (m, 10H), 2.54-2.60 (m, 4H), 2.87 (t, J=5.90 Hz, 2H), 4.05 (br s, 4H), 4.29 (t, J=5.76 Hz, 2H), 6.52 (d, J=5.76 Hz, 1H), 7.96 (d, J=5.76 Hz, 1H), 8.20-8.27 (m, 3H), 8.40 (d, J=2.74 Hz, 1H), 9.13 (d, J=1.37 Hz, 1H), 13.05 (br s, 1H), 13.89 (br s, 1H); ESIMS found for C 28 H 31 N 9 O m/z 510.3 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-Methoxypyridin-3-yl)-3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 612 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.71 (br s, 6H), 3.97 (s, 3H), 4.04 (br s, 4H), 6.52 (d, J=5.76 Hz, 1H), 7.96 (d, J=5.76 Hz, 1H), 8.17-8.27 (m, 3H), 8.39 (d, J=2.47 Hz, 1H), 9.14 (s, 1H), 13.08 (br s, 1H), 13.82 (br s, 1H); ESIMS found for C 23 H 22 N 8 O m/z 427.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-ol 613 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.71 (br d, J=9.06 Hz, 6H), 4.01 (br s, 4H), 6.50 (d, J=5.76 Hz, 1H), 7.88-7.94 (m, 2H), 7.99 (t, J=2.20 Hz, 1H), 8.15 (d, J=8.78 Hz, 1H), 8.19 (d, J=2.74 Hz, 1H), 8.92 (d, J=1.65 Hz, 1H); ESIMS found for C 22 H 20 N 8 O m/z 413.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-Methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine 618 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.27 (s, 3H), 2.96 (br dd, J=6.31, 2.74 Hz, 2H), 3.26 (br s, 2H), 3.74 (br s, 2H), 6.86 (br s, 1H), 7.64 (d, J=5.49 Hz, 1H), 7.86 (d, J=8.78 Hz, 1H), 8.15 (d, J=8.78 Hz, 1H), 8.35 (s, 1H), 8.39 (d, J=5.49 Hz, 1H), 9.18 (s, 1H); ESIMS found for C 21 H 19 N 9  m/z 398.15 (M+1). 
     
       
         
         
             
             
         
       
     
     1-(6-(3-(7-(4-Methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyrazin-2-yl)azetidin-3-amine 622 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.33 (s, 3H), 3.89 (br dd, J=8.37, 5.35 Hz, 2H), 4.00-4.05 (m, 1H), 4.38 (br t, J=7.82 Hz, 2H), 7.67 (d, J=5.49 Hz, 1H), 8.02 (s, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.41 (d, J=5.49 Hz, 1H), 8.48 (d, J=8.78 Hz, 2H), 9.12 (s, 1H), 9.25 (s, 1H); ESIMS found for C 23 H 20 N 12  m/z 465.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-Dimethyl-2-((5-(3-(7-(4-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)oxy)ethan-1-amine 627 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.34 (s, 3H), 2.95 (s, 3H), 3.25 (s, 3H), 3.67-3.71 (m, 1H), 3.91-3.97 (m, 1H), 4.66 (br t, J=5.08 Hz, 1H), 4.79 (dd, J=3.29, 1.10 Hz, 1H), 7.66 (dd, J=5.21, 1.92 Hz, 1H), 8.27-8.31 (m, 2H), 8.32-8.35 (m, 1H), 8.35-8.39 (m, 1H), 8.45 (d, J=5.21 Hz, 1H), 8.49 (t, J=2.61 Hz, 1H), 9.22 (br d, J=6.86 Hz, 1H), 9.51 (br s, 1H), 13.93-14.02 (m, 1H), 14.24 (s, 1H); ESIMS found for C 25 H 24 N 10 O m/z 481.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Cyclohexyloxy)pyridin-3-yl)-3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 639 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.25-1.34 (m, 1H), 1.38-1.47 (m, 2H), 1.47-1.59 (m, 3H), 1.75 (br dd, J=9.06, 3.84 Hz, 2H), 1.98-2.06 (m, 2H), 2.30 (s, 3H), 2.61 (br t, J=4.80 Hz, 4H), 4.06 (br s, 4H), 4.56-4.65 (m, 1H), 6.55 (d, J=5.76 Hz, 1H), 8.00 (d, J=5.76 Hz, 1H), 8.18-8.22 (m, 2H), 8.22-8.25 (m, 1H), 8.40 (d, J=2.74 Hz, 1H), 9.09 (d, J=1.65 Hz, 1H), 13.87 (br s, 1H); ESIMS found for C 28 H 31 N 9 O m/z 510.3 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Benzyloxy)pyridin-3-yl)-3-(7-(4-methylpiperazin-1-yl)-3H-imidazo [4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 646 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.53 (s, 3H), 3.03 (br s, 4H), 4.18 (br s, 4H), 5.35 (s, 2H), 6.62 (d, J=5.76 Hz, 1H), 7.32-7.37 (m, 1H), 7.38-7.44 (m, 2H), 7.55 (d, J=7.14 Hz, 2H), 8.05 (d, J=5.76 Hz, 1H), 8.18-8.23 (m, 1H), 8.23-8.29 (m, 1H), 8.31-8.35 (m, 1H), 8.46 (d, J=2.74 Hz, 1H), 9.14 (d, J=1.65 Hz, 1H), 13.97 (br s, 1H); ESIMS found for C 29 H 27 N 9 O m/z 518.25 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyrazin-2-yl)-1H-pyrazolo[4,3-b]pyridine 648 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.92 (s, 3H), 3.40 (br s, 2H), 3.64 (br s, 4H), 5.30 (br s, 2H), 6.88 (br d, J=4.39 Hz, 1H), 8.18 (br d, J=4.94 Hz, 1H), 8.36 (d, J=8.78 Hz, 1H), 8.53 (d, J=8.78 Hz, 1H), 8.77 (d, J=2.74 Hz, 1H), 8.80 (dd, J=2.33, 1.51 Hz, 1H), 9.89 (s, 1H), 13.84 (br s, 1H), 14.24 (br s, 1H); ESIMS found for C 21 H 20 N 10  m/z 413.0 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(3H-Imidazo[4,5-b]pyridin-2-yl)-5-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine 651 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.29 (dd, J=7.82, 4.80 Hz, 1H), 7.82-7.91 (m, 1H), 8.07-8.18 (m, 2H), 8.33-8.48 (m, 2H), 8.60 (br s, 1H), 12.61 (br s, 1H), 13.14 (br s, 1H), 13.97 (br s, 1H); ESIMS found for C 15 H 10 N 8  m/z 303.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(3H-Imidazo[4,5-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 656 
       1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.78-1.87 (m, 2H), 2.13-2.20 (m, 2H), 3.00 (ddd, J=12.56, 9.26, 3.43 Hz, 2H), 3.21-3.28 (m, 2H), 4.88 (td, J=7.89, 3.98 Hz, 1H), 7.30 (dd, J=7.96, 4.67 Hz, 1H), 8.20 (d, J=8.78 Hz, 1H), 8.26-8.33 (m, 3H), 8.42 (br d, J=4.39 Hz, 1H), 8.46 (d, J=2.74 Hz, 1H), 9.12 (d, J=1.37 Hz, 1H); ESIMS found for C 22 H 20 N 8 O m/z 413.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(3H-Imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl) pyridin-3-ol 661 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 7.29 (dd, J=7.96, 4.67 Hz, 1H), 8.08 (br s, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.24 (d, J=2.74 Hz, 1H), 8.26 (d, J=3.02 Hz, 1H), 8.28 (s, 1H), 8.41 (br s, 1H), 8.92 (br s, 1H), 13.40 (br s, 1H), 14.12 (br s, 1H); ESIMS found for C 17 H 11 N 7 O m/z 330.1 (M+1). 
     
       
         
         
             
             
         
       
     
