NZ793551A - Methods of using indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors - Google Patents

Abstract

This disclosure features the use of one or more indazole-3-carboxamide compounds or salts or analogs thereof, in the treatment of one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease; and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3-carboxamide compounds or salts or analogs thereof as described anywhere herein. Darier's disease; and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3-carboxamide compounds or salts or analogs thereof as described anywhere herein.

Description

This sure features the use of one or more indazolecarboxamide compounds or salts or s thereof, in the treatment of one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease; and/or for promoting wound g. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazolecarboxamide compounds or salts or analogs thereof as described anywhere herein.

NZ 793551 METHODS OF USING LECARBOXAMIDES AND THEIR USE AS WNT/B-CATENIN ING PATHWAY INHIBITORS RELATED APPLICATIONS [001[ This application claims the benefit of US. Provisional Application No. 62/411,4?8, filed October 21, 2016, which is incorporated herein by reference in its entirety.

BACKGROUND Technical Field [002[ This disclosure features the use of one or more indazolecarboxamide nds or salts or analogs thereof, in the treatment of one or more diseases or conditions independently ed from the group consisting of a tendinopathy, dermatitis, psoriasis, a, ichthyosis, Raynaud's syndrome, and Darier's disease, and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole -3 -carboxamide compounds or salts or s thereof as described anywhere herein.

Background [003[ Pattem formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the isms underlying these patterning effects usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the fication of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene es. [004[ 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 les mediate many important short-and long-range ning processes during invertebrate and rate development. The Wnt signaling pathway is known for its important role in the inductive interactions that regulate growth and differentiation, and plays important roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic B-catenin, which stimulates the expression of genes including c-myc, c jun, fra—l, and cyclin D1. In addition, misregulation ofWnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. More recently, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues that now includes skin, blood, gut, prostate, muscle and the s system. [005[ Pathological activation ofthe Wnt y is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world.

Activation ofthe Wnt y has also been extensively reported for hepatocellular oma, breast cancer, ovarian , pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of the Wnt y can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as diabetic pathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma as well as mycotic and viral infections and bone and cartilage diseases. As such, it is a therapeutic target that is of great interest to the field. [006[ In addition to cancer, there are many cases of genetic es due to mutations in Wnt signaling components. Examples of some of the many diseases are Alzheimer's disease [Proc Natl. Acad. Sci. U S A , 104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991), 253(5020), 665-669], bone density and vascular defects in the eye (osteoporosis-pseudoglioma syndrome, OPPG) [N Engl. J. Med. (2002), 346(20), 1513- 21], familial exudative vitreoretinopathy [Hum Mutat. (2005), 26(2), ], retinal angiogenesis [Nat Genet. (2002), 32(2), 326-30], early coronary disease [Science (2007), 315(5816), 1278-82], tetra-amelia syndrome [Am J. Hum Genet. (2004), 74(3), 558-63], Mullerian-duct regression and virilization [Eng]. J. Med. (2004), 351(8), 792-8], SERKAL syndrome [Am J Hum Genet. (2008), 82(1), 39-47], diabetes mellitus type 2 [Am J Hum Genet. (2004), 75(5), 832-43, N. Engl. J Med. (2006), 355(3), 241-50], Fuhrmann syndrome [Am J Hum Genet. , 79(2), 402-8], Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome [Am J Hum Genet. , 79(2), 402-8], odonto-onycho-dermal dysplasia [Am J Hum Genet. , 81(4), 821-8], obesity [Diabetologia , 49(4), 678-84], split- hand/foot malformation [Hum Mol. Genet. (2008), , 2644-53], caudal ation syndrome [Am J Hum Genet. (2006), 79(1), 155-62], tooth agenesis [Am J Hum Genet. (2004), 74(5), 1043-50], Wilms tumor [Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat Genet. (2009), 41(1), ], focal dermal hypoplasia [Nat Genet. (2007), 39(7), 836- 8], mal recessive anonychia [Nat Genet. (2006), 38(11), 1245-7], neural tube defects [N Eng]. J Med (2007), 356(1 4), 1432-7], alpha-thalassemia (ATRX) syndrome [The Journal of Neuroscience (2008), 28(47), 12570 —125 80], fragile X me [PLoS Genetics (2010), 6(4), e1000898], ICF syndrome, Angelman syndrome [Brain Research Bulletin (2002), 57(1), 109- 119], Prader-Willi syndrome [Journal ofNeuroscience (2006), 26(20), 392], Beckwith- Wiedemann me [Pediatric and Developmental Pathology (2003), 6(4), 299-306] and Rett syndrome. [007[ Regulation of cell signaling by the Wnt signaling pathway is critical for the formation ofneuronal circuits. Wnt pathway modulates in neural tissue, among other things, axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnt pathway activates and/or regulates diverse ing pathways and other processes that lead to local changes on the cytoskeleton or global ar changes involving nuclear fill’lCthl’l.

Recently, a link between neuronal activity, essential for the formation and refinement of al connections, and Wnt signaling has been red. Indeed, neuronal activity regulates the release of various Wnt proteins and the localization of their receptors. Wnt pathway mediates synaptic structural changes induced by neuronal activity or experience.

Evidence suggests that dysfiinction in Wnt signaling contributes to neurological disorders [Brain Research Reviews (2000), 33(1), 1—12, ne (2006) 25(5 7), 7545-7553, Molecular Neuroclegeneraiion (2008), 3, 9, Neurobiology ofDisease (2010), 38(2), 148—153, Journal of Neurodevelopmenial Disorders (2011), 3(2), 162—174 and Cold Spring Harbor Perspectives in y February (2012), 4(2)]. [008[ Tendinopathies are chronic ers or es of the tendons, that typically result from gradual wear and tear to the tendon, e.g., from overuse or aging, and leading to is tendon degeneration, weakness, tearing, and pain. Individuals who tend to make multiple, repeated motions in their jobs, sports, or regular daily activities tend to be more likely to develop tendinopathies. Tendinopathy usually causes pain, stiffness, and loss of strength in the affected area. [009[ Skin disorders are common afflictions for many people. Some of the most common are dermatitis (also known as eczema) and psoriasis. Both itis and psoriasis can cause serious physical and/or psychological suffering to the subject less of the location on the body that these conditions occur. [010[ and their use as Wnt/B-catenin signaling y inhibitors. 0 / R4 NH R‘ (I) SUMMARY [011[ This disclosure features the use of one or more indazolecarboxamide nds or salts or analogs thereof, in the treatment of one or more diseases or conditions independently ed from the group ting of a tendinopathy, dermatitis, psoriasis, a, ichthyosis, Raynaud's syndrome, and Darier's disease, and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3 -carboxamide compounds or salts or analogs thereof as described anywhere herein. [012[ One ment disclosed herein es administering an indazole carboxamide compound having the structure of Formula 1: o / R4 NH R2 N as well as prodrugs and pharmaceutically acceptable salts thereof. [013[ In some embodiments of Formula (1): R1, R2 and R4 are independently selected from the group ting of H, C1.9 alkyl, halide, —N(R10)2, —XR10, CN, —OCF3 and —CF3, R3 is selected from the group ting of carbocyclle6, heterocyclle6, arle6 and heteroarle6, R5 is selected from the group consisting of -(C1-9 alkyl)ncarbocyclle7, -(C1-9 alkyl)nheterocyclle7, -(C1_9 alkyl)narle7 and -(C1_9 alkyl)nheteroarle7, each R6 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle8, -(C1_9 alkyl)narle8, -(C1_9 alkyl)nheteroarle8, -C(=O)R11, - N(R10)C(=O)R“, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR“ and -SOzR11, each R7 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1_9 alkyl)ncarbocyclle9, -(C1_9 nheterocyclle9, -(C1_9 alkyl)narle9, -(C1_9 alkyl)nheteroarle9, -C(=O)R11, - N(R10)C(=O)R”, -(C1_9 nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR11 and -SOzR”, each R8 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, OCF3, -CF3 -CN, -XR12, -C(=O)R13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, - (C1_9 alkyl)nN(R12)SOZR13 and -SOle3, each R9 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3 -CN, -XR12, Rl3, -N(R12)C(=O)R13, -(C1.9alkyl)nN(R12)2, - (C1_9 nN(R12)SOZR13 and -SOle3, each R10 is independently ed from the group consisting of H, C1.9 alkyl, -(C1-9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1_9 alkyl)narle8 and -(C1_9 alkyl)nheteroarle8, each R11 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, - (C1.9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle8, -(C1-9 alkyl)narle8 and -(C1-9 alkyl)nheteroarle8, each R12 is independently selected from the group consisting of H, C1.9 alkyl, -(C1-9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl, each R13 is independently selected from the group ting of C1_9 alkyl, -N(R14)2, - (C1.9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl, each R14 is independently selected from the group consisting of H, C1_3 alkyl, yclyl and aryl, each X is ed from the group consisting of a bond, and -S-, and eachn is 0 or 1. [014[ In another embodiment of Formula (1): R1, R2 and R4 are independently selected from the group consisting of H, C1_9 alkyl, halide, -N(R10)2, -XR10, CN, -OCF3 and -CF3, R3 is selected from the group consisting of carbocyclle6, heterocyclle6, arle6 and heteroarle6, in some embodiments, it is provided that when R3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole, R5 is selected from the group consisting of -(C1-9 ncarbocyclle7, -(C1-9 alkyl)nheterocyclle7, -(C1_9 narle7 and -(C1_9 alkyl)nheteroarle7, in some embodiments, it is provided that R5 is not 4-pyridle7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, 4-pyridle6, 2-pyridle6, phenle6, "Jun,H 0 Hmfi‘iN/ 6/15 H0 \ Lg leR6, imidazoleR6,pyrimidineR6, oxazoleRé, N / / N , , F :1WY W ° o “I /.

Fiji \ M "\ N5 "W? N/ M N/ N/ N/ 3 3 3 3 3 3 (1 ° \ ‘7’”? U \ N \ a H .

CI N and N and R6 and R7 are both H. 3 , in some ments, it is provided that R5 is not —(CH2)(3-pyridyl)R7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, 4-pyridle6 and thiazoleR6, and R6 and R7 are both H, in some embodiments, it is provided that R5 is not phenle7 when R1, R2 and R4 are H, R3 is 4-pyridle6 and R6 and R7 are both H, in some embodiments, it is provided that R3 is not dle6 when R1, R2 and R4 are gig,0‘ ,0 is selected from the group consisting of phenle7, it H, R5 0‘:01? LED/FsozuH2 cu LL; sozun2 300WHO E/©:CI ":2 54,,33 ii}F ‘eI)“ and R6 and R7 are both H, in some embodiments, it is ed that R3 is not oxazoleR6 when R1, R2 and R4 are J: :L \ N N\/ H, R5 is selected from the group consisting of c" p and ‘7{©\/ ‘/ and R6 is H, in some embodiments, it is provided that R3 is not thiazoleR6 when R1, R2 and R4 are H, R5 is selected from the group consisting of and v, and R6 is H, each R6 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle8, -(C1_9 narle8, -(C1_9 alkyl)nheteroarle8, -C(=O)R11, - N(R10)C(=O)R”, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR11 and -SOzR“, each R7 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclle9, -(C1-9 alkyl)nheterocyclle9, -(C1_9 alkyl)narle9, -(C1_9 alkyl)nheteroarle9, -C(=O)R11, - N(R10)C(=O)R”, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR11 and -SOzR“, each R8 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, OCF3, -CF3 -CN, -XR12, -C(=O)R13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, - (C1_9 alkyl)nN(R12)SOZR13 and , each R9 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3 -CN, -XR12, -C(=O)Rl3, )C(=O)R13, -(C1.9alkyl)nN(R12)2, - (C1_9 nN(R12)SOZR13 and -SOle3, each R10 is independently selected from the group consisting of H, C1.9 alkyl, -(C1-9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1-9 alkyl)narle8 and -(C1-9 alkyl)nheteroarle8, each R11 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, - (C1.9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle8, -(C1-9 alkyl)narle8 and -(C1-9 alkyl)nheteroarle8, each R12 is independently ed from the group ting of H, C1.9 alkyl, -(C1-9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 nheteroaryl, each R13 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, - (C1.9 ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl, each R14 is independently selected from the group consisting of H, C1_3 alkyl, carbocyclyl and aryl, each X is selected from the group ting of a bond, and -S-, and eachn is 0 or 1. [015[ Some embodiments include administering stereoisomers and pharmaceutically acceptable salts of a compound of general Formula (I). [016[ Some embodiments include administering pro-drugs of a compound of general Formula (I). [017[ Some embodiments e administering pharmaceutical compositions comprising a nd of general Formula (I) or in a pharmaceutically acceptable carrier, diluent, or ent. [018[ 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 ofthe ion, as claimed.

BRIEF DESCRIPTION OF THE FIGURES [019[ depicts a plot showing that exposure of a human ctal cancer cell line (SW480) to compound 175 inhibited Wnt/B-catenin activity in these cells in a dose- dependent manner (EC50= 152.9 nM). The human ctal cancer cell line (SW480) with constitutive tion of the Wnt pathway and engineered to express a Wnt responsive promoter linked to luciferase were treated with compound 175 at test concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 and 0.0003 uM. [020[ FIGS. 2A-C depict plots of the percentage of human mesenchymal stem cells (hMSC) expressing SCXA, tenacinC, and tenomodulin, respectively vs. concentration of compound 175. Human Mesenchymal Stem Cells were treated with compound 175 at test concentrations of 750, 333.3, 166.6, 83.3, 41.7, 21.7, 10.8 and 5.8 nM. Exposure ofthe cells to compound 175 for 7 days induced the expression of markers of tenocyte differentiation- SCXA, TenacinC and Tenomodulin in a dose-dependent manner (EC50= 139- 189 nM). [021[ are images ofthe expression of SCXA, tenacinC, and tenomodulin in hMSCs d with DMSO, bone morphogenic protein (BMP) and fibroblast growth factor (FGF), and compound 175 at 333 nM concentration. [022[ FIGS. 4A-B depict plots of tumor necrosis factor alpha concentration in THP-1 cells vs. the logarithm of the concentration of compound 175 the THP-1 cells were eXposed to, and interleukin-6 concentration in THP-1 cells vs. the logarithm of the concentration of compound 175 the THP-1 cells were eXposed to, respectively. THP-1 cells, a human monocyte cell line (6 X 10e4 cells/well in a 96-well plate) were treated with DMSO (vehicle) or compound 175 at trations of 10, 3.5, 1, 0.5, 0.1, 0.035, 0.01, 0.005 uM.

After 2 hours, treated cells were stimulated with LPS (50 ng/mL for 5 hours [TNFa] and 500 ng/ml for 22 hours [IL6]) at 37°C to induce production ofthe cytokines. Supematants (diluted 1:1 or 1:4) were collected and analyzed for TNFa and IL6 levels using the TNFa and IL6 ELISA kits. Inhibition profile and EC50 was calculated using Prism 5. Representative images te that eXposure ofthe cells to compound 175 inhibited the production of TNFa (4A) and IL6 (4B) in THP-1 cells in a dose-dependent manner, with an average EC50 of 342 - 547 nM for TNFa and 356 - 629 nM for IL6 (2 independent assays and 3 replicates per assay). [023[ is a grid of images of a rat Achilles tendon, a rat Achilles tendon treated with a collagenase with a vehicle, a rat Achilles tendon treated with a enase, compound 175, and benzyl alcohol, and a rat Achilles tendon treated with a collagenase and nd 175. Tendinopathy in rats was induced by injecting collagenase (50 pl, 10 mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) or sham needle puncture for control in the Achilles tendon. After 1 day, rats were dosed once daily for 21 days via topical application with vehicle control or compound 175 (10 . 24 hours after the last dose, tendons were isolated, fixed with 10% buffered formalin, sectioned and stained with H&E. Group 1 (sham injection), Group 2 (Collagenase-Vehicle), Group 3 (Collagenase-compound 175 with 1% BA) and Group 4 (Collagenase-compound 175 with 0.5% Tween 80, t BA). [024[ is a plot of tendon histology scores of rat Achilles tendon, a rat Achilles tendon treated with a collagenase with a vehicle, a rat Achilles tendon treated with a enase, compound 175, and benzyl l, and a rat Achilles tendon treated with a collagenase and compound 175. Tendinopathy in rats was d by injecting collagenase (50 pl, 10 mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) or sham needle puncture for control in the es tendon. After 1 day, rats were dosed once daily for 21 days via topical ation with e l or compound 175 (10 mg/ml). 24 hours after the last dose, tendons were isolated, fixed with 10% buffered formalin, sectioned and stained with H&E.

Group 1 (sham injection), Group 2 (Collagenase-Vehicle), Group 3 (Collagenase-compound 175 with 1% BA) and Group 4 (Collagenase-compound 175 with 0.5% Tween 80, without BA).

Blinded ogy scoring oftendon injury and inflammation indicated that nd 175 with or t BA preservative significantly ameliorated collagenase-induced tendinopathy (**p<0.01 and *p<0.05 respectively) by student’s t test. For this study, a total of 64 sections were scored for Group 1 and ~96 sections each for Group 2-4. [025[ is series of plots of plasma concentrations of KC/GRO in rats vs. the number of days elapsed after administration of a vehicle, compound 175 with benzyl alcohol, and compound 175. Tendinopathy in rats was induced by injecting collagenase (50 pl, mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) in the Achilles tendon. After 1 day, rats were dosed once daily for 21 days via topical application with vehicle control or nd 175 (10 mg/ml). Blood was collected at various timepoints and plasma was analyzed for KC/GRO by ELISA. Measurement of inflammatory cytokine KC/GRO in the plasma of rats from Group 2 (Collagenase-Vehicle), Group 3 genase-compound 175 10 mg/mL with 1% BA) and Group 4 (Collagenase- compound 175 10 mg/mL without BA, with 0.5% Tween 80).

Compound 175 with or t BA preservative significantly decreased the levels of KC/GRO in plasma (p<0.05, student’s t test as indicated in Error! Reference source not ), indicating an anti-inflammatory effect of compound 175. These data were generated from 3 replicates per timepoint per group (n=3). [026[ is a grid of images of a rat Achilles tendon, a rat Achilles tendon treated with a collagenase with a vehicle, a rat Achilles tendon treated with a collagenase, 3 mg/ml compound 175, and benzyl alcohol, a rat Achilles tendon treated with a collagenase, 10 mg/ml compound 175 and benzyl alcohol, a rat Achilles tendon treated with a enase, 3 mg/ml compound 175, and PhX, and a rat Achilles tendon treated with a collagenase, 10 mg/ml compound 175, and PhX. Tendinopathy in rats was d by injecting enase (50 pl, 10 mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) or sham needle puncture for control in the Achilles tendon. After 1 day, rats were dosed once daily for 21 days via topical application with vehicle or compound 175 topical formulations. 24 hours after the last dose, tendons were isolated, fixed with 10% buffered formalin, sectioned and d with H&E. Group 1 (sham injection), Group 2 (Collagenase-Vehicle with 0.5% PhX), Group 3 (Collagenase-compound 175 3 mg/ml with 0.5% BA), Group 4 (Collagenase-compound 175 10 mg/ml with 0.5% BA), Group 5 (Collagenase-compound 175 3 mg/ml with 0.5% PhX) and Group 6 (Collagenase- COMPOUND 175 10 mg/ml with 0.5% PhX). [027[ is a plot of tendon histology scores of a rat Achilles , a rat Achilles tendon treated with a collagenase with a vehicle, a rat Achilles tendon treated with a collagenase, 3 mg/ml compound 175, and benzyl alcohol, a rat es tendon treated with a collagenase, 10 mg/ml compound 175, and benzyl alcohol, a rat Achilles tendon treated with a collagenase, 3 mg/ml compound 175, and PhX, and a rat Achilles tendon treated with a collagenase, 10 mg/ml compound 175, and PhX. opathy in rats was induced by ing collagenase (50 pl, 10 mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) or sham needle puncture for control in the Achilles tendon. After 1 day, rats were dosed once daily for 21 days via topical application with vehicle or COMPOUND 175 topical formulations. 24 hours after the last dose, tendons were isolated, fixed with 10% buffered formalin, sectioned and stained with H&E.

Group 1 (sham injection), Group 2 (Collagenase-Vehicle with 0.5% PhX), Group 3 (Collagenase-compound 175 3 mg/ml with 0.5% BA), Group 4 (Collagenase-compound 175 mg/ml with 0.5% BA), Group 5 (Collagenase-compound 175 3 mg/ml with 0.5% PhX) and Group 6 (Collagenase- compound 175 10 mg/ml with 0.5% PhX). d histology scoring of tendon injury and inflammation indicates that nd 175 at both 3 and 10mg/mL, with either BA or PhX as a vative, significantly ameliorated collagenase-induced tendinopathy (**p<0.01 and ***p<0.001) by student’s ttest. For this study, atotal of 94 sections were scored for Group 1 and 92-116 sections for Groups 2-6. [028[ is series of plots of plasma concentrations of KC/GRO in rats vs. the number of days elapsed after stration of a vehicle, 3 mg/ml COMPOUND 175 with benzyl alcohol, 10 mg/ml COMPOUND 175 with benzyl alcohol, 3 mg/ml COMPOUND 175 with PhX, and 10 mg/ml compound 175 with PhX. Tendinopathy in rats was induced by injecting collagenase (50 pl, 10 mg/ml Type IA in PBS, pH 7.4, ~469 units/mg) in the Achilles tendon. After 1 day, rats were dosed once daily for 21 days via topical application with vehicle l or topical compound 175. Blood was collected at various timepoints and plasma was analyzed for KC/GRO by ELISA. Measurement of inflammatory cytokine KC/GRO in the plasma of rats from Group 2 (Collagenase -Vehicle containing 0.5% Phx), Group 3 (Collagenase-compound 175 3 mg/mL with 0.5% BA), Group 4 (Collagenase— compound 175 mg/mL with 0.5% BA), Group 5 (Collagenase—compound 175 3 mg/mL with 0.5% PhX) and Group 6 (Collagenase—compound 175 10 mg/mL with 0.5% PhX). Compound 175 at both 3 and 10mg/mL dose concentrations, with either BA or PhX as preservative icantly decreased the levels of KC/GRO in plasma compared to vehicle (p<0.05 and p<0.01, student’s t test as indicated in Table 5), indicating an anti-inflammatory effect of compound 175. These data were generated from 3 replicates per timepoint per group (n=3). [029[ is a series of plots of compound 175 concentrations vs. time in Sprague-Dawley rat tendons, plasma, and skin after atopical ation of 1 mg/mL compound 175 and benzyl alcohol, 10 mg/mL compound 175 and benzyl alcohol, and 10 mg/mL compound 175.

DETAILED DESCRIPTION [030[ This disclosure features the use of one or more indazolecarboxamide compounds or salts or s thereof, in the treatment of one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, d's syndrome, and Darier's disease; and/or for promoting wound healing. The methods include stering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3 -carboxamide compounds or salts or analogs thereof as bed anywhere herein.

Definitions [031[ Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ry 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. [032[ In this ication and in the claims, the following terms have the meanings as defined. As used herein, "alkyl" means a branched, or straight chain chemical group containing only carbon and en, such as methyl, ethyl, n-propyl, pyl, n-butyl, isobutyl, tyl and pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, y, carbonyl, benzyloxy, aryl, heteroaryl, or other fimctionality that may be suitably d, if ary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing -C=C- or -CEC- subunits), at one or several positions. Typically, alkyl groups will comprise l to 9 carbon atoms, ably 1 to 6, more preferably 1 to 4, and most preferably 1 to 2 carbon atoms. [033[ 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 filSCd rings. yclyls 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, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, y, yl, benzyloxy, aryl, heteroaryl, or other fimctionality that may be suitably blocked, ssary for purposes ofthe invention, with a protecting group. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6. [034[ As used herein, “lower alkyl” means a subset of alkyl having 1 to 3 carbon atoms, and thus is a hydrocarbon substituent, which is linear, or branched. Examples of lower alkyl include methyl, ethyl, n-propyl and isopropyl. Likewise, radicals using the terminology “lower” refer to radicals preferably with l to about 3 carbons in the alkyl portion ofthe radical. [035[ As used herein, “amido” means a H-CON- or alkyl-CON—, carbocyclyl- CON—, ON—, aryl-CON- or heterocyclyl-CON group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described. [036[ As used , “aryl” means an aromatic radical having a single -ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone. Aryl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, amino, cyano, hydroxyl, lower alkyl, kyl, alkoxy, nitro, halo, mercapto, and other substituents. A preferred carbocyclic aryl is phenyl. [037[ As used herein, the term “heteroaryl” means an aromatic radical having one or more heteroatom(s) (e.g., N, O, or S) in the ring backbone and may include a single ring (e.g., ne) or multiple condensed rings (e.g., quinoline). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. Examples of heteroaryl include thienyl, pyridinyl, fierl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, azolyl, pyrazolyl, isoxazolyl, thiadiazolyl, l, 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, olyl, and others. [038[ In these definitions it is clearly contemplated that substitution on the aryl and heteroaryl rings is within the scope of certain embodiments. Where substitution occurs, the radical is called substituted aryl or substituted heteroaryl. ably one to three and more preferably one or two substituents occur on the aryl ring. Though many substituents will be , preferred substituents include those commonly found in aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like. [039[ As used , “amide” includes both - (in the case ofR = alkyl, alkaminocarbonyl-) and RCONR’- (in the case of R = alkyl, alkyl carbonylamino-). [040[ As used herein, the term “ester” includes both ROCO- (in the case of R = alkyl, carbonyl-) and RCOO- (in the case of R = alkyl, alkylcarbonyloxy-). [041[ As used herein, "acyl" means an H-CO- or alkyl-CO-, carbocyclyl-CO-, aryl-CO-, heteroaryl-CO- or heterocyclyl-CO- group n the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary alkyl acyl groups e formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl. [042[ As used herein, "halo”, “halide” or “halogen” is a chloro, bromo, fluoro or iodo atom radical. , bromo and fluoro are red halides. Most red halide is fluorine. [043[ As used , "haloalkyl" means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are lkyls, wherein one or more of the hydrogen atoms have been tuted by fluoro. Preferred haloalkyls are of l to about 3 carbons in length, more preferred haloalkyls are l to about 2 s, and most preferred are 1 carbon in length.

The skilled artisan will recognize then that as used herein, "haloalkylene" means a cal variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another fiinctional group. [044[ As used herein, “heterocyclyl” means a cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple filSCd rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Heterocyclyls may be tuted or unsubstituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents, and are attached to other groups via any available valence, preferably any available carbon or nitrogen.

More preferred heterocycles are of 5-7 s. In siX membered monocyclic heterocycles, the atom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or two atoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2- dithiazolyl, nzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, l,3-dioxanyl, l,4-dioxanyl, l,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofierl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. [045[ As used herein, “substituted amino” means an amino radical which is substituted by one or two alkyl, cycloalkyl, aryl, aryl or heterocyclyl groups, wherein the alkyl, aryl, heteroaryl or heterocyclyl are defined as above. [046[ As used herein, ituted thiol” means RS- group wherein R is an alkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above. [047[ As used herein, “sulfonyl” means an alkylSOz, arylSOz, arylSOz, carbocyclylSOz, or heterocyclyl-$02 group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.

WO 75858 [048[ As used herein, "sulfamido" means an N-S(O)2N-, aryl-NS(O)2N-, heteroaryl-NS(O)2N-, carbocyclyl-NS(O)2N or heterocyclyl-NS(O)2N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein bed. [049[ As used herein, "sulfonamido" means an alkyl-S(O)2N-, aryl-S(O)2N-, heteroaryl-S(O)2N-, carbocyclyl-S(O)2N- or cyclyl-S(O)2N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described. [050[ As used herein, "ureido" means an alkyl-NCON-, aryl-NCON-, heteroaryl-NCON- or heterocyclyl-NCON— group wherein the , carbocyclyl-NCON— alkyl, yclyl, aryl, heteroaryl or heterocyclyl group is as herein described. [051[ 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 n 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 aryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the purview of the d artisan to both envision such rings and the methods of their formations. Preferred are rings having from 3-7 members, more preferably 5 or 6 members. As used herein the term “ring” or “rings” when formed by the combination of two radicals refers to heterocyclic, carbocyclic, aryl, or heteroaryl rings. [052[ The d artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly ented 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 ofthis invention, though such resonance forms or tautomers may not be itly represented herein. [053[ The compounds provided herein may encompass s stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g. mixtures of enantiomers ing 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 ying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. [054[ The term “administration” or “administering” refers to a method of giving 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, aneously, intravenously, intranasally, topically, transdermally, intraperitoneally, WO 75858 intramuscularly, intrapulmonarilly, vaginally, ly, 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, ynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of ed bone, or via application as part of any admixture with a prosthetic devices. The preferred method of administration can vary ing on various factors, 6. g. , the ents of the pharmaceutical composition, the site of the e, the disease involved, and the severity of the disease. [055[ A “diagnostic” as used herein is a nd, method, system, or device that assists in the identification and characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art. [056[ The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species. [057[ The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” es any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, 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 atible 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 ture, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e. g. , in Gilman er al. (Eds) (2010), Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed. The McGraw- Hill ies. [058[ The term aceutically acceptable salt” refers to salts that retain the biological effectiveness and ties of the compounds of the preferred embodiments and, which are not biologically or otherwise undesirable. In many cases, the compounds of the preferred embodiments are e of g acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived e, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, WO 75858 nitric acid, oric acid, and the like. Organic acids from which salts can be d include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fiimaric acid, tartaric acid, citric acid, c 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 e, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, particularly red 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 ing naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, pylamine, and ethanolamine. Many such salts are known in the art, as described in World Patent ation 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein). [059[ “Solvate” refers to the nd formed by the ction of a solvent and a Wnt pathway tor, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates. [060[ “Subject” 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. [061[ By “therapeutically effective amount” or “pharmaceutically effective amount” is one which is sufficient to achieve the desired effect and may vary ing to the nature and severity ofthe disease condition, and the potency ofthe 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 inhibit Wnt d diseases and/or conditions. The combination of compounds is preferably a synergistic combination.

Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect ofthe compounds when stered 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 fithher depend upon the t’s height, weight, sex, age and medical history. [062[ A therapeutic effect relieves, to some extent, one or more ofthe symptoms of the disease, and es curing a disease. “Curing” means that the symptoms of active disease are eliminated. However, certain erm or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage). [063[ ,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for therapeutic purposes. The term “therapeutic ent” refers to stering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, rating or preventing the underlying metabolic causes of symptoms, postponing or preventing the fithher development of a disorder and/or ng the severity of symptoms that will or are expected to develop. [064[ “Morphea” as used herein refers to a skin condition wherein discolored and/or hardened patches appear on the skin (e.g., one or more outer layers ofthe skin) resulting from excessive collagen tion. [065[ “Raynaud’s syndrome” as used herein refers to a disease in which certain parts ofthe body (e.g., s and/or toes) feel numb and/or cold in response to various stimuli (e.g., cold temperatures and/or stress) due to arterial narrowing. [066[ “Darier’s e” as used herein refers to an mal dominant disorder characterized by the appearance of dark crusty patches on the skin (e.g., keratotic papules, keratosis follicularis or dyskeratosis ularis) that may contain pus. [067[ “Wound healing” as used herein refers to a process by which skin and/or other bodily tissue repairs itself after experiencing, for example, damage and/or . [068[ “Ichthyosis” as used herein refers to a group of genetic skin ers characterized by the presence of dry, scaly, cracked, and/or flaky skin. [069[ “Tendinopathy” as used herein refers to a disease or disorder of a tendon characterized by inflammation, deterioration, and/or injury of the tendon and/or tissue contacting, near, or associated with the tendon. Tendinopathy includes, for example, inflammation of the tendon (e.g., tendonitis), non-inflammatory degeneration of, for example, the structure and/or composition of a tendon (e.g., tendinosis), inflammation of the paratenon near or in contact with a tendon (e.g., paratenonitis), micro-trauma to the tendon, and rupture ofthe tendon (e.g., acute, chronic, partial and/or complete rupture). The term also encompasses tenosynovitis, a tendinopathy of the outer lining of the tendon which occurs in certain tendons such as flexor tendons and the es tendon. ms oftendinopathy include pain at rest, upon palpation of the tendon, and/or with movement of, for example, the tendon, tissue, joint, or bone near or associated with the tendon, joint stiffi1ess, difficulty , weakness of the joint or muscles surrounding the tendon, redness of the skin near the tendon, swelling of the tendon and/or oftissue near the tendon, and/or crepitus. [070[ "Tendinosis" as used herein, refers to a non-inflammatory injury to the tendon characterized by intratendinous degeneration of the tendon typically in the form of microtears in the tissue in and around the tendon caused by overuse, leading to an increase in the number of tendon repair cells around the area of damage. Degeneration of the tendon is caused by damage to or disorganization of the collagen fibers, cells, and vascular components of the tendon, which can reduce the tendon's tensile strength and can lead to tendon rupture if not treated. [071[ nitis" as used herein refers to an inflammatory injury to the tendon, characterized by degeneration like that observed in tendinosis, but also accompanied by ation of the tendon, vascular disruption and an inflammatory repair response.

Tendinitis is often associated with fibroblastic and myofibroblastic proliferation, as well as hemorrhage and organizing granulation tissue. Generally, tendinitis is referred to by the body part involved, such as Achilles tendinitis (affecting the es tendon), or patellar tendinitis (also known as "jumper's knee," affecting the patellar tendon), though there are certain exceptions, such as l epicondylitis (also known as s elbow," affecting the Extensor Carpi Radialis Brevis tendon). Symptoms can vary from aches or pains and local stiffi1ess to a burning sensation surrounding the entire joint around the inflamed tendon. In some cases, tendonitis is characterized by ng, sometimes anied by heat and redness, there may also be visible knots surrounding the joint. For many patients, the pain is usually worse during and after ty, and the tendon and joint area can become stiffer the following day as muscles tighten from the movement of the tendon. [072[ “Psoriasis” as used herein refers to an autoimmune disease in which skin cells build up and causes raised, red, scaly patches to appear on the skin. [073[ “Dermatitis” (also known as eczema) as used herein refers to generic inflammation ofthe skin. Specific types of dermatitis include atopic, contact, nummular, photo- induced, and stasis dermatitis. These diseases are characterized by itchiness, red skin, and a rash.

Compounds [074[ Some ments of the t invention include compounds, salts, pharmaceutically acceptable salts or pro-drug thereof of Formula (1): 0 / R4 NH R2 N/ [075[ In some embodiments of Formula 1, R1, R2 and R4 are independently selected from the group ting of H, C1_9 alkyl, halide, -N(R10)2, -XR10, CN, -OCF3 and - [076[ In some embodiments of Formula I, R3 is selected from the group consisting of carbocyclle6, heterocyclle6, arle6 and heteroarle6. [077[ In some embodiments of Formula I, when R3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole. [078[ In some embodiments of Formula I, R5 is selected from the group consisting of -(C1-9 alkyl)ncarbocyclle7, -(C1-9 alkyl)nheterocyclle7, -(C1_9 alkyl)narle7 and - (C1.9 alkyl)nheteroarle7. [079[ In some ments of Formula I, R5 is not 4-pyridle7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, 4-pyridle6, 2-pyridle6, 0 Ni“: phenle6, thiazoleR6, oleR6, pyrimidineR6, oxazoleR6, ""06; 6 6 306 fig 306 306 "1606 06 ‘ N/ 1606 c' N/ and N/ and R6 and R7 are both H. , , [080[ In some embodiments of Formula I, R5 is not —(CH2)(3-pyridyl)R7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, dle6 and thiazoleR6, and R6 and R7 are both H. [081[ In some embodiments of Formula I, R5 is not phenle7 when R1, R2 and R4 are H, R3 is 4-pyridle6 and R6 and R7 are both H. [082[ In some embodiments of Formula I, R3 is not dle6 when R1, R2 and R4 are H, R5 is ed from the group consisting of phenle7, 0;, ,0 M1,0"0 06“:363 ,0?) ,0; ,0*""" ,0“ ,00 3 7 Ye\/©\ F and Ye\/©/F and R6 and R7 are both H. [083[ In some embodiments of Formula I, R3 is not oxazoleR6 when R1, R2 and J: 1 I r, / N R4 are H, R5 is selected from the group consisting of c", IL/(?(0Me and and R6 is H. [084[ In some embodiments of Formula I, R3 is not thiazoleR6 when R1, R2 and R4 are H, R5 is selected from the group consrstrng of. . . Yfilnv and ,DVL and R6 is H. [085[ In some embodiments of Formula I, each R6 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, - (C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1_9 alkyl)narle8, -(C1_9 alkyl)nheteroarle8, R“, -N(R10)C(=O)R“, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR” and -SOzR“. [086[ In some embodiments of Formula I, each R7 is 1-5 substituents each selected from the group consisting of H, C1-9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, - (C1.9 alkyl)ncarbocyclle9, -(C1-9 alkyl)nheterocyclle9, -(C1_9 alkyl)narle9, -(C1_9 alkyl)nheteroarle9, -C(=O)R“, -N(R1°)C(=O)R“, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR“ and . [087[ In some embodiments of Formula I, each R8 is 1-5 substituents each ed from the group consisting of H, C1.3 alkyl, halide, amino, OCF3, -CF3 -CN, -XR12, - C(=O)R13, -N(R12)C(=O)R13, -(C1_9 nN(R12)2, -(C1_9 alkyl)nN(R12)SOZRl3 and -SOzR13. [088[ In some embodiments of Formula I, each R9 is 1-5 tuents each ed from the group consisting of H, C1.3 alkyl, halide, amino, -OCF3, -CF3 -CN, -XR12, - 13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, -(C1_9 alkyl)nN(R12)SOZRl3 and -SOzR13. [089[ In some ments of Formula I, each R10 is independently selected from the group consisting of H, C1.9 alkyl, -(C1—9 alkyl)nN(R14)2, -(C1—9 alkyl)ncarbocyclle8, - (C1_9 alkyl)nheterocyclle8, -(C1-9 alkyl)narle8 and -(C1-9 alkyl)nheteroarle8. [090[ In some embodiments of Formula I, each R11 is independently selected from the group ting of C1_9 alkyl, -N(R14)2, -(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1_9 alkyl)narle8 and -(C1_9 alkyl)nheteroarle8. [091[ In some embodiments of Formula I, each R12 is independently selected from the group consisting of H, C1_9 alkyl, -(C1_9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1_ 9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl. [092[ In some embodiments of Formula I, each R13 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, -(C1-9 alkyl)ncarbocyclyl, -(C1—9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl. [093[ In some embodiments of a I, each R14 is independently selected from the group consisting of H, C1.3 alkyl, carbocyclyl and aryl. [094[ In some embodiments of Formula I, each X is ed from the group consisting of a bond, and -S-. [095[ In some embodiments of Formula I, each n is 0 or 1. [096[ In some embodiments of Formula I, X is O. [097[ In some embodiments of Formula I, R1, R2 and R4 are H. [098[ Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drug thereof of Formula (Ia): 0 / wherein: R3 is ed from the group consisting of 3-pyridle6, 5-pyrimidinle6, and 4- pyridazinleG, R5 is selected from the group consisting of oarle7, R6 is a substituent selected from the group ting of -(C1-2 heterocyclle8 and -heterocyclle8, R7 is 1-2 substituents each independently selected from the group consisting of H, C1.3 alkyl, halide, -NH2, -OCF3, -CF3, -CN, -OR10, -(C1-2 alkyl)heterocyclle9, -heterocyclle9, and 802R”, R8 is 1-2 substituents each independently selected from the group ting of H, C1_3 alkyl, halide, and -OR12, each R9 is 1-2 substituents each independently selected from the group consisting ofH, C1_3 alkyl, halide, amino, -OCF3, -CF3, —CN, and -OR12, R10 is selected from the group consisting ofH and C1_3 alkyl, R11 is C1—3 alkyl, and each R12 is independently selected from the group consisting ofH and C1.3 alkyl. [099[ Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drug thereof of a (Ia): 0 / wherein: R3 is 3-pyridle6, R5 is selected from the group consisting of pyridle7, -pyrimidinle7, and - pyridazinle7, R6 is —CH2heterocyclle8, R7 is 1-2 substituents each independently selected from the group consisting of H, F, OH $.43 ,1; OOOéUNN E I N N N N N J methyl, -NH2, -CF3, -CN, -OMe, -SOzMe, wlw Wlw ml” ml” “I” ‘17?" , , , , , , and «VLF ,and R8 is 1-2 substituents each ndently selected from the group ting of H and halide. [0100[ In some ments of Formula Ia, R3 is selected from the group consisting of 3-pyridle6, 5-pyrimidinle6, and 4-pyridazinle6, [0101[ In some ments of a Ia, R5 is selected from the group consisting of -heteroarle7. [0102[ In some embodiments of Formula Ia, R5 is selected from the group consisting of -piperazinle7, -tetrahydropyranle7, —piperidinle7, pyrazolle7, pyrimidinle7, pyridazinle7, benzo[d][l,3]dioxolle7, 2,3-dihydrobenzo[b][l,4]dioxinle7, pyrazinle7, and 3-pyridle7. [0103[ In some embodiments of Formula Ia, R6 is a substituent selected from the group consisting of -(C1-2 alkyl)heterocyclle8 and -heterocyclle8. [0104[ In some embodiments ofFormula Ia, R6 is each R6 is 1-2 substituents each selected from the group consisting of -(C1-2 alkyl)heterocyclle8, -heterocyclle8, -(C1_2 alkyl)arle8, )C(=O)R11 and -(C1.2 alkyl)N(R10)2. [0105[ In some ments of Formula Ia, R7 is 1-2 substituents each independently selected from the group consisting of H, C1_3 alkyl, halide, -NH2, -OCF3, -CF3, - CN, -OR10, -(C1-2 alkyl)heterocyclle9, -heterocyclle9, and -SOzR”. [0106[ In some embodiments of Formula Ia, each R7 is 1-2 substituents each selected from the group ting ofunsubstituted C1-3 alkyl, halide, amino, -OCF3, -CF3, -CN, -OR10, -C(=O)R“, -N(R10)C(=O)R”, -N(R10)2, -(C1_2 alkyl)N(R10)2, and )SOZR”. [0107[ In some embodiments of Formula Ia, R8 is 1-2 substituents each independently selected from the group consisting of H, C1.3 alkyl, halide, and -OR12. [0108[ In some embodiments of Formula Ia, each R9 is 1-2 substituents each independently selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3, —CN, and -OR12. [0109[ In some embodiments of Formula Ia, R10 is selected from the group consisting ofH and C1_3 alkyl. [0110[ In some ments of Formula Ia, each R10 is independently selected from the group consisting of H, C1_3 alkyl, -(C1_3 alkyl)N(R14)2 and -arle8. [0111[ In some embodiments of Formula Ia, R11 is C1.3 alkyl. [0112[ In some embodiments of Formula Ia, R11 is each R11 is independently selected from the group consisting of C1.3 alkyl, -N(R14)2, -carbocyclle8 and -heterocyclle8. [0113[ In some embodiments of Formula Ia, each R12 is independently selected from the group ting ofH and C1.3 alkyl. [0114[ In some embodiments of Formula Ia, R3 is ed from the group consisting of arle6 and heteroarle6. [0115[ In some embodiments of Formula Ia, when R3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole. [0116[ In some embodiments of Formula Ia, R5 is selected from the group consisting of -carbocyclle7, -heterocyclle7, -arle7, -heteroarle7, and -(C1-2 alkyl)heteroarle7. [0117[ In some embodiments of Formula Ia, R5 is not 4-pyridle7 when R3 is selected from the group ting of 3-pyridle6, 4-pyridle6, 2-pyridle6, phenle6, o N HzNfij/fiz; NH2 HO \ “‘9 thiazoleR6,imidazoleR6, FYrimidineR6,oxazoleR6, N/ N /6/52, /N , , F <1 ° 0 "W /. my N? M \ M "\ .v~~~WN/ 1“" N/ N/ N/ 3 3 3 3 3 3 (1 ° \ ‘15 \ N \ 19 I/ H I/ CI N and N and R6 and R7 are both H. 3 , [0118[ In some embodiments of Formula Ia, R5 is not —(CH2)(3-pyridyl)R7 when R3 is selected from the group consisting of 3-pyridle6, 4-pyridle6 and thiazoleRG, and R6 and R7 are both H. [0119[ In some embodiments of Formula Ia, R5 is not phenle7 when R3 is 4- pyridle6 and R6 and R7 are both H. [0120[ In some embodiments of Formula Ia, R3 is not 3-pyridle6 when R5 is QVNN\ / 30%? selected from the “a fl group consisting of phenle7, 3 0 F QF NHNH2 0% Lil. 0V(\0 clj‘i ark/G ,LLL Nd);\/©\Fand ;\/©/F and R6 and R7 are both H. [0121[ In some embodiments of Formula Ia, R3 is not eR6 when R5 is £1 /N selected from the group consisting of c" £0.“ nd and R6 , , is H. [0122[ In some embodiments of Formula Ia, R3 is not thiazoleR6 when R5 is ed from the group cons1st1ng of and and R is H. [0123[ In some embodiments of Formula Ia, each R6 is 1-2 substituents each selected from the group consisting of H, C1.3 alkyl, halide, amino, -OCF3, -CF3, -CN, -OR10, - (C14 heterocyclle8, -heterocyclle8, -(C1_2 arle8, -C(=O)R”, -N(R10)C(=O)R11 and -(C1_2 alkyl)N(R10)2. [0124[ In some embodiments of Formula Ia, each R7 is 1-2 substituents each selected from the group consisting of H, C1.3 alkyl, halide, amino, -OCF3, -CF3, -CN, -OR10, - (C14 alkyl)heterocyclle9, -heterocyclle9, , -(C1_2 alkyl)arle9, -C(=O)R”, - N(R10)C(=O)R”, )2, -(C1_2 alkyl)N(R10)2, -N(R10)SOZR” and -SOzR“. [0125[ In some embodiments of Formula Ia, each R8 is 1-2 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, OCF3, -CF3 —CN and -OR12. [0126[ In some embodiments of Formula Ia, each R9 is 1-2 substituents each selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3 —CN and -OR12. [0127[ In some embodiments of Formula Ia, each R10 is independently selected from the group consisting of H, C1_3 alkyl, -(C1_3 alkyl)N(R14)2 and -arle8. [0128[ In some embodiments of Formula Ia, each R11 is independently selected from the group consisting of C1.3 alkyl, -N(R14)2, -carbocyclle8 and -heterocyclle8. [0129[ In some embodiments of Formula Ia, each R12 is independently ed from the group consisting ofH and C1.3 alkyl. [0130[ In some embodiments of Formula Ia, each R14 is independently selected from the group consisting of H, C1_3 alkyl and carbocyclyl. [0131[ In some embodiments of Formula I or Formula Ia, halide is e. [0132[ In some embodiments of Formula I or Formula Ia, R3 is —arle6. [0133[ In some embodiments of Formula I or Formula Ia, R3 is —heteroarle6. [0134[ In some ments of Formula I or Formula Ia, R5 is —arle7. [0135[ In some embodiments of Formula I or Formula Ia, R5 is —heteroarle7. [0136[ In some embodiments of a I or Formula Ia, R5 is —heterocyclle7. [0137 [ In some embodiments of Formula I or Formula Ia, R3 is —heteroarle6 and R5 is oarle7. [0138[ In some embodiments of Formula I or Formula Ia, R3 is —phenle6 and R5 is —heteroarle7. [0139[ In some embodiments of Formula I or Formula Ia, R3 is —heteroarle6 and R5 is —phenle7. [0140[ In some embodiments of Formula I or Formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7. [0141[ In some embodiments of Formula I or a Ia, R3 is —3-pyridle6 and R5 is —CH2pyridle7. [0142[ In some embodiments of Formula I or Formula Ia, R3 is —3-pyridle6 and R5 is —pyridazinle7. [0143[ In some embodiments of a I or Formula Ia, R3 is —3-pyridle6 and R5 is —pyrazinle7. [0144[ In some embodiments of Formula I or a Ia, R3 is —3-pyridle6 and R5 is — pyrimidinle7. [0145[ In some embodiments of Formula I or Formula Ia, R3 is —3-pyridle6 and R5 is benzo[d][l,3]dioxolyl. [0146[ In some ments of Formula I or Formula Ia, R3 is idle6 and R5 is 2,3-dihydrobenzo[b][l,4]dioxinyl. [0147[ In some embodiments of Formula I or Formula la, the aryl is phenyl. [0148[ In some embodiments of Formula I or Formula Ia, when R3 is heteroaryl, the heteroaryl is dyl. [0149[ In some ments of Formula I or Formula Ia, when R5 is heteroaryl, the heteroaryl is 3-pyridyl. [0150[ In some embodiments of Formula I or Formula Ia, when R5 is aryl, the heteroaryl is 5-pyrimidinyl. [0151[ In some embodiments of Formula I or a Ia, when R5 is heteroaryl, the heteroaryl is dazinyl. [0152[ In some embodiments of Formula I or Formula Ia, when R5 is heteroaryl, the heteroaryl is pyrazolyl. [0153[ In some embodiments of Formula I or Formula Ia, when R5 is heteroaryl, the heteroaryl is benzo[d][l,3]dioxolyl. [0154[ In some embodiments of Formula I or Formula Ia, when R5 is heteroaryl, the heteroaryl is 2,3-dihydrobenzo[b] [ l ,4]dioxinyl. [0155[ In some embodiments of Formula I or Formula Ia, R6 is a heterocyclyl.

For example, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R6 is morpholinyl. In another embodiment, R6 is piperazinyl. In another embodiment, R6 is piperidinyl. In another ment, R6 is pyrrolidinyl. [0156[ In some embodiments of Formula I or Formula Ia, R7 is a heterocyclyl.

For example, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R7 is morpholinyl. In another embodiment, R7 is piperazinyl. In another embodiment, R7 is dinyl. In another embodiment, R7 is pyrrolidinyl. In another embodiment, R7 is azetidinyl. [0157[ In some embodiments of Formula I or Formula Ia, R10 is a carbocyclyl.

For example, the carbocyclyl can be ed from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In n embodiments, R10 is cyclopropyl. In another embodiment, R10 is cyclobutyl. In another ment, R10 is cyclopentyl. In another embodiment, R10 is cyclohexyl. [0158[ In some embodiments of Formula I or a Ia, R11 is a heterocyclyl.

For example, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R11 is morpholinyl. In another embodiment, R11 is piperazinyl. In another embodiment, R11 is piperidinyl. In another embodiment, R11 is pyrrolidinyl. In another embodiment, R11 is azetidinyl. [0159[ In some embodiments of Formula I or Formula Ia, R11 is a carbocyclyl.

For example, the yclyl can be ed from the group consisting of ropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R11 is cyclopropyl. In another embodiment, R11 is cyclobutyl. In another embodiment, R11 is cyclopentyl. In another embodiment, R11 is cyclohexyl. [0160[ In some embodiments of Formula I or Formula Ia, R12 is a carbocyclyl.

For example, the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 is cyclopropyl. In another embodiment, R12 is cyclobutyl. In another embodiment, R12 is cyclopentyl. In r embodiment, R12 is cyclohexyl. [0161[ In some ments of Formula I or a Ia, R13 is a heterocyclyl.

For e, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R13 is morpholinyl. In another ment, R13 is piperazinyl. In another ment, R13 is piperidinyl. In another ment, R13 is idinyl. In another embodiment, R13 is azetidinyl. [0162[ In some embodiments of Formula I or Formula Ia, R13 is a carbocyclyl.

For example, the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R13 is cyclopropyl. In another embodiment, R13 is cyclobutyl. In another embodiment, R13 is cyclopentyl. In another embodiment, R13 is cyclohexyl. [0163[ In some embodiments of Formula I or Formula Ia, R6 is one substituent. [0164[ In some embodiments of Formula I or Formula Ia, R6 is 1-2 substituents. [0165[ In some embodiments of Formula I, R6 is 1-3 substituents. [0166[ In some embodiments of Formula I, R6 is 1-4 substituents. [0167[ In some embodiments of a I or Formula Ia, R6 is H. [0168[ In some embodiments of a I or Formula Ia, R6 is one substituent and the substituent is a halide. [0169[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is —NH2. [0170[ In some embodiments of a I or Formula Ia, R6 is one substituent and the substituent is -OCF3. [0171[ In some embodiments of Formula I or Formula Ia, R6 is one tuent and the substituent is -OCH3. [0172[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -CF3. [0173[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the tuent is —heterocyclle8. [0174[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is heterocyclle8. [0175[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is —(CH2)pyrrolidinle8. [0176[ In some embodiments of a I or Formula Ia, R6 is one substituent and the substituent is —(CH2)pyrrolidinle8 where R8 is two tuents and both substituents are halides. [0177[ In some embodiments of Formula I or Formula Ia, R6 is one tuent and the substituent is —(CH2)piperidinle8. [0178[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is —(CH2)phenle8. [0179[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is — phenoxyRS. [0180[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is :lW. [0181[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -N(R10)2. [0182[ In some embodiments of Formula I or Formula Ia, R6 is one tuent and the substituent is -N(R10)2 where each R10 is independently selected from C1_3 alkyl. [0183[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is —(CH2)N(R10)2. [0184[ In some embodiments of a I or Formula Ia, R6 is one substituent and the tuent is —(CH2)N(R10)2 where each R10 is ndently selected from C1-3 alkyl. [0185[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -N(R10)SOzR”. [0186[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -N(R10)C(=O)R”. [0187[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -N(R10)C(=O)R11 where R11 is a heterocyclyl. [0188[ In some embodiments of Formula I or Formula Ia, R6 is one substituent and the substituent is -N(R10)C(=O)R11 where R11 is a carbocyclyl. [0189[ In some embodiments of Formula I, R6 is two substituents and the substituents are fluorine and -(C1-9 nheterocyclle8. [0190[ In some embodiments of Formula Ia, R6 is two substituents and the substituents are fluorine and -heterocyclle8. [0191[ In some embodiments of Formula Ia, R6 is two tuents and the substituents are fluorine and -(C1-2 alkyl)heterocyclle8. [0192[ In some embodiments of a I or Formula Ia, R6 is one tuent and the substituent is select from the group consisting of [0193[ In some ments of Formula I or Formula Ia, R7 is one substituent. [0194[ In some embodiments of Formula I or Formula Ia, R7 is 1-2 substituents. [0195[ In some embodiments of Formula I, R7 is 1-3 substituents. [0196[ In some ments of Formula I, R7 is 1-4 substituents. [0197[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is a halide. [0198[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is —NH2. [0199[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is —OH. [0200[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -CF3. [0201[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -CN. [0202[ In some embodiments of Formula I, R7 is one substituent and the substituent is -XR10 where X is O and R10 is C1_3 alkyl. [0203[ In some embodiments of Formula Ia, R7 is one substituent and the substituent is -OR10 and R10 is C1_3 alkyl. [0204[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is —phenle9. [0205[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the tuent is —(CH2)N(R10)2. [0206[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is —(CH2)N(R10)2 where each R10 is independently selected from C1-3 alkyl. [0207[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the tuent is —(CH2)heterocyclle9. [0208[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is —(CH2)pyrrolidinle9. [0209[ In some embodiments of a I or Formula Ia, R7 is one substituent and the substituent is —heterocyclle9. [0210[ In some embodiments of Formula I or a Ia, R7 is one substituent and the substituent is — ng. [0211[ In some embodiments of Formula I or a Ia, R7 is one substituent and the substituent is —(CH2)phenle9. [0212[ In some embodiments of a I or Formula Ia, R7 is one substituent and the substituent is —phenle9. [0213[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -N(R10)C(=O)R”. [0214[ In some ments of Formula I or a Ia, R7 is one substituent and the substituent is -N(R10)C(=O)R11 where R11 is a carbocyclyl. [0215[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -N(R10)2. [0216[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -C(=O)R11 where R11 is select from the group consisting of — cyclle8 and -N(R10)2. [0217[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is -SOzR”. [0218[ In some ments of Formula I or Formula Ia, R7 is one substituent and the substituent is -SOzR”; and R11 is C1_3 alkyl. [0219[ In some ments of Formula I or Formula Ia, R7 is two substituents and the substituents are C1.3 alkyl and —heterocyclle9. [0220[ In some embodiments of Formula I or Formula Ia, R7 is one substituent and the substituent is select from the group consisting of [0221[ In some embodiments of Formula I or Formula Ia, R8 is one substituent. [0222[ In some embodiments of Formula I or Formula Ia, R8 is 1-2 substituents. [0223[ In some embodiments of Formula I, R8 is 1-3 substituents. [0224[ In some embodiments of a I, R8 is 1-4 substituents. [0225[ In some embodiments of Formula I or Formula Ia, R8 is H. [0226[ In some embodiments of Formula I or Formula Ia, R8 is one substituent and the substituent is C1_3 alkyl. [0227[ In some embodiments of Formula I or Formula Ia, R8 is one tuent and the substituent is —OH. [0228[ In some embodiments of Formula I or a Ia, R8 is one substituent and the tuent is a halide. [0229[ In some embodiments of Formula I or Formula Ia, R8 is two substituents and the substituents are halides. [0230[ In some embodiments of Formula I, R8 is three substituents and the substituents are halides. [0231[ In some embodiments of Formula I or Formula Ia, R9 is one tuent. [0232[ In some embodiments of Formula I or Formula Ia, R9 is 1-2 substituents. [0233[ In some embodiments of a I, R9 is 1-3 substituents. [0234[ In some embodiments of Formula I, R9 is 1-4 substituents. [0235[ In some embodiments of Formula I or Formula Ia, R9 is H. [0236[ In some ments of Formula I or Formula Ia, R9 is one substituent and the substituent is C1.3 alkyl. [0237[ In some embodiments of Formula I or Formula Ia, R9 is one substituent and the substituent is —OH. [0238[ In some embodiments of Formula I or Formula Ia, R9 is one substituent and the substituent is a halide. [0239[ In some embodiments of Formula I or Formula Ia, R9 is two substituents and the tuents are halides. [0240[ In some embodiments of Formula I or a Ia, R8 is a -C1.3 alkyl. For example, the -C1_3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and isopropyl. In certain embodiments, R8 is methyl. In another embodiment, R8 is ethyl. [0241[ In some embodiments of Formula I or a Ia, R10 is a -C1_3 alkyl. For e, the -C1_3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R10 is methyl. In another embodiment, R10 is ethyl. In another embodiment, R10 is n-propyl. In another embodiment, R10 is iso-propyl. [0242[ In some embodiments of Formula I or Formula Ia, R11 is a -C1.3 alkyl. For example, the -C1.3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R11 is methyl. In another embodiment, R11 is ethyl. In another embodiment, R11 is n-propyl. In r embodiment, R11 is iso-propyl. [0243[ In some embodiments of Formula I or Formula Ia, R14 is a -C1.3 alkyl. For example, the -C1.3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R14 is methyl. In another embodiment, R14 is ethyl. In r embodiment, R14 is n-propyl. In another embodiment, R14 is iso-propyl. [0244[ In some embodiments of Formula I or Formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7, R6 is one tuent consisting of -(C1-2 alkyl)N(R10)2, and R7 is one substituent consisting of -CF3, and each R10 is -C1_3 alkyl. [0245[ In some embodiments of Formula I or Formula Ia, R3 is —3-pyridle6 and R5 is —3 -pyridle7, R6 is one substituent ting of -(C1_2 alkyl)heterocyclle8, R7 and R8 are both H, and the cycle is a 5-member ring. [0246[ In some embodiments of Formula I or Formula Ia, R3 is idle6 and R5 is —3 -pyridle7, R6 is one substituent consisting of -(C1-2 heterocyclle8, R7 and R8 are both H, and the heterocycle is a 6-member ring. [0247[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one tuent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of CN; R8 is H; and the heterocycle is a 5-member ring. [0248[ In some embodiments of Formula I or Formula Ia; R3 is idle6 and R5 is —3-py1idle7; R6 is one tuent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of CN; R8 is H; and the cycle is a 6-member ring. [0249[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 heterocyclle8; R7 is one substituent consisting of CF3; R8 is H; and the heterocycle is a 6-member ring. [0250[ In some embodiments of Formula I or Formula Ia; R3 is idle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent ting of -heterocyclle8; each R8 is H; and the heterocycles are independently selected from a 5 or 6-member ring. [0251[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)N(R10)2; and R7 is one substituent consisting of -CN; and each R10 is -C1_3 alkyl. [0252[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of -(C1-2 alkyl)N(R10)2; and R7 is one tuent consisting of -(C1-2 alkyl)heterocyclle8; R8 is H; each R10 is -C1_3 alkyl; and the heterocycle is a 6-member ring. [0253[ In some ments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of ocyclle8; each R8 is one substituent independently selected from H and -OH; and the heterocycles are ndently selected from a 5 or 6-member ring. [0254[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of -C(=O)R”; R11 is -heterocyclle8; each R8 is H; and the heterocycles are independently selected from a 5 or 6-member ring. [0255[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of -heterocyclle8; each R8 is 1-3 substituents independently selected from H and F with the proviso that at least one substituent on one heterocycle is fluorine; and each heterocycle is a 5-member ring. [0256[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one tuent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of -C(=O)R”; R11 is ; R10 is heterocyclle8; each R8 is H; and the heterocycles are independently selected from a 5 or 6-member ring. [0257[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of 802R”; R8 is H; R11 is -C1.3 alkyl; and the heterocycle is a 6-member ring. [0258[ In some embodiments of Formula I or Formula Ia; R3 is —3-pyridle6 and R5 is —3-py1idle7; R6 is one substituent consisting of -(C1_2 alkyl)heterocyclle8; R7 is H; R8 is 1-4 substituents independently selected from H and F with the proviso that at least one substituent is fluorine; and the cycle is a er ring. [0259[ Illustrative compounds of Formula (I) are shown in Table 1.

Table 1.

WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 WO 75858 Com ound re aration [0260[ The starting als used in ing 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 fimctionality related to the compounds claimed herein are lly described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any ofthe compounds. [0261[ It is recognized that the skilled artisan in the art of organic try can readily carry out lations without fithher 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 nds to their ponding 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 's Advanced c Chemistry: Reactions, Mechanisms, and Structure 6111 Ed., John Wiley & Sons (2007), Carey and Sundberg, Advanced Organic Chemistry 5111 Ed., er (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 211d Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like. [0262[ The skilled artisan will readily appreciate that certain reactions are best carried out when other fimctionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the on. Often the skilled artisan es 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 ofmany ofthese manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons , incorporated herein by reference in its ty. [0263[ To finther 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 WO 75858 skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will ize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the ion without exhaustive examples. [0264[ Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The d 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. [0265[ (H) nuclear magnetic resonance spectra (NMR) were measured in the indicated ts on a Bruker NMR spectrometer (Avance TM , 300 MHz for 1H or Avance TM DRXSOO, 500 MHz for 1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 1H). 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, d/ABq, doublet of AB quartet, dt, doublet of triplets, td, t of doublets, m, multiplet. [0266[ The following abbreviations have the indicated meanings: brine = saturated aqueous sodium chloride CDC13 = deuterated chloroform DCE = dichloroethane DCM = dichloromethane DHP = dihydropyran DIPEA = diisopropylethylamine DMF = methylformamide DMSO'd6 = deuterated dimethylsulfoxide ESIMS = electron spray mass spectrometry EtOAc = ethyl acetate EtOH = ethanol h = hour HATU = 2-( l Hazabenzotriazol- l -yl)- l , 1,3 ,3 -tetramethyluronium orophosphate HCl = hydrochloric acid HOAc = acetic acid H2804 = sulfiJric acid iPrOH = iso-propyl alcohol KOAc = potassium acetate K3PO4 = ium phosphate LAH = m aluminum hydride mCPBA = meta-Chloroperoxybenzoic acid VleOH = methanol VlgSO4 = magnesium sulfate min. = minute VIW = microwave \IaBH(OAc)3 = sodium triacetoxyborohydride \IaHC03 = sodium bicarbonate \IaH803 = sodium bisulfite \IaHSO4 = sodium bisulfate \IaOH = sodium hydroxide \IH4OH = ammonium hydroxide \IMR = nuclear magnetic resonance Pd/C = palladium(0) on carbon PdClz(dppf)2 = l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) PPTS = nium p-toluenesulfonate r.t. = room temperature satd. = saturated sol“. = solution Reflx. = heated to reflux TEA = triethylamine TFA = trifluoroacetic acid THF = ydrofiJran TLC = thin layer chromatography Tr-Cl = trityl chloride or triphenylmethyl chloride [0267[ The following example schemes are provided for the guidance of the reader, and tively represent an example method for making the compounds provided herein. Furthermore, other methods for ing compounds of the invention will be y apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is ghly 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 procedures [0268[ Compounds of Formula I of the present ion can be prepared as depicted in Scheme 1.

"W"" 0 / co H2 <\’/N HNJ N R‘ N \0/ i(P \o/ I i I \N Me)*HC1, \N Fac 0’ 0 CF: \N 12, DCM, m.

R2 N/ imidazole, DMF, 65°C N/ R2 R2 N/ H H H R1 R1 R1 II I" IV DHP,PPTS DCM, reflux o / Q R‘ R4 we "\ B o \N LAH \N KOAcsPdClz(dPPf)2 / THF 0°C / R2 R‘ N ’ R2 N DMF, 90°C, 2h R1 R1 R1 0 o 0 VII VI V R3—Br K3P04 Pd(PPh3)4 H20, 90°C, 3 11 O / R4 R‘ R‘ cHo CO2” NH R _NH25 R3 R3 R3 \N AgNOs, NaOH, 112 \N HATU, DIPEA \ / Dioxane, rt, overnight / DMF, rt, overnight /N R2 N R2 N R2 N R1 R1 R1 0 o 0 VIII IX x TFA, DCM, Et3§iH,rt,3h o /R R4 NH R2 N/ Scheme 1 [0269[ Scheme 1 describes a method for preparation of indazolecarboxamide derivatives (1) by first g the Weinreb amide (III) of a 1H-indazole-3 -carboxylic acid (11).

The Weinreb amide (III) is reacted with (bis(trifluoroacetoxy)iodo)benzene to produce the 5- iodo-lH-indazolecarboxylic acid (IV) followed by THP tion ofthe indazole nitrogen.

The Weinreb amide of protected indazole V is reduced to de VI followed by reaction with bis(pinacolato)diboron to give the pinacol ester (VII). Suzuki coupling with a variety of aromatic and nonaromatic bromides yields the R3 tuted indazole VIII. Oxidation of the aldehyde to the acid (IX) followed by HATU mediated coupling of a variety of amines and sequent deprotection produces the desired indazolecarboxamide derivatives (1). [0270[ Compounds of Formula I of the present invention can also be prepared as depicted in Scheme 2.

R4 R4 R4 “I" “I“ COzR Br Br \ HOAc, Brz \ ROH, 1.12504 \ N," 90°C, 16 h R2 R2 N,"W R2 N/N H H R = Me, Et H R1 R1 R1 " x' XII DHP, PPTS DCM, reflux R4 NIH R4 R4 cozH cozR Br Br Br \N “S‘Nflz \N .w \N 90°C, 1 h R2 N’ HATU, DIPEA R2 N/ R2 N, DMF, rt, overnight R1 R1 R1 0 0 O XV XIV XIII Route' 2 Route: 1 0 0 R3— \B—B’ B(0H)2 1, id bi , KOAc, Pdc11(dpp01,DMF, 90°C, 2 h KOAc, PdClz(dppf)2 DMF, 90°C, 2 h 2- R3-Br 3 1‘ , K3P04, Pd(PPh3)4,H20: 90°C, R5 R5 R4 NH R4 N” R3 R3 \N TFA, DCM, \N , Et3SiH, rt, 3 h R2 R2 N/ Scheme 2 [0271[ Scheme 2 describes an ative method for preparation of indazole carboxamide derivatives (1) by bromination of the indazole 5-position followed by esterification to form ester XII. The indazole nitrogen is THP protected and the ester is hydrolyzed to acid XIV. The acid is coupled with a variety of amines to produce amide XV which is then coupled with a variety of boronic acids (Route 1) to give X. Alternatively, XV can be converted to the boronate ester and then couple to a variety of bromides (Route 2) to yield X. Final deprotection of the indazole nitrogen yields the desired indazolecarboxamide derivatives (1). [0272[ nds of Formula I of the t invention can also be prepared as depicted in Scheme 3.

R4 R4 R4 cozH cozH 002R Br Br \N HOAc, Br2 ROH, st04 \N 90°C 16h reflux 4h ’ R2 bf 2fig"If ’ R R2 N H H H R1 R1 R = Me, Et R1 II XI XII Route: 1 Tr-CI, DMF Tr-Clo DCM Route. 2.

TEA, l1: DIPEA, rt NH R4 R4 COzH cozR Br Br Rs—Nl’lz \ NaOH, H20 \ /N N 90°C, 1 h HATU, DIPEA R2 N R2 ,f DMF, rt, overnight \ \ R1 TI' R1 Tr XVIII XVII XVI Route: 4 Route: 3 R —B(0H)23 1. o’o‘B-Blofi‘0 , KOAc, PdC12(dppf)2, DMF, 90°C, 2 h KOAc, PdClz(dppf)2 DMF, 90°C, 2 h 2. R3—Br 3 11 , K3P04, 3)4, H20, 90°C, R4 NIH TFA, DCM, \N Et38iH, rt, 3 h / R2 u Scheme 3 [0273[ Scheme 3 describes another alternative method for preparation zole- 3-carboxamide derivatives (I) by bromination of the indazole 5-position ed by either Route 1: esterification to form ester XII, then trityl protection ofthe indazole en and then finally hydrolyzed of the ester to acid XVII, or Route 2: trityl protection of the le nitrogen directly to acid XVII. The acid is coupled with a variety of amines to produce amide XVIII which is then coupled with a y of boronic acids (Route 3) to give XIX.

Alternatively, XVIII can be converted to the boronate ester and then couple to a y of bromides (Route 4) to yield XIX. Final deprotection ofthe indazole nitrogen yields the desired indazolecarboxamide derivatives (I).

Illustrative Com ound Exam les [0274[ Preparation of intermediate 3-(5 -bromopyridin-3 -yl)-l, l-dimethylurea (XXII) is depicted below in Scheme 4. o E Br H2" Br I \ l /N Cl Pyridine Y l + N / (WC-60°C, overnight / \ / N N \(Ll/ XX XXI XXII Scheme 4 Sip—1 [0275[ 3-Aminobromo pyridine (XX) (1.0 g, 5.78 mmol) was dissolved in pyridine and cooled to 0°C before adding dimethyl carbamyl chloride (XXI) (0.683 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated overnight at 60°C under argon. The solution was cooled to room temperature, poured into ice water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated to a residue to afford 3-(5-bromopyridinyl)-l, l-dimethylurea (XXII) as a brown solid, (1.24 g, .09 mmol, 88% yield). 1H NMR (DMSO-ds) 5 ppm 8.67-8.64 (m, 2H), 8.23 (d, J: 7.8 Hz, 1H), 2.93 (s, 6H), ESIMS found for Ngo m/z 245.05(M+H). [0276[ The ing intermediates were prepared in accordance with the procedure described in the above Scheme 4.

N\”/ Br 0 / XXIII [0277[ N—(5-bromopyridinyl)morpholinecarboxamide ): Tan solid (0.82 g, 48%). 1H NMR (DMSO-dg) 3.43-3.45 (m, 4H), .62 (m, 4H), 8.21 (t, J: 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.91 (s, 1H), ESIMS found for C10H12BrN302 m/z 286 (M+H). 0 N/ [0278[ N-(5-bromopyridinyl)cyclopropanecarboxamide (XXIV): Off white solid, (83% yield), 1HNMR(CDC13, 400 MHz) 5 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 C9H9BrN20 m/z 240.85 (M+H). [0279[ ation of intermediate (XXVI) is depicted below in Scheme 5.

OHC Br Br \ MezNI-I*HC1 / 1 l N/ NaBH(OAc)3 \N TEA, DCE XXV XXVI Scheme 5 S£p_1 [0280[ To a solution of 5-bromonicotinaldehyde (XXV) (5.0 g, 26.9 mmol) in DCE (108 mL) was added dimethylamine-HCl (4.39 g, 53.8 mmol) and TEA (7.5 g, 53.8 mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc)3 was added and the on was stirred overnight at room temperature. The reaction was diluted with DCM and sat. aq. NaHCOg. The organic layer was separated, washed with water, brine, dried and concentrated under vacuum to produce 1-(5-bromopyridinyl)-N,N-dimethylmethanamine (XXVI) as a brown liquid (92.6% yield). 1H NMR (CDCl3) 5 ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.59 (d, J=3Hz, 1H), ESIMS found for C8H11B1‘N2 m/z 215 (MBI79+H) and 217 (MBI81+H). [0281[ The following ediates were prepared in accordance with the procedure described in the above Scheme 5.

XXVII [0282[ 3 -Bromo-5 -(pyrrolidinylmethyl)py1idine (XXVII): Golden liquid (1 .3 5 g, 97% yield). 1H NMR (DMSO-dg) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C10H13BrN2 m/z 242 (M+H).

O IN/ XXVIII [0283[ o(pipe1idinylmethyl)py1idine (XXVIII): Brown liquid (13.1 g, 94% yield). 1H NMR (DMSO-dg) 1.36-1.39 (m, 2H), .51 (m, 4H), 2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C11H15B1‘N2 m/Z 257 (M+H).

(\N \ \2 l [0284[ 4-((5-Bromopy1idinyl)methyl)morpholine (XXIX): Brown oil (1.02 g, .6% yield). ESIMS found for C10H13BrN20 m/z 258 (M+H). /’©‘/\[j3rN [0285[ Bromopy1idinyl)methyl)methylpiperazine (XXX): Brown oil (0.93 g, 64% yield). 1H NMR (DMSO-dg) 2.14 (s, 3H), 2.27-2.37 (m, 8H), 3.49 (s, 2H), 7.95 (s, 1H), 8.47 (d, J=1.7Hz, 1H), 8.59 (d, J=2.2Hz, 1H); ESIMS found for C11H16BrN3 m/z 272 (M+H). [0286[ 1-(3-Bromofluorobenzyl)methylpiperazine (XXXI): Light yellow oil (2.07 g, 68% yield). 1H NMR (DMSO-dg) 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found for C12H16BrFN2 m/z 288 (M+H). [0287[ 1-(5-Bromopyridinyl)piperidinol (XXXII): Brown oil (2.15 g, 7.93mmol, 72.7% yield). 1H NMR (DMSO-dg) 1.34-1.41 (m, 2H), 1.67-1.71 (m, 2H), 2.03- 2.07 (m, 2H), 2.62-2.64 (m, 2H), 3.42-3.46 (m, 1H), 3.47 (s, 2H), 4.55 (d, z, 1H), 7.93- 7.94 (m, 1H), 8.46 (d, J=1.6Hz, 1H), 8.58 (d, J=2.2Hz, 1H), ESIMS found for C11H15BrN20 m/z 272 (M+H).

XXXIII [0288[ 3-Bromo((3,3-difluoropyrrolidinyl)methyl)pyridine (XXXIII): Brown liquid (7.38 g, 26.64 mmol, 94.9% yield). 1HNMR (DMSO-dg) 2.21-2.30 (m, 2H), 2.70 (t, J=7Hz, 2H), 2.89 (t, J=13Hz, 2H), 3.66 (s, 2H), 7.95-7.98 (m, 1H), 8.57 (d, J=1.7Hz, 1H), 8.61 (d, J=2.2Hz, 1H), ESIMS found for BrF2N2 m/z 276 (M+H). [0289[ Preparation of 3-benzylbromopyridine (XXXVI) is depicted below in Scheme 6. rXXXV BI' Bl' Br \ / l PdClz(dppf)2,CuI l N/ THF,50°C \N XXXIV XXXVI Scheme 6 [0290[ To a on of 3,5-dibromopyridine (XXXIV) (1.03 g, 4.36 mmol) in THF (7 mL) under argon was added CuI (50 mg, 0.26 mmol) and PdClz(dppf)2 (178 mg, 0.22 mmol). Benzylzinc(II) bromide (XXXV) (0.5M in THF) (13.09 mL, 6.55 mmol) was slowly added by syringe. The reaction was heated at 50°C over the weekend. The reaction was quenched with water and extracted with EtOAc. The EtOAc was separated, washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes —> 5:95 hexanes) to afford 3-benzylbromopyridine (XXXVI) (0.614 g, 2.47 mmol, 57% yield) as a light brown oil. 1H NMR (DMSO-dg) 5 ppm 3.98 (s, 2H), 7.19-7.23 (m, 1H), 7.27-7.32 (m, 4H), .93 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.54 (d, J=3Hz, 1H), ESIMS found for C12H10BrN m/z 248 (M+H). [0291[ Preparation of 3-bromophenoxypyridine (XXXIX) is depicted below in Scheme 7.

WO 75858 XXXVIII Br Br O \ CsCO3 l mBr / NMP, 100°C \ N N XXXVII XXXIX Scheme 7 Sip—1 [0292[ To a solution of 3,5-dibromopyridine (XXXVII) (1.00 g, 4.24 mmol) in NMP (11 mL) was added phenol (XXXVIII) (398 mg, 4.24 mmol) and CsC03 (1.38 g, 4.24 mmol). The reaction was heated at 100°C over the weekend. The reaction was then partitioned between EtzO/water. The EtzO was separated, washed with 2X water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% s —> 2:98 EtOAczhexanes) to afford 3-bromo-5 -phenoxypyridine (XXXIX) (535 mg, 2.14 mmol, 50% yield) as a clear oil. 1H NMR (DMSO-dg) 5 ppm 7.13-7.15 (m, 2H), 7.23-7.26 (m, 1H), 7.43-7.46 (m, 2H), 7.69-7.70 (m, 1H), 8.37 (d, J=3Hz, 1H), 8.49 (d, J=2Hz, 1H), ESIMS found for C11H8BrNO m/z 250 (M+H). [0293[ Preparation of 1-(5 -bromopyridinyl)methylpiperazine (XL) is ed below in Scheme 8.

/ \ \ HN N— N/fi 31' Br N Br \ K/ K2C03, DMF / l I / 120°C, overnight N \N XXXVIII XL Scheme 8 Sip—1 [0294[ To a solution of 3,5-dibromopyridine (XXXVIII) (2.90 g, 12.24 mmol) in dry DMF (20 mL) was added 1-methylpiperazine (2.987 mL, 26.93 mmol) and K2C03 (5.58 g, 40.39 mmol). The reaction was heated at 120°C overnight. An additional portion of 1- methylpiperazine (6 mL) was added and heating was continued for r 24 h. The reaction was poured into ice water and filtered. The filtrate was extracted with 66% MeOH/CHClg. The organic layer was dried over MgSO4, filtered and trated under vacuum to yield 1-(5- bromopyridin-3 -yl)methylpiperazine (XL) as a brown viscous oil (2.49 g, 9.76 mmol, 79.8% yield). ESIMS found for C10H14BrN3 m/z 256 (M+H). [0295[ The following intermediate was prepared in accordance with the procedure described in the above Scheme 8. [0296[ 4-(5-Bromopyridinyl)morpholine (XLI): Yellow solid (1.12 g, 4.61 mmol, 64.9% yield). ESIMS found for C9H11BerO m/z 244.1 (M+H). [0297[ Preparation of 5-bromo-N-cyclohexylnicotinamide (XLIV) is depicted below in Scheme 9. 0/NH2 o XLIII Q H026 Br Br \ HATU, DIPEA / l 12 / DMF \ Scheme 9 [0298[ To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added exanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0°C before adding HATU (947 mg, 2.49 mmol). The reaction was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2X water, brine, dried over MgSO4 and concentrated under vacuum to yield crude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was used without filI'tl’lCl‘ purification. ESIMS found for C12H15BrN20 m/z 283 (M+H). [0299[ Preparation of 3 -5 -(((2R,6S)-2,6-dimethylpiperidin yl)methyl)pyridine (XLVII) is ed below in Scheme 10.

OHC Br Br \ NaBH4 HO \ l MeOH ‘ N/ N/ XXV XLV 1. 4M HCl/dioxane 2. $002 Br Br N \ K2CO3 c| \ / MeCN, 80°C l N N XLVII XLVI Scheme 10 [0300[ To a on of 5-bromonicotinaldehyde (XXV) (2.05 g, 11.0 mmol) in MeOH (85 mL) was added NaBH4 (832 mg, 21.99 mmol). The reaction was stirred at room temperature for 1 h. The on was quenched with saturated aqueous NH4Cl (5 mL). The reaction was concentrated under vacuum and the residue was partitioned between saturated s NH4Cl/EtOAc. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated under vacuum to yield crude (5 -bromopyridin-3 -yl)methanol (XLV) as a golden oil (1.54 g, 8.2 mmol, 74% yield). The product was used without filI'tl’lCl‘ purification. ESIMS found for C6H6BrNO m/z 188 (M+H).

SE1;2 [0301[ mopyridinyl)methanol (XLV) (1.54 g, 8.2 mmol) was treated with 4M HCl in dioxane (10 mL) at 0°C and then evaporated. The residue was dissolved in SOClz (4 mL) and refluxed for 2 hrs. The SOClz was d and the residue was triturated with hexane to produce HCl salt of 3-bromo-5 -(chloromethyl)pyridine (XLVI) as a brown solid (1.30 g, 5 .4 mmol, 66% yield). The t was used without fiirtherpurification. ESIMS found for C6H5BrClN m/z 206 (M+H).

Sip—3 [0302[ To a solution of 3-bromo(chloromethyl)pyridine (XLVI) (1.17 g, 4.8 mmol) in MeCN (0.2 mL) and (2S,6R)-2,6-dimethylpiperidine (2.6 mL, 19.3 mmol) was added K2C03 (667 mg, 4.8 mmol). The reaction was refluxed for 5 hrs. TLC showed the presence of starting material so additional (2S,6R)-2,6-dimethylpiperidine (2.0 mL, 14.8 mmol) was added and the reaction was refluxed for an additional 5 hrs. The solvent was removed and the e was partitioned between EtOAc/water. The EtOAc was separated and washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes —> 6:94 EtOAczhexanes) to afford 3-bromo(((2R,6S)-2,6-dimethylpiperidin- 1-yl)methyl)pyridine ) as a clear oil (728 mg, 2.57 mmol, 53% yield). 1H NMR (DMSO-ds) 5 ppm 0.92 (d, J=8Hz, 6H), 1.21-1.32 (m, 3H), 1.52-1.55 (m, 2H), 1.59-1.63 (m, 1H), 2.42-2.46 (m, 2H), 3.73 (s, 2H), 7.97-7.98 (m, 1H), 8.50 (d, J=3Hz, 1H), 8.55-8.56 (m, 1H), ESIMS found for C13H19BrN2 m/z 283 (M+H). [0303[ Preparation of intermediate 3'-fluorobiphenyl-3 -amine (L1) is depicted below in Scheme 11.

F F <5 xux OzN Br Ila OZN HzN OH O Pd/C-Hz K3P04, Pd(PPh3)4, H20, EtOH, rt, 5 h O Dionne, MW, 95°C, 2 h L LI XLVIII Scheme 11 SE1;1 [0304[ A 25 mL microwave vessel was charged with 1-bromonitrobenzene (XLVIII) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g, 3.3 mmol), potassium ate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane (15.0 mL), and water (3.0 mL).

Tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) was added, and the reaction was placed in a microwave reactor for 1 h at 95°C. An additional 3-fluorophenylboronic acid (0.20 g) and is(triphenylphosphine)palladium(0) (0.05 g) were added, and the reaction was heated for another 1 h at 95°C in a microwave r. The organic solvent was separated from the water and concentrated to a residue. The residue was then purified by flash chromatography using a 25 g n normal phase silica gel cartridge (100% hexanes —> 1:99 hexanes) to afford 3'-fluoronitrobiphenyl (L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. 1H NMR ds) 5 ppm 8.48 (t, J: 2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78 (t, J=8Hz, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), 7.32- 7.28 (m, 1H).

Sip—2 [0305[ 10% Palladium on carbon g) was added to a solution of 3'-fluoro nitrobiphenyl (L) (0.63 g, 2.88 mmol) in EtOH (20.0 mL). The flask was evacuated and replaced with a hydrogen atmosphere. The solution was stirred at room temperature for 5 h under hydrogen. The catalyst was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes —> 15:85 EtOAczhexanes) to afford 3'-fluorobiphenylamine (LI) (0.34 g, 1.81 mmol, 63% yield) as a light yellow oil. 1H NMR (DMSO-ds) 5 ppm 7.47-7.44 (m, 1H), 7.40-7.39 (m, 1H), 7.36-7.33 (m, 1H), 7.15-7.14 (m, 1H), 7.10 (t, z, 1H), 6.85-6.84 (m, 1H), 6.80-6.79 (m, 1H), 6.60-6.58 (m, 1H), 5.18 (s, 2H), ESIMS found for C12H10FN m/z 188 (M+H). [0306[ Preparation of intermediate 5-(3-fluorophenyl)pyridinamine (LIII) is depicted below in Scheme 12.

HZN Br Ho‘s/Q \ HZN | OH N/ K3P04, 3)4, H20, N/ DMF, MW, 180°C, 1 h LII LlII Scheme 12 Sip—1 [0307[ To a microwave vial was added 3-aminobromopyridine (LII) (0.400 g, 2.31 mmol), 3-fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for l h at 180°C. The solution was filtered through a pad of Celite and trated under vacuum. The residue was purified by column chromatography (4:6 EtOAczhexanes —> 7:3 EtOAczhexanes) to afford the 5-(3- fluorophenyl)pyridinamine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow-white solid.

ESIMS found for C11H9FN2 m/z 189.1 (M+H). [0308[ Preparation of intermediate methylamino)methyl)pyridinamine (LVII) is depicted below in Scheme 13.

OHC Br \N Br \ \ I (CH3)2NH*HCI, EtaN, NaBH(0Ac)3 I I N/ DCE, rt, overnight N/ XXV LIV MeOOm Cs2C03, Xanthphos Pd2(dba)3, Xylene. MW 130°C, 5 h \T NH2 \ \ \ I TFA, rt, 111 T I N/ / LVII LVI Scheme 13 [0309[ 5-Bromonicontinaldehyde (XXV) (5.01g, 26.9 mmol) and dimethylamine hloride (4.39 g, 53.8 mmol) were suspended in 1,2-dichloroethane (108 mL).