     2-(Piperidin-4-yl)-N-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 673 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35-1.46 (m, 2H), 1.85 (br d, J=14.82 Hz, 2H), 2.04-2.14 (m, 1H), 2.39 (d, J=6.86 Hz, 2H), 2.80-2.89 (m, 2H), 3.23 (br d, J=12.62 Hz, 2H), 7.68 (d, J=4.94 Hz, 1H), 7.75 (dd, J=4.94, 3.02 Hz, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.27 (br s, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.38 (d, J=4.94 Hz, 1H), 8.85 (d, J=2.20 Hz, 1H), 8.88 (s, 1H), 9.10 (br s, 1H), 9.23 (d, J=1.65 Hz, 1H), 10.40 (s, 1H); ESIMS found for C 28 H 25 N 9 OS m/z 536.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(1,2-Dimethyl-1H-imidazol-5-yl)-3-(7-(furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 685 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.66 (s, 3H), 4.41 (s, 3H), 7.49 (s, 1H), 7.56 (d, J=5.21 Hz, 1H), 7.95 (t, J=1.65 Hz, 1H), 7.97 (d, J=8.78 Hz, 1H), 8.21 (s, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.35 (d, J=4.94 Hz, 1H), 8.90 (s, 1H), 13.65 (br s, 1H), 14.23 (br s, 1H); ESIMS found for C 21 H 16 N 8 O m/z 397.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(Furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(2-(pyrrolidin-1-yl) ethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 690 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.74 (br s, 4H), 2.66 (br s, 4H), 3.00 (br s, 2H), 4.37 (br s, 2H), 7.53 (d, J=1.10 Hz, 1H), 7.58 (d, J=4.94 Hz, 1H), 7.93 (t, J=1.65 Hz, 1H), 8.23-8.28 (m, 1H), 8.28-8.31 (m, 1H), 8.31-8.34 (m, 1H), 8.36 (d, J=4.94 Hz, 1H), 8.43 (d, J=2.47 Hz, 1H), 9.06 (s, 1H), 9.15 (s, 1H), 13.56 (br s, 1H), 14.14 (br s, 1H); ESIMS found for C 27 H 24 N 8 O 2  m/z 493.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(Furan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-methoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 692 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 4.01 (br s, 3H), 7.50 (br s, 1H), 7.57 (br s, 1H), 7.90 (br s, 1H), 8.20-8.45 (m, 5H), 9.06 (br s, 1H), 9.14 (br s, 1H), 13.67 (br s, 1H); ESIMS found for C 22 H 15 N 7 O 2  m/z 410.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(1-Methyl-1H-pyrazol-4-yl)-3-(7-(thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 700 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.96 (s, 3H), 7.34 (dd, J=4.94, 3.84 Hz, 1H), 7.60 (d, J=5.21 Hz, 1H), 7.82 (d, J=8.78 Hz, 1H), 7.84-7.89 (m, 1H), 8.15 (d, J=8.78 Hz, 1H), 8.27 (s, 1H), 8.36 (d, J=5.21 Hz, 1H), 8.51 (s, 1H), 8.55 (d, J=3.02 Hz, 1H), 13.95 (br s, 1H); ESIMS found for C 20 H 14 N 8 S m/z 399.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N,N-Dimethyl-2-((5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)oxy)ethan-1-amine 707 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.61 (s, 6H), 3.20 (br s, 2H), 4.43-4.51 (m, 2H), 7.31 (t, J=4.12 Hz, 1H), 7.73 (d, J=4.94 Hz, 1H), 8.27-8.32 (m, 1H), 8.32-8.36 (m, 1H), 8.38 (br s, 1H), 8.43 (br d, J=1.92 Hz, 1H), 8.47 (d, J=2.74 Hz, 1H), 8.75 (s, 1H), 8.88 (s, 1H), 9.26 (s, 1H), 13.36 (br s, 1H), 14.25 (br s, 1H); ESIMS found for C 25 H 22 N 8 OS m/z 483.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(5-Methylthiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine 730 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.59 (s, 3H), 2.93 (br s, 2H), 3.18 (br t, J=5.76 Hz, 2H), 3.65 (br d, J=2.47 Hz, 2H), 6.88 (br s, 1H), 6.99 (d, J=2.47 Hz, 1H), 7.48 (d, J=5.21 Hz, 1H), 7.82 (d, J=9.06 Hz, 1H), 8.12 (d, J=8.78 Hz, 1H), 8.27-8.30 (m, 2H); ESIMS found for C 22 H 19 N 7 S m/z 414.1 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(5-(Cyclohexyloxy)pyridin-3-yl)-3-(7-(5-methylthiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridine 735 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.26-1.33 (m, 1H), 1.36-1.45 (m, 2H), 1.48-1.59 (m, 3H), 1.74 (br dd, J=9.19, 3.70 Hz, 2H), 1.98-2.06 (m, 2H), 2.61 (s, 3H), 4.60-4.67 (m, 1H), 7.01-7.07 (m, 1H), 7.48 (d, J=5.21 Hz, 1H), 8.22-8.27 (m, 1H), 8.27-8.30 (m, 2H), 8.31 (d, J=5.21 Hz, 1H), 8.42 (d, J=2.74 Hz, 1H), 8.44 (d, J=3.57 Hz, 1H), 9.25 (d, J=1.37 Hz, 1H), 13.56 (s, 1H), 14.07 (s, 1H) ESIMS found for C 28 H 25 N 7 OS m/z 508.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(3-Fluoro-5-(2-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)methanesulfonamide 764 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.96 (s, 3H), 3.95 (s, 3H), 4.36 (d, J=6.31 Hz, 2H), 7.37 (br d, J=9.61 Hz, 1H), 7.69 (d, J=5.21 Hz, 1H), 7.75 (t, J=6.31 Hz, 1H), 7.82 (d, J=8.78 Hz, 1H), 8.11 (br s, 1H), 8.14 (d, J=8.78 Hz, 1H), 8.25 (s, 1H), 8.47 (d, J=5.21 Hz, 1H), 8.48 (s, 1H), 8.76 (br s, 1H), 13.95 (br s, 1H); ESIMS found for C 24 H 20 FN 9 O 2 S m/z 518.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-Fluoro-5-(methylsulfonamidomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-2-(piperidin-4-yl)acetamide 769 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35-1.46 (m, 2H), 1.85 (br d, J=11.80 Hz, 2H), 2.07 (ddt, J=14.75, 7.48, 3.70, 3.70 Hz, 1H), 2.36 (d, J=6.86 Hz, 2H), 2.86 (td, J=12.69, 2.61 Hz, 2H), 2.94 (s, 3H), 3.24 (br d, J=12.62 Hz, 2H), 4.35 (s, 2H), 7.32 (br d, J=9.06 Hz, 1H), 7.68 (br d, J=1.37 Hz, 1H), 7.78 (br s, 1H), 8.07 (d, J=9.06 Hz, 1H), 8.19 (br s, 1H), 8.33 (d, J=8.78 Hz, 1H), 8.48 (d, J=5.21 Hz, 1H), 8.57 (br s, 1H), 8.78 (s, 1H), 8.88 (d, J=2.20 Hz, 1H), 9.24 (br s, 1H), 10.37 (s, 1H); ESIMS found for C 32 H 31 FN 10 O 3 S m/z 655.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-(2-(5-(1,2-Dimethyl-1H-imidazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 781 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.39 (s, 3H), 2.59 (br s, 6H), 2.96 (br s, 2H), 3.39 (br s, 2H), 4.14 (s, 3H), 6.15 (br s, 1H), 6.61 (br d, J=11.80 Hz, 1H), 7.30 (s, 1H), 7.52 (d, J=5.21 Hz, 1H), 7.54 (s, 1H), 7.63 (br d, J=10.15 Hz, 1H), 7.84 (d, J=9.06 Hz, 1H), 8.15 (d, J=9.06 Hz, 1H), 8.39 (d, J=4.94 Hz, 1H), 13.58 (br s, 1H), 14.00 (br s, 1H); ESIMS found for C 27 H 27 FN 10  m/z 511.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-Fluoro-5-(2-(5-(5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 786 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68 (dt, J=6.66, 3.12 Hz, 4H), 2.18 (s, 6H), 2.47 (br d, J=6.59 Hz, 2H), 2.54-2.59 (m, 4H), 2.87 (t, J=5.76 Hz, 2H), 3.19 (br d, J=5.21 Hz, 2H), 4.26 (br s, 2H), 5.89 (br s, 1H), 6.48-6.58 (m, 1H), 7.47 (br d, J=1.92 Hz, 1H), 7.52-7.64 (m, 2H), 8.22 (d, J=9.06 Hz, 1H), 8.25 (br s, 1H), 8.27-8.33 (m, 1H), 8.40 (d, J=2.74 Hz, 1H), 8.42 (br d, J=5.21 Hz, 1H), 9.11 (br s, 1H), 13.53 (br s, 1H); ESIMS found for C 33 H 35 FN 10 O m/z 607.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-(2-(5-(5-(Benzyloxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-5-fluorophenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 790 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.26 (s, 6H), 2.55-2.60 (m, 2H), 3.22 (br d, J=1.92 Hz, 2H), 5.30 (s, 2H), 5.96 (br s, 1H), 6.48 (dt, J=11.66, 1.99 Hz, 1H), 7.32-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.53 (br s, 2H), 7.51 (d, J=7.14 Hz, 1H), 7.55 (br s, 1H), 8.19-8.24 (m, 3H), 8.30 (d, J=8.78 Hz, 1H), 8.35 (br d, J=1.37 Hz, 1H), 8.43 (d, J=5.21 Hz, 1H), 8.46 (d, J=2.74 Hz, 1H), 9.13 (s, 1H), 13.52 (br s, 1H); ESIMS found for C 34 H 30 FN 9 O m/z 600.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N 1 -(3-Fluoro-5-(2-(5-(pyrazin-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N 2 ,N 2 -dimethylethane-1,2-diamine 792 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.17 (s, 6H), 2.45-2.49 (m, 2H), 3.17-3.24 (m, 2H), 5.89 (br s, 1H), 6.55 (dt, J=11.66, 1.99 Hz, 1H), 7.41 (br d, J=2.20 Hz, 1H), 7.54-7.63 (m, 1H), 7.71-7.81 (m, 1H), 8.35 (d, J=8.78 Hz, 1H), 8.43 (br d, J=4.94 Hz, 1H), 8.54 (d, J=8.78 Hz, 1H), 8.76 (d, J=2.47 Hz, 1H), 8.77-8.82 (m, 1H), 10.02 (br s, 1H), 13.30 (br s, 1H); ESIMS found for C 26 H 23 FN 10  m/z 495.0 (M+1). 
     
       
         
         
             
             
         
       
     
     2-(dimethylamino)-N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 969 
     Off-white solid (4.3 mg, 0.008 mmol, 13.2% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.59 (br s, 6H), 3.65 (br s, 2H), 7.36 (td, J=8.37, 2.47 Hz, 1H), 7.62-7.70 (m, 1H), 7.73 (d, J=5.21 Hz, 1H), 8.11 (d, J=9.06 Hz, 1H), 8.33 (d, J=8.78 Hz, 1H), 8.45 (d, J=5.21 Hz, 1H), 8.48 (br d, J=7.96 Hz, 1H), 8.56 (br d, J=10.98 Hz, 1H), 8.79-8.84 (m, 1H), 8.95 (d, J=2.20 Hz, 1H), 9.34 (d, J=1.92 Hz, 1H), 10.49 (br s, 1H), 13.65 (s, 1H), 14.16 (br s, 1H); ESIMS found for C 27 H 22 FN 9 O m/z 508.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 994 
     Brown solid (7.2 mg, 0.017 mmol, 14.0% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.88 (s, 3H), 7.12 (dd, J=8.23, 2.47 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.60 (dd, J=7.96, 4.67 Hz, 1H), 7.66 (d, J=5.21 Hz, 1H), 8.16-8.24 (m, 3H), 8.30 (d, J=8.78 Hz, 1H), 8.43 (d, J=5.21 Hz, 1H), 8.67-8.76 (m, 2H), 9.59 (d, J=1.92 Hz, 1H), 13.58 (br s, 1H), 14.10 (br s, 1H); ESIMS found for C 24 H 17 N 7 O m/z 420.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-2-phenylacetamide 1000 
     Brown solid (5.6 mg, 0.010 mmol, 8.9% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.74 (s, 2H), 3.82 (s, 3H), 7.07 (dd, J=8.10, 2.06 Hz, 1H), 7.23-7.29 (m, 1H), 7.30-7.39 (m, 4H), 7.53 (t, J=7.96 Hz, 1H), 7.65 (d, J=5.21 Hz, 1H), 8.00-8.18 (m, 2H), 8.07 (d, J=9.06 Hz, 1H), 8.32 (d, J=8.78 Hz, 1H), 8.45 (d, J=4.94 Hz, 1H), 8.77 (s, 1H), 8.93 (d, J=2.20 Hz, 1H), 9.26 (s, 1H), 10.61 (s, 1H), 14.14 (br s, 1H); ESIMS found for C 32 H 24 N 8 O 2  m/z 553.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide 1006 
     White solid (5.7 mg, 0.011 mmol, 7.4% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.05 (s, 9H), 2.27 (s, 2H), 3.83 (s, 3H), 7.07 (dd, J=8.23, 2.20 Hz, 1H), 7.53 (t, J=7.96 Hz, 1H), 7.64 (br d, J=3.29 Hz, 1H), 8.06 (d, J=8.78 Hz, 1H), 8.14 (br s, 2H), 8.32 (d, J=8.78 Hz, 1H), 8.44 (br d, J=4.94 Hz, 1H), 8.74 (s, 1H), 8.89 (d, J=2.20 Hz, 1H), 9.23 (br s, 1H), 10.20 (s, 1H), 13.56 (br s, 1H), 14.12 (s, 1H); ESIMS found for C 30 H 28 N 8 O 2  m/z 533.3 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(3-Methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 1012 
     Yellow solid (5.4 mg, 0.010 mmol, 9.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.18-1.36 (m, 3H), 1.45 (qd, J=12.35, 3.02 Hz, 2H), 1.63-1.71 (m, 1H), 1.74-1.82 (m, 2H), 1.87 (br d, J=12.90 Hz, 2H), 2.35-2.45 (m, 2H), 3.84 (s, 3H), 7.04 (dd, J=7.96, 2.20 Hz, 1H), 7.48-7.55 (m, 2H), 7.67 (br d, J=8.51 Hz, 1H), 7.99-8.11 (m, 2H), 8.15 (d, J=8.51 Hz, 1H), 8.29 (d, J=5.21 Hz, 1H), 8.65 (t, J=1.92 Hz, 1H), 8.89 (d, J=2.47 Hz, 1H), 9.13 (d, J=1.65 Hz, 1H), 10.15 (s, 1H); ESIMS found for C 31 H 28 N 8 O 2  m/z 545.2 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(3-Methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(piperidin-4-yloxy)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 1025 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68-1.76 (m, 2H), 2.06-2.14 (m, 2H), 2.79-2.86 (m, 2H), 3.09-3.15 (m, 2H), 3.86 (s, 3H), 4.75-4.82 (m, 1H), 7.10 (dd, J=8.37, 2.06 Hz, 1H), 7.58 (t, J=7.96 Hz, 1H), 7.65 (br s, 1H), 8.22 (d, J=8.78 Hz, 1H), 8.26-8.33 (m, 4H), 8.44 (br d, J=4.94 Hz, 1H), 8.47 (d, J=2.74 Hz, 1H), 9.17 (s, 1H); ESIMS found for C 29 H 26 N 8 O 2  m/z 519.2 (M+1). 
     