Triethylamine (7.50 mL, 53.8 mmol) was added, and the reaction was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (8.56 g, 40.4 mmol) was added, and the reaction was fithher stirred at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and DCM. The organic layer was separated, washed sequentially with water and brine, dried over MgSO4, filtered and concentrated to give 1-(5- bromopyridinyl)-N,N-dimethylmethanamine (LIV) (1.19 g, 23.9 mmol, 89% yield) as a brown oil: 1H NMR (DMSO-dg) 5 ppm 8.59 (d, J =3Hz, 1H), 8.47 (d, J=2Hz, 1H), 7.94 (s, 1H), 3.43 (s, 2H), 2.15 (s, 6H), ESIMS found for C8H11B1‘N2 m/z 215 (M+H).

S£p_2 [0310[ In a 25 mL microwave vessel, 1-(5-bromopyridinyl)-N,N- dimethylmethanamine (LIV) (1.27 g, 5.92 mmol), 4-methoxybenzylamine (LV) (0.77 mL, 5.92 mmol), cesium carbonate (2.70 g, 8.29 mmol) and xanthphos , 0.30 mmol) were suspended in xylenes (12.0 mL). The solvent was degassed, and tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.30 mmol) was added. The vessel was sealed, and the reaction was heated to 130°C for 5 h in a microwave reactor. The solvent was ed away from the solid material and concentrated to a residue. The residue was d by silica gel tography using a 40 g Thomson normal-phase silica gel cartridge (100% CHC13 —> 3:97 MeOH[7N HC13) to afford 5-((dimethylamino)methyl)-N-(4- methoxybenzyl)pyridinamine (LVI) (0.68 g, 2.49 mmol, 42% yield) as a yellow solid. 1H NMR (DMSO-ds) 5 ppm 7.84 (d, J=3Hz, 1H), 7.64 (d, J=2Hz, 1H), 7.27 (d, J=11Hz, 2H), 6.88 (d, J=11Hz, 2H), 6.83-6.82 (m, 1H), 6.35 (t, J=8Hz, 1H), 4.20 (d, J=8Hz, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.08 (s, 6H), ESIMS found for C16H21N30 m/z 272 (M+H). [031 1 [ 5 -((dimethylamino)methyl)-N-(4-methoxybenzyl)pyridin-3 -amine (LVI) (0.15 g, 0.56 mmol) was dissolved in TFA (2.0 mL) and stirred at room temperature for 1 h.

The TFA was removed, and the e was treated with 7N ammonia in hloroform mixture (7/93) to neutralize the TFA and concentrated again to a residue. The residue was purified by flash silica gel chromatography utilizing a 4 g Thomson normal-phase silica gel cartridge (100% CHC13 —> 3:97 MeOH[7N NH3]:CHC13) to afford 5- ((dimethylamino)methyl)pyridinamine (LVII) (0.044 g, 0.29 mmol, 52% yield) as a brown oil. ESIMS found for C8H13N3 m/z 152 (M+H). [0312[ The following ediate was prepared in accordance with the procedure described in the above Scheme 13.

HzN / | ”/W \N K/ LVIII [0313[ 5 -((4-Methylpiperazin- l -yl)methyl)pyridin-3 -amine ): Dark yellow solid (138 mg, 0.67 mmol, 71% yield). ESIMS found for C11H18N4 m/z 207 (M+H). [0314[ Preparation of intermediate 6-(pyrrolidin-l-ylmethyl)pyridin-3 -amine (LXIII) is depicted below in Scheme 14. o N o N 2 m 2 DIBAL,DCM, \ / mm to rt 3h’ / N COZMe N CHO LIX LX i / EtaN,NaBH(OAc)3 DCE, rt, overnight H N O N o ‘0 o N/ N EtOH,rt,5h N/ N LXIII LXII Scheme 14 [0315[ To a sion of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) d at -78°C under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room ature over 3 h. An aqueous solution of potassium sodium tartrate was added, d fithher with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2X DCM, combined with the organic layer, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-ds) 5 ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9Hz, J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H). [0316[ Preparation of 5-nitro(pyrrolidin-l-ylmethyl)pyridine (LXII) was performed following the procedure listed in Scheme 5, Step 1. Purple oil (0.41 g, 1.98 mmol, 86% yield). 1H NMR (DMso-dé) 8 ppm 9.28 (d, J=3Hz, 1H), 8.56 (dd, J=11Hz, 3H2, 1H), 7.72 (d, J=11Hz, 1H), 3.85 (s, 2H), 2.53-2.50 (m, 4H), 1.75-1.70 (m, 4H). [0317[ Preparation of intermediate 6-(pyrrolidinylmethyl)pyridin-3 -amine (LXIII) was performed following the ure listed in Scheme 11, Step 2. Dark brown oil (0.35 g, 1.97 mmol, quantitative). ESIMS found for C10H15N3 m/z 178 (M+H). [0318[ The following intermediate was prepared in accordance with the procedure described in the above Scheme 14.

\ N/ [0319[ 6-((4-Methylpiperazinyl)methyl)pyridinamine (LXIV): Brown oil (120 mg, 0.58 mmol, 100% yield). ESIMS found for C11H18N4 m/z 207 (M+H). [0320[ Preparation of intermediate 6-(3 phenoxy)pyridin-3 -amine (LXVIII) is depicted below in Scheme 15. 120°C’ overni htg C I N/ o LXV LXVII Pd/C- EtOH, db, :1 N/ O LXVIII Scheme 15 [0321[ A solution of 2-chloronitropyridine (LXV) (1.98 g, 12.5 mmol) and 3- fluorophenol (LXVI) (1.4 g, 12.5 mmol) in pyridine (20 mL) was heated at 120°C overnight under argon. The solution was cooled to room temperature and trated under vacuum.

The residue was dissolved in EtOAc, washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (100% hexane —> 2:98 EtOAczhexane) to give 2-(3 -fluorophenoxy)-5 -nitropyridine (LXVII) as a yellow viscous oil (2.27 g, 9.7 mmol, 77% . 1H NMR (DMSO-ds) 5 ppm 7.11 (dd, J=8Hz, J=2Hz, 1H), 7.17 (dt, J=8Hz, J=6Hz, 1H), 7.23 (td, J=10Hz, J=2Hz, 1H), 7.31 (d, J=9Hz, 1H), 7.52 (q, J=9Hz, 1H), 8.64 (dd, J=9Hz, J=3Hz, 1H), 9.05 (d, J=3Hz, 1H), ESIMS found for C11H7FN203 m/Z 234.9 (M+H).

Sip—2 [0322[ Preparation of intermediate 6-(3-fluorophenoxy)pyridinamine (LXVIII) was performed following the procedure listed in Scheme 11, Step 2. Black green s oil (1.90 g, 9.3 mmol, 96% yield). 1H NMR (DMSO-dg) 5 ppm 5.18 (brs, 2H), 6.74- 6.83 (m, 3H), 6.90 (dt, 1H), 7.09 (dd, J=9Hz, J=3Hz, 1H), 7.34 (q, J=7Hz, 1H), 7.57 (d, J=3Hz, 1H), ESIMS found for C11H9FN20 m/z 204.4 (M+). [0323[ The following intermediates were prepared in accordance with the procedure described in the above Scheme 15. [0324[ 6-(4-Fluorophenoxy)pyridinamine (LXIX): Dark brown oil (870 mg, 4.3 mmol, 100% . 1HNMR (DMSO-dg) 5ppm 5.08 (brs, 2H), 6.75 (d, J=15Hz, 1H), 6.90- 7.01 (m, 2H), 7.07 (dd, J=9Hz, J=3Hz, 1H), 7.16 (t, 9Hz, 1H), 7.26-7.30 (m, 1H), 7.73 (d, J=3Hz, 1H), ESIMS found for C11H9FN20 m/z 204.9 (M+H).

N/ o [0325[ 6-(2-Fluorophenoxy)pyridin-3 -amine (LXX): Dark brown oil (61 1 mg, 3 .0 mmol, 91% yield). ESIMS found for N20 m/z 204.9 (M+H). [0326[ Preparation ofintermediate 6-phenylpyridin-3 -amine (LXXIV) is depicted below in Scheme 16.

LXXII B(OH)2 O N O N 2 \ 2 \ I Pd(PPh3)4,K3P04 N/ dioxane/HZO, 95°C Br N/ LXXI LXXIII EtOH,6h,rt HZN \ LXXIV Scheme 16 Sip—1 [0327[ To a solution of 2-bromonitropyridine (LXXI) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95°C for 1h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane —> 5:95 EtOAczhexane) to give 5-nitrophenylpyridine (LXXIII) as off-white needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for C11H8N202 m/z 200.9 (M+H).

SE1;2 [0328[ Preparation of intermediate 6-phenylpyridinamine ) was performed following the ure listed in Scheme 11, Step 2. Black green viscous oil (211 mg, 1.24 mmol, 98% yield). 1H NMR (DMSO-ds) 5 ppm 5.45 (s, 2H), 6.99 (dd, J=11Hz, J=3Hz, 1H), 7.25-7.28 (m, 1H), 7.38-7.40 (m, 2H), 7.62 (d, J=11Hz, 1H0, .91 (m, 1H), 8.02 (d, J=3Hz, 1H), ESIMS found for C11H10N2 m/z 171 (M+H). [0329[ The following intermediates were ed in accordance with the procedure described in the above Scheme 16.

HZN \ / F [0330[ 6-(3-Fluorophenyl)pyridinamine (LXXV): Brown oil (252 mg, 1.34 mmol, 98% yield). ESIMS found for C11H9FN2 m/z 189 (M+H).

HZN / LXXVI [0331[ 6-(4-Fluorophenyl)pyridinamine (LXXVI): Deep purple oil (202 mg, 1.07 mmol, 98% yield). ESIMS found for C11H9FN2 m/z 189 (M+H). [0332[ ation of intermediate ylpyridinamine (LXXX) is depicted below in Scheme 17.

O‘B/ I OZN Br OZN \ \ | Pdc12(dppf)z,K3P04 | N/ dioxane/HZO, 90°C N/ LXXVII LXXIX Pd/C-Hz EtOH,6h,rt HZN \ Scheme 17 Sir;1 [0333[ To a solution of 3-bromonitropyridine (LXXVII) (295 mg, 1.45 mmol) in dioxane (14 mL) was added 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (LXXVIII) (420 uL, 1.89 mmol), PdClz(dppf)2, (120 mg, 0.15 mmol) and 2M s K3PO4 (2.2 mL, 4.36 mmol). The reaction was microwaved at 90°C for 2h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column tography (100% hexane —> 6:94 EtOAczhexane) to give 3-benzylnitropyridine (LXXIX) as brown oil (117 mg, 0.54 mmol, 37% yield). 1H NMR (DMSO-dg) 5 ppm 4.16 (s, 2H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 4H), 8.45-8.46 (m, 1H), 8.93 (d, J=2Hz, 1H), 9.21 (d, J=3Hz, 1H), ESIMS found for C12H10N202 m/z 215 (M+H).

Sip—2 [0334[ Preparation of 5-benzylpyridinamine (LXXX) was performed following the procedure listed in Scheme 11, Step 2. Black green viscous oil (139 mg, 0.75 mmol, 98% yield). ESIMS found for C12H12N2 m/z 185 (M+H). [0335[ Preparation of intermediate 2-(4-methylpiperazinyl)pyridin-3 -amine (LXXXIV) is depicted below in Scheme 18.

O N2 H N \ HN\) LXXXJI 02" \ 2 l Pd/C-Hz I Cs2C03, Xanthphos, Pd2(dba)3, MeOH, rt, 16 h Cl N/ (\N N/ N N/ Xylene, MW, 90°C, 2 h N\J N / / Q LXXXI LXXXJII LXXXIV Scheme 18 Sip—1 [0336[ To a microwave vial was added 2-chloronitropyridine (LXXXI) (1.00 g, 6.31 mmol), ylpiperazine (LXXXII) (0.758 g, 7.57 mmol), cesium carbonate (2.88 g, 8.83 mmol), Pd2(dba)3 (0.173 g, 0.189 mmol), xanthphos (0.109 g, 0.189 mmol), and dioxane (5 mL). The reaction vial was capped and purged with argon. The solution into the reaction vial was heated under microwave irradiation for 2 h at 90°C. The solution was filtered through a pad of Celite and trated to a residue under vacuum. The residue was purified by column chromatography (1:99 MeOHzCHC13 —> 8:92 MeOHzCHClg) to afford l-methyl(3-nitro- nyl)-piperazine (LXXXIII) (1.30 g, 5.85 mmol, 93% yield) as a brown oil.

Sip—2 [0337[ To a ng solution of 1-methyl(3-nitro-pyridinyl)-piperazine (LXXXIII) (1.30 g, 5.85 mmol) in MeOH (15 mL) was added 10% Pd/C. The solution was purged with hydrogen. The solution was d at room temperature for 16 h under hydrogen.

The solution was filtered through a pad of Celite and concentrated to a residue under vacuum.

The residue was purified by column chromatography (100% CHC13 —> 2:98 MeOH[7N NH3]:CHC13) to afford ethylpiperazinyl)pyridinamine V) (0.466 g, 2.42 mmol, 52% yield) as a tan solid. ESIMS found for C10H16N4 m/z 192.4 (M+H). [0338[ The following intermediates were prepared in accordance with the procedure described in the above Scheme 18.

HZN / ~ "0 LXXXV [0339[ 6-(Pyrrolidinyl)pyridinamine (LXXXV): Deep purple oil (1.43 g, 8.77 mmol, 100% yield). ESIMS found for C9H13N3 m/z 164 (M+H).

N N/fi LXXXVI [0340[ 6-(4-Methylpiperazinyl)pyridinamine (LXXXVI): Purple solid (598 mg, 3.11 mmol, 32% yield). ESIMS found for C10H16N4 m/z 193 (M+H).

LXXXVII [0341[ 6-Morpholinopyridinamine (LXXXVII): Purple solid (782 mg, 4.36 mmol, 95% yield). ESIMS found for C9H13N30 m/z 180 (M+H).

HzN / \N N/\/N\ LXXXVIII [0342[ NZ-(Z-(Dimethylamino)ethyl)-N2-methylpyridine-2,5 -diamine (LXXXVIII): Deep purple oil (1.55 g, 7.98 mmol, 96% yield). ESIMS found for C10H18N4 m/z 195 (M+H). [0343[ ation of intermediate 1-(5-aminopyridinyl)piperidinol (XCI) is depicted below in Scheme 19. moron LXXXIX 0mm 02" DMF \ N/ 85°C, overnight CI N/ N LXV xc QC” EtOH, 6h, rt Scheme 19 S£p_1 [0344[ To a solution of 2-chloronitropyridine (LXV) (5.0 g, 31.5 mmol) in DMF (50 mL) was added piperidinol (LXXXIX) (3.5 g, 34.65 mmol) and K2C03 (8.7 g, 63 .0 mmol). The reaction was headed at 85°C overnight. The solution was poured into ice water, stirred for 15 min and then filtered. The solid was washed with cold water and dried under vacuum to produce 1-(5-aminopyridinyl)piperidinol (XC) as ayellow solid (6.62 g, 29.67 mmol, 94.2% yield). 1H NMR (DMSO-ds) 5 ppm 1.34-1.42 (m, 2H), 1.77-1.83 (m, 2H), 3.40- 3.56 (m, 2H), 3.76-3.83 (m, 1H), 4.12 (brd, 2H), 4.81 (d, J=4Hz, 1H), 6.94 (d, J=10Hz, 1H), 8.17 (dd, J=10Hz, J=3Hz, 1H), 8.94 (d, J=3Hz, 1H), ESIMS found for C10H13N303 m/z 224.1 (M+H).

Sfip_2 [0345[ Preparation of intermediate 1-(5-aminopyridinyl)piperidinol (XCI) was performed ing the procedure listed in Scheme 11, Step 2. Dark brown oil (5.7 g, 29.5 mmol, 99.5% yield). 1H NMR (DMSO-dg) 5 ppm 1.36 (tq, J=13Hz, J=4Hz, 2H), 1.72-1.76 (m, 2H), 2.79 (dt, J=13Hz, J=3Hz, 2H), 3.54-3.61 (m, 1H), 3.70-3.78 (m, 2H), 4.49 (s, 2H), 4.61 (d, J=4Hz, 1H), 6.61 (d, J=9Hz, 1H), 6.88 (dd, J=9Hz, J=3Hz, 1H), 7.57 (d, J=3Hz, 1H), ESIMS found for C10H15N30 m/z 194.1 (M+H). [0346[ The following intermediates were ed in accordance with the procedure described in the above Scheme 19. [0347[ 6-(Piperidinyl)pyridinamine (XCII): Dark red Viscous oil (4.93 g, 27.81 mmol, 95.9% yield). 1H NMR (DMSO-dg) 5 ppm 1.48-1.71 (m, 8H), 3.42-3.53 (m, 2H), 4.48 (brs, 2H), 6.59 (d, J=9Hz, 1H), 6.89 (dd, J=9Hz, J=3Hz, 1H), 7.58 (d, J=3Hz, 1H), ESIMS found for C10H15N3 m/z 178.0 (M+H).

HZNKID\ XCIII [0348[ 5-Methyl(pyrrolidinyl)pyridinamine (XCIII): Dark blue Viscous oil (2.06 g, 12.62 mmol, 100% yield). 1H NMR (DMSO-ds) 5 ppm 1.76-1.82 (m, 4H), 2.13 (s, 3H), .20 (m, 4H), 4.53 (brs, 2H), 6.74 (d, J=3.5Hz, 1H), 7.42 (d, J=2.7Hz, 1H), ESIMS found for C10H15N3 m/Z 178.1 (M+H). [0349[ 6-(Azetidinyl)-5 -methylpyridin-3 -amine (XCIV): Dark red solid (2.0 g, 11.29 mmol, 86.9% yield). 1H NMR (DMSO-dg) 5 ppm 2.11 (quin, J=7Hz, 2H), 3.76-3.87 (m, 4H), 4.50 (brs, 2H), 6.72 (d, J=2.5Hz, 1H), 7.38 (d, J=2.5Hz, 1H); ESIMS found for C9H13N3 m/z 164.4 (M+H). [0350[ 6-(Azetidinyl)pyridinamine (XCV): Burgundy solid (1.45 g, 9.70 mmol, 99.3% yield). ESIMS found for C8H11N3 m/z 149.0 (M+H). [0351[ Preparation of intermediate tert—butyl 4-(5-aminopyridinyl)piperazine- 1-carboxylate (XCVIII) is depicted below in Scheme 20.

OzN HN N—Boc XCVI OZNU N/ EtOH, 70 C, 16 h0 CI N LXV XCVII K/N\Boc EtOH, 6h, rt N N XCVIII K/N\ Scheme 20 [0352[ To a solution of 2-chloronitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert—butyl piperazinecarboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70°C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridinyl)piperazinecarboxylate ) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).

Sflp_2 [0353[ Preparation of intermediate tert—butyl 4-(5-aminopyridinyl)piperazine- 1-carboxylate (XCVIII) was med following the ure listed in Scheme 11, Step 2.

Purple solid (990 mg, 3.56 mmol, quantitative). ESIMS found for C14H22N402 m/z 278.8 (M+H). [0354[ Preparation of intermediate N—(3 -aminopyridinyl) cyclopropanecarboxamide (C11) is depicted below in Scheme 21.

XCIX CI Pd/C-Hz EtOH, 6h, rt Scheme 21 [0355[ Preparation of N—(3 -nitropyridinyl)cyclopropanecarboxamide (CI) was performed following the procedure listed in Scheme 4, Step 1. Orange solid (130 mg, 0.93 mmol, 13% yield). ESIMS found for C9H9N303 m/z 207.8 (M+H).

S£p_2 [0356[ Preparation of intermediate N—(3-aminopyridinyl) cyclopropanecarboxamide (CII) was performed following the procedure listed in Scheme 11, Step 2. Dark grey solid (100 mg, 0.56 mmol, quantitative). ESIMS found for 30 m/z 178.3 (M+H). [0357[ Preparation of intermediate (5 -aminopyridinyl)(pyrrolidin- l - hanone (CV) is depicted below in Scheme 22. ‘3sz HATU, DIPEA N/ DMF, rt,2h D Pd/C-Hz EtOH,6h,rt HZN \ K .0 CV 0 Scheme 22 [0358[ To a solution of 5-nitropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF (15 mL) was added pyrrolidine (244 pl, 2.47 mmol) and DIPEA (1.03 mL, 5.95 mmol). The reaction was cooled at 0°C before adding HATU (1.13 g, 2.47 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was concentrated under vacuum and then dissolved in a mixture of water and 10% CHClg. The organic layer was separated and the aqueous phase was washed again with 10% CHClg. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to yield (5 -nitropyridin yl)(pyrrolidinyl)methanone (CIV) as a red solid (849 mg). ESIMS found for C10H11N303 m/z 222.1 (M+H).

S£p_2 [0359[ Preparation of intermediate (5-aminopyridinyl)(pyrrolidin yl)methanone (CV) was performed following the procedure listed in Scheme 1 1, Step 2. Yellow solid (708 mg, 7.3 mmol, 96.4% yield). ESIMS found for C10H13N30 m/z 191.4 (M+H). [0360[ The following intermediate was prepared in ance with the procedure described in the above Scheme 22. [0361[ 5-Amino-N-cyclopentylpicolinamide (CVI): Yellow solid (450 mg, 2.19 mmol, 93.7% yield). ESIMS found for C11H15N30 m/z 206.1 (M+H). [0362[ Preparation of intermediate 6-(methylsulfonyl)pyridinamine (CIX) is depicted below in Scheme 23. 02" \ NaSMe 02" \ 02" mCPBA \ I THF/H o | | N/ 2 DCM Cl N/ SMe /°,/s<o LXV CVII CVIII Pd/C-H2 EtOH,6h,rt HZN \ N 052;, Scheme 23 Sip—1 [0363[ To a solution of sodium thiomethoxide in THF (53 mL) and H20 (20 mL) cooled to 0°C was added 2-chloronitropyridine (LXV) (5.09 g, 32.09 mmol). The reaction was warmed to room temperature and d for 2 hrs. The reaction was poured into ice water and stirred for 10 minutes, filtered, washed with water, dried under vacuum to yield 2- (methylthio)nitropyridine (CVII) as a yellow solid (5.14 g, 30.20 mmol, . 1H NMR dg) 8ppm 2.62 (s, 3H), 7.57 (d, J=8.9Hz, 1H), 8.38 (d,J=8.9Hz, 1H), 9.22 (d, J=2.7Hz, 1H); ESIMS found for C6H6N2028 m/z 171.1 (M+H).

S£p_2 [0364[ To a solution of 2-(methylthio)nitropyridine (CVII) (502 mg, 2.95 mmol) in DCM (60 mL) was mCPBA (1.33 g, 5.90 mmol). The reaction was stirred at room temperature for 1 hr. Two additional portions of mCPBA (2 X 250 mg) were added at 1 hr intervals for a total reaction time of 4 hr. The reaction was poured into saturated aqueous . The organic phase was separated and washed with water, brine and then dried over MgSO4. The solvent was removed under vacuum to produce crude 2-(methylsulfonyl) nitropyridine (CVIII) (854 mg) which was used without purification for step 3. ESIMS found for 04S m/z 203.0 (M+H).

Sip—3 [0365[ Preparation ofintermediate 6-(methylsulfonyl)pyridin-3 -amine (CIX) was performed following the procedure listed in Scheme 11, Step 2. The crude product was used as is without purification. ESIMS found for CgHgNzozs m/z 173.0 (M+H). [0366[ Preparation of ediate 5-iodo(tetrahydro-2H-pyranyl)-1H- indazolecarbaldehyde (CXIV) is depicted below in Scheme 24.

{I"NJ :3chozlxk \N NHOMe(Me)*HCl, o N’ imidazole,DMF, 65°C , r..t "x" DHP,PPTS DCM, reflux \©:<:oXIVOLASTHF, 0°C CXIH ob Scheme 24 Step 1 [0367[ 1H—indazolecarboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until the evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65°C for 2 h and then allowed to cool to room temperature. methylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the e was heated to 65°C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed uently with water and 2 N HCl. The product could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were ed, triturated with 1: 1 mixture of DCM-ether, filtered, and dried to produce N—methoxy- N—methyl-1H-indazolecarboxamide (CXI) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-ds) 8 ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H), ESIMS found for C10H11N302 m/z 206 (M+H). [0368[ To N-methoxy-N—methyl-1H-indazolecarboxamide (CXI) (20 g, 97.4 mmol) in DCM (1 L) was added (Bis(trifluoroacetoxy)iodo)benzene (46 g, 107 mmol) followed by portionwise addition ofiodine (14.84 g, 58.5 mmol) at room temperature. After 1 h, saturated aqueous NaHS03 (600 mL) was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was ated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole carboxamide (CXII) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-ds) 5 ppm 3.45 (s, 3H), 3.77 (s, 3H), 7.45-7.54 (m, 1H), 7.66 (dd, , 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H), ESIMS found for IN302 m/Z 331 (M+H).

Sip—3 [0369[ A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazolecarboxamide (CXII) (16.5 g, 50 mmol), 3,4-dihydro-2H—pyran (10.3 mL, 113 mmol) and PPTS (0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 h. The solution was poured into a saturated aqueous NaHC03 solution, the layers were separated, and the aqueous layer was extracted with DCM.

The combined organic layers were washed with 5% aqueous citric acid and brine, dried over MgSO4, and concentrated. The crude product was purified on a silica gel column (100% EtOAc —> 3:97 MeOHzDCM) to provide 5-iodo-N-methoxy-N-methyl(tetrahydro-2H-pyranyl)- 1H-indazolecarboxamide (CXIII) as a white Viscous oil (19.1 g, 46 mmol, 92% yield). 1H NMR (DMSO-ds) 8 ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H), 5.86-6.08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H), ESIMS found for C15H181N303 m/z 416 (M+H).

Step 4 [0370[ Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to a cooled (0°C) solution of 5-iodo-N-methoxy-N-methyl(tetrahydro-2H-pyranyl)-1H- indazolecarboxamide (CXIII) (1.46 g, 3.5 mmol) in THF. Stirring was ued at 0°C until the reaction was completed, approximately 30 min. The on was quenched by the slow addition ofEtOAc at 0°C, and the whole mixture was poured into 0.4 N aqueous NaHSO4.

The organic layer was washed with brine, dried over MgSO4, concentrated, and purified on a silica gel column (100% EtOAc —> 3:97 MeOHzDCM) to give (tetrahydro-2H-pyran- lH-indazolecarbaldehyde (CXIV) as a white solid (0.90 g, 3.15 mmol, 72% yield). 1H NMR (DMSO-ds) 5 ppm 1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m, 1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H), ESIMS found for C13H131N202 m/z 357 (M+H). [0371[ Preparation of intermediate 5-bromo(tetrahydro-2H-pyranyl)-1H- indazolecarboxylic acid (CXVIII) is depicted below in Scheme 25.

COZH step 1 cozH step 2 cone Br Br \ HOAc, Brz \ MeOH, H2504 \N N/ 90°C, 16 h N/ reflux, 4h M H H H CX CXV CXVI p-toluenesulfonic acid, DHP, PPTS step 5 step 3 THF, 60 0C, 16 h DCM, reflux COZH COzMe Br Br \ NaOH, H20 \ N/N 90°C, 1 h N/ step 4 O O CXVlII CXVII Scheme 25 [0372[ A suspension of indazolecarboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120°C to get a clear solution. The solution was cooled to 90°C. A solution of e (0.633 mL, 12.33 mmol) in l acetic acid (2 mL) was added slowly to the solution while heating at 90°C. The solution was ’lCl‘ heated 16 h at 90°C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-lH-indazole-3 -carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-dg) 5 ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J: 1.2 Hz, 1H), 7.65 (d, J: 7.0 Hz, 1H), 7.56 (dd, J: 7.0, 1.2 Hz, 1H), ESIMS found for C8H4BrN202 m/z 242.0 (M+H).