       
         
         
             
             
         
       
     
     5-(3-(7-(3-Methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-ol 1030 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.86 (s, 3H), 7.09 (dd, J=7.96, 2.20 Hz, 1H), 7.58 (br t, J=8.10 Hz, 1H), 7.66 (br d, J=4.39 Hz, 1H), 8.04 (br s, 1H), 8.09 (br s, 1H), 8.12 (d, J=9.06 Hz, 1H), 8.22-8.30 (m, 3H), 8.43 (br d, J=4.94 Hz, 1H), 9.01 (br s, 1H), 10.12 (br s, 1H), 13.53 (br s, 1H), 14.08 (br s, 1H); ESIMS found for C 24 H 17 N 7 O 2  m/z 436.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(5-chlorothiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)-3-methylbutanamide 1037 
     Beige solid (5.0 mg, 0.009 mmol, 7.3% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.96 (d, J=6.59 Hz, 6H), 2.11 (tt, J=13.69, 6.62 Hz, 1H), 2.27 (d, J=7.14 Hz, 2H), 7.29 (d, J=3.84 Hz, 1H), 7.62 (d, J=5.21 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.29-8.34 (m, 2H), 8.36 (d, J=5.21 Hz, 1H), 8.85 (s, 2H), 9.26 (s, 1H), 10.24 (s, 1H), 13.66 (br s, 1H), 14.14 (br s, 1H); ESIMS found for C 26 H 21 ClN 8 OS m/z 529.1 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(5-chlorothiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)pivalamide 1043 
     Beige solid (11.5 mg, 0.022 mmol, 17.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.27 (s, 9H), 7.28 (d, J=4.12 Hz, 1H), 7.62 (d, J=5.21 Hz, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.29-8.34 (m, 2H), 8.36 (d, J=5.21 Hz, 1H), 8.83 (t, J=2.20 Hz, 1H), 8.95 (d, J=2.20 Hz, 1H), 9.29 (d, J=1.92 Hz, 1H), 9.58 (s, 1H), 13.67 (s, 1H), 14.14 (s, 1H); ESIMS found for C 26 H 21 ClN 8 OS m/z 529.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(5-chlorothiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine 1049 
     Brown solid (26.1 mg, 0.049 mmol, 37.1% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.84 (br s, 4H), 2.95 (br s, 4H), 4.20 (br s, 2H), 7.33 (d, J=4.12 Hz, 1H), 7.65 (d, J=5.21 Hz, 1H), 8.21 (d, J=9.06 Hz, 1H), 8.28 (d, J=4.12 Hz, 1H), 8.32-8.40 (m, 2H), 8.71 (br d, J=16.74 Hz, 2H), 9.63 (br s, 1H), 13.67 (br s, 1H), 14.19 (br s, 1H); ESIMS found for C 26 H 21 ClN 8 S m/z 513.2 (M+1). 
     
       
         
         
             
             
         
       
     
     N-(5-(3-(7-(5-chlorothiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo [4,3-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 1056 
     White solid (2.5 mg, 0.005 mmol, 4.8% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.78-1.88 (m, 1H), 1.92-2.05 (m, 1H), 2.11-2.20 (m, 2H), 2.21-2.32 (m, 2H), 3.26-3.30 (m, 1H), 7.28 (d, J=4.12 Hz, 1H), 7.62 (d, J=5.21 Hz, 1H), 8.10 (d, J=8.78 Hz, 1H), 8.29-8.35 (m, 2H), 8.36 (d, J=4.94 Hz, 1H), 8.86 (s, 2H), 9.24 (d, J=0.82 Hz, 1H), 10.10 (s, 1H), 13.66 (s, 1H), 14.14 (s, 1H); ESIMS found for C 26 H 19 ClN 8 OS m/z 527.1 (M+1). 
     
       
         
         
             
             
         
       
     
     1-(6-(3-(7-(5-Chlorothiophen-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyrazin-2-yl)azetidin-3-amine 1068 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.80 (br dd, J=7.82, 5.90 Hz, 2H), 3.92-3.99 (m, 1H), 4.34 (br t, J=7.68 Hz, 2H), 7.31 (d, J=3.84 Hz, 1H), 7.66 (d, J=5.21 Hz, 1H), 7.98 (s, 1H), 8.23-8.28 (m, 1H), 8.31 (d, J=9.06 Hz, 1H), 8.37 (d, J=5.21 Hz, 1H), 8.48 (d, J=8.78 Hz, 1H), 9.34 (s, 1H); ESIMS found for C 23 H 17 ClN 10 S m/z 501.1 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridine 1108 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.97-2.08 (m, 2H), 2.16 (br d, J=12.08 Hz, 2H), 2.95-3.02 (m, 2H), 3.18-3.25 (m, 1H), 3.34 (br d, J=12.35 Hz, 2H), 6.15 (s, 2H), 7.14 (d, J=8.23 Hz, 1H), 7.47 (d, J=8.78 Hz, 1H), 7.58 (br d, J=4.12 Hz, 1H), 8.11 (br s, 1H), 8.13 (d, J=8.78 Hz, 1H), 8.32 (br s, 1H), 8.36 (d, J=5.21 Hz, 1H); ESIMS found for C 24 H 21 N 7 O 2  m/z 440.15 (M+1). 
     
       
         
         
             
             
         
       
     
     3-(7-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine 1109 
       1 H NMR (499 MHz, METHANOL-d 4 ) δ ppm 3.23 (br s, 2H), 3.58 (t, J=6.17 Hz, 2H), 4.01 (br s, 2H), 6.13 (s, 2H), 6.83 (br s, 1H), 7.08 (d, J=7.96 Hz, 1H), 7.56 (d, J=5.49 Hz, 1H), 7.67 (br d, J=7.96 Hz, 1H), 7.88 (d, J=8.78 Hz, 1H), 7.90 (br s, 1H), 8.11 (d, J=8.78 Hz, 1H), 8.44 (d, J=5.49 Hz, 1H); ESIMS found for C 24 H 19 N 7 O 2  m/z 438.15 (M+1). 
     
       
         
         
             
             
         
       
     
     2,2,2-trifluoro-N-(5-(3-(7-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 1126 
     Yellow solid (3.4 mg, 0.007 mmol, 6.5% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 7.39-7.49 (m, 3H), 7.53-7.61 (m, 1H), 8.10-8.28 (m, 1H), 8.14 (d, J=9.06 Hz, 1H), 8.34 (d, J=9.06 Hz, 1H), 8.49 (br d, J=4.94 Hz, 1H), 8.82 (t, J=2.06 Hz, 1H), 8.96 (d, J=2.20 Hz, 1H), 9.41 (s, 1H), 11.70 (s, 1H), 14.17 (br s, 1H); ESIMS found for C 25 H 14 F 4 N 8 O m/z 519.1 (M+1). 
     
       
         
         
             
             
         
       
     
     2,2,2-trifluoro-N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)acetamide 1127 
     Yellow solid (2.5 mg, 0.005 mmol, 4.7% yield).  1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.24 (s, 3H), 2.51-2.57 (m, 4H), 4.02 (br s, 4H), 6.55 (d, J=5.76 Hz, 1H), 8.00 (d, J=6.04 Hz, 1H), 8.10 (d, J=9.06 Hz, 1H), 8.23-8.30 (m, 2H), 8.78 (s, 1H), 8.84 (d, J=1.92 Hz, 1H), 9.26 (s, 1H), 13.08 (br s, 1H), 13.96 (br s, 1H); ESIMS found for C 24 H 21 F 3 N 10 O m/z 523.2 (M+1). 
     
       
         
         
             
             
         
       
     
     (4-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methyl-1H-pyrazol-3-yl)methanol 1129 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.89 (s, 3H), 4.73 (s, 2H), 7.40 (t, J=8.92 Hz, 2H), 7.59 (d, J=5.21 Hz, 1H), 7.86 (d, J=8.78 Hz, 1H), 8.21 (d, J=9.06 Hz, 1H), 8.42 (d, J=5.21 Hz, 1H), 8.48 (s, 1H), 8.54 (br dd, J=8.23, 5.76 Hz, 2H), 14.06 (br s, 1H); ESIMS found for C 23 H 17 FN 8 O m/z 441.2 (M+1). 
     
       
         
         
             
             
         
       
     
     (1-Methyl-4-(3-(7-(piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrazol-3-yl)methanol 1134 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.66 (br s, 6H), 3.87 (s, 3H), 3.96 (br s, 4H), 4.65 (s, 2H), 6.50 (d, J=5.76 Hz, 1H), 7.81 (d, J=9.06 Hz, 1H), 7.94 (d, J=5.76 Hz, 1H), 8.15 (d, J=9.06 Hz, 1H), 8.43 (s, 1H), 13.79 (br s, 1H); ESIMS found for C 22 H 23 N 9 O m/z 430.2 (M+1). 
     
       
         
         
             
             
         
       
     
     (4-(3-(7-(Benzo[d][1,3]dioxol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methyl-1H-pyrazol-3-yl)methanol 1152 
       1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 3.89 (s, 3H), 4.73 (s, 2H), 6.14 (s, 2H), 7.12 (d, J=8.23 Hz, 1H), 7.56 (d, J=5.21 Hz, 1H), 7.88 (d, J=8.78 Hz, 1H), 8.00 (br d, J=7.96 Hz, 1H), 8.10 (br s, 1H), 8.21 (d, J=8.78 Hz, 1H), 8.39 (d, J=5.21 Hz, 1H), 8.48 (s, 1H), 14.06 (br s, 1H); ESIMS found for C 24 H 18 N 8 O 3  m/z 467.1 (M+1). 
     Example 2 
     The screening assay for Wnt activity is described as follows. Reporter cell lines can be generated by stably transducing cancer cell lines (e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells) with a lentiviral construct that includes a Wnt-responsive promoter driving expression of the firefly luciferase gene. 
     SW480 colon carcinoma cells were transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and a hygromycin resistance gene were selected by treatment with 150 μg/mL of hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening activities. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 μM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well white solid bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. For Sp5-Luc reporter gene assays, the cells were plated at 4,000 cells/well in 384-well plates with medium containing 1% fetal bovine serum and incubated overnight at 37° C. and 5% CO 2 . Following incubation, 20 μl of BrightGlo luminescence reagent (Promega) was added to each well of the 384-well assay plates. The plates were placed on an orbital shaker for 2 min and then luminescence was quantified using the Envision (Perkin Elmer) plate reader. Readings were normalized to DMSO only treated cells, and normalized activities were utilized for EC 50  calculations using the dose-response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics). For EC 50  of &gt;10 μM, the percent inhibition at 10 μM is provided. 
     Table 2 shows the measured activity for representative compounds of Formula I as described herein. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                 Compound 
                 EC 50  (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1 
                 &gt;10 
                 (51.6%) 
               
            
           
           
               
               
               
            
               
                   
                 2 
                 0.495 
               
               
                   
                 7 
                 0.929 
               
               
                   
                 13 
                 2.882 
               
            
           
           
               
               
               
               
            
               
                   
                 18 
                 &gt;10 
                 (21.0%) 
               
               
                   
                 20 
                 &gt;10 
                 (51.2%) 
               
            
           
           
               
               
               
            
               
                   
                 26 
                 0.885 
               
            
           
           
               
               
               
               
            
               
                   
                 36 
                 &gt;10 
                 (28.4%) 
               
            
           
           
               
               
               
            
               
                   
                 42 
                 3.726 
               
               
                   
                 49 
                 0.908 
               
            
           
           
               
               
               
               
            
               
                   
                 55 
                 &gt;10 
                 (20.2%) 
               
               
                   
                 59 
                 &gt;10 
                 (46.5%) 
               
               
                   
                 65 
                 &gt;10 
                 (14.3%) 
               
            
           
           
               
               
               
            
               
                   
                 72 
                 1.987 
               
            
           
           
               
               
               
               
            
               
                   
                 78 
                 &gt;10 
                 (39.4%) 
               
            
           
           
               
               
               
            
               
                   
                 81 
                 1.125 
               
               
                   
                 84 
                 0.670 
               
               
                   
                 88 
                 1.603 
               
            
           
           
               
               
               
               
            
               
                   
                 93 
                 &gt;10 
                 (10.2%) 
               
            
           
           
               
               
               
            
               
                   
                 96 
                 1.958 
               
               
                   
                 108 
                 4.861 
               
            
           
           
               
               
               
               
            
               
                   
                 117 
                 &gt;10 
                 (4.8%) 
               
               
                   
                 122 
                 &gt;10 
                 (8.4%) 
               
               
                   
                 129 
                 &gt;10 
                 (4.3%) 
               
               
                   
                 130 
                 &gt;10 
                 (12.1%) 
               
               
                   
                 135 
                 &gt;10 
                 (10.4%) 
               
               
                   
                 146 
                 &gt;10 
                 (10.6%) 
               
               
                   
                 151 
                 &gt;10 
                 (6.4%) 
               
               
                   
                 159 
                 &gt;10 
                 (12.6%) 
               
               
                   
                 169 
                 &gt;10 
                 (44.2%) 
               
               
                   
                 175 
                 &gt;10 
                 (0%) 
               
               
                   
                 181 
                 &gt;10 
                 (2.2%) 
               
            
           
           
               
               
               
            
               
                   
                 188 
                 3.996 
               
               
                   
                 194 
                 4.135 
               
            
           
           
               
               
               
               
            
               
                   
                 198 
                 &gt;10 
                 (27.6%) 
               
               
                   
                 204 
                 &gt;10 
                 (12.2%) 
               
               
                   
                 210 
                 &gt;10 
                 (31.5%) 
               
               
                   
                 217 
                 &gt;10 
                 (13.9%) 
               
               
                   
                 227 
                 &gt;10 
                 (8.2%) 
               
               
                   
                 233 
                 &gt;10 
                 (2.3%) 
               
               
                   
                 246 
                 &gt;10 
                 (4.2%) 
               
               
                   
                 251 
                 &gt;10 
                 (16.5%) 
               
               
                   
                 256 
                 &gt;10 
                 (43.4%) 
               
               
                   
                 262 
                 &gt;10 
                 (7.6%) 
               
               
                   
                 268 
                 &gt;10 
                 (1.9%) 
               
               
                   
                 275 
                 &gt;10 
                 (3.1%) 
               
            
           
           
               
               
               
            
               
                   
                 280 
                 0.687 
               
            
           
           
               
               
               
               
            
               
                   
                 281 
                 &gt;10 
                 (28.3%) 
               
            
           
           
               
               
               
            
               
                   
                 285 
                 0.865 
               
               
                   
                 291 
                 0.527 
               
               
                   
                 297 
                 0.822 
               
               
                   
                 304 
                 1.974 
               
               
                   
                 306 
                 0.533 
               
               
                   
                 314 
                 3.831 
               
               
                   
                 320 
                 0.341 
               
               
                   
                 327 
                 0.803 
               
               
                   
                 333 
                 2.722 
               
            
           
           
               
               
               
               
            
               
                   
                 343 
                 &gt;10 
                 (31.7%) 
               
            
           
           
               
               
               
            
               
                   
                 349 
                 3.959 
               
               
                   
                 354 
                 0.731 
               
               
                   
                 356 
                 2.278 
               
               
                   
                 395 
                 0.047 
               
               
                   
                 401 
                 0.565 
               
            
           
           
               
               
               
               
            
               
                   
                 414 
                 &gt;10 
                 (47.0%) 
               
               
                   
                 454 
                 &gt;10 
                 (43.4%) 
               
            
           
           
               
               
               
            
               
                   
                 460 
                 1.181 
               
            
           
           
               
               
               
               
            
               
                   
                 467 
                 &gt;10 
                 (34.1%) 
               
            
           
           
               
               
               
            
               
                   
                 473 
                 3.639 
               
            
           
           
               
               
               
               
            
               
                   
                 476 
                 &gt;10 
                 (15.5%) 
               
            
           
           
               
               
               
            
               
                   
                 481 
                 1.247 
               
            
           
           
               
               
               
               
            
               
                   
                 487 
                 &gt;10 
                 (7.1%) 
               
               
                   
                 493 
                 &gt;10 
                 (14.8%) 
               
            
           
           
               
               
               
            
               
                   
                 500 
                 3.584 
               
            
           
           
               
               
               
               
            
               
                   
                 503 
                 &gt;10 
                 (14.1%) 
               
               
                   
                 505 
                 &gt;10 
                 (16.0%) 
               
            
           
           
               
               
               
            
               
                   
                 506 
                 &gt;10 
               
            
           
           
               
               
               
               
            
               
                   
                 507 
                 &gt;10 
                 (17.0%) 
               
               
                   
                 508 
                 &gt;10 
                 (41.0%) 
               
            
           
           
               
               
               
            
               
                   
                 509 
                 0.120 
               
               
                   
                 510 
                 3.710 
               
            
           
           
               
               
               
               
            
               
                   
                 512 
                 &gt;10 
                 (45.0%) 
               
            
           
           
               
               
               
            
               
                   
                 514 
                 4.106 
               
               
                   
                 515 
                 2.843 
               
               
                   
                 516 
                 0.338 
               
               
                   
                 517 
                 0.423 
               
               
                   
                 520 
                 3.615 
               
            
           
           
               
               
               
               
            
               
                   
                 559 
                 &gt;10 
                 (12.4%) 
               
               
                   
                 565 
                 &gt;10 
                 (14.1%) 
               
               
                   
                 576 
                 &gt;10 
                 (8.9%) 
               
               
                   
                 582 
                 &gt;10 
                 (5.8%) 
               
               
                   
                 584 
                 &gt;10 
                 (8.5%) 
               
               
                   
                 593 
                 &gt;10 
                 (29.3%) 
               
               
                   
                 610 
                 &gt;10 
                 (4.8%) 
               
               
                   
                 612 
                 &gt;10 
                 (5.8%) 
               
            
           
           
               
               
               
            
               
                   
                 613 
                 3.291 
               
            
           
           
               
               
               
               
            
               
                   
                 618 
                 &gt;10 
                 (8.7%) 
               
               
                   
                 622 
                 &gt;10 
                 (9.8%) 
               
               
                   
                 627 
                 &gt;10 
                 (22.4%) 
               
            
           
           
               
               
               
            
               
                   
                 639 
                 4.060 
               
               
                   
                 646 
                 1.811 
               
               
                   
                 648 
                 4.344 
               
            
           
           
               
               
               
               
            
               
                   
                 651 
                 &gt;10 
                 (12.0%) 
               
               
                   
                 656 
                 &gt;10 
                 (22.1%) 
               
               
                   
                 661 
                 &gt;10 
                 (7.2%) 
               
               
                   
                 673 
                 &gt;10 
                 (26.9%) 
               
            
           
           
               
               
               
            
               
                   
                 685 
                 2.818 
               
            
           
           
               
               
               
               
            
               
                   
                 690 
                 &gt;10 
                 (37.6%) 
               
               
                   
                 692 
                 &gt;10 
                 (15.3%) 
               
               
                   
                 700 
                 &gt;10 
                 (3.4%) 
               
            
           
           
               
               
               
            
               
                   
                 707 
                 3.572 
               
               
                   
                 730 
                 3.165 
               
               
                   
                 735 
                 0.984 
               
            
           
           
               
               
               
               
            
               
                   
                 764 
                 &gt;10 
                 (20.9%) 
               
               
                   
                 769 
                 &gt;10 
                 (12.1%) 
               
            
           
           
               
               
               
            
               
                   
                 781 
                 0.620 
               
               
                   
                 786 
                 6.245 
               
               
                   
                 790 
                 2.655 
               
               
                   
                 792 
                 3.930 
               
               
                   
                 969 
                 4.362 
               
               
                   
                 994 
                 1.870 
               
               
                   
                 1000 
                 2.804 
               
               
                   
                 1006 
                 1.547 
               
               
                   
                 1012 
                 1.908 
               
            
           
           
               
               
               
               
            
               
                   
                 1025 
                 &gt;10 
                 (39.2%) 
               
               
                   
                 1030 
                 &gt;10 
                 (33.5%) 
               
            
           
           
               
               
               
            
               
                   
                 1037 
                 1.491 
               
               
                   
                 1043 
                 0.644 
               
               
                   
                 1049 
                 7.697 
               
               
                   
                 1056 
                 0.354 
               
               
                   
                 1068 
                 2.300 
               
            
           
           
               
               
               
               
            
               
                   
                 1108 
                 &gt;10 
                 (9.3%) 
               
               
                   
                 1109 
                 &gt;10 
                 (14.5%) 
               
               
                   
                 1126 
                 &gt;10 
                 (43.0%) 
               
               
                   
                 1127 
                 &gt;10 
                 (15.7%) 
               