Sip—2 [0373[ Concentrated sulfuric acid (1 mL) was added to a suspension of 5-bromo- 1H-indazolecarboxylic acid (CXV) (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The solution was cooled to room temperature and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl o-1H- indazolecarboxylate (CXVI) as a white solid (1.35 g, 5.29 mmol, 98% yield). 1H NMR (DMSO-ds) 8 ppm 14.13 (s, 1H), 8.21 (d, J: 1.6 Hz, 1H), 7.67 (d, J: 7.2 Hz, 1H), 7.59 (dd, J = 7.2, 1.2 Hz, 1H), 3.92 (s, 3H), ESIMS found for C9H7BrN202 m/z 256.0 (M+H). [0374[ A suspension of methyl 5-bromo-1H-indazolecarboxylate (CXVI) (1.35 g, 5.29 mmol), nium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4 dihydro-2H- pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20 mL) was d 5 h under argon. The suspension was turned into the clear solution. The solution was cooled and the excess solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with dilute NaHC03 solution (satd. NaHC03 soln/HzO: 1:9). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (100% hexanes —> 5:95 hexanes) to get methyl 5-bromo(tetrahydro-2H-pyranyl)-1H- indazolecarboxylate (CXVII) as a white solid (1.47 g, 4.34 mmol, 82% yield). 1H NMR (DMSO-ds) 5 ppm 8.22 (d, J: 1.4 Hz, 1H), 7.89 (d, J: 7.2 Hz, 1H), 7.68 (dd, J: 7.2, 1.6 Hz, 1H), ), 6.02 (dd, J: 8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79 (m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.73 (m, 1H). 1.60-1.58 (m, 2H), ESIMS found for C14H15BrN203 m/z 340.0 (M+H).

Step 4 [0375[ 2 N Aqueous NaOH solution (10 mL) was added to a sion ofmethyl -bromo(tetrahydro-2H-pyranyl)-1H-indazole-3 -carboxylate (CXVII) (1.30 g, 3.83 mmol) in water (20 mL) and heated at 90°C for 1 h. The solution was cooled to room temperature, diluted with ice water and acidified to pH 3.0 with 10% aqueous HCl. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo(tetrahydro-2H-pyranyl)-1H-indazole-3 -carboxylic acid I) as a white solid (0.87 g, 2.68 mmol, 70% yield). ESIMS found for C13H13BrN203 m/z 326.0 (M+H). [0376[ To a on of 5-bromo-1H-indazolecarboxylic acid (CXV) (59.8 g, 248 mmol) in THF (800 mL) under argon was added 3,4 dihydro-2H-pyran (50.6 mL, 558 mmol) and p-TsOH (4.72 g, 24.8 mmol). The reaction was heated to reflux at 60°C for 16 h.

An additional portion ofp-TsOH (0.025 eq) and 3,4 dihydro-2H—pyran (0.56 eq) was added and the reflux continued for 5 h. The solution was concentrated under vacuum. EtOAc was added to the residue and the suspension was filtered and dried under high vacuum overnight to e -bromo(tetrahydro-2H-pyranyl)-1H-indazole-3 -carboxylic acid (CXVIII) as a white solid (49.07 g, 150.9 mmol, 60.8% yield). ESIMS found for C13H13BrN203 m/z 326.3 (M+H). [0377 [ Preparation of intermediate 5-bromotrityl-1H-indazole-3 -carboxylic acid (CXXI) is depicted below in Scheme 26. cozH step 1 COzEt Br Br \N MeOH, 11st4 \N N/ , 4h N/ H H CXV CXIX Tr-Cl, DMF Tr-Cl DCM’ Step 4 step 2 TEA, rt DIPEA, rt cozH COzEt Br Br \N NaOH, H20 \N N/ 90°C, 1 h N/ \ \ Tr step 3 Tr CXXI CXX Scheme 26 S£p_1 [0378[ Preparation of intermediate ethyl 5-bromo-1H-indazolecarboxylate (CXIX) was performed following the procedure listed in Scheme 25, Step 2. White solid. (3.60 g, 13.38 mmol, 64.5% . 1H NMR (DMSO-ds) 5 ppm 1.37 (t, J=7Hz, 3H), 4.40 (q, J=7Hz, 2H), 7.57 (dd, J=9Hz, J=2Hz, 1H), 7.66 (d, J=9Hz, 1H), 8.20 (d, J=2Hz, 1H), 14.11 (brs, 1H); ESIMS found for C10H9BrN202 m/z 269.0 (M+H).

Sip—2 [0379[ To a solution of ethyl 5-bromo-1H-indazolecarboxylate (CXIX) and trityl chloride in DCM was slowly added DIPEA. The solution was d at room temperature overnight. The reaction was poured into water and stirred for 5 min. The organic layer was separated, dried over MgSO4 and concentrated under vacuum. The residue was purified by column tography using a ISCO 200RF system with a SiO2 column (12 g) (100% hexanes —> 10:90 EtOAczhexanes) to produce a white solid. (357 mg, 0.70 mmol, 69.8% yield). 1H NMR (DMSO-ds) 5 ppm 1.34 (t, J=7Hz, 3H), 4.38 (q, J=7Hz, 2H), 6.43 (d, J=9.5Hz, 1H), 7.11-7.14 (m, 6H), 7.31-7.35 (m, 10H), 8.23 (d, J=2Hz, 1H); ESIMS found for C29H23BrN202 m/z 511.0 (M+H).

Ste 3 [0380[ Preparation Of intermediate 5 -bromotrityl-1H-indazole'3 -carboxy 110 acid (CXXI) by hydrolysis of ethyl 5-bromotrityl-1H-indazolecarboxylate (CXX) can be performed following the procedure listed in Scheme 25, Step 3.

Step 4 [0381[ Preparation of intermediate otrityl-1H-indazolecarboxylic acid (CXXI) by tritylation of 5-bromo-1H-indazole-3 -carboxylic acid (CXV) can be performed following the procedure listed in the l ofMedicinal Chemistry (2003), 46(25), 5458- 5470.

Example 1 [0382[ Preparation of 5-(5-(3,3-dimethylureido)pyridinyl)-N-(pyridinyl)- 1H-indazolecarboxamide (1) is depicted below in Scheme 27.

O O 0 cm :B_B< E CHO \ /N\ / I N o o >2\ \ \ 0/3 \ XXIIN \ N —> N —> N N/ KOAc, Pd<:1,(dppf)2 NI K3P04, Pd(PPh3)4 N/ DMF, 90°C, 2 h H20, 90°C, 3 h o o o CXIV cxxn cxxm AgNOs, NaOH, Hz Dionne, rt overnight TFA, DCM, \ EtSSiI-I, rt, 3 h N’N DMF, rt, overnight 1 CXXVI ob CXXIV 05 Scheme 27 SEN—4 [0383[ A solution of 5-iodo(tetrahydro-2H-pyranyl)-1H-indazole carbaldehyde (CXIV) (1.780 g, 5.0 mmol), bis(pinacolato)diboron (1.523 g, 6.0 mmol), KOAc (1.471 g, 15 mmol) and dry DMF (20 mL) was purged with argon. PdClz(dppf)2 (0.245 g, 0.3 mmol) 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 , the solution was cooled to room temperature. To this solution was added K3PO4 (1.592 g, 7.5 mmol), 3-(5 -bromopyridinyl)- 1,1-dimethylurea (XXII) (1.220 g, 5.0 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and water (2 mL). The solution was purged with argon and heated at 90°C for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, d and then evaporated under vacuum.

The residue was d on a silica gel column (100% DCM —> 2:98 MeOHzDCM) to give 3- (5 -(3 -formyl(tetrahydro-2H-pyranyl)-1H-indazol-5 -yl)pyridin-3 -yl)-1, 1-dimethylurea (CXXIII) as a brown s oil which solidified under vacuum at room temperature (354 mg, 0.90 mmol, 18% yield for 2 steps). 1H NMR (DMSO-dg) 5 ppm 10.22 (s, 1H), 8.76 (d, J: 1.6 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J: 1.6 Hz, 1H), 8.36 (s, 1H), 8.24 (m, 1H), 8.05 (d, J: 7.2 Hz, 1H), 7.91 (dd, J: 7.2, 1.4 Hz, 1H), 6.13 (dd, J: 7.6, 2.0 Hz, 1H), 3.93 (m, 1H), 3.85 (m, 1H), 2.98 (s, 6H), 2.47-2.42 (m, 1H), 2.11-2.06 (m, 2H), 1.82-1.79 (m, 1H) 1.64 (m, 2H), ESIMS found for N503 m/z 394.0(M+H). [0384[ A solution of sodium ide (0.173 g, 4.33 mmol) in water (5 mL) was added to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5 mL) to give a brown precipitate. 3 -(5 -(3 -formyl(tetrahydro-2H-pyranyl)-1H-indazol-5 -yl) pyridin-3 -yl)-1, 1- dimethylurea (CXXIII) (0.340 g, 0.86 mmol) was dissolved in 1,4-dioxane (10 mL) and added to the reaction which was stirred overnight at room temperature. The solution was diluted with water and then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH = 3 with aqueous HCl. The aqueous layer was then extracted with 10% iPrOH/chloroform. The combined organic layers were then dried (Na2SO4), filtered and concentrated to give 5-(5 -(3,3-dimethylureido)pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H- indazolecarboxylic acid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield). 1H NMR (DMSO-ds) 8 ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J: 7.1 Hz, 1H), 7.86 (dd, J: 7.2, 1.3 Hz, 1H), 6.06 (dd, J: 8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98 (s, 6H), 2.42-2.39 (m, 1H), 2.03-2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61 (m, 2H), ESIMS found for C21H23N504 m/z M+H).

Step4 [0385[ HATU (0.190 g, 0.5 mmol) was added to a on of 5-(5-(3,3- dimethylureido)pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H-indazole-3 xylic acid ) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol) in DMF stirred at room temperature under argon. After ng 5 min, the solution was added with 3- aminopyridine (CXXV) (0.047 g, 0.5 mmol). The solution was stirred overnight at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by column chromatography using a 4 g Thomson normal phase silica gel cartridge (100% DCM —> 5:95 MeOHzDCM) to afford 5-(5- (3 , 3 -dimethylureido)pyridin-3 -yl)-N-(pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H- indazolecarboxamide (CXXVI) as an off white solid (323 mg, 0.67 mmol, 55% yield). 1H NMR (DMSO-ds) 5 ppm 10.56 (s, 1H), 9.06 (d, J: 2.0 Hz, 1H), 8.75 (d, J: 1.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d,J= 1.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.29 (m, 2H), 8.26 (m, 1H), 8.03 (d, J: 7.0 Hz, 1H), 7.88 (dd, J: 7.0, 1.2 Hz, 1H), 7.43 (dd, J: 6.64, 3.84 Hz, 1H), 6.07 (dd, J: 8.0, 1.8 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.98 (s, 6H), 2.63-2.60 (m, 1H), 2.11-2.06 (m, 2H), 1.83- 1.81 (m, 1H) 1.52 (m, 2H), ESIMS found for C21H23N504 m/z M+H). [0386[ TFA (5 mL) was added to a on of 5-(5-(3,3-dimethylureido)pyridinyl)-N-(pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H-indazole-3 -carboxamide (CXXVI) (0.134 g, 0.27 mmol) and triethylsilane (0.110 mL, 0.69 mmol) in DCM (5 mL) and stirred 3 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and purified by column chromatography (100% DCM —> 5:95 MeOH[7N NH3]:DCM) to afford 3,3-dimethylureido)pyridinyl)- N—(pyridinyl)-1H-indazolecarboxamide (1) as a white solid (35.8 mg, 0.09 mmol, 33% yield). 1H NMR (DMSO-ds) 5 ppm 13.99 (s, 1H), 10.69 (s, 1H), 9.08 (d, J: 1.2 Hz, 1H), 8.74 (d,J= 1.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J: 1.5 Hz, 1H), 8.47 (s, 1H), 8.33-8.30 (m, 2H), 8.26 (m, 1H), 7.80 (s, 2H), 7.41 (dd, J: 6.6, 3.6 Hz, 1H), 2.98 (s, 6H), ESIMS found for C21H19N702 m/z 402.3(M+H). [0387[ The ing compound was prepared in accordance with the procedure described in the above Example 1. [0388[ N—(5 -Fluoropyridin-3 -yl)-5 -(pyridin-3 -yl)-1H-indazole-3 -carboxamide [0389[ Light tan solid. 1H NMR dg) 5 ppm 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.82-7.86 (m, 2H), 8.13-8.15 (m, 1H), .34 (m, 2H), 8.47-8.48 (m, 1H), 8.60 (dd, J=5Hz, J=2Hz, 1H), 894 (d, J=2Hz, 1H), 8.99 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.05 (s, 1H), ESIMS found for C13H12FN50 m/z 334 (M+1).

Example 2 [0390[ Preparation of 5-(5-fluoropyridinyl)-N-(6-(trifluoromethyl)pyridin yl)-1H-indazolecarboxamide (2) is depicted below in Scheme 28.

CF: CF, / \N / \N CXXVII CXXIX ?” F / / 0 F \ B\ o NH 0H cozfl / \ Hz" cF, Br Br \U N t~ —-—N \ \ HATU, DIPEA KOAc, PdClz(dppf)1 N N/ N," DMF, rt, overnight DMF, 90"C, 2 h o o o cxvrn cxxvrn cxxx TFA, DCM, , rt, 3 h Scheme 28 [0391[ HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo (tetrahydro-2H-pyranyl)-1H-indazole-3 xylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon.

After stirring 5 min, the solution was added with 5-aminotrifluoromethyl pyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, ted briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes —> 7:93 hexanes) to afford 5-bromo(tetrahydro-2H-pyranyl)-N-(6- (trifluoromethyl)pyridinyl)-1H-indazolecarboxamide II) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO-ds) 5 ppm 10.93 (s, 1H), 9.23 (d, J: 1.9 Hz, 1H), 8.60 (dd, J: 6.8,1.4 Hz, 1H), 8.38 (d, J: 4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J: 7.1,1.5 Hz, 1H), ), 6.04 (dd, J: 8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H), ESIMS found for C19H16BrF3N402 m/z 470.0 (M+H).

S£p_2 [0392[ A solution of 5-bromo(tetrahydro-2H-pyranyl)-N-(6- (trifluoromethyl) pyridinyl)-1H-indazolecarboxamide (CXXVIII) (0.469 g, 1 mmol), 5- fluoro-pyridylboronic acid (CXXIX) (0.156 g, 1.1 mmol), potassium phosphate tribasic (0.318 g, 1.5 mmol) and water (degassed, 1 mL) in DMF (10 mL) was purged with argon.

Tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.03 mmol) was added and the solution was purged again with argon. The reaction was heated to 90°C for 3 h when TLC showed disappearance of starting material. The solution was cooled to room temperature and excess solvent was removed under . The residue was treated with water, sonicated briefly and the solids formed were filtered. The solids were washed with cold water and dried under vacuum at room temperature which was purified by silica gel column chromatography (2:8 EtOAczhexanes —> 3:7 EtOAczhexanes) to afford uoropyridinyl)(tetrahydro-2H- pyranyl)-N-(6-(trifluoromethyl) nyl)-1H-indazolecarboxamide (CXXX) as a white solid (427 mg, 0.88 mmol, 88% . 1H NMR (DMSO-dg) 5 ppm 10.95 (s, 1H), 9.25 (d, J: 1.8 Hz, 1H), 8.85 (m, 1H), 8.63 (d, J: 1.8 Hz, 1H), 8.61 (d, J: 2.1 Hz, 1H), 8.53 (m, 1H), 8.16-8.13 (m, 1H), 8.08 (d, J: 7.1 Hz, 1H), 7.97-7.94 (m, 2H), 6.11 (dd, J: 8.1, 1.8 Hz, 1H), 4.01 (m, 1H), 3.88-3.83 (m, 1H), 2.63-2.60 (m, 1H), 2.11-2.07 (m, 2H), 1.83-1.80 (m, 1H). .65 (m, 2H), ESIMS found for C24H19F4N502 m/z 486.0 (M+H).

S£p_3 [0393[ TFA (10 mL) was added to a solution of 5-(5-fluoropyridinyl) (tetrahydro-2H-pyranyl)-N-(6-(trifluoromethyl)pyridin-3 -yl)-1H-indazole-3 -carboxamide (CXXX) (0.420 g, 0.86 mmol) and triethylsilane (0.345 mL, 2.16 mmol) in DCM ( 10 mL) and stirred 5 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and air dried at room temperature. The solids were suspended in DCMzMeOH (1:1) mixture and boiled to get a clear solution. The solution was cooled to room temperature. The solids formed were ed washed with DCM and dried under vacuum at room temperature to get 5-(5-fluoropyridin yl)-N-(6-(trifluoromethyl)pyridinyl)-1H-indazolecarboxamide (2) as a white solid (72.9 mg, 0.18 mmol, 21% yield). 1H NMR (DMSO-dg) 5 ppm 14.13 (br. s, 1H), 11.11 (s, 1H), 9.27 (d, J: 1.8 Hz, 1H), 8.84 (m, 1H), 8.63 (dd, J: 6.8, 1.8 Hz, 1H), 8.60 (d, J: 2.0 Hz, 1H), 8.53 (m, 1H), 8.14-8.11 (m, 1H), 7.94 (d, J: 6.9 Hz, 1H), .83 (m, 2H), ESIMS found for C19H11F4N50 m/z 402.30 (M+H). [0394[ The following compound was prepared in accordance with the procedure described in the above Example 2.

WO 75858 [0395[ 5-(Py1idinyl)-N-(6-(t1ifluoromethyl)pyridinyl)-1H-indazole carboxamide 3. [0396[ White solid (19% yield). 1H NMR (DMSO-dg) 5 ppm 14.03 (br. s, 1H), 11.10 (s, 1H), 9.27 (d, J: 1.8 Hz, 1H), 8.94 (d, J: 1.6 Hz, 1H), 8.63 (dd, J: 6.8,1.7 Hz, 1H), 8.60 (m, 1H), 8.48 (s, 1H), 8.15-8.13 (m, 1H), 7.93 (d, J: 6.9 Hz, 1H), 7.85 (s, 2H), 7.54 (m, 1H), ESIMS found for C19H12F3N50 m/z 384.0 (M+H). [0397[ N—( 1-Methyl(t1ifluoromethyl)-1H-pyrazolyl)(pyridinyl)-1H- indazolecarboxamide 37. [0398[ Light green solid (76.7 mg, 0.20 mmol, 48.4% yield). 1H NMR (DMSO- d6) 5 ppm 3.93 (s, 3H), 7.18 (s, 1H), 7.55 (dt, J=8Hz, J=3Hz, 1H), 7.81 (dd, J=15Hz, J=9Hz, 2H), 8.16 (d, J=8Hz, 1H), 8.45 (s, 1H), 8.61 (d, J=4Hz, 1H), 8.95 (s, 1H), 10.81 (s, 1H), 13.96 (s, 1H), ESIMS found for C18H13F3N60 m/z 387.1 (M+H).

/ NH [0399[ 5 -(Py1idin-3 -yl)-N-(pyiidin-3 -ylmethyl)-1H-indazole-3 -carboxamide 42. [0400[ White solid (54.5 mg, 0.17 mmol, 78% yield). 1H NMR dG) 5 ppm 4.53 (d, J=6Hz, 2H), 7.35 (dd, J=8Hz, J=5Hz, 1H), 7.49-7.52 (m, 1H), 7.74-7.78 (m, 3H), 8.09- 8.11 (m, 1H), 8.41-8.42 (m, 1H), 8.45 (dd, J=5Hz, J=2Hz, 1H), 8.57 (dd, J=5Hz, J=2Hz, 1H), 8.59 (d, J=2Hz, 1H), 8.90 (d, J=2Hz, 1H), 9.16 (t, J=6Hz, 1H), 13.77 (s, 1H), ESIMS found for C19H15N50 m/Z 330 (M+H). [0401 [ 5 -(PyIidin-3 -yl)-N-(4-(tiifluoromethyl)pyridin-3 -yl)-1H-indazole-3 - carboxamide 48. [0402[ White solid (67 mg, 0.17 mmol, 62% yield). 1H NMR (DMSO-dg) 5 ppm 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.83-7.87 (m, 3H), 8.12 (td, J=8Hz, J=2Hz, 1H), 8.41 (t, J=1Hz, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.92 (d, J=3Hz, 1H), 9.08 (s, 1H), .21 (s, 1H), 14.06 (hrs, 1H), ESIMS found for C19H12F3N50 m/z 384.0 (M+H). [0403[ 5-(PyIidinyl)-N-(6-(pyrrolidinyl)pyiidinyl)-1H-indazole carboxamide 53. [0404[ Beige solid (23.8 mg, 0.06 mmol, 44.5% yield). 1H NMR (DMSO'dG) 5 ppm 1.92-1.97 (m, 4H), 3.38 (t, J=7Hz, 4H), 6.46 (d, J=9Hz, 1H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.80 (dq, J=9Hz, J=2Hz, 2H), 7.97 (dd, J=9Hz, J=3Hz, 1H), 8.12 (dd, J=8Hz, J=4Hz, 1H), 8.47 (s, 1H), 8.50 (d, J=3Hz, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.92 (d, J=2Hz, 1H), .22 (s, 1H), 13.86 (s, 1H), ESIMS found for NGO m/Z 385.1 (M+H).

QN o NH 54% [0405[ N-(4-(Cyclopropanecarboxamido)pyiidinyl)(pyIidinyl)-1H- indazolecarboxamide 58. [0406[ White solid (32.7 mg, 0.08 mmol, 37.0% yield). 1H NMR (DMSO-ds) 5 ppm 0.84-0.88 (m, 2H), 0.88-0.92 (m, 2H), 1.91-1.99 (m, 1H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.73 (d, J=6Hz, 1H), 7.82 (dd, J=12Hz, J=9Hz, 2H), 8.12 (dt, J=9Hz, J=4Hz, 1H), 8.34 (d, J=6Hz, 1H), 8.44 (s, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.80 (s, 1H), 8.92 (d, J=2Hz, 1H), .03 (s, 1H), 10.31 (s, 1H), 13.98 (s, 1H), ESIMS found for C22H18N602 m/Z 399.0 (M+H). [0407[ N-(6-(Cyclopentylcarbamoyl)pyiidinyl)(pyIidinyl)-1H-indazole- 3-carboxamide 181. [0408[ Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). 1H NMR (DMSO- d6) 5 ppm .64 (m, 4H), 1.67-1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin, J=8Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8Hz, 1H), 8.45 (d, J=8Hz, 1H), 8.48 (s, 1H), 8.54 (dd, J=9Hz, J=2,5Hz, 1H), 8.60 (d, J=4Hz, 1H), 8.94 (d, J=2Hz, 1H), 9.16 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.08 (brs, 1H), ESIMS found for C24H22N602 m/z 427.1 (M+H).

Example 3 [0409[ Preparation of N,5-di(pyIidin-3 -yl)-1H-indazolecarboxamide (4) is depicted below in Scheme 29.

CXXXI ?H CHO UOH / / I CHO l COZH I / N N \ N \ \ \ AgNo,, NaOH, 112 N N \N N/ KOAc, PdC12(dPPf)2 N/ Dioxane, rt, overnight N/ DMF, 90°C, 2 h 0 0 O CXIV le CXXXH] CXXV [I HATU, Dll’EA DMF, rt, overnight / \N / \N o o / NH / NH 1 1 N\ N\ \N TFA,DCM, \N 1': EthiI-I,rt,3h N/ 4 o cxxxrv Scheme 29 S£p_1 [0410[ 5 -Iodo(tetrahydro-2H-pyranyl)-1H-indazole-3 -carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridineboronic acid (CXXXI) (0.58 g, 4.73 mmol), and ium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the on was heated to 95°C for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), trated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes —> 1:1 EtOAczhexanes) to afford 5-(pyridinyl)(tetrahydro-2H-pyranyl)-1H- indazolecarbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as atan amorphous solid. 1H NMR (DMSO-ds) 5 ppm 10.23 (s, 1H), 8.95 (d, J: 2.3 Hz, 1H), 8.61 (dd, J: 4.8, 1.5 Hz, 1H), 8.39 (d, J: 0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J: 8.8 Hz, 1H), 7.95-7.93 (m, 1H), .60 (m, 1H), 6.13 (dd, J: 9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45- 2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H), ESIMS found for C18H17N302 m/z 308 (M+H).

SE1;2 [0411[ To a on of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) was added a solution of sodium hydroxide (0.26 g, 6.50 mmol) in water (5 mL) to give a brown precipitate. 5 -(pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H-indazole-3 -carbaldehyde (CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was added to the reaction which was stirred at room temperature for 2 h. The reaction was then extracted with diethyl ether. The aqueous layer was separated and carefiJlly brought to pH = 3 with 10% aqueous HCl. The aqueous layer was then extracted five times with iPrOH/chloroform (1/9). The combined organic layers were then dried (MgSO4) and concentrated to afford 5-(pyridin-3 -yl)- 1-(tetrahydro-2H-pyranyl)-1H-indazolecarboxylic acid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. 1H NMR (DMSO-dg) 5 ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J: 4.1 Hz, 1H), 8.32 (d, J = 0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J: 8.8 Hz, 1H), 7.86 (dd, J: 8.8, 1.7 Hz, 1H), 7.52 (dd, J: 7.8, 4.7 Hz, 1H), 6.04 (dd, J: 9.3, 2.3 Hz, 1H), 3.92- 3.90 (m, 1H), 3.83-3.78 (m, 1H), 2.44-2.37 (m, 1H), 2.08-2.02 (m, 2H), 1.79-1.76 (m, 1H), .61 (m, 2H). [0412[ To a solution of idin-3 -yl)(tetrahydro-2H-pyranyl)-1H- indazolecarboxylic acid (CXXXIII) (0.39 g, 1.21 mmol) and 3-aminopyridine (CXXVII) (0.11 g, 1.21 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (0.42 mL, 1.21 mmol). The on was cooled to 0°C before adding HATU (0.46 g, 1.21 mmol). The ice bath was d, and the reaction warmed to room temperature and stirred for 2 h. The DMF was removed under reduced pressure, and the residue was partitioned n chloroform and water. The organic phase was separated and washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography using a 25 g Thomson normal phase silica gel cartridge (100% CHC13 —> 2:98 MeOHzCHClg) to afford N,5 -di(pyridin-3 -yl)(tetrahydro-2H-pyranyl)- 1H-indazole-3 -carboxamide (CXXXIV) (0.36 g, 0.90 mmol, 75% yield) as an off-white solid. 1H NMR (DMSO-ds) 5 ppm .56 (s, 1H), 9.06 (d, J: 2.4 Hz, 1H), 8.94 (d, J: 2.3 Hz, 1H), 8.60 (dd, J: 4.8, 1.5 Hz, 1H), 8.47 (d, J: 1.1 Hz, 1H), 8.34-8.33 (m, 1H), 8.31-8.29 (m, 1H), 8.16-8.14 (m, 1H), 8.04 (d, J: 8.8 Hz, 1H), 7.90 (dd, J: 8.8, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.43-7.41 (m, 1H), 7.43-7.41 (m, 1H), 6.08-6.06 (m, 1H), 4.01-3.99 (m, 1H), 3.87-3.82 (m, 1H), 2.64-2.57 (m, 1H), 2.11- 2.06 (m, 2H), .80 (m, 1H), 1.69-1.65 (m, 2H), ESIMS found for C23H21N502 m/z 400 (M+H).

Step4 [0413[ TFA (5.0 mL) was added to a solution of N,5-di(pyridinyl) (tetrahydro-2H-pyranyl)-1H-indazolecarboxamide (CXXXIV) (0.36 g, 0.90 mmol) and triethylsilane (0.29 mL, 1.81 mmol) in DCM (5.0 mL). The solution was stirred overnight at room ature. An additional 5.0 mL of TFA was added, and the solution was again d overnight. The ts were removed, and the residue was treated with 7 N ammonia in MeOH. The solvents were again removed, and the product was purified by flash chromatography using a 12 g Thomson normal phase silica gel cartridge (100% CHC13 —> 5:95 MeOH[7N NH3]:CHC13) to afford N,5-di(pyridinyl)-1H-indazolecarboxamide (4) (0.23 g, 0.73 mmol, 82% yield) as a white solid. 1H NMR (DMSO-dg) 5 ppm 14.00 (s, 1H), 10.69 (s, 1H), 9.08 (d, J: 2.0 Hz, 1H), 8.93 (d, J: 2.0 Hz, 1H), 8.60 (dd, J = 4.8, 1.3 Hz, 1H), 8.48- 8.47 (m, 1H), 8.33-8.31 (m, 2H), 8.15-8.12 (m, 1H), .81 (m, 2H), 7.54-7.51 (m, 1H), 7.41-7.39 (m, 1H), ESIMS found for C18H13N50 m/z 316 (M+H). [0414[ The following compounds were prepared in accordance with the procedure described in the above Example 3. [0415[ N—(3 '-Fluorobiphenyl-3 -yl)-5 -(pyridin-3 H-indazole -3 -carboxamide [0416[ White solid (77 mg, 0.19 mmol, 69% yield). 1H NMR (DMSO'dG) 5 ppm 13.95 (s, 1H), 10.50 (s, 1H), 8.94 (d, J : 2.3 Hz, 1H), 8.59 (dd, J: 4.6, 1.5 Hz, 1H), 8.51 (d, J = 1.0 Hz, 1H), 8.31-8.30 (m, 1H), 8.15-8.13 (m, 1H), 7.99-7.97 (m, 1H), 7.83-7.82 (m, 2H), .45 (m, 6H), 7.24-7.22 (m, 1H), ESIMS found for C25H17FN4O m/z 409 (M+H). [0417 [ 5-(Pyridinyl)-N-(pyridinyl)-1H-indazolecarboxamide 6. [0418[ Off-white solid (52 mg, 0.16 mmol, 77% yield). 1H NMR dG) 5 ppm 14.05 (br, 1H), 10.83 (s, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.60 (dd, J = 4.6, 1.2 Hz, 1H), 8.48-8.47 (m, 3H), 8.15-8.13 (m, 1H), 7.94 (dd, J: 5.0, 1.4 Hz, 2H), 7.86-7.82 (m, 2H), 7.54- 7.52 (m, 1H), ESIMS found for C18H13N50 m/z 316 (M+H).