               
                   
                 1129 
                 &gt;10 
                 (14.8%) 
               
               
                   
                 1134 
                 &gt;10 
                 (4.0%) 
               
               
                   
                 1152 
                 &gt;10 
                 (15.4%) 
               
               
                   
                   
               
            
           
         
       
     
     Example 3 
     Representative compounds were screened using the following assay procedure to assess the effect on cell viability as described below. 
     Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 8-point dose-response curves from 10 μM to 0.0045 μM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 96-well clear bottom, black-walled plates (Corning-Costar). 
     Approximately 2×103 SW480 colon cancer cells were seeded into each well and allowed to incubate in the presence or absence of compound for four days at 37° C./5% CO 2 . Eight replicates of DMSO-treated cells served as controls and cells treated with compound were performed in duplicate. 
     After incubation, 20 μL of CellTiter-Blue (Promega) was added to each well allowed to incubate for approximately 3 hours. This reagent was a buffered solution which contains resazurin, metabolically active cells were able to reduce rezarurin (blue) into resorufin (pink) which was highly fluorescent. This measured fluorescence was used as a readout for cell viability. 
     After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation 3, BioTek). Dose-response curves were generated and EC 50  concentration values were calculated using non-linear regression curve fit in the GraphPad Prism (San Diego, Calif.) or Dotmatics&#39; Studies Software (Bishops Stortford, UK). For EC 50  of &gt;10 μM, the percent inhibition at 10 μM is provided. 
     Table 3 shows the activity of representative compounds of Formula I as provided herein. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                 Compound 
                 EC 50  (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1 
                 &gt;10 
                 (19.9%) 
               
            
           
           
               
               
               
            
               
                   
                 2 
                 0.400 
               
               
                   
                 7 
                 0.540 
               
               
                   
                 13 
                 1.133 
               
            
           
           
               
               
               
               
            
               
                   
                 18 
                 &gt;10 
                 (0%) 
               
               
                   
                 20 
                 &gt;10 
                 (2.8%) 
               
            
           
           
               
               
               
            
               
                   
                 26 
                 0.409 
               
            
           
           
               
               
               
               
            
               
                   
                 36 
                 &gt;10 
                 (15.0%) 
               
            
           
           
               
               
               
            
               
                   
                 42 
                 1.081 
               
               
                   
                 49 
                 0.551 
               
               
                   
                 55 
                 0.171 
               
            
           
           
               
               
               
               
            
               
                   
                 59 
                 &gt;10 
                 (21.5%) 
               
               
                   
                 65 
                 &gt;10 
                 (7.5%) 
               
               
                   
                 72 
                 &gt;10 
                 (0%) 
               
               
                   
                 78 
                 &gt;10 
                 (12.3%) 
               
            
           
           
               
               
               
            
               
                   
                 81 
                 2.642 
               
            
           
           
               
               
               
               
            
               
                   
                 84 
                 &gt;10 
                 (0%) 
               
               
                   
                 88 
                 &gt;10 
                 (42.2%) 
               
               
                   
                 93 
                 &gt;10 
                 (8.1%) 
               
            
           
           
               
               
               
            
               
                   
                 96 
                 2.005 
               
               
                   
                 108 
                 3.317 
               
            
           
           
               
               
               
               
            
               
                   
                 117 
                 &gt;10 
                 (1.7%) 
               
               
                   
                 122 
                 &gt;10 
                 (4.4%) 
               
               
                   
                 129 
                 &gt;10 
                 (5.7%) 
               
               
                   
                 130 
                 &gt;10 
                 (0%) 
               
               
                   
                 135 
                 &gt;10 
                 (3.8%) 
               
               
                   
                 146 
                 &gt;10 
                 (23.3%) 
               
               
                   
                 151 
                 &gt;10 
                 (2.7%) 
               
               
                   
                 159 
                 &gt;10 
                 (6.7%) 
               
            
           
           
               
               
               
            
               
                   
                 169 
                 4.653 
               
            
           
           
               
               
               
               
            
               
                   
                 175 
                 &gt;10 
                 (13.6%) 
               
            
           
           
               
               
               
            
               
                   
                 181 
                 5.551 
               
               
                   
                 188 
                 3.908 
               
               
                   
                 194 
                 0.832 
               
            
           
           
               
               
               
               
            
               
                   
                 198 
                 &gt;10 
                 (46.0%) 
               
               
                   
                 204 
                 &gt;10 
                 (0%) 
               
               
                   
                 210 
                 &gt;10 
                 (12.6%) 
               
               
                   
                 217 
                 &gt;10 
                 (2.1%) 
               
               
                   
                 227 
                 &gt;10 
                 (0%) 
               
               
                   
                 233 
                 &gt;10 
                 (0%) 
               
               
                   
                 246 
                 &gt;10 
                 (0%) 
               
               
                   
                 251 
                 &gt;10 
                 (0%) 
               
               
                   
                 256 
                 &gt;10 
                 (22.2%) 
               
               
                   
                 262 
                 &gt;10 
                 (5.5%) 
               
               
                   
                 268 
                 &gt;10 
                 (0%) 
               
               
                   
                 275 
                 &gt;10 
                 (2.6%) 
               
            
           
           
               
               
               
            
               
                   
                 280 
                 2.294 
               
            
           
           
               
               
               
               
            
               
                   
                 281 
                 &gt;10 
                 (24.2%) 
               
            
           
           
               
               
               
            
               
                   
                 285 
                 0.944 
               
            
           
           
               
               
               
               
            
               
                   
                 291 
                 &gt;10 
                 (2.0%) 
               
            
           
           
               
               
               
            
               
                   
                 297 
                 2.642 
               
               
                   
                 304 
                 1.395 
               
               
                   
                 306 
                 0.580 
               
               
                   
                 314 
                 2.821 
               
               
                   
                 320 
                 0.378 
               
            
           
           
               
               
               
               
            
               
                   
                 327 
                 &gt;10 
                 (4.9%) 
               
            
           
           
               
               
               
            
               
                   
                 333 
                 2.594 
               
            
           
           
               
               
               
               
            
               
                   
                 343 
                 &gt;10 
                 (17.5%) 
               
            
           
           
               
               
               
            
               
                   
                 349 
                 1.157 
               
               
                   
                 354 
                 0.405 
               
            
           
           
               
               
               
               
            
               
                   
                 356 
                 &gt;10 
                 (12.4%) 
               
            
           
           
               
               
               
            
               
                   
                 395 
                 0.084 
               
               
                   
                 401 
                 0.270 
               
            
           
           
               
               
               
               
            
               
                   
                 414 
                 &gt;10 
                 (14.7%) 
               
               
                   
                 454 
                 &gt;10 
                 (42.2%) 
               
            
           
           
               
               
               
            
               
                   
                 460 
                 0.695 
               
            
           
           
               
               
               
               
            
               
                   
                 467 
                 &gt;10 
                 (2.7%) 
               
            
           
           
               
               
               
            
               
                   
                 473 
                 2.825 
               
               
                   
                 476 
                 9.021 
               
               
                   
                 481 
                 5.571 
               
            
           
           
               
               
               
               
            
               
                   
                 487 
                 &gt;10 
                 (0.6%) 
               
               
                   
                 493 
                 &gt;10 
                 (3.9%) 
               
            
           
           
               
               
               
            
               
                   
                 500 
                 8.837 
               
            
           
           
               
               
               
               
            
               
                   
                 503 
                 &gt;10 
                 (0.9%) 
               
            
           
           
               
               
               
            
               
                   
                 505 
                 8.300 
               
               
                   
                 506 
                 2.800 
               
            
           
           
               
               
               
               
            
               
                   
                 507 
                 &gt;10 
                 (0%) 
               
               
                   
                 508 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 509 
                 0.115 
               
               
                   
                 510 
                 1.600 
               
            
           
           
               
               
               
               
            
               
                   
                 512 
                 &gt;10 
                 (15.7%) 
               
            
           
           
               
               
               
            
               
                   
                 514 
                 8.646 
               
               
                   
                 515 
                 1.100 
               
               
                   
                 516 
                 0.120 
               
               
                   
                 517 
                 0.768 
               
               
                   
                 520 
                 2.040 
               
            
           
           
               
               
               
               
            
               
                   
                 559 
                 &gt;10 
                 (4.0%) 
               
               
                   
                 565 
                 &gt;10 
                 (5.9%) 
               
               
                   
                 576 
                 &gt;10 
                 (1.7%) 
               
               
                   
                 582 
                 &gt;10 
                 (2.6%) 
               
               
                   
                 584 
                 &gt;10 
                 (10.8%) 
               
               
                   
                 593 
                 &gt;10 
                 (16.7%) 
               
               
                   
                 610 
                 &gt;10 
                 (3.5%) 
               
               
                   
                 612 
                 &gt;10 
                 (6.1%) 
               
            
           
           
               
               
               
            
               
                   
                 613 
                 3.561 
               
            
           
           
               
               
               
               
            
               
                   
                 618 
                 &gt;10 
                 (2.8%) 
               
               
                   
                 622 
                 &gt;10 
                 (4.7%) 
               
               
                   
                 627 
                 &gt;10 
                 (14.8%) 
               
            
           
           
               
               
               
            
               
                   
                 639 
                 5.851 
               
               
                   
                 646 
                 1.156 
               
               
                   
                 648 
                 3.905 
               
            
           
           
               
               
               
               
            
               
                   
                 651 
                 &gt;10 
                 (3.1%) 
               
               
                   
                 656 
                 &gt;10 
                 (11.4%) 
               
               
                   
                 661 
                 &gt;10 
                 (13.0%) 
               
               
                   
                 673 
                 &gt;10 
                 (0.6%) 
               
            
           
           
               
               
               
            
               
                   
                 685 
                 4.192 
               
            
           
           
               
               
               
               
            
               
                   
                 690 
                 &gt;10 
                 (26.6%) 
               
               
                   
                 692 
                 &gt;10 
                 (17.6%) 
               
               
                   
                 700 
                 &gt;10 
                 (0.1%) 
               
            
           
           
               
               
               
            
               
                   
                 707 
                 3.865 
               
               
                   
                 730 
                 3.475 
               
            
           
           
               
               
               
               
            
               
                   
                 735 
                 &gt;10 
                 (10.9%) 
               
               
                   
                 764 
                 &gt;10 
                 (0%) 
               
               
                   
                 769 
                 &gt;10 
                 (8.5%) 
               
            
           
           
               
               
               
            
               
                   
                 781 
                 0.927 
               
               
                   
                 786 
                 9.867 
               
               
                   
                 790 
                 2.222 
               
               
                   
                 792 
                 4.370 
               
            
           
           
               
               
               
               
            
               
                   
                 969 
                 &gt;10 
                 (27.7%) 
               
            
           
           
               
               
               
            
               
                   
                 994 
                 0.897 
               
               
                   
                 1000 
                 1.096 
               
               
                   
                 1006 
                 1.175 
               
               
                   
                 1012 
                 2.913 
               
            
           
           
               
               
               
               
            
               
                   
                 1025 
                 &gt;10 
                 (15.8%) 
               
               
                   