WO 75858 [0419[ N—(5-((Dimethylamino)methyl)py1idinyl)(pyIidinyl)-1H- indazolecarboxamide 7. [0420[ Off-white solid (37 mg, 0.10 mmol, 47% . 1H NMR (DMSO-ds) 5 ppm 14.00 (s, 1H), 10.68 (s, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.91 (d, J: 2.3 Hz, 1H), 8.60 (dd, J = 4.7, 1.2 Hz, 1H), 8.49-8.48 (m, 1H), 8.38-8.37 (m, 1H), 8.21 (d, J: 2.2 Hz, 1H), 8.16-8.13 (m, 1H), 7.85-7.81 (m, 2H), 7.52 (dd, J: 7.9, 4.9 Hz, 1H), 3.44 (s, 2H), 2.19 (s, 6H), ESIMS found for C21H20N60 m/z 373 (M+H). [0421[ 5 -(Py1idin-3 -yl)-N-(6-(pyrrolidinylmethyl)py1idin-3 -yl)-1H-indazole- 3-carboxamide 8. [0422[ Off-white solid (38 mg, 0.10 mmol, 77% yield). 1H NMR (DMSO-ds) 5 ppm 13.99 (br, 1H), 10.64 (s, 1H), 8.96 (d, J: 2.5 Hz, 1H), 8.93 (d, J: 2.4 Hz, 1H), 8.59 (dd, J: 4.8, 1.5 Hz,1H), 8.48 (d, J=1.2 Hz,1H), 8.27 (dd, J: 8.5, 2.5 Hz, 1H), 8.16-8.12 (m, 1H), 7.84-7.80 (m, 2H), 7.54-7.51 (m, 1H), 7.41 (d, J: 8.5 Hz, 1H), 2.37 (s, 2H), 2.50-2.47 (m, 4H), 1.72-1.70 (m, 4H); ESIMS found for C23H22N60 m/z 399 (M+H). [0423[ N-(5-(3-Fluorophenyl)pyridinyl)(py1idinyl)-1H-indazole carboxamide 9. [0424[ White solid (35 mg, 0.09 mmol, 47% yield). 1H NMR ds) 5 ppm 14.05 (br s, 1H), 10.79 (s, 1H), 9.13 (d, J: 2.0 Hz, 1H), 8.94 (d,J= 1.9 Hz, 1H), 8.68-8.65 (m, 2H), 8.60 (dd,J= 4.83, 4.83 Hz, 1H), 8.52-8.49 (m, 1H), 8.16-8.12 (m, 1H), 7.85-7.81 (m, 2H), 7.62-7.56 (m, 3H), 7.54-7.50 (m, 1H), 7.31-7.26 (m, 1H). ESIMS found for FN50 m/z 410.5 (M+H). [0425[ N-(2-(4-Methylpiperazinyl)pyIidin-3 -yl)-5 -(py1idin-3 -yl)-1H- indazole-3 -carboxamide 1 1. [0426[ White solid (11 mg, 0.03 mmol, 65% yield). 1H NMR (DMSO-ds) 5 ppm 14.10 (s, 1H), 9.63 (s, 1H), 8.93 (d, J: 2.1 Hz, 1H), 8.65-8.59 (m, 2H), 8.48 (s, 1H), 8.16-8.12 (m, 1H), .09 (m, 1H), 7.87-7.80 (m, 2H), 7.55-7.51 (m, 1H), 7.20-7.17 (m, 1H), 3.10- 3.06 (m, 4H), 2.80-2.40 (m, 4H), 2.30 (s, 3H). ESIMS found for C23H23N7O m/z 414.0 (M+H).

/ \N [0427[ N—(6-(4-Methylpiperazin- 1-yl)py1idinyl)(py1idinyl)-1H- indazolecarboxamide 12. [0428[ White solid (31 mg, 0.07 mmol, 39% yield). 1H NMR (DMSO-ds) 5 ppm 13.86 (br s, 1H), 10.33 (s, 1H), 8.92 (d, J: 2.1 Hz, 1H), .58 (m, 2H), 8.46 (s, 1H), 8.14- 8.11 (m, 1H), 8.10-8.02 (m, 1H), 7.83-7.78 (m, 2H), 7.54-7.50 (m, 1H), 6.86 (d, J: 9.1 Hz, 1H), 3.45-3.42 (m, 4H), 2.42-2.39 (m, 4H), 2.21 (s, 3H). ESIMS found for C23H23N7O m/z 414.3 (M+H). [0429[ N—(Pyridazinyl)-5 -(py1idin-3 -yl)- lH-indazole-3 xamide 14. [0430[ Off-white solid (50 mg, 0.16 mmol, 99% yield). 1H NMR (DMSO-ds) 5 ppm 14.20-13.90 (br, 1H), 11.15 (s, 1H), 9.71-9.70 (m, 1H), 9.09-9.08 (m, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.61-8.60 (m, 1H), 8.47-8.46 (m, 1H), 8.25 (dd, J: 5.9, 2.8 Hz, 1H), .13 (m, 1H), 7.86-7.85 (m, 2H), 7.53 (dd, J: 7.8, 5.0 Hz, 1H), ESIMS found for C17H12N60 m/z 317 (M+H). [0431 [ N-(6-((4-Methylpiperazin- l -yl)methyl)py1idin-3 -yl)(py1idin-3 -yl) - lH- indazolecarboxamide 15. [0432[ White solid (42 mg, 0.10 mmol, 81% yield). 1H NMR (DMSO-ds) 5 ppm 13.97 (br, 1H), 10.65 (s, 1H), 8.97 (d, J: 2.4 Hz, 1H), 8.93 (d, J: 2.1 Hz, 1H), 8.59 (dd, J: 4.7, 1.5 Hz, 1H), 8.48-8.47 (m, 1H), 8.28 (dd, J: 8.5, 2.5 Hz, 1H), 8.15-8.12 (m, 1H), 7.85- 7.81 (m, 2H), 7.54-7.51 (m, 1H), 7.40 (d, J: 8.5 Hz, 1H), 3.55 (s, 2H), 2.42-2.28 (m, 8H),2.15 (s, 3), ESIMS found for C24H25N7O m/z 428 (M+H).

Example 4 [0433[ Preparation of 5 -(5 py1idin-3 -yl)-N-(py1idin-3 -yl) - lH-indazole-3 - carboxamide (13) is depicted below in Scheme 30.

CXXIX / ?” o F \ B\ 0H cozH NH H N / \ | Br 2 Br N/ \N ——N- \N —, N/ HATU, DIPEA N/ KOAc, dppf)2 H DMF, 0°C-rt, 2 h H DMF, MW, 180°C, 1 h CXV cxxxv Scheme 30 S£p_1 [0434[ To a stirring solution of 3-aminopyridine (CXXV) (0.195 g, 0.2.07 mmol) in DMF (10 mL) was added 5-bromo-1H—indazolecarboxylic acid (CXV) (0.500 g, 0.2.07 mmol) and N,N—diisopropylethylamine (0.723 mL, 4.15 mmol). The reaction e was cooled to 0°C and added with HATU (0.787 g, 2.07 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The solution was concentrated under vacuum. The residue was purified by column tography (1:99 MeOH[7N NH3]:CHC13 —> 4:96 MeOH[7N NH3]:CHCl3) to afford 5-bromo-N-(pyridinyl)-1H- indazolecarboxamide ) (0.200 g, 0.63 mmol, 30% yield) as a white solid. ESIMS found for C13H9BrN4O m/z 318.0 (M+H).

Sip—2 [0435[ To a microwave vial was added 5-bromo-N-(pyridin-3 -yl)-1H-indazole carboxamide (CXXXV) (0.200 g, 0.63 mmol), 5-fluoropyridineboronic acid (CXXIX) (0.098 g, 0.694 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.032 mmol), potassium phosphate (0.201 g, 0.947 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The crude product was purified by column tography (100% CHC13 —> 2:98 N NH3]: CHCl3) to afford 5-(5-fluoropyridinyl)-N-(pyridinyl)-1H-indazolecarboxamide (13) (4 mg, 0.01 mmol, 2% yield) as a white solid. 1H NMR (DMSO-dg) 5 ppm 14.02 (br s, 1H), 10.70 (s, 1H), 9.08 (d, J: 2.5 Hz, 1H), 8.83 (t, J: 1.8 Hz, 1H), 8.60 (d, J: 2.7 Hz, 1H), 8.53-8.52 (m, 1H), 8.34-8.29 (m, 2H), 8.14-8.09 (m, 1H), 7.89-7.81 (m, 2H), 7.42-7.38 (m, 1H). ESIMS found for ClngzFNso m/z 334.0 (M+H).

Example 5 [0436[ Preparation of N-(pyridin-3 -yl)-5 -(5 -(trifluoromethyl)pyridin-3 -yl)-1H- indazolecarboxamide (16) is depicted below in Scheme 31.

CXXVII c0211 NH H N / \ 2 :3“— Br Br \N N 39039° u’ HATED“? N’ KOAc, PdC12(dPP02 DMF, rt, overnight DMF, 900C 2 h o o cxvrn cxxxv cxxxvr0 cxxxvn F30 Br K3P04, Pd(PPh3)4 H20, 90°C, 3 h TFA, DCM, EtSSiH, rt, 3 n Scheme 31 [0437[ Preparation of intermediate 5-bromo-N-(pyridinyl)(tetrahydro-2H- pyranyl)-1H-indazolecarboxamide (CXXXV) was med following the ure listed in Scheme 19, Step 4. Light yellow solid (5.5 g, 13.7 mmol, 88% yield). ESIMS found for C18H17BrN402 m/Z 401.1 (M793‘+H) and 403.1 (M813‘+H). [0438[ Preparation of intermediate N—(pyridinyl)(tetrahydro-2H-pyran yl)(5-(trifluoromethyl)pyridinyl)-1H-indazolecarboxamide (CXXXVIII) was performed following the procedure listed in Scheme 26, Steps 1-2. Tan solid (295 mg, 0.63 mmol, 84% yield). ESIMS found for C24H20F3N502 m/z 468.1 (M+H).