                 1030 
                 &gt;10 
                 (3.0%) 
               
            
           
           
               
               
               
            
               
                   
                 1037 
                 0.110 
               
            
           
           
               
               
               
               
            
               
                   
                 1043 
                 &gt;10 
                 (14.5%) 
               
            
           
           
               
               
               
            
               
                   
                 1049 
                 2.747 
               
               
                   
                 1056 
                 0.109 
               
            
           
           
               
               
               
               
            
               
                   
                 1068 
                 &gt;10 
                 (17.8%) 
               
               
                   
                 1108 
                 &gt;10 
                 (0%) 
               
               
                   
                 1109 
                 &gt;10 
                 (10.9%) 
               
               
                   
                 1126 
                 &gt;10 
                 (35.6%) 
               
               
                   
                 1127 
                 &gt;10 
                 (12.9%) 
               
               
                   
                 1129 
                 &gt;10 
                 (16.9%) 
               
               
                   
                 1134 
                 &gt;10 
                 (18.1%) 
               
               
                   
                 1152 
                 &gt;10 
                 (28.2%) 
               
               
                   
                   
               
            
           
         
       
     
     Example 4 
     Representative compounds were screened using primary human fibroblasts (derived from IPF patients) treated with TGF-β1 to determine their ability to inhibit the fibrotic process. 
     Human Fibroblast Cell Culture: 
     Primary human fibroblasts derived from IPF patients (LL29 cells) [ 1 Xiaoqiu Liu, et. al., “Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation”,  Journal of Pharmacology and Experimental Therapeutics  (2005), 315(2), 678-687;  2 Watts, K. L., et. al., “RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis”,  Respiratory Research  (2006), 7(1), 88] were obtained from American Type Culture Collection (ATCC) and expanded in F12 medium supplemented with 15% Fetal Bovine Serum and Penicillin/Streptomycin. 
     Compound Screening: 
     Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:2, 11-point dose-response curves from 10 μM to 1.87 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. LL29 cells are plated at 1,500 cells/well in 80 μL/well F12 medium supplemented with 1% Fetal Bovine Serum. One hour after addition of the cells, TGF-β1 (Peprotech; 20 ng/mL) was added to the plates to induce fibrosis (ref. 1 and 2 above). Wells treated with TGF-β1 and containing DMSO were used as controls. Cells were incubated at 37° C. and 5% CO 2  for 4 days. Following incubation for 4 days, SYTOX green nucleic acid stain (Life Technologies [Thermo Fisher Scientific]) was added to the wells at a final concentration of 1 μM and incubated at room temperature for 30 min. Cells were then fixed using 4% formaldehyde (Electron Microscopy Sciences), washed 3 times with PBS followed by blocking and permeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS. Cells were then stained with antibody specific to α-smooth muscle actin (αSMA; Abcam) (ref. 1 and 2 above) in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS, and incubated overnight at 4° C. Cells were then washed 3 times with PBS, followed by incubation with Alexa Flor-647 conjugated secondary antibody (Life Technologies [Thermo Fisher Scientific]) and DAPI at room temperature for 1 hour. Cells were then washed 3 times with PBS and plates were sealed for imaging. αSMA staining was imaged by excitation at 630 nm and emission at 665 nm and quantified using the Compartmental Analysis program on the CellInsight CX5 (Thermo Scientific). Dead or apoptotic cells were excluded from analysis based on positive SYTOX green staining. % of total cells positive for αSMA were counted in each well and normalized to the average of 11 wells treated with TGF-β1 on the same plate using Dotmatics&#39; Studies Software. The normalized averages (fold change over untreated) of 3 replicate wells for each compound concentration were used to create dose-responses curves and EC 50  values were calculated using non-linear regression curve fit in the Dotmatics&#39; Studies Software. For EC 50  of &gt;10 μM, the percent inhibition at 10 μM is provided. 
     Table 4 shows the activity of representative compounds of Formula I as provided herein. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 Compound 
                 EC 50  (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1 
                 &gt;10 
                 (3.0%) 
               
            
           
           
               
               
               
            
               
                   
                 2 
                 0.292 
               
               
                   
                 7 
                 2.172 
               
               
                   
                 13 
                 1.437 
               
            
           
           
               
               
               
               
            
               
                   
                 18 
                 &gt;10 
                 (21.4%) 
               
               
                   
                 20 
                 &gt;10 
                 (20.2%) 
               
            
           
           
               
               
               
            
               
                   
                 26 
                 0.344 
               
               
                   
                 36 
                 2.564 
               
               
                   
                 42 
                 1.849 
               
               
                   
                 49 
                 1.368 
               
               
                   
                 55 
                 0.063 
               
               
                   
                 59 
                 2.413 
               
            
           
           
               
               
               
               
            
               
                   
                 65 
                 &gt;10 
                 (0%) 
               
               
                   
                 72 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 78 
                 2.833 
               
               
                   
                 81 
                 1.600 
               
            
           
           
               
               
               
               
            
               
                   
                 84 
                 &gt;10 
                 (29.4%) 
               
            
           
           
               
               
               
            
               
                   
                 88 
                 0.747 
               
            
           
           
               
               
               
               
            
               
                   
                 93 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 96 
                 1.765 
               
               
                   
                 108 
                 8.893 
               
            
           
           
               
               
               
               
            
               
                   
                 117 
                 &gt;10 
                 (2.8%) 
               
               
                   
                 122 
                 &gt;10 
                 (0%) 
               
               
                   
                 129 
                 &gt;10 
                 (0%) 
               
               
                   
                 130 
                 &gt;10 
                 (39.3%) 
               
               
                   
                 135 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 146 
                 1.134 
               
            
           
           
               
               
               
               
            
               
                   
                 151 
                 &gt;10 
                 (0%) 
               
               
                   
                 159 
                 &gt;10 
                 (15.4%) 
               
            
           
           
               
               
               
            
               
                   
                 169 
                 5.300 
               
               
                   
                 175 
                 2.531 
               
               
                   
                 181 
                 1.364 
               
            
           
           
               
               
               
               
            
               
                   
                 188 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 194 
                 1.188 
               
            
           
           
               
               
               
               
            
               
                   
                 198 
                 &gt;10 
                 (0%) 
               
               
                   
                 204 
                 &gt;10 
                 (38.8%) 
               
            
           
           
               
               
               
            
               
                   
                 210 
                 6.744 
               
               
                   
                 217 
                 6.104 
               
            
           
           
               
               
               
               
            
               
                   
                 227 
                 &gt;10 
                 (32.8%) 
               
            
           
           
               
               
               
            
               
                   
                 233 
                 4.840 
               
               
                   
                 246 
                 2.242 
               
               
                   
                 251 
                 4.357 
               
            
           
           
               
               
               
               
            
               
                   
                 256 
                 &gt;10 
                 (10.4%) 
               
               
                   
                 262 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 268 
                 7.200 
               
               
                   
                 275 
                 3.962 
               
               
                   
                 280 
                 3.875 
               
            
           
           
               
               
               
               
            
               
                   
                 281 
                 &gt;10 
                 (21.4%) 
               
            
           
           
               
               
               
            
               
                   
                 285 
                 2.046 
               
            
           
           
               
               
               
               
            
               
                   
                 291 
                 &gt;10 
                 (42.5%) 
               
            
           
           
               
               
               
            
               
                   
                 297 
                 0.410 
               
               
                   
                 304 
                 1.344 
               
               
                   
                 306 
                 0.165 
               
            
           
           
               
               
               
               
            
               
                   
                 314 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 320 
                 0.277 
               
               
                   
                 327 
                 0.277 
               
               
                   
                 333 
                 1.419 
               
               
                   
                 343 
                 1.180 
               
               
                   
                 349 
                 1.417 
               
               
                   
                 354 
                 0.387 
               
               
                   
                 356 
                 4.858 
               
               
                   
                 395 
                 0.097 
               
               
                   
                 401 
                 0.158 
               
               
                   
                 414 
                 0.066 
               
               
                   
                 454 
                 3.513 
               
               
                   
                 460 
                 2.449 
               
               
                   
                 467 
                 2.260 
               
               
                   
                 473 
                 1.534 
               
               
                   
                 476 
                 4.408 
               
               
                   
                 481 
                 5.185 
               
            
           
           
               
               
               
               
            
               
                   
                 487 
                 &gt;10 
                 (0%) 
               
               
                   
                 493 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 500 
                 9.260 
               
            
           
           
               
               
               
               
            
               
                   
                 503 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 505 
                 4.932 
               
            
           
           
               
               
               
               
            
               
                   
                 506 
                 &gt;10 
                 (0%) 
               
               
                   
                 507 
                 &gt;10 
                 (16.2%) 
               
               
                   
                 508 
                 &gt;10 
                 (8.1%) 
               
               
                   
                 509 
                 &gt;10 
                 (0%) 
               
               
                   
                 510 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 512 
                 1.658 
               
            
           
           
               
               
               
               
            
               
                   
                 514 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 515 
                 2.608 
               
               
                   
                 516 
                 1.575 
               
               
                   
                 517 
                 1.150 
               
               
                   
                 520 
                 5.330 
               
               
                   
                 559 
                 5.181 
               
            
           
           
               
               
               
               
            
               
                   
                 565 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 576 
                 4.067 
               
               
                   
                 582 
                 0.648 
               
            
           
           
               
               
               
               
            
               
                   
                 584 
                 &gt;10 
                 (4.5%) 
               
            
           
           
               
               
               
            
               
                   
                 593 
                 0.913 
               
               
                   
                 610 
                 2.275 
               
            
           
           
               
               
               
               
            
               
                   
                 612 
                 &gt;10 
                 (30.3%) 
               
            
           
           
               
               
               
            
               
                   
                 613 
                 2.442 
               
            
           
           
               
               
               
               
            
               
                   
                 618 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 622 
                 4.823 
               
               
                   
                 627 
                 4.805 
               
               
                   
                 639 
                 3.269 
               
               
                   
                 646 
                 1.706 
               
            
           
           
               
               
               
               
            
               
                   
                 648 
                 &gt;10 
                 (0%) 
               
               
                   
                 651 
                 &gt;10 
                 (28.6%) 
               
            
           
           
               
               
               
            
               
                   
                 656 
                 6.266 
               
            
           
           
               
               
               
               
            
               
                   
                 661 
                 &gt;10 
                 (6.2%) 
               
            
           
           
               
               
               
            
               
                   
                 673 
                 4.751 
               
            
           
           
               
               
               
               
            
               
                   
                 685 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 690 
                 4.753 
               
               
                   
                 692 
                 1.322 
               
               
                   
                 700 
                 0.438 
               
               
                   
                 707 
                 2.428 
               
               
                   
                 730 
                 0.489 
               
               
                   
                 735 
                 0.139 
               
            
           
           
               
               
               
               
            
               
                   
                 764 
                 &gt;10 
                 (26.8%) 
               
            
           
           
               
               
               
            
               
                   
                 769 
                 4.464 
               
               
                   
                 781 
                 4.799 
               
               
                   
                 786 
                 2.899 
               
               
                   
                 790 
                 2.503 
               
               
                   
                 792 
                 2.240 
               
               
                   
                 969 
                 4.928 
               
               
                   
                 994 
                 0.590 
               
            
           
           
               
               
               
               
            
               
                   
                 1000 
                 &gt;10 
                 (23.4%) 
               
            
           
           
               
               
               
            
               
                   
                 1006 
                 2.491 
               
               
                   
                 1012 
                 1.169 
               
               
                   
                 1025 
                 2.908 
               
            
           
           
               
               
               
               
            
               
                   
                 1030 
                 &gt;10 
                 (48.0%) 
               
            
           
           
               
               
               
            
               
                   
                 1037 
                 0.511 
               
               
                   
                 1043 
                 0.419 
               
               
                   
                 1049 
                 0.681 
               
               
                   
                 1056 
                 0.284 
               
               
                   
                 1068 
                 0.938 
               
            
           
           
               
               
               
               
            
               
                   
                 1108 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 1109 
                 6.1985 
               
            
           
           
               
               
               
               
            
               
                   
                 1126 
                 &gt;10 
                 (45.0%) 
               
               
                   
                 1127 
                 &gt;10 
                 (24.8%) 
               
            
           
           
               
               
               
            
               
                   
                 1129 
                 0.342 
               
               
                   
                 1134 
                 0.149 
               
               
                   
                 1152 
                 0.317 
               
               
                   
                   
               
            
           
         
       
     
     Example 5 
     Representative compounds were screened using primary human mesenchymal stem cells (hMSCs) to determine their ability to induce chondrogenesis (process by which cartilage is developed). 
     Human Mesenchymal Stem Cell Culture: 
     Primary human mesenchymal stem cells (hMSCs) were purchased from Lonza (Walkersville, Md.) and expanded in Mesenchymal Stem Cell Growth Media (Lonza). Cells between passage 3 and 6 were used for the experiments. 
     Compound Screening: 
     Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. For the 96 well assay, serial dilution (1:3, 6-point dose-response curves from 2700 nM to 10 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 96-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.03%. hMSCs were plated at 20,000 cells/well in 250 μL/well Incomplete Chondrogenic Induction Medium (Lonza; DMEM, dexamethasone, ascorbate, insulin-transferrin-selenium [ITS supplement], gentamycin-amphotericin [GA-1000], sodium pyruvate, proline and L-glutamine). TGF-−3 (10 ng/mL) was used as a positive control for differentiation while negative control wells were treated with 75 nL DMSO for normalization and calculating EC 50  values. For the 384 well assay, serial dilution (1:3, 8-point dose-response curves from 5000 nM to 2.2 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.03%. hMSCs were plated at 8,000 cells/well in 80 μL/well Incomplete Chondrogenic Induction Medium (Lonza; DMEM, dexamethasone, ascorbate, insulin-transferrin-selenium [ITS supplement], gentamycin-amphotericin [GA-1000], sodium pyruvate, proline and L-glutamine). TGF-β3 (10 ng/mL) was used as a positive control for differentiation while negative control wells were treated with 25 nL DMSO for normalization and calculating EC 50  values. Cells were incubated at 37° C. and 5% CO 2  for 6 days. To image chondrogenic nodules, the cells were fixed using 4% formaldehyde (Electron Microscopy Sciences), and stained with 2 μg/mL Rhodamine B (Sigma-Aldrich) and 20 μM Nile Red (Sigma-Aldrich) [Johnson K., et. al, A Stem Cell-Based Approach to Cartilage Repair,  Science , (2012), 336(6082), 717-721]. The nodules imaged (25 images per well for 96 well plates and 9 images per well for 384 well plates at 10× magnification) by excitation at 531 nm and emission at 625 nm and quantified using the CellInsight CX5 (Thermo Scientific). Area of nodules in each well was normalized to the average of 3 DMSO treated wells on the same plate using Excel (Microsoft Inc.). The normalized averages (fold change over DMSO) of 2 or 3 replicate wells for each compound concentration were calculated. Due to solubility limitations of some of the compounds, curve fitting was incomplete leading to inaccurate EC 50  determinations. 
     Using TGF-β3 as a positive control, the concentration of representative compounds required to induce 50% levels of chondrogenesis is reported. In addition, the maximum activity of each compound and the respective dose that each compound reached maximum chondrogenesis activity is reported. Table 5 shows the activity of representative compounds as provided herein. 
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                   
                   
                 Max. 
                   
               
               
                   
                   
                   
                 Activity as 
                 Conc (nM) of 
               
               
                   
                   
                 Conc (nM) of 
                 % TGF-β3 
                 50% TGF-β3 
               
               
                   
                 Compound 
                 Max. activity 
                 activity 
                 activity 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 62 
                 29 
                 NA 
               
               
                   
                 2 
                 21 
                 56 
                 21 
               
               
                   
                 7 
                 30 
                 84 
                 10 
               
               
                   
                 13 
                 0 
                 29 
                 NA 
               
               
                   
                 18 
                 7 
                 42 
                 NA 
               
               
                   
                 26 
                 2700 
                 247 
                 900  
               
               
                   
                 36 
                 0 
                 63 
                 10 
               
               
                   
                 42 
                 2 
                 17 
                 NA 
               
               
                   
                 49 
                 900 
                 69 
                 30 
               
               
                   
                 55 
                 900 
                 99 
                 30 
               
               
                   
                 59 
                 100 
                 127 
                 10 
               
               
                   
                 65 
                 2700 
                 197 
                 10 
               
               
                   
                 88 
                 300 
                 95 
                 300  
               
               
                   
                 93 
                 62 
                 26 
                 NA 
               
               
                   
                 96 
                 100 
                 113 
                 10 
               
               
                   
                 117 
                 30 
                 147 
                 100  
               
               
                   
                 122 
                 100 
                 63 
                 10 
               
               
                   
                 129 
                 30 
                 50 
                 NA 
               
               
                   
                 135 
                 30 
                 69 
                 10 
               
               
                   
                 146 
                 2 
                 28 
                 NA 
               
               
                   
                 159 
                 30 
                 60 
                 100  
               
               
                   
                 169 
                 21 
                 38 
                 NA 
               
               
                   
                 175 
                 10 
                 42 
                 NA 
               
               
                   
                 181 
                 100 
                 44 
                 NA 
               
               
                   
                 198 
                 556 
                 27 
                 NA 
               
               
                   
                 204 
                 100 
                 70 
                 10 
               
               
                   
                 210 
                 2 
                 49 
                 NA 
               
               
                   
                 217 
                 100 
                 69 
                 300  
               
               
                   
                 227 
                 10 
                 47 
                 NA 
               
               
                   
                 233 
                 900 
                 62 
                 900  
               
               
                   
                 256 
                 30 
                 74 
                 10 
               
               
                   
                 281 
                 2 
                 38 
                 NA 
               
               
                   
                 285 
                 1667 
                 33 
                 NA 
               
               
                   
                 297 
                 2 
                 40 
                 NA 
               
               
                   
                 306 
                 30 
                 77 
                 30 
               
               
                   
                 314 
                 1667 
                 32 
                 NA 
               
               
                   
                 320 
                 100 
                 64 
                 100  
               
               
                   
                 327 
                 10 
                 83 
                 10 
               
               
                   
                 343 
                 900 
                 57 
                 900  
               
               
                   
                 349 
                 900 
                 108 
                 30 
               
               
                   
                 395 
                 900 
                 118 
                 100  
               
               
                   
                 401 
                 1667 
                 66 
                 1667  
               
               
                   
                 454 
                 21 
                 149 
                 21 
               
               
                   
                 460 
                 900 
                 63 
                 30 
               
               
                   
                 467 
                 10 
                 71 
                 10 
               
               
                   
                 481 
                 556 
                 47 
                 NA 
               
               
                   
                 493 
                 2 
                 43 
                 NA 
               
               
                   
                 505 
                 0 
                 51 
                 10 
               
               
                   
                 506 
                 21 
                 47 
                 NA 
               
               
                   
                 507 
                 7 
                 57 
                  7 
               
               
                   
                 508 
                 5000 
                 43 
                 NA 
               
               
                   
                 509 
                 900 
                 97 
                 10 
               
               
                   
                 510 
                 7 
                 46 
                 NA 
               
               
                   
                 512 
                 2 
                 93 
                  2 
               
               
                   
                 515 
                 7 
                 45 
                 NA 
               
               
                   
                 516 
                 62 
                 47 
                 NA 
               
               
                   
                 517 
                 21 
                 59 
                  2 
               
               
                   
                 520 
                 185 
                 63 
                  2 
               
               
                   
                 969 
                 7 
                 72 
                  7 
               
               
                   
                 994 
                 30 
                 50 
                 100  
               
               
                   
                 1000 
                 100 
                 46 
                 NA 
               
               
                   
                 1037 
                 30 
                 67 
                 10 
               
               
                   
                 1043 
                 30 
                 65 
                 30 
               
               
                   
                 1049 
                 0 
                 74 
                 10 
               
               
                   
                 1056 
                 100 
                 102 
                 10 
               
               
                   
                 1126 
                 10 
                 74 
                 10 
               
               
                   
                 1127 
                 300 
                 99 
                 10 
               
               
                   
                   
               
            
           
         
       
     
     Example 6 
     Representative compounds were screened using the following assay procedure to determine their ability to inhibit IL-6 and therefore demonstrate their anti-inflammatory properties. 
     Human Monocyte Cell Culture: 
     Human monocyte cell line (THP-1 cells; Catalog # TIB-202, ATCC, Manassas, Va.) were cultured in Roswell Park Memorial Institute (RPMI) 1640 Medium (Catalog #21870-100, Buffalo, N.Y.) with 1% L-glutamine, 1% HEPES, 1% Sodium Pyruvate, 2% Sodium Bicarbonate supplemented with 100 units/mL penicillin, 50 μg/mL streptomycin, 2-mercaptoethanol (0.05 mM) [basal medium] and 10% fetal bovine serum (Catalog #16140089, Life Technologies, Carlsbad, Calif.) at 37° C. and 5% CO 2 . 
     Compound Screening: 
     THP-1 cells were cultured in basal media with 1% FBS for 24 hours before the start of the assay. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 μM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well white low volume assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. THP-1 cells were plated at 5000 cells/well in the 384-well plates and incubated at 37° C. for 2 h. 500 ng/mL of LPS was added after 2 hours and cells were incubated for another 22 hours at 37° C. Plates were spun in a centrifuge for 1 minute at 10,000 rpm and a mixture of anti-IL6 XL665, and anti-IL6 Cryptate diluted in reconstitution buffer (Cisbio Inc.) was added to each well. Following incubation for 3 hrs at room temperature, Homogeneous Time-Resolved Fluorescence (HTRF) was measured using the Envision (Perkin Elmer) at 665 nm and 620 nM. The ratio of fluorescence at 665 nm to 620 nm was used as a readout for IL6 quantification. All samples were processed in duplicate. Readings were normalized to DMSO treated cells and normalized activities were utilized for EC 50  calculations using the dose-response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics). For EC 50  of &gt;10 μM, the percent inhibition at 10 μM is provided. 
     Table 6 shows the activity of representative compounds of Formula I as provided herein. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 Compound 
                 EC 50  (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1 
                 &gt;10 
                 (3.5%) 
               