S£p_4 [0439[ Preparation of N-(pyridinyl)(5-(trifluoromethyl)pyridinyl)-1H- lecarboxamide (16) was performed following the procedure listed in Scheme 28, Step 4. White solid (95 mg, 0.25 mmol, 39.3% . 1H NMR (DMSO-dg) 5 ppm 7.40 (dd, J=2.2Hz, J=2Hz, 1H), 7.84 (d, J=6.7Hz, 1H), 7.93 (dd, J=1.5Hz, J=7Hz, 1H), 8.29-8.34 (m, 2H), 8.50 (s, 1H), 8.57 (s, 1H), 8.99 (s, 1H), 9.09 (d, J=2Hz, 1H), 9.25 (d, J=1.6Hz, 1H), 10.72 (brs, 1H), ESIMS found for C19H12F3N50 m/z 383.9 (M+H). [0440[ The following compounds were prepared in accordance with the procedure described in the above Example 5. [0441 [ 5 -(5 -((Dimethylamino)methyl)pyridin-3 -yl)-N-(6-(trifluoromethyl) pyridin-3 -yl)- lH-indazole-3 -carboxamide 26. [0442[ White solid (93 mg, 0.21 mmol, 78% yield). 1H NMR (DMSO-ds) 5 ppm 2.24 (s, 6H), 3.57 (s, 2H), 7.86 (Abq, J=8Hz, 2H), 7.93 (d, J=9Hz, 1H), 8.04 (brs, 1H), 8.50 (d, J=7Hz, 1H), 8.63 (dd, J=9Hz, J=2Hz, 1H), 8.85 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, lH), 11.11 (s, 1H), 14. 11 (s, 1H), ESIMS found for C22H19F3N60 m/z 441.0 (M+H) [0443[ N—(5 -(3 din-3 -ylcarbamoyl)- azol-S -yl)pyridin-3 -yl) morpholinecarboxamide 32. [0444[ White solid (132 mg, 0.30 mmol, 56% yield). 1H NMR (DMSO-ds) 5 ppm 3.49 (t, J=5Hz, 4H), 3.64 (t, J=5Hz, 4H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.82 (d, J=le, 1H), 8.26 (t, J=2Hz, 1H), 8.30-8.34 (m, 2H), 8.47 (s, 1H), 8.54 (d, J=2Hz, 1H), 8.72 (d, J=2Hz, 1H), 8.87 (s, 1H), 9.09 (d, 2H2, 1H), 10.71 (s, 1H), 14.01 (s, 1H), ESIMS found for C23H21N703 m/Z 444.3 (M+H). [0445[ 5 -(5 -((Dimethylamino)methyl)py1idin-3 -yl)-N-(6-(2-fluorophenoxy) pyIidinyl)-1H-indazolecarboxamide 36. [0446[ White solid (137 mg, 0.28 mmol, 53% yield). 1H NMR (DMSO-ds) 5 ppm 2.20 (s, 6H), 3.53 (s, 2H), 7.16 (d, J=9Hz, 1H), 7.22-7.40 (m, 4H), 7.82 (d/Abq, J=9Hz, J=1Hz, 2H), 8.00 (t, J=2Hz, 1H), 8.38 (dd, J=9Hz, J=3Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2Hz, 1H), 8.55 (d, J=3Hz, 1H), 8.83 (d, J=2Hz, 1H), 10.67 (s, 1H), 13.97 (brs, 1H), ESIMS found for C27H23FN602 m/z 383.1 (M+H). [0447[ 5-(5-(Cyclopropanecarboxamido)pyIidinyl)-N-(6-(4-methylpiperazin- 1-yl)py1idin-3 -yl)-1H-indazole-3 xamide 38. [0448[ White solid (39 mg, 0.08 mmol, 61% yield). 1H NMR (DMSO-dg) 5 ppm 0.83-0.90 (m, 4H), 1.80-1.86 (m, 1H), 2.25 (brs, 3H), 2.45 (brs, 4H), 3.45 (brs, 4H), 6.86 (d, J=9Hz, 1H), 7.79 (d, J=1Hz, 1H), 8.04 (dd, J=9Hz, J=3Hz, 1H), 8.42 (t, J=2Hz, 1H), 8.46 (s, 1H), 8.60 (dd, J=10Hz, J=3Hz, 2H), 8.76 (d, J=2Hz, 1H), 10.34 (s, 1H), 10.56 (s, 1H), 13.90 (s, 1H), ESIMS found for C27H27N802 m/z 497.4 (M+H). [0449[ 5 -(5 -(Cyclopropanecarboxamido)py1idin-3 -yl)-N-(6-(trifluoromethyl) pyIidinyl)-1H-indazolecarboxamide 39. [0450[ White solid (128 mg, 0.27 mmol, 45% yield). 1H NMR (DMSO-ds) 5 ppm 0.82-0.90 (m, 4H), 1.80-1.86 (m, 1H), 7.84 (s, 2H0, 7.92 (d, J=9Hz, 1H), 8.43 (d, J=2Hz, 1H), 8.48 (s, 1H), 8.61-8.65 (m, 2H), 8.77 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, 1H), 10.57 (s, 1H), 11.11 (s, 1H), 14.11 (s, 1H), ESIMS found for C23H17F3N602 m/z 467.1 (M+H). [0451 [ 5 -(5 -((Dimethylamino)methyl)py1idin-3 -yl)-N-(pyIidin-3 -yl)-1H- indazolecarboxamide 40. [0452[ White solid (312 mg, 0.84 mmol, 77% yield). 1H NMR (DMSO-ds) 5 ppm 2.21 (s, 6H), 3.53 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2Hz, 2H), 8.01 (t, J=2Hz, 1H), 8.29-8.34 (m, 2H), 8.48 (dd, J=4Hz, J=1Hz, 1H), 8.83 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.70 (s, 1H), 13.99 (brs, 1H), ESIMS found for C21H20N60 m/Z 373.0 (M+H). [0453[ 5-(5-(Cyclopropanecarboxamido)py1idinyl)-N-(py1idinyl)-1H- indazolecarboxamide 41. [0454[ White solid (148 mg, 0.37 mmol, 71% . 1H NMR (DMSO-ds) 5 ppm 0.83-0.90 (m, 4H), 1.80-1.87 (m, 1H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.82 (d, J=1Hz, 1H), 8.29- 8.34 (m, 2H), 8.43 (t, J=2Hz, 1H), 8.47 (s, 1H), 8.62 (d, J=2Hz, 1H), 8.76 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.57 (s, 1H), 10.70 (s, 1H), 14.01 (s, 1H), ESIMS found for C22H18N602 m/z 399.0 (M+H). [0455[ N—(Pyridin-3 -yl)-5 -(5 -(pyrrolidinylmethyl)py1idin-3 -yl)-1H-indazole- oxamide 43. [0456[ White solid (157 mg, 0.39 mmol, 76% yield). 1H NMR (DMSO-ds) 5 ppm 1.70-1.74 (m, 4H), 2.46-2.52 (m, 4H), 3.71 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2Hz, 2H), 8.02 (t, J=2Hz, 1H), 8.29-8.34 (m, 2H), 8.48 (s, 1H), 8.51 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.00 (s, 1H), ESIMS found for N60 m/Z 399.0 (M+H). [0457[ N—(6-Ethoxypy1idin-3 -yl)-5 -(5 -(pyrrolidinylmethyl)py1idin-3 -yl)-1H- lecarboxamide 44. [0458[ White solid (62 mg, 0.14 mmol, 39% yield). 1H NMR (DMSO-ds) 5 ppm 1.32 (t, J=7Hz, 3H), 1.70-1.74 (m, 4H), 2.47-2.52 (m, 4H), 3.71 (s, 2H), 4.29 (q, J=7Hz, 2H), 6.81 (d, J=9Hz, 1H), 7.82 (d/Abq, J=9Hz, J=2Hz, 2H), 8.01 (t, J=2Hz, 1H), 8.16 (dd, J=9Hz, J=3Hz, 1H), 8.46 (s, 1H), 8.51 (d,J=2Hz, 1H), 8.63 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.51 (s, 1H), 13.94 (hrs, 1H), ESIMS found for C25H26N602 m/z 443.4 (M+H). [0459[ N—(6-Ethoxypy1idin-3 -yl)-5 -(5 -(piperidinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 45. [0460[ White solid (98 mg, 0.21 mmol, 44% yield). 1H NMR (DMSO-ds) 5 ppm 1.32 (t, J=7Hz, 3H), 1.34-1.42 (m, 2H), 1.47-1.53 (m, 4H), 2.38 (brs, 4H), 3.56 , (s, 2H), 4.29 (q, J=7Hz, 2H), 6.81 (d, J=9Hz, 1H), 7.81 (d/Abq, J=9Hz, J=2Hz, 2H), 7.99 (t, J=2Hz, 1H), 8.16 (dd, J=9Hz, J=3Hz, 1H), 8.46 (d, J=1Hz, 1H), 8.49 (d, J=2Hz, 1H), 8.63 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.51 (s, 1H), 13.92 (hrs, 1H), ESIMS found for C26H28N602 m/z 457.3 (M+H). [0461[ 5 -(5 -(Pipe1idinylmethyl)pyridin-3 -yl)-N-(pyridin-3 -yl)-1H-indazole-3 - amide 46. [0462[ White solid (126 mg, 0.31 mmol, 52% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.57 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2Hz, 2H), 7.99 (t, J=2Hz, 1H), 8.30-8.34 (m, 2H), 8.48 (d, J=1Hz, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.00 (hrs, 1H), ESIMS found for C24H24N60 m/z 413.0 (M+H). [0463[ 5 -(5 -(Pipe1idinylmethyl)pyridin-3 -yl)-N-(4-(trifluoromethyl) pyridinyl)-1H-indazole-3 -carboxamide 47. [0464[ White solid (150 mg, 0.31 mmol, 71% yield). 1H NMR (DMSO-ds) 5 ppm .42 (m, 2H), 1.46-1.53 (m, 4H), 2.37 (brs, 4H), 3.55 (s, 2H), 7.81-7.87 (m, 3H), 7.98 (s, 1H), 8.41 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.07 (s, 1H), .22 (s, 1H), 14.06 (hrs, 1H), ESIMS found for C25H23F3N60 m/z 481.0 (M+H). [0465[ N—(Pyridin-3 -yl)-5 -(3 -(pyrrolidinylmethyl)phenyl)-1H-indazole-3 - carboxamide 49. [0466[ Tan amorphous solid (53.4 mg, 0.13 mmol, 72% yield). 1H NMR (DMSO- d6) 5 ppm 1.70-1.71 (m, 4H), 2.47-2.49 (m, 4H), 3.67 (s, 2H), 7.31 (d, J=8Hz, 1H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.44 (t, J=8Hz, 1H), 7.58-7.60 (m, 1H), 7.63-7.64 (m, 1H), .78 (m, 2H), 8.30-8.34 (m, 2H), 8.44 (s, 1H), 9.08 (d, J=2Hz, 1H), 10.68 (s, 1H), 13.93 (s, 1H), ESIMS found for C24H23N50 m/Z 398 (M+H). [0467[ N—(6-Phenylpy1idin-3 -yl)-5 -(5 -(pyrrolidinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 50. [0468[ Tan flaky solid (61.3 mg, 0.13 mmol, 74% yield). 1H NMR (DMSO-ds) 5 ppm 1.71-1.72 (m, 4H), 3.72 (s, 2H), 7.39-7.42 (m, 1H), 7.47-7.50 (m, 2H), 7.81-7.86 (m, 2H), 8.00 (d,J=9Hz, 1H), 8.02-8.03 (m, 1H), 8.08-8.10 (m, 2H), 8.45 (dd, J=9Hz, J=3Hz, 1H), 8.49- 8.50 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.83 (d, J=2Hz, 1H), 9.18 (d, J=3Hz, 1H), 10.81 (s, 1H), 14.03 (s, 1H), ESIMS found for C29H26N60 m/z 475 (M+H). [0469[ idin-3 -yl)-5 -(6-(pyrrolidinyl)py1idin-3 -yl)-1H-indazole-3 - carboxamide 51. [0470[ Yellow solid (32 mg, 0.08 mmol, 37.8% yield). 1H NMR (DMSO-ds) 5 ppm 1.94-2.01 (m, 4H), 3.42-3.48 (m, 4H), 6.57 (d, J=9Hz, 1H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.72 (d, J=1Hz, 2H), 7.85 (dd, J=9Hz, J=3Hz, 1H), 8.29-8.34 (m, 3H), 8.43 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.63 (s, 1H), 13.87 (s, 1H), ESIMS found for szHzoNsO m/z 385.0 (M+H). [0471 [ yanopy1idinyl)(5-(pyrrolidinylmethyl)py1idinyl)-1H- indazolecarboxamide 52. [0472[ Beige solid (52 mg, 0.12 mmol, 49.1% yield). 1H NMR (DMSO-ds) 5 ppm 1.70-1.75 (m, 4H), 3.31-3.36 (m, 4H), 7.85 (dq, J=9Hz, J=2Hz, 2H), 8.02 (s, 1H), 8.05 (d, J=9Hz, 1H), 8.47 (s, 1H), 8.52 (d, J=2Hz, 1H), 8.58 (dd, J=9Hz, J=3Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.28 (d, J=2Hz, 1H), 11.18 (s, 1H), 14.13 (hrs, 1H), ESIMS found for C24H21N7O m/Z 424.3 (M+H). [0473[ 5-(6-Methoxypyn'dinyl)-N-(pyIidinyl)-1H-indazolecarboxamide [0474[ White solid (79.7 mg, 0.23 mmol, 44.2% yield). 1H NMR dg) 5 ppm 3.91 (s, 3H), 6.95 (d, J=9Hz, 1H), 7.40 (dd, J=9Hz, J=5Hz, 1H), 7.78 (dd, J=11Hz, J=2Hz, 2H), 8.06 (dd, J=9Hz, J=3Hz, 1H), 8.29-8.34 (m, 2H), 8.39 (s, 1H), 8.51 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.67 (s, 1H), 13.91 (hrs, 1H), ESIMS found for C19H15N502 m/z 346.0 (M+H). [0475 [ 5 -(5 -Benzylpyridin-3 -yl)-N-(pyIidin-3 -yl)-1H-indazole-3 -carboxamide [0476[ Yellow solid (101.9 mg, 0.25 mmol, 76% yield). 1H NMR dg) 5 ppm 4.09 (s, 2H), 7.19-7.23 (m, 1H), 7.30-7.35 (m, 4H), 7.39-7.41 (m, 1H), 7.78-7.82 (m, 2H), 7.99 (t, J=2Hz, 1H), 8.31-8.33 (m, 2H), 8.45 (s, 1H), 8.51 (d, J=2Hz, 1H), 8.76 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.00 (s, 1H), ESIMS found for C25H19N50 m/Z 406 (M+H). 00 Q [0477 [ 5 -(5 xypy1idin-3 -yl)-N-(py1idin-3 -yl)-1H-indazole-3 -carboxamide [0478[ White solid (73.6 mg, 0.18 mmol, 75%yield). 1H NMR (DMSO-ds) 5 ppm 7.17-7.18 (m, 2H), 7.22-7.23 (m, 1H), 7.38-7.41 (m, 1H), 7.44-7.47 (m, 2H), 7.72-7.73 (m, 1H), 7.80-7.81 (m, 2H), 8.29-8.31 (m, 2H), 8.37-8.38 (m, 1H), 8.44-8.45 (m, 1H), 8.74 (d, J=2Hz, 1H), 9.06 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.00 (s, 1H), ESIMS found for C24H17N502 m/z 408 (M+H). [0479[ 5 -(5 -(Pyrrolidinylmethyl)pyridin-3 -yl)-N-(4-(t1ifluoromethyl) pyIidinyl)-1H-indazole-3 -carboxamide 57 . [0480[ White solid (64 mg, 0.14 mmol, 35.2% yield). 1H NMR (DMSO-ds) 5 ppm 1.67-1.74 (m, 4H), 2.44-2.52 (m, 4H), 3.70 (s, 2H), 7.81-7.88 (m, 3H), 8.00 (d, J=2Hz, 1H), 8.41 (s, 1H), 8.50 (d, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.81 (d,J=2Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H), 14.01 (brs, 1H), ESIMS found for C24H21F3N60 m/z 467.3 (M+H). [0481[ 5-(5-(Cyclohexylcarbamoyl)py1idinyl)-N-(py1idinyl)-1H-indazole- 3-carboxamide 59. [0482[ Light brown solid (117 mg, 0.27 mmol, 49.7% yield). 1H NMR (DMSO- d6) 5ppm 1.10-1.21 (m, 1H), 1.28-1.39 (m, 4H), 1.63 (d,J=12Hz, 1H), 1.72-1.78 (m, 2H), 1.86- 1.91 (m, 2H), 3.77-3.87 (m, 1H), 7.41 (dd, J=8Hz, J=5Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.91 (d, J=9Hz, 1H), .36 (m, 2H), 8.48 (t, J=2Hz, 1H), 8.55 (s, 1H), 8.59 (d, J=8Hz, 1H), 8.99 (d, J=2Hz, 1H), 9.04 (d, J=2Hz, 1H), 9.09 (d,J=2Hz, 1H), 10.72 (s, 1H), 14.04 (s, 1H), ESIMS found for C25H24N602 m/z 441.0 (M+H). [0483[ 5 -(3 o-5 -((4-methylpiperazinyl)methyl)phenyl)-N-(4- (tiifluoromethyl)pyridinyl)-1H-indazole-3 -carboxamide 60. [0484[ White solid (43 mg, 0.08 mmol, 76.3% yield). 1H NMR (DMSO-ds) 5 ppm 1.23 (s, 3H), 2.22-2.50 (m, 8H), 3.56 (s, 2H), 7.12 (d, J=9Hz, 1H), 7.42 (dd, J=8Hz, J=2Hz, 1H), 7.47 (s, 1H), 7.80 (d, J=1Hz, 2H), 7.85 (d, J=5Hz, 1H), 8.39 (s, 1H), 8.75 (d, J=5Hz, 1H), 9.08 (s, 1H), 10.22 (s, 1H), 14.02 (hrs, 1H), ESIMS found for C26H24F4N60 m/z 513.3 (M+H). [0485[ 5 -(5 -((4-Methylpiperazinyl)methyl)py1idin-3 -yl)-N-(pyIidin-3 -yl)-1H- lecarboxamide 61. [0486[ White solid (81.6 mg, 0.19 mmol, 55% yield). 1H NMR (DMSO-ds) 5 ppm 2.14 (s, 3H), 2.33-2.42 (m, 8H), 3.60 (s, 2H), .41 (m, 1H), 7.81-7.85 (m, 2H), 8.00-8.01 (m, 1H), 8.31-8.33 (m, 2H), 8.47-8.48 (m, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.74 (s, 1H), 14.00 (s, 1H), ESIMS found for C24H25N7O m/Z 427.8 (M+H). [0487[ N—(6-Cyanopy1idin-3 -yl)-5 -(5 -(pipe1idinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 62. [0488[ Off-white solid (42 mg, 0.10 mmol, 36.9% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.42 (m, 2H), 1.47-1.54 (m, 4H), 2.38 (brs, 4H), 3.57 (s, 2H), 7.85 (d, J=1Hz, 2H), 8.00 (t, J=2Hz, 1H), 8.05 (d, J=9Hz, 1H), 8.47 (d, J=1Hz, 1H), 8.50 (d, J=2Hz, 1H), 8.58 (dd, J=9Hz, J=3Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.28 (d, J=2Hz, 1H), 11.18 (s, 1H), 14.12 (hrs, 1H); ESIMS found for C25H23N7O m/Z 438.1 (M+H). [0489[ 5 -(5 -(PipeIidinylmethyl)pyridin-3 -yl)-N-(6-(trifluoromethyl) pyridin- 3-yl)-1H-indazolecarboxamide 63. [0490[ White solid (78 mg, 0.16 mmol, 49% yield). 1H NMR (DMSO-ds) 5 ppm 1.35-1.44 (m, 2H), .57 (m, 4H), 2.40 (brs, 4H), 3.59 (brs, 2H), 7.85 (s, 2H), 7.93 (d, J=9Hz, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 8.50 (s, 1H), 8.63 (d, J=8Hz, 1H), 8.83 (s, 1H), 9.27 (s, 1H), 11.11 (s, 1H), 14.11 (hrs, 1H); ESIMS found for C25H23F3N60 m/z 481.1 (M+H). [0491 [ 5 -(5 -(Morpholinomethyl)pyridin-3 -yl)-N-(pyIidin-3 -yl)-1H-indazole-3 - amide 64. [0492[ White solid (77 mg, 0.19 mmol, 66% yield). 1H NMR (DMSO-ds) 5 ppm 2.41-2.43 (m, 4H), 3.58-3.60 (m, 4H), 3.61 (s, 2H), 7.39-7.41 (m, 1H), 7.81-7.85 (m, 2H), 8.02- 8.03 (m, 1H), 8.31-8.33 (m, 2H), 8.47-8.48 (m, 1H), 8,51 (d,J=2Hz, 1H), 8.83 (d,J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.00 (s, 1H); ESIMS found for C23H22N602 m/Z 415 (M+H). [0493[ N—(6-Phenylpy1idin-3 -yl)-5 -(5 1idinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 65. [0494[ White solid (61.5 mg, 0.13 mmol, 68% yield). 1H NMR (DMSO-ds) 5 ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.38-2.39 (m, 4H), 3.57 (s, 2H), 7.39-7.43 (m, 1H), 7.47- 7.50 (m, 2H), 7.82-7.86 (m, 2H), 7.99-8.01 (m, 2H), 8.08-8.10 (m, 2H), 8.44 (dd, J=9Hz, J=3Hz, 1H), 8.50-8.51 (m, 2H), 8.83 (d,J=2Hz, 1H), 9.18 (d,J=3Hz, 1H), 10.81 (s, 1H), 14.02 (s, 1H), ESIMS found for N60 m/z 489 (M+H). [0495[ 5-(5-Cyanopyridinyl)-N-(py1idinyl)-1H-indazolecarboxamide [0496[ Beige solid (107 mg, 0.31 mmol, 66.7% yield). 1H NMR (DMSO-ds) 5 ppm 7.40 (dd, J=8Hz, J=4Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.91 (dd, J=9Hz, J=2Hz, 1H), 8.30- 8.34 (m, 2H), 8.57 (s, 1H), 8.72 (t, J=2Hz, 1H), 9.03 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 9.23 (d, J=2Hz, 1H), 10.72 (s, 1H), 14.06 (s, 1H), ESIMS found for C19H12N60 m/z 340.8 (M+H). [0497[ 5 -(3 -Fluoro-5 1idinylmethyl)phenyl)-N-(py1idin-3 -yl)-1H- indazolecarboxamide 67. [0498[ Yellow solid (84 mg, 0.20 mmol, 66% yield). 1H NMR (DMSO-ds) 5 ppm 1.37-1.39 (m, 2H), 1.49-1.54 (m, 4H), 2.37-2.38 (m, 4H), 3.54 (s, 2H), 7.12-7.13 (m, 1H), 7.39- 7.43 (m, 2H), 7.47-7.48 (m, 1H), 7.77-7.81 (m, 2H), 8.31-8.33 (m, 2H), 8.44-8.45 (m, 1H), 9.08 (d, J=2Hz, 1H), 10.69 (s, 1H), 13.97 (s, 1H), ESIMS found for C25H24FN50 m/z 430 (M+H). [0499[ 5 -(5 -(Morpholinomethyl)pyridin-3 -yl)-N-(6-(t1ifluoromethyl)py1idin-3 - yl)-1H-indazolecarboxamide 68. [0500[ White solid (72 mg, 0.15 mmol, 30.5% yield). 1H NMR (DMSO-ds) 5 ppm 2.43 (brs, 4H), 3.56-3.63 (m, 4H), 3.62 (s, 2H), 7.85 (Abq, J=9Hz, 2H), 7.93 (d, J=9Hz, 1H), 8.04 (s, 1H), 8.49 (s, 1H), 8.52 (d, J=1Hz, 1H), 8.63 (dd, J=9Hz, J=3Hz, 1H), 8.84 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, 1H), 11.11 (s, 1H), 14.11 (hrs, 1H), ESIMS found for C24H21F3N602 m/z 483.3 (M+H). [0501 [ N-(6-Morpholinopy1idinyl)-5 -(5 -(pipe1idinylmethyl)py1idin-3 -yl)- 1H-indazole-3 -carboxamide 69. [0502[ Light yellow solid (58 mg, 0.12 mmol, 36.4% yield). 1H NMR (DMSO- d6) 5 ppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5Hz, 4H), .40 (m, 4H), 3.40 (t, J=5Hz, 4H), 3.56 (s, 2H), 3.71 (t, 5Hz, 4H), 6.89 (d, J=9Hz, 1H), 7.78 (d, J=8Hz, 1H), 7.81 (d, J=9Hz, 1H), 7.97 (t, J=2Hz, 1H), 8.06 (dd, J=9Hz, J=2Hz, 1H), 8.46 (d, J=10Hz, 1H), 8.60 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 10.35 (s, 1H), 13.90 (hrs, 1H), ESIMS found for C28H31N702 m/Z 498.0 (M+H). [0503[ 4-Methylpiperazinyl)pyIidin-3 -yl)-5 -(5 -(piperidin ylmethyl)pyn'din-3 -yl)-1H-indazole-3 -carboxamide 70. [0504[ Light yellow solid (37 mg, 0.07 mmol, 39.2% yield). 1H NMR (DMSO- d6) 5 ppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.22 (s, 3H), 2.35-2.42 (m, 8H), 3.44 (t, J=5Hz, 4H), 3.56 (s, 2H), 6.86 (d, J=9Hz, 1H), 7.79 (d, J=9Hz, 1H), 7.82 (d, , 1H), 7.98 (d, J=2Hz, 1H), 8.03 (dd,J=9Hz,J=3Hz, 1H), 8.48 (d, J=11Hz, 1H), 8.58 (d, J=3Hz, 1H), 8.81 (d, J=3Hz, 1H), 10.34 (s, 1H), 13.89 (hrs, 1H); ESIMS found for C29H34N80 m/z 511.5 (M+H). [0505[ 5 -(5 -(PipeIidinylmethyl)pyridin-3 -yl)-N-(6-(pyrrolidinyl) pyIidinyl)-1H-indazole-3 -carboxamide 71. [0506[ Tan solid (53.9 mg, 0.11 mmol, 53% yield). 1H NMR (DMSO-ds) 5 ppm .39 (m, 2H), 1.51-1.52 (m, 4H), 1.93-1.96 (m, 4H), 2.36-2.38 (m, 4H), 3.36-3.39 (m, 4H), 3.56 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.78-7.83 (m, 2H), 7.96 (dd, J=9Hz, J=3Hz, 1H), 7.98- 7.99 (m, 1H), 8.46-8.47 (m, 2H), 8.49 (, d, J=3Hz, 1H), 8.80-8.81 (m, 1H), 10.23 (s, 1H), 13.87 (s, 1H); ESIMS found for C28H31N7O m/z 482 (M+H). [0507[ N—(6-(3 ophenyl)pyridin-3 -yl)-5 -(5 -(piperidin- l -ylmethyl) pyIidin- 3-yl)- lH-indazole-3 -carboxamide 72. [0508[ White solid (54.8 mg, 0.11 mmol, 64% yield). 1H NMR (DMSO'dG) 5 ppm 1.39-1.40 (m, 2H), 1.50-1.54 (m, 4H), 2.38-2.39 (m, 4H), 3.57 (s, 2H), 7.22-7.26 (m, 1H), 7.51- 7.55 (m, 1H), 7.82-7.86 (m, 2H), 7.88-7.91 (m, 1H), 7.94-7.96 (m, 1H), 8.00-8.01 (m, 1H), 8.06 (d, J=9Hz, 1H), 8.46 (dd, J=9Hz, J=3Hz, 1H), 8.50 (s, 2H), 8.82 (d, J=2Hz, 1H), 9.20 (d, J=2Hz, 1H), 10.86 (s, 1H), 14.03 (s, 1H); ESIMS found for C30H27FN60 m/Z 507 (M+H). [0509[ N-(6-(4-Fluorophenyl)pyridin-3 -yl)-5 -(5 -(piperidin- l -ylmethyl) pyIidin- 3-yl)- lH-indazole-3 -carboxamide 73. [0510[ White solid (50.8 mg, 0.10 mmol, 55% yield). 1H NMR (DMSO'dG) 5 ppm .40 (m, 2H), 1.49-1.53 (m, 4H), .39 (m, 4H), 3.57 (s, 2H), 7.29-7.32 (m, 2H), 7.82- 7.86 (m, 2H), 7.98-8.01 (m, 2H), 8.12-8.15 (m, 2H), 8.43 (dd, J=9Hz, J=3Hz, 1H), 8.49 (s, 2H), 8.82 (d, J=2Hz, 1H), 9.17 (d, J=3Hz, 1H), 10.81 (s, 1H), 14.02 (s, 1H); ESIMS found for C30H27FN60 m/Z 507 (M+H). [051 1[ N-(6-((2-(Dimethylamino)ethyl)(methyl)amino)py1idin-3 -yl)-5 -(5 - (piperidinylmethyl)pyridin-3 -yl)-1H-indazole-3 -carboxamide 74. [0512[ Light yellow solid (88.5 mg, 0.17 mmol, 61.7% yield). 1H NMR (DMSO- d6) 5 ppm 1.38-1.42 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.18 (s, 6H), .40 (m, 6H), 2.99 (s, 3H), 3.56 (s, 2H), 3.61 (t, J=7Hz, 2H), 6.61 (d, J=9Hz, 1H), 7.79 (d, J=9Hz, 1H), 7.81 (d, J=9Hz, 1H), 7.95 (dd, J=9Hz, J=3Hz, 1H), 7.98 (t, J=2Hz, 1H), 8.46 (s, 1H), 8.48 (d, J=2Hz, 2H), 8.81 (d, J=2Hz, 1H), 10.24 (s, 1H), 13.84 (hrs, 1H), ESIMS found for C29H36N80 m/z 513.5 (M+H). [0513[ 5 -(5 -(Pipe1idinylmethyl)pyridin-3 -yl)-N-(pyridazinyl)-1H- indazolecarboxamide 75. [0514[ White solid (53 mg, 0.13 mmol, 33.7% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.33-2.42 (m, 4H), 3.57 (s, 2H), 7.85 (s, 2H), 8.00 (t, J=2Hz, 1H), 8.25 (dd, J=6Hz, J=3Hz, 1H), 8.47 (t, J=1Hz, 1H), 8.50 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.09 (d, J=6Hz, 1H), 9.71 (dd, J=3Hz, J=1Hz, 1H), 11.16 (s, 1H), 14.16 (hrs, 1H), ESIMS found for C23H23N7O m/z 414.1 (M+H). [0515[ 5 -(5 -(PipeIidinylmethyl)pyridin-3 -yl)-N-(pyridin-3 -ylmethyl)-1H- indazolecarboxamide 76. [0516[ White solid (26.8 mg, 0.06 mmol, 27% yield). 1H NMR (DMSO-ds) 5 ppm 1.38-1.39 (m, 2H), .51 (m, 4H), 2.36-2.37 (m, 4H), 3.55 (s, 2H), 4.53 (d, J=6Hz, 2H), 7.35 (dd, J=8Hz, J=5Hz, 1H), 7.74-7.80 (m, 3H), 7.95-7.96 (m, 1H), .42 (m, 1H), 8.45- 8.46 (m, 1H), 8.48-8.49 (m, 1H), 8.58-8.59 (m, 1H), 8.78 (d, J=2Hz, 1H), 9.17 (t, J=6Hz, 1H), 13.77 (s, 1H), ESIMS found for C25H26N60 m/z 427 (M+H). [0517[ ohexyl(5-(pipeIidinylmethyl)pyIidinyl)-1H-indazole carboxamide 77. [0518[ White solid (50.4 mg, 0.12 mmol, 72.5% yield). 1H NMR (DMSO-ds) 5 ppm 1.12-1.47 (m, 7H), 1.50-1.53 (m, 4H), 1.60-1.63 (m, 1H), 1.73-1.75 (m, 2H), 1.83-1.84 (m, 2H), 2.37-2.38 (m, 4H), 3.55 (s, 2H), 3.81-3.87 (m, 1H), 7.73-7.78 (m, 2H), 7.95-7.96 (m, 1H), 8.14 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 13.67 (s, 1H), ESIMS found for C25H31N50 m/z 418 (M+H). [0519[ N-(Benzo[d][1,3]dioxol-5 -yl)-5 -(5 -(pipeIidinylmethyl)pyIidin-3 -yl)- 1H-indazolecarboxamide 78. [0520[ White solid (48.6 mg, 0.11 mmol, 22.1% yield). 1H NMR (DMSO-dg) 5 ppm 1.37-1.43 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.36-2.42 (m, 4H), 3.56 (s, 2H), 6.01 (s, 2H), 6.90 (d, J=9Hz, 1H), 7.37 (dd, J=9Hz, J=2Hz, 1H), 7.57 (d, J=2Hz, 1H), 7.91 (dd, J=9Hz, J=Hz, 1H), 7.82 (dd, J=9Hz, J=1Hz, 1H), 7.99 (t, J=2Hz, 1H), 8.47 (dd, , J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.34 (s, 1H), 13.89 (s, 1H), ESIMS found for C26H25N503 m/z 456.0 (M+H). [0521[ N—(2,3-Dihydrobenzo[b][1,4]di0Xinyl)(5-(pipe1idinylmethyl) pyn'din-3 -yl)-1H-indazole-3 xamide 79. [0522[ White solid (98.4 mg, 0.21 mmol, 38.7% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.42 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.34-2.41 (m, 4H), 3.56 (s, 2H), 4.20-4.27 (m, 4H), 6.82 (d,J=9Hz, 1H), 7.35 (dd, J=9Hz, J=3Hz, 1H), 7.51 (d, J=3Hz, 1H), 7.78 (dd, J=9Hz, J=1Hz, 1H), 7.81 (dd, J=9Hz, J=1Hz, 1H), 7.98 (t, J=2Hz, 1H), 8.47 (dd, J=12Hz,J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.26 (s, 1H), 13.87 (hrs, 1H), ESIMS found for C27H27N503 m/z 470.4 (M+H). [0523[ N—(5 -Benzylpy1idin-3 -yl)-5 -(5 -(pipe1idinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 80. [0524[ White solid (81.9 mg, 0.16 mmol, 59% yield). 1H NMR (DMSO-ds) 5 ppm 1.39-1.41 (m, 2H), .53 (m, 4H), 2.37-2.39 (m, 4H), 3.56 (s, 2H), 4.00 (s, 2H), 7.20-7.23 (m, 1H), 7.28-7.34 (m, 4H), 7.79-7.84 (m, 2H), 7.98-7.99 (m, 1H), 8.23-8.24 (m, 1H), 8.25 (d, J=2Hz, 1H), .46 (m, 1H), 8.49 (d,J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 8.89 (d, J=2Hz, 1H), .65 (s, 1H), 13.97 (s, 1H), ESIMS found for C31H30N60 m/z 503 (M+H). [0525[ 5 -(5 -(Pipe1idin- l -ylmethyl)pyridin-3 -yl)-N-(pyrazinyl)- lH-indazole- 3-carboxamide 81. [0526[ White solid (104 mg, 0.25 mmol, 41.7% yield). 1H NMR (DMSO-ds) 5 ppm 1.35-1.42 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.33-2.42 (m, 4H), 3.57 (s, 2H), 7.83 (d, J=9Hz, 1H), 7.85 (d, J=9Hz, 1H), 8.00 (s, 1H), 8.45 (d, J=2Hz, 1H), 8.46 (s, 1H), 8.50 (s, 1H), 8.83 (d, J=2Hz, 1H), 9.50 (s, 1H), 10.36 (s, 1H), 14.11 (brs, 1H), ESIMS found for C23H23N7O m/z 413.9 (M+H). [0527 [ N—Phenyl-5 -(5 -(pipe1idin-l-ylmethyl)py1idin-3 -yl)- lH-indazole-3 - carboxamide 82. [0528[ White solid (97.8 mg, 0.24 mmol, 81% . 1H NMR (DMSO-ds) 5 ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.37-2.39 (m, 4H), 3.57 (s, 2H), 7.09-7.12 (m, 1H), 7.34- 7.37 (m, 2H), 7.80 (d, J=9Hz, 1H), 7.83 (dd, J=9Hz, 2Hz, 1H), 7.907.92 (m, 2H), 7.99-8.00 (m, 1H), 8.47-8.48 (m, 1H), 8.49 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.40 (s, 1H), 13.92 (s, 1H), ESIMS found for C25H25N50 m/z 412 (M+H). [0529[ (4-Methylpiperazin- l -yl)(5 -(5 -(pipe1idin-l-ylmethyl)py1idin-3 -yl)- lH- indazol-3 -yl)methanone 83. [0530[ Light yellow ous solid (74.6 mg, 0.18 mmol, 93% yield). 1H NMR (DMSO-dg) 5 ppm 1.38-1.39 (m, 2H), 1.48-1.53 (m, 4H), 2.22 (s, 3H), 2.36-2.41 (m, 8H), 3.55 (s, 2H), .73 (m, 2H), .02 (m, 2H), 7.73 (d, J=9Hz, 1H), 7.79 (dd, J=9Hz, J=2Hz, 1H), 7.95-7.96 (m, 1H), 8.22 (d, J=1Hz, 1H), 8.46 (d, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 13.64 (s, 1H), ESIMS found for C24H30N60 m/z 419 (M+H). [0531[ 5-(5-(((2R,6S)-2,6-Dimethylpipe1idinyl)methyl)py1idinyl)-N- (pyridinyl)-1H-indazolecarboxamide 84. [0532[ Beige solid (76.5 mg, 0.17 mmol, 75.5% yield). 1H NMR (DMSO-ds) 5 ppm 1.00 (d, J=6Hz, 6H), .35 (m, 3H), 1.55 (d, J=11Hz, 2H), 1.60-1.65 (m, 1H), 2.45- 2.53 (m, 2H), 3.84 (s, 1H), 7.40 (dd, J=7Hz, 3Hz, 1H), 7.79 (dd, J=9Hz, J=2Hz, 1H), 7.83 (dd, J=9Hz, J=1Hz, 1H), 8.04 (s, 1H), 8.29-8.35 (m, 2H), 8.46 (s, 1H), 8.60 (d, J=2Hz, 1H), 8.73 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.70 (s, 1H), 14.00 (hrs, 1H), ESIMS found for C26H28N60 m/z 441.3 (M+H). [0533[ (Dimethylamino)methyl)py1idin-3 -yl)-5 -(5 -(pipe1idin ylmethyl)py1idinyl)-1H-indazolecarboxamide 86. [0534[ White solid (41.5 mg, 0.09 mmol, 72% yield). 1H NMR (DMSO-ds) 5 ppm 1.39-1.40 (m, 2H), 1.49-1.54 (m, 4H), 2.19 (s, 6H), 2.36-2.39 (m, 4H), 3.44 (s, 2H), 3.58 (s, 2H), 7.81 (d, J=9Hz, 1H), 7.85 (dd, J=9Hz, J=2Hz, 1H), 8.00-8.01 (m, 1H), 8.21 (d, J=2Hz, 1H), 8.37-8.38 (m, 1H), 8.49-8.50 (m, 2H), 8.83 (d, J=2Hz, 1H), 8.91 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.01 (hrs, 1H), ESIMS found for C27H31N7O m/z 470 (M+H). [0535[ N-(1-Methylpipe1idinyl)-5 -(5 -(piperidinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 87. [0536[ White ous solid (18.2 mg, 0.04 mmol, 59.8% . 1H NMR (DMSO-dg) 5 ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 1.66-1.75 (m, 4H), 1.95-2.00 (m, 2H), 2.18 (s, 3H), 2.37-2.38 (m, 4H), 2.77 (d, J=11Hz, 2H), 3.55 (s, 2H), 3.81-3.83 (m, 1H), 7.73- 7.75 (m, 1H), 7.77-7.79 (m, 1H), 7.95-7.96 (m, 1H), 8.25 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 13.70 (s, 1H); ESIMS found for C25H32N60 m/z 433 (M+H). [0537[ N-(5-((Dimethylamino)methyl)py1idinyl)(5-(pyrrolidin ylmethyl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 106. [0538[ White solid (39.4 mg, 0.09 mmol, 74% yield). 1H NMR (DMSO-ds) 5 ppm 1.71-1.73 (m, 4H), 2.49-2.50 (m, 4H), 2.18 (s, 6H), 3.43 (s, 2H), 3.71 (s, 2H), 7.81 (d, J=9Hz, 1H), 7.84 (ABq, J=9Hz, 1H), 8.02-8.03 (m, 1H), 8.21 (d, J=2Hz, 1H), .38 (m, 1H), 8.48- 8.49 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.83 (d, J=2Hz, 1H), 8.91 (d, J=2Hz, 1H), 10.68 (s, 1H), 13.98 (s, 1H); ESIMS found for C26H29N7O m/z 456 (M+H). [0539[ N-(5-((4-Methylpiperazinyl)methyl)py1idinyl)(5-(pipe1idin ylmethyl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 124. [0540[ N—(6-(Pipe1idinyl)py1idin-3 -yl)-5 -(5 -(pipe1idinylmethyl)py1idin-3 - yl)-1H-indazolecarboxamide 126. [0541[ Grey solid (92.7 mg, 0.19 mmol, 29.0% yield). 1H NMR (DMSO-ds) 5 ppm 1.48-1.64 (m, 12H), .43 (m, 4H), 3.48 (t, J=4.5Hz, 4H), 3.56 (s, 2H), 6.83 (d, J=9Hz, 1H), 7.80 (ABq, J=10Hz, 2H), 7.98 (s, 1H), 8.00 (d, J=2.4Hz, 1H), 8.47 (d, J=10Hz, 2H), 8.55 (d, J=2.5Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.27 (s, 1H), 13.86 (s, 1H), ESIMS found for C29H33N7O m/z 496.5 (M+H). [0542[ N—(3 -Fluorophenyl)-5 -(5 ridinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 162. [0543[ White solid (176 mg, 0.41 mmol, 56.8% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.47-1,55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 6.93 (dt, J=9Hz, J=3Hz, 1H), 7.39 (q, J=8Hz, 1H), 7.75 (dd, J=8Hz, J=1Hz, 1H), 7.82 (d/Abq, J=9Hz, J=1Hz, 2H), 7.89 (td, J=12Hz, J=2Hz, 1H), 7.99 (t, J=2Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 10.66 (s, 1H), 13.97 (hrs, 1H), ESIMS found for C25H24FN50 m/z 430.0 (M+H). [0544[ 5 -(5 -(Pipe1idinylmethyl)pyridin-3 -yl)-N-(tetrahydro-2H-pyranyl)- 1H-indazolecarboxamide 163. [0545[ Tan amorphous solid (88 mg, 0.21 mmol, 88% yield). 1H NMR (DMSO- d6) 5 ppm 1.39-1.40 (m, 2H), .53 (m, 4H), 1.69-1.76 (m, 4H), 2.37-2.38 (m, 4H), 3.39- 3.42 (m, 2H), 3.56 (s, 2H), 3.88-3.90 (m, 2H), 4.05-4.10 (m, 1H), 7.74 (d, J=9Hz, 1H), 7.77- 7.79 (m, 1H), 7.95-7.96 (m, 1H), 8.37 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 13.72 (s, 1H), ESIMS found for C24H29N502 m/z 420 (M+H). [0546[ N—(5 -Fluoropy1idin-3 -yl)-5 -(5 -(pipe1idinylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 168. [0547[ White solid (286 mg, 0.66 mmol, 56% yield). 1H NMR (DMSO-ds) 5 ppm 1.39 (m, 2H), 1.49-1.53 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.81-7.86 (m, 2H), 7.99 (s, 1H), .34 (m, 2H), 8.47 (s, 1H), 8.49 (d, J=1.3 Hz, 1H), 8.82 (d, z, 1H), 8.99 (s, 1H), .97 (s, 1H), 14.07 (hrs, 1H), ESIMS found for C24H23FN60 m/z 431.4 (M+H). [0548[ N—(6-(4-Hydroxypiperidinyl)pyridin-3 -yl)-5 -(5 -(pipe1idin yl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 169. [0549[ Off-white solid (33 mg, 0.06 mmol, 53.8% yield). 1H NMR (DMSO-ds) 5 ppm 1.32-1.43 (m, 4H), 1.45-1.57 (m, 4H), 1.74-1.83 (m, 2H), 2.33-2.44 (m, 4H), 3.04 (t, J=10Hz, 2H), 3.56 (s, 2H), 3.63-3.73 (m, 1H), 3.93-4.02 (m, 2H), 4.72 (s, 1H), 6.85 (d, J=9Hz, 1H), 7.80 (ABq, J=10Hz, 2H), 7.99 (d, J=7Hz, 2H), 8.47 (d, J=10Hz, 2H), 8.54 (s, 1H), 8.81 (s, 1H), 10.28 (s, 1H), 13.87 (s, 1H), ESIMS found for C29H33N702 m/z 512.3 (M+H).