            
           
           
               
               
               
            
               
                   
                 2 
                 0.296 
               
               
                   
                 7 
                 7.495 
               
               
                   
                 13 
                 5.932 
               
            
           
           
               
               
               
               
            
               
                   
                 18 
                 &gt;10 
                 (18.4%) 
               
               
                   
                 20 
                 &gt;10 
                 (16.0%) 
               
            
           
           
               
               
               
            
               
                   
                 26 
                 0.985 
               
            
           
           
               
               
               
               
            
               
                   
                 36 
                 &gt;10 
                 (19.2%) 
               
               
                   
                 42 
                 &gt;10 
                 (46.1%) 
               
               
                   
                 49 
                 &gt;10 
                 (44.0%) 
               
               
                   
                 55 
                 &gt;10 
                 (43.9%) 
               
            
           
           
               
               
               
            
               
                   
                 59 
                 2.117 
               
               
                   
                 65 
                 0.151 
               
            
           
           
               
               
               
               
            
               
                   
                 72 
                 &gt;10 
                 (27.8%) 
               
            
           
           
               
               
               
            
               
                   
                 78 
                 7.915 
               
               
                   
                 81 
                 5.755 
               
            
           
           
               
               
               
               
            
               
                   
                 84 
                 &gt;10 
                 (23.0%) 
               
               
                   
                 88 
                 &gt;10 
                 (36.6%) 
               
            
           
           
               
               
               
            
               
                   
                 93 
                 0.984 
               
               
                   
                 96 
                 0.424 
               
               
                   
                 108 
                 0.131 
               
            
           
           
               
               
               
               
            
               
                   
                 117 
                 &gt;10 
                 (18.6%) 
               
               
                   
                 122 
                 &gt;10 
                 (27.0%) 
               
               
                   
                 129 
                 &gt;10 
                 (14.9%) 
               
               
                   
                 130 
                 &gt;10 
                 (18.9%) 
               
               
                   
                 135 
                 &gt;1.0 
                 (22.1%) 
               
               
                   
                 146 
                 &gt;10 
                 (4.5%) 
               
               
                   
                 151 
                 &gt;10 
                 (39.1%) 
               
               
                   
                 159 
                 &gt;10 
                 (33.6%) 
               
               
                   
                 169 
                 &gt;10 
                 (12.7%) 
               
               
                   
                 175 
                 &gt;10 
                 (27.6%) 
               
            
           
           
               
               
               
            
               
                   
                 181 
                 8.297 
               
            
           
           
               
               
               
               
            
               
                   
                 188 
                 &gt;10 
                 (28.0%) 
               
            
           
           
               
               
               
            
               
                   
                 194 
                 5.424 
               
            
           
           
               
               
               
               
            
               
                   
                 198 
                 &gt;10 
                 (29.1%) 
               
               
                   
                 204 
                 &gt;10 
                 (36.3%) 
               
               
                   
                 210 
                 &gt;10 
                 (21.7%) 
               
               
                   
                 217 
                 &gt;10 
                 (35.6%) 
               
               
                   
                 227 
                 &gt;10 
                 (51.9%) 
               
               
                   
                 233 
                 &gt;10 
                 (16.4%) 
               
               
                   
                 246 
                 &gt;10 
                 (15.7%) 
               
               
                   
                 251 
                 &gt;10 
                 (8.3%) 
               
               
                   
                 256 
                 &gt;10 
                 (24.4%) 
               
               
                   
                 262 
                 &gt;10 
                 (17.3%) 
               
               
                   
                 268 
                 &gt;10 
                 (32.5%) 
               
               
                   
                 275 
                 &gt;10 
                 (33.1%) 
               
            
           
           
               
               
               
            
               
                   
                 280 
                 0.115 
               
            
           
           
               
               
               
               
            
               
                   
                 281 
                 &gt;10 
                 (25.0%) 
               
            
           
           
               
               
               
            
               
                   
                 285 
                 9.880 
               
            
           
           
               
               
               
               
            
               
                   
                 291 
                 &gt;10 
                 (21.0%) 
               
            
           
           
               
               
               
            
               
                   
                 297 
                 9.908 
               
               
                   
                 304 
                 4.256 
               
               
                   
                 306 
                 1.330 
               
            
           
           
               
               
               
               
            
               
                   
                 314 
                 &gt;10 
                 (23.9%) 
               
            
           
           
               
               
               
            
               
                   
                 320 
                 0.456 
               
            
           
           
               
               
               
               
            
               
                   
                 327 
                 &gt;10 
                 (42.4%) 
               
            
           
           
               
               
               
            
               
                   
                 333 
                 2.622 
               
               
                   
                 343 
                 0.004 
               
               
                   
                 349 
                 4.779 
               
               
                   
                 354 
                 1.385 
               
            
           
           
               
               
               
               
            
               
                   
                 356 
                 &gt;10 
                 (38.0%) 
               
            
           
           
               
               
               
            
               
                   
                 395 
                 0.250 
               
               
                   
                 401 
                 0.161 
               
               
                   
                 414 
                 1.848 
               
            
           
           
               
               
               
               
            
               
                   
                 454 
                 &gt;10 
                 (36.4%) 
               
            
           
           
               
               
               
            
               
                   
                 460 
                 1.803 
               
            
           
           
               
               
               
               
            
               
                   
                 467 
                 &gt;10 
                 (23.0%) 
               
            
           
           
               
               
               
            
               
                   
                 473 
                 2.615 
               
            
           
           
               
               
               
               
            
               
                   
                 476 
                 &gt;10 
                 (33.0%) 
               
            
           
           
               
               
               
            
               
                   
                 481 
                 1.031 
               
            
           
           
               
               
               
               
            
               
                   
                 487 
                 &gt;10 
                 (0%) 
               
               
                   
                 493 
                 &gt;10 
                 (23.4%) 
               
               
                   
                 500 
                 &gt;10 
                 (45.6%) 
               
               
                   
                 503 
                 &gt;10 
                 (29.6%) 
               
            
           
           
               
               
               
            
               
                   
                 505 
                 3.476 
               
            
           
           
               
               
               
               
            
               
                   
                 506 
                 &gt;10 
                 (27.9%) 
               
               
                   
                 507 
                 &gt;10 
                 (35.9%) 
               
               
                   
                 508 
                 &gt;10 
                 (15.5%) 
               
               
                   
                 509 
                 &gt;10 
                 (17.5%) 
               
            
           
           
               
               
               
            
               
                   
                 510 
                 0.023 
               
            
           
           
               
               
               
               
            
               
                   
                 512 
                 &gt;10 
                 (35.7%) 
               
               
                   
                 514 
                 &gt;10 
                 (49.5%) 
               
            
           
           
               
               
               
            
               
                   
                 515 
                 5.539 
               
               
                   
                 516 
                 8.233 
               
               
                   
                 517 
                 1.535 
               
            
           
           
               
               
               
               
            
               
                   
                 520 
                 &gt;10 
                 (19.5%) 
               
               
                   
                 559 
                 &gt;10 
                 (31.6%) 
               
            
           
           
               
               
               
            
               
                   
                 565 
                 9.477 
               
            
           
           
               
               
               
               
            
               
                   
                 576 
                 &gt;10 
                 (38.1%) 
               
               
                   
                 582 
                 &gt;10 
                 (3.2%) 
               
               
                   
                 584 
                 &gt;10 
                 (22.0%) 
               
               
                   
                 593 
                 &gt;10 
                 (41.8%) 
               
               
                   
                 610 
                 &gt;10 
                 (25.3%) 
               
               
                   
                 612 
                 &gt;10 
                 (44.6%) 
               
            
           
           
               
               
               
            
               
                   
                 613 
                 9.178 
               
               
                   
                 618 
                 1.551 
               
               
                   
                 622 
                 0.920 
               
               
                   
                 627 
                 0.404 
               
            
           
           
               
               
               
               
            
               
                   
                 639 
                 &gt;10 
                 (33.5%) 
               
            
           
           
               
               
               
            
               
                   
                 646 
                 1.496 
               
            
           
           
               
               
               
               
            
               
                   
                 648 
                 &gt;10 
                 (9.9%) 
               
               
                   
                 651 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 656 
                 7.600 
               
            
           
           
               
               
               
               
            
               
                   
                 661 
                 &gt;10 
                 (27.9%) 
               
               
                   
                 673 
                 &gt;10 
                 (35.9%) 
               
               
                   
                 685 
                 &gt;10 
                 (24.3%) 
               
               
                   
                 690 
                 &gt;10 
                 (42.9%) 
               
               
                   
                 692 
                 &gt;10 
                 (39.0%) 
               
               
                   
                 700 
                 &gt;10 
                 (0%) 
               
               
                   
                 707 
                 &gt;10 
                 (35.1%) 
               
            
           
           
               
               
               
            
               
                   
                 730 
                 0.558 
               
               
                   
                 735 
                 1.785 
               
            
           
           
               
               
               
               
            
               
                   
                 764 
                 &gt;10 
                 (24.2%) 
               
            
           
           
               
               
               
            
               
                   
                 769 
                 0.036 
               
               
                   
                 781 
                 0.638 
               
            
           
           
               
               
               
               
            
               
                   
                 786 
                 &gt;10 
                 (0%) 
               
            
           
           
               
               
               
            
               
                   
                 790 
                 4.767 
               
            
           
           
               
               
               
               
            
               
                   
                 792 
                 &gt;10 
                 (23.3%) 
               
               
                   
                 969 
                 &gt;10 
                 (26.3%) 
               
               
                   
                 994 
                 &gt;10 
                 (50.2%) 
               
               
                   
                 1000 
                 &gt;10 
                 (12.3%) 
               
               
                   
                 1006 
                 &gt;10 
                 (32.7%) 
               
               
                   
                 1012 
                 &gt;10 
                 (43.3%) 
               
               
                   
                 1025 
                 &gt;10 
                 (26.5%) 
               
               
                   
                 1030 
                 &gt;10 
                 (40.9%) 
               
            
           
           
               
               
               
            
               
                   
                 1037 
                 5.050 
               
            
           
           
               
               
               
               
            
               
                   
                 1043 
                 &gt;10 
                 (7.6%) 
               
               
                   
                 1049 
                 &gt;10 
                 (36.2%) 
               
               
                   
                 1056 
                 &gt;10 
                 (40.6%) 
               
            
           
           
               
               
               
            
               
                   
                 1068 
                 1.771 
               
            
           
           
               
               
               
               
            
               
                   
                 1108 
                 &gt;10 
                 (30.1%) 
               
               
                   
                 1109 
                 &gt;10 
                 (20.5%) 
               
               
                   
                 1126 
                 &gt;10 
                 (27.6%) 
               
               
                   
                 1127 
                 &gt;10 
                 (47.7%) 
               
               
                   
                 1129 
                 &gt;10 
                 (24.8%) 
               
               
                   
                 1134 
                 &gt;10 
                 (12.6%) 
               
               
                   
                 1152 
                 &gt;10 
                 (28.4%)