WO 75858 [0550[ 5 -(5 -((4-Hydroxypipeiidinyl)methyl)py1idin-3 -yl)-N-(6-(pyrrolidin yl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 170. [0551[ Off-white solid (125.4 mg, 0.25 mmol, 73.2% yield). 1H NMR (DMSO- d6) 5 ppm 1.93-1.96 (m, 4H), 2.09-2.12 (m, 2H), .72 (m, 2H), 3.37-3.39 (m, 4H), 3.46- 3.47 (m, 1H), 3.58 (s, 1H), 4.52 (d, J=4Hz, 1H), 6.46 d, J=9Hz, 1H), 7.77-7.82 (m, 2H), 7.95- 7.98 (m, 2H), 8.44-8.48 (m, 2H), 8.49 (d, J=2.5Hz, 1H), 8.80 (d, J=2.1Hz, 1H), 10.20 (s, 1H), 13.85 (s, 1H); ESIMS found for C28H31N702 m/z 498 (M+H). [0552[ N-(5-Methyl(pyrrolidinyl)py1idinyl)(5-(pipeIidin ylmethyl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 172. [0553[ Off-white solid (186 mg, 0.38 mmol, 72.2% yield). 1H NMR (DMSO-dg) ppm 1.34-1.43 (m, 2H), 1.47-1.55 (m, 4H), 1.82-1.89 (m, 4H), 2.30 s, 3H), .42 (m, 4H), 3.43 (t, J=6.6Hz, 4H), 3.56 (s, 2H), 7.81 (ABq, J=10Hz, 2H), 7.89 (d, J=2Hz, 1H), 7.98 (s, 1H), 8.38 (d, J=2Hz, 1H), 8.47 (d, J=8Hz, 2H), 8.81 (d, J=2Hz, 1H), 10.24 (s, 1H), 13.86 (s, 1H); ESIMS found for C29H33N7O m/z 496.4 (M+H). [0554[ N—(6-(Azetidinyl)methylpy1idinyl)(5-(pipe1idin ylmethyl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 173. [0555[ ite solid (184 mg, 0.38 mmol, 62.6% yield). 1H NMR (DMSO-dg) ppm 1.35-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.16 (s, 3H), 2.22 (quin, J=7Hz, 2H), 2.34-2.42 (m, 4H), 3.56 (s, 2H), 4.00 (t, J=7Hz, 4H), 7.81 (ABq, J=10Hz, 2H), 7.85 (d, J=2Hz, 1H), 8.39 (d,J=2Hz, 1H), 8.47 (d,J=10Hz, 2H), 8.81 (d,J=2Hz, 1H), 10.24 (s, 1H), 13.87 (s, 1H), ESIMS found for C28H31N7O m/z 482.0 (M+H). [0556[ N—(6-(Azetidinyl)pyridin-3 -yl)-5 -(5 -(piperidinylmethyl)py1idin-3 - -indazolecarboxamide 174. [0557[ White solid (14.9 mg, 0.03 mmol, 11.0% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.32 (quin, J=7Hz, 2H), 2.35-2.42 (m, 4H), 3.56 (s, 2H), 3.92 (t, J=7Hz, 4H), 6.39 (d, J=9Hz, 1H), 7.77-7.83 (m, 2H), 7.98 (dd, J=9Hz, J=2Hz, 2H), 8.42-8.53 (m, 3H), 8.78-8.84 (m, 1H), 10.27 (s, 1H), 13.87 (s, 1H); ESIMS found for C27H29N7O m/z 468.0 (M+H). [0558[ N-(6-Methoxypyridin-3 -yl)-5 -(5 1idinylmethyl)pyridin-3 H- indazolecarboxamide 175. [0559[ White solid (31.2 mg, 0.07 mmol, 25.8% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.47-1.55 (m, 4H), 2.33-2.42 (m, 4H), 3.56 (s, 2H), 3.85 (s, 3H), 6.84 (d, J=9Hz, 1H), 7.81 (ABq, J=12Hz, 2H), 7.98 (s, 1H), 8.18 (dd, J=9Hz, J=2.7Hz, 1H), 8.47 (dd, J=10Hz, J=1Hz, 2H), 8.65 (d, J=2.6Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.50 (s, 1H), 13.91 (hrs, 1H), ESIMS found for C25H26N602 m/z 443.4 (M+H). [0560[ N—(2-Aminopyiimidin-5 -yl)-5 -(5 -(pipe1idinylmethyl)pyridin-3 -yl) - 1H-indazolecarboxamide 176. [0561[ Yellow solid (412 mg, 0.96 mmol, 52.5% . 1H NMR dG) 5 ppm 1.37-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.35-2.41 (m, 4H), 3.56 (s, 2H), 6.49 (s, 2H), 7.81 (ABq, J=10Hz, 2H), 7.98 (s, 1H), 8.47 (dd, , J=2Hz, 2H), 8.63 (s, 1H), 8.81 (d, J=2Hz, 1H), 10.32 (s, 1H), 13.91 (s, 1H), ESIMS found for C23H24N80 m/Z 429.3 (M+H). [0562[ N-(6-(Piperazinyl)py1idin-3 -yl)-5 -(5 -(pipe1idin- 1-ylmethyl)py1idin-3 - yl)-1H-indazolecarboxamide 177. [0563[ Tan solid (160 mg, 0.32 mmol, 28.5% yield). 1H NMR (DMSO-dg) 5 ppm 1.37-1.43 (m, 2H), 1.48-1.54 (m, 4H), 2.34-2.41 (m, 4H), 2.79 (t, J=5Hz, 4H), 3.36 (t, J=5Hz, 4H), 3.56 (s, 2H), 6.82 (d, J=9Hz, 1H), 7.81 (ABq, J=10Hz, 2H), 7.98 (s, 1H), 8.02 (dd, J=9Hz, J=2.7Hz, 1H), 8.47 (dd, J=9Hz, J=2Hz, 2H), 8.57 (d, J=2.5Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.29 (s, 1H), ESIMS found for C28H32N80 m/z 497.1 (M+H). [0564[ N-(6-Hydroxypyiidin-3 -yl)-5 -(5 -(pipe1idin- 1-ylmethyl)py1idin-3 -yl)-1H- indazolecarboxamide 178. [0565[ Off-white solid (78.3 mg, 0.18 mmol, 52.4% . 1H NMR (DMSO-dg) ppm 1.36-1.43 (m, 2H), 1.48-1.54 (m, 4H), .42 (m, 4H), 3.56 (s, 2H), 6.38 (d, J=10Hz, 1H), 7.80 (ABq, J=11Hz, 2H), 7.83 (dd, J=10Hz, J=3Hz, 1H), 7.97 (s, 1H), 8.04 (d, z, 1H), 8.44 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 10.27 (s, 1H), 11.42 (hrs, 1H), 13.87 (hrs, 1H), ESIMS found for C24H24N602 m/z 429.1 (M+H). [0566[ 5-(5-(Pipe1idinylmethyl)pyridinyl)-N-(6-(pyrrolidine carbonyl)py1idinyl)-1H-indazolecarboxamide 179. [0567[ Light yellow solid (61 mg, 0.12 mmol, 37.8% yield). 1H NMR (DMSO- d6) 5 ppm 1.37-1.43 (m, 2H), 1.48-1.55 (m, 4H), 1.82-1.90 (m, 4H), 2.38 (brs, 4H), 3.17 (d, J=5Hz, 2H), 3.51 (t, J=7Hz, 2H), 3.57 (s, 2H), 3.70 (t, J=7Hz, 2H), 7.79 (d, J=9Hz, 1H), 7.84 (Abq, J=11Hz, 2H), 8.00 (s, 1H), 8.46 (dd, J=9Hz, J=2.5Hz, 1H), 8.48 (dd, J=9Hz, J=2Hz, 2H), 8.82 (d, J=2Hz, 1H), 9.10 (d, J=2Hz, 1H), 10.91 (s, 1H), 14.05 (hrs, 1H), ESIMS found for C29H31N702 m/z 510.6 (M+H). [0568[ N-(6-(Cyclopentylcarbamoyl)py1idinyl)(py1idinyl)-1H-indazole- 3-carboxamide 181. [0569[ Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). 1H NMR (DMSO- d6) 5 ppm 1.50-1.64 (m, 4H), 1.67-1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin, J=8Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8Hz, 1H), 8.45 (d, J=8Hz, 1H), 8.48 (s, 1H), 8.54 (dd, J=9Hz, J=2,5Hz, 1H), 8.60 (d, J=4Hz, 1H), 8.94 (d, J=2Hz, 1H), 9.16 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.08 (hrs, 1H), ESIMS found for C24H22N602 m/z 427.1 (M+H). [0570[ 5 -(5 -Aminopy1idin-3 -yl)-N-(6-(pipeiidinyl)py1idin-3 H-indazole- 3-carboxamide 182. [0571[ Off-white solid (23.4 mg, 0.06 mmol, 19.4% yield). 1H NMR (DMSO-dg) ppm 1.51-1.63 (m, 6H), 3.47 (t, J=5Hz, 4H), 5.45 (s, 2H), 6.83 (d, J=10Hz, 1H), 7.24 (t, J=2Hz, 1H), 7.73 (dq, J=9Hz, J=2Hz, 2H), 7.94 (d, J=2.5Hz, 1H), 8.00 (dd, J=9Hz, J=2.5Hz, 1H), 8.08 (d, J=2Hz, 1H), 8.40 (s, 1H), 8.56 (d, J=2.5Hz, 1H), 10.27 (s, 1H), 13.84 (s, 1H), ESIMS found for C23H23N7O m/z 414.3 (M+H). [0572[ 5 -(5 -((3 ,3 -Difluoropyrrolidinyl)methyl)py1idin-3 -yl)-N-(6-(pyrrolidin- 1-yl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 183. [0573[ Off-white solid (307 mg, 0.61 mmol, 39.6% . 1H NMR dg) ppm 1.95 (t, J=6.5Hz, 4H), 2.28 (tt, J=13.5Hz, J=7Hz, 2H), 2.76 (t, J=7Hz, 2H), 2.94 (t, J=13.5Hz, 2H), 3.38 (t, J=6.5Hz, 4H), 3.77 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.81 (dq, J=8.5Hz, J=1.5Hz, 2H), 7.97 (dd, J=9Hz, J=2.5Hz, 1H), 8.03 (s, 1H), 8.48 (s, 1H), 8.49 (d, J=2.5Hz, 1H), 8.52 (s, 1H), 8.84 (d, J=2Hz, 1H), 10.23 (s, 1H), 13.87 (s, 1H), ESIMS found for C27H27F2N7O m/z 504.0 (M+H). [0574[ N—(6-(Cyclopentylcarbamoyl)py1idin-3 -yl)-5 -(5 -(pipe1idin yl)py1idin-3 -yl)-1H-indazole-3 -carboxamide 184. [0575[ White solid (3.2 mg, 0.01 mmol, 18.5% yield). 1HNMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.43-1.64 (m, 8H), 1.64-1.76 (m, 2H), 1.82-1.93 (m, 2H), 2.38 (brs, 4H), 3.57 (s, 2H), 4.24 (quin, J=7Hz, 1H), 7.84 (ABq, , 2H), 8.00 (s, 1H), 8.03 (d, J=9Hz, 1H), 8.44 (d, J=8Hz, 1H), 8.48 (dd, J=8Hz, J=2Hz, 2H), 8.55 (dd, J=9Hz, J=2.5Hz, 1H), 8.82 (d, J=2.5Hz, 1H), 9.16 (d, J=2.5Hz, 1H), 10.98 (s, 1H), 14.06 (hrs, 1H), ESIMS found for C30H33N702 m/z 524.5 (M+H). [0576[ N-(6-(Methylsulfonyl)py1idin-3 -yl)-5 -(5-(pipe1idinylmethyl) pyIidin- 3-yl)-1H-indazolecarboxamide 185. [0577[ White solid (72 mg, 0.15 mmol, 56.4% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.27 (s, 3H), 3.57 (s, 2H), 7.85 (s, 2H), 8.00 (s, 1H), 8.08 (d, J=8.5Hz, 1H), 8.49 (dd, J=10Hz, J=1.5Hz, 2H), 8.83 (d, J=2.5Hz, 1H), 9.26 (d, J=2.5Hz, 1H), 11.19 (s, 1H), 14.13 (hrs, 1H), ESIMS found for C25H26N603S m/z 491.1 (M+H). if) p" [0578[ 5 -(5 -(4-Methylpiperazinyl)pyridin-3 -yl)-N-(6-(pyrrolidin idin-3 -yl)-1H-indazole-3 -carboxamide 186. [0579[ Off-white solid (196 mg, 0.41 mmol, 47.8% yield). 1H NMR (DMSO-dg) ppm 1.89-1.98 (m, 4H), 2.27 (brs, 3H), 3.25-3.42 (m, 12H), 6.45 (d, J=9Hz, 1H), 7.53 (s, 1H), 7.77 (q, J=8.5Hz, 2H), 7.96 (d, J=6.5Hz, 1H), 8.31 (d,J=5.5Hz, 2H), 8.43 (s, 1H), 8.48 (s, 1H), .21 (s, 1H), 13.83 (s, 1H), ESIMS found for C27H30N80 m/z 483.4 (M+H). [0580[ 5-(5-Morpholinopy1idinyl)-N-(6-(pyrrolidinyl)py1idinyl)-1H- lecarboxamide 187. [0581[ White solid (92 mg, 0.20 mmol, 43.5% yield). 1H NMR (DMSO-ds) 5 ppm 1.94 (t, J=6.5 Hz, 4H), 3.28 (t, J=4.5Hz, 4H), 3.38 (t, J=6.5Hz, 4H), 3.78 (t, J=4.5Hz, 4H), 6.45 (d, J=9Hz, 1H), 7.55 (s, 1H), 7.77 (dq, J=8.5Hz, J=1.5Hz, 2H), 7.96 (dd, J=9Hz, J=2.5Hz 1H), 8.33 (dd, J=6.5Hz, J=3Hz, 2H), 8.44 (s, 1H), 8.49 (d, J=2.5Hz, 1H), 10.21 (s, 1H), 13.83 (s, 1H); ESIMS found for C26H27N702 m/z 470.5 (M+H). [0582[ 5-(5-((3,3-Difluoropyrrolidinyl)methyl)py1idinyl)-N-(py1idinyl)- 1H-indazolecarboxamide 188. [0583[ White solid (209 mg, 0.48 mmol, 56.6% yield). 1H NMR dg) 5 ppm 2.23-2.32 (m, 2H), 2.76 (t, J=7Hz, 2H), 2.94 (t, J=13.5Hz, 2H), 3.77 (s, 2H), 7.40 (q, J=8Hz, 1H), 7.83 (dq, J=8Hz, J=2Hz, 2H), 8.04 (s, 1H), 8.31-8.34 (m, 2H), 8.49 (s, 1H), 8.53 (d, J=2Hz, 1H), 8.85 (d, J=2.5Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.01 (hrs, 1H); ESIMS found for C23H20F2N60 m/z 435.2 (M+H). [0584[ N-(Pyridinyl)(5-(pyrrolidinyl)py1idinyl)-1H-indazole carboxamide 189. [0585[ White solid (30 mg, 0.08 mmol, 26.0% yield). 1H NMR (DMSO-ds) 5 ppm 1.91-2.05 (m, 4H), 3.33-3.39 (m, 4H), 7.09 (s, 1H), 7.40 (q, J=8Hz, 1H), 7.79 (s, 2H), 7.96 (d, J=2.5Hz, 1H), 8.14 (s, 1H), 8.30-8.34 (m, 2H), 8.44 (s, 1H), 9.07 (d,J=2Hz, 1H), 10.68 (s, 1H), 13.97 (brs, 1H), ESIMS found for C22H20N6O m/z 385.2 (M+H).

J. / \N [0586[ 5 -(5 -((Dimethylamino)methyl)pyiidin-3 -yl)-N-(6-(pyrrolidin yl)pyIidin-3 -yl)-1H-indazole-3 -carboxamide 190. [0587[ White solid (142 mg, 0.32 mmol, 39.7% yield). 1H NMR (DMSO-dg) 5 ppm 1.92-1.97 (m, 4H), 2.20 (s, 6H), 3.35-3.40 (m, 4H), 3.53 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.80 (dq, J=9Hz, J=1.5Hz, 2H), 7.97 (dd, J=9Hz, J=3Hz, 1H), 8.00 (s, 1H), 8.46-8.50 (m, 3H), 8.82 (d, J=2.5Hz, 1H), 10.22 (s, 1H), 13.86 (brs, 1H), ESIMS found for C25H27N7O m/z 442.4 (M+H). [0588[ Preparation of 2-fluorophenoxy)pyridin-3 -yl)-5 -(pyIidin-3 -yl)-1H- indazolecarboxamide (18) is depicted below in Scheme 32.

CXXXI \ \°"' / / cone U l cone l cozH Br N/ N \ N\ \N \N NaOH, H20 \N N/ Pd(PPh3)4, K3P04 N’ 9000, 111 N’ H20, DMF, we 0 o o CXVH CXXXIX CXL HATU, DIPEA DMF, rt, overnight F Q. 0 Q" 0 @~ / NH / NH/ 1 I N \ N \ \ TFA, DCM, u’ ‘— , Egsm, rt, 3 h N 18 o Scheme 32 [0589[ To a solution of methyl 5-bromo(tetrahydro-2H-pyranyl)-1H- indazolecarboxylate (CXVII) (7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K3PO4 (6.56 g, 30.9 mmol), pyridinylboronic acid (CXXXI) (2.79 g, 22.7 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and. The solution was purged with argon and heated at 90°C for 3 h. The on was cooled to room temperature and then concentrated under d pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The residue was d on a silica gel column (100% DCM —> 15985 MeOHzDCM) to give methyl 5-(pyridinyl)(tetrahydro-2H-pyranyl)- 1H-indazolecarboxylate (CXXXIX) as an orange oil which solidified at rt (6.28 g, 18.6 mmol, 90% yield). ESIMS found for N303 m/z 338.0 (M+H).

Sfip_2 [0590[ Preparation of intermediate 5-(pyridin-3 -yl)(tetrahydro-2H-pyran yl)-1H-indazolecarboxylic acid (CXL) was performed following the procedure listed in Scheme 25, Step 4. White solid (900 mg, 2.78 mmol, 15% yield). ESIMS found for C18H17N303 m/Z 324.1 (M+H). [0591[ Preparation of intermediate N-(6-(2-fluorophenoxy)pyridinyl) (pyridin-3 -yl)(tetrahydro-2H-pyranyl)-1H-indazole-3 -carboxamide (CXLI) was performed following the procedure listed in Scheme 28, Step 3. Off-white solid (207 mg, 0.41 mmol, 66% yield). 1H NMR (DMSO-dg) 5 ppm 1.60-1.69 (m, 2H), 1.76-1.87 (m, 1H), 2.03- 2.13 (m, 2H), 2.56-2.65 (m, 1H), 3.84 (dt, , J=4Hz, 1H), 3.99 (t, J=11Hz, 1H), 6.07 (dd, J=10Hz, J=2Hz, 1H), 6.98 (dd, J=3Hz, J=2Hz, 1H), 7.03-7.08 (m, 2H), 7.14 (d, J=9Hz, 1H), 7.46 (t, J=7Hz, 1H), 7.61 (dd, J=8Hz, J=5Hz, 1H), 7.91 (dd, J=9Hz, J=2Hz, 1H), 8.05 (d, J=9Hz, 1H), 8.25 (d, J=8Hz, 1H), 8.37 (dd, J=3Hz, 1H), 8.49 (s, 1H), 8.64 (dd, J=5Hz, J=2Hz, 1H), 8.66 (d, J=3Hz, 1H), 9.00 (d, J=2Hz, 1H), 10.59 (s, 1H), ESIMS found for C29H24FN503 m/z 509.2 (M+H).

S£p_4 [0592[ Preparation of N—(6-(2-fluorophenoxy)pyridinyl)(pyridinyl)-1H- indazolecarboxamide (18) was performed following the procedure listed in Scheme 28, Step 4. White solid (128 mg, 0.30 mmol, 54.7% yield). 1H NMR (DMSO-dg) 5 ppm 7.16 (d, J=9Hz, 1H), 7.23-7.39 (m, 4H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.79-7.85 (m, 2H), 8.13 (td, J=8Hz, J=2Hz, 1H), 8.38 (dd, J=9Hz, J=3Hz, 1H), 8.46 (s, 1H), 8.56 (d, J=3Hz, 1H), 8.59 (dd, J=5Hz, J=1Hz, 1H), 8.93 (d, J=2Hz, 1H), 10.65 (s, 1H), 13.96 (brs, 1H), ESIMS found for C24H16FN502 m/z 426.0 (M+H). [0593[ The ing compounds were prepared in accordance with the procedure described in the above Example 6. [0594[ N-(6-(3-Fluorophenoxy)pyridinyl)(pyridinyl)-1H-indazole carboxamide 19. [0595[ ite solid (148 mg, 0.35 mmol, 89.3% yield). 1H NMR (DMSO-dg) ppm 6.98 (dd, J=8Hz, J=2Hz, 1H), 7.01-7.06 (m, 2H), 7.13 (d, J=9Hz, 1H), 7.44 (q, J=7Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.80-7.85 (m, 2H), 8.14 (td, J=6Hz, J=2Hz, 1H), 8.40 (dd, J=9Hz, J=3Hz, 1H), 8.47 (s, 1H), 8.60 (dd, J=5Hz, J=1Hz, 1H), 8.69 (d, J=3Hz, 1H), 8.93 (d, J=2Hz, 1H), 10.71 (s, 1H), 13.99 (s, 1H), ESIMS found for C24H16FN502 m/z 426.0 (M+H). [0596[ 4-Fluorophenoxy)pyridinyl)(pyridinyl)-1H-indazole carboxamide 20. [0597[ White solid (82 mg, 0.19 mmol, 91.8% . 1H NMR (DMSO-ds) 5 ppm 7.08 (d, J=9Hz, 1H), 7.15-7.21 (m, 2H), 7.22-7.27 (m, 2H), 7.67 (dd, J=8Hz, J=5Hz, 1H), 7.81- 7.88 (m, 2H), 8.31 (d, J=8Hz, 1H), 8.36 (dd, J=9Hz, J=3Hz, 1H), 8.51 (s, 1H), 8.63 (d, J=3Hz, 1H), 8.66 (dd, J=5Hz, J=1Hz, 1H), 9.02 (d, 2Hz, 1H), 10.67 (s, 1H), 14.00 (s, 1H), ESIMS found for C24H16FN502 m/z 426.0 (M+H).

Example 7 [0598[ Preparation of N—(6-carbamoylpyridinyl)-5 -(5-(piperidin ylmethyl)pyridinyl)-1H-indazolecarboxamide (180) is depicted below in Scheme 33.

H2504, HOAc 85"C, 20 min Scheme 33 [0599[ To a solution of N—(6-cyanopyridin-3 -yl)-5 -(5 -(piperidin ylmethyl)pyridinyl)-1H-indazolecarboxamide (62) (200 mg, 0.45 mmol) in glacial acetic acid (2 mL) heated at 85°C was carefiilly added dropwise sulfimc acid (2 mL). The reaction was heated at 85°C for r 20 minutes before pouring into ice. The solution was basified with cold 5N NH4OH. The solids formed were filtered, washed with cold washed and dried under vacuum. The dry solid was suspended in DCM and a few drops of MeOH were added.

The insoluble solids were filtered and discarded. The e was concentrated and suspended again in DCM, boiled for 15 minutes and filtered. The solid was dried under vacuum to give N—(6-carbamoylpyridinyl)(5-(piperidinylmethyl)pyridinyl)-1H-indazole carboxamide (180) as a white solid (192 mg, 0.42 mmol, 93.7% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.49 (s, 1H), 7.65 (d, J=9Hz, 1H), 7.80 (d, J=9Hz, 1H), 7.97 (s, 1H), 8.03 (s, 2H), 8.41 (s, 1H), 8.45 (d, J=2Hz, 1H), 8.54 (dd, J=9Hz, z, 1H), 8.80 (d, J=2Hz, 1H), 9.15 (d, J=2Hz, 1H), 10.83 (brs, 1H), ESIMS found for C25H25N702 m/z 456.4 (M+H).

Administration and Pharmaceutical Compositions [0600[ Some ments include administration of the compounds described herein as pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the indazolecarboxamide, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt, and (b) a pharmaceutically acceptable carrier. [0601[ In some embodiments, the methods bed herein fithher include administering the compounds of this invention in combination (administered together or sequentially) with other known agents. [0602[ Administration ofthe compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of stration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, eritoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber ion, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intraaurally , intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via ostomy tion, epidurally, intratympanically, intracistemally, intravascularly, entricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. Oral and parenteral administrations are customary in treating the tions. [0603[ Compounds of the invention intended for pharmaceutical use may be administered as lline or amorphous products. Pharmaceutically acceptable compositions may include solid, olid, liquid, solutions, dal, 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 e, 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 lled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or es), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. [0604[ The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. Pharmaceutically acceptable ents include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as ocopherol polyethylene glycol 1000 succinate, tants 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, l glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen ate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, hylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as (x-, [3, and y-cyclodextrin, or chemically modified derivatives such as yalkylcyclodextrins, including 2- and 3-hydroxypropyl-b- cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance ry of compounds of the formulae 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 r may be prepared. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 01-95%, in r embodiment 75-85%, in a fithher embodiment , 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 ofPharmacy, 21st Edition (Lippincott Williams & Wilkins. 2005). [0605[ In one red 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 the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like, a lubricant such as magnesium te 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 , marume, solution or sion (e. g. , in propylene ate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the two active ingredients are physically separated are also contemplated, e. g., capsules with granules (or tablets in a capsule) of each drug, two-layer tablets, two- tment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. [0606[ Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous se, 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 , pH buffering agents and the like (6. g. , sodium e, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). [0607 [ In some ments, the unit dosage ofcompounds ula (I) is 0.25 mg/Kg to 50 mg/Kg in humans. [0608[ In some embodiments, the unit dosage ofcompounds ofFormula (I) is 0.25 mg/Kg to 20 mg/Kg in humans. [0609[ In some embodiments, the unit dosage ofcompounds ofFormula (I) is 0.50 mg/Kg to 19 mg/Kg in humans. [0610[ In some embodiments, the unit dosage ofcompounds ofFormula (I) is 0.75 mg/Kg to 18 mg/Kg in humans. [0611[ In some ments, the unit dosage of nds of Formula (I) is 1.0 mg/Kg to 17 mg/Kg in humans. [0612[ In some embodiments, the unit dosage ofcompounds ula (I) is 1.25 mg/Kg to 16 mg/Kg in . [0613[ In some embodiments, the unit dosage ofcompounds ofFormula (I) is 1.50 mg/Kg to 15 mg/Kg in humans. [0614[ In some embodiments, the unit dosage ofcompounds ofFormula (I) is 1.75 mg/Kg to 14 mg/Kg in humans. [0615[ In some embodiments, the unit dosage of compounds of Formula (I) is 2.0 mg/Kg to 13 mg/Kg in humans. [0616[ In some embodiments, the unit dosage of compounds of Formula (I) is 3.0 mg/Kg to 12 mg/Kg in humans. [0617[ In some embodiments, the unit dosage of compounds of Formula (I) is 4.0 mg/Kg to 11 mg/Kg in humans. [0618[ In some embodiments, the unit dosage of compounds of Formula (I) is 5.0 mg/Kg to 10 mg/Kg in humans. [0619[ In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose. [0620[ In some embodiments, the itions are provided in unit dosage forms suitable for twice a day administration of a precise dose. [0621[ In some ments, the compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose. [0622[ 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 tage of active compound 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 subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the ition is a solid or suspension, which could be subsequently diluted to the above percentages. [0623[ In some ments, the injection can be an intra-tendon inj ection. [0624[ In some embodiments, the composition will se 01-10% of the active agent in solution. [0625[ In some embodiments, the composition will comprise 0. 1-5% ofthe active agent in solution. [0626[ In some embodiments, the composition will comprise 0. 1-4% ofthe active agent in solution. [0627[ In some embodiments, the composition will se 0.15-3% of the active agent in solution. [0628[ In some embodiments, the composition will comprise 0.2-2% ofthe active agent in solution. [0629[ In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous ll’lfilSlOI’l over a period of 1-96 hours. [0630[ In some embodiments, the compositions are ed in dosage forms suitable for continuous dosage by intravenous ll’lfilSlOI’l over a period of l-72 hours. [0631[ In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous ll’lfilSlOI’l over a period of 1-48 hours. [0632[ In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous SlOI’l over a period of 1-24 hours. [0633[ In some embodiments, the compositions are provided in dosage forms le for continuous dosage by intravenous ll’lfilSlOI’l over a period of l-12 hours. [0634[ In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous ll’lfilSlOI’l over a period of 1-6 hours. [0635[ In some embodiments, these compositions can be administered by intravenous ll’lfilSlOI’l to humans at doses of 5 mg/m2 to 300 mg/mz. [0636[ In some embodiments, these compositions can be administered by intravenous ll’lfilSlOI’l to humans at doses of 5 mg/m2 to 200 mg/mz. [0637[ In some embodiments, these compositions can be administered by enous ll’lfilSlOl’l to humans at doses of 5 mg/m2 to 100 mg/mz. [0638[ In some ments, these itions can be administered by intravenous ll’lfilSlOl’l to humans at doses of 10 mg/m2 to 50 mg/m2. [0639[ In some embodiments, these compositions can be administered by intravenous ll’lfilSlOl’l to humans at doses of 50 mg/m2 to 200 mg/mz. [0640[ In some embodiments, these compositions can be administered by intravenous ll’lfilSlOl’l to humans at doses of 75 mg/m2 to 175 mg/mz. [0641[ In some embodiments, these compositions can be administered by intravenous ll’lfilSlOl’l to humans at doses of 100 mg/m2 to 150 mg/mz. [0642[ In one preferred embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., h a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique. [0643[ 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 red. For nasal ry, a larger inhaled particle size is d to maximize ion 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 optimal delivery to the lung, inhaled namic particle sizes of equal or less than 10 um are USCfill, with an aerodynamic particle size of about 0.1 to 10 microns being preferred. 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 t which contain embedded drug nanoparticles. [0644[ In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either ic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or ons 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 s may use suitable pressurized d-dose inhalers (pMDIs). Dry powders may use dry powder r s (DPIs), which are e of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device. [0645[ In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by s methods. For example, a round window catheter (e.g., US. Pat. Nos. 6,440,102 and 6,648,873) can be used. [0646[ Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., US. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., US. Pat. No. 4,164,559). [0647[ If desired, formulations of the invention can be incorporated into a gel formulation (e.g., US. Pat. Nos. 4,474,752 and 6,911,211). [0648[ In some embodiments, compounds of a (I) disclosed herein intended for delivery to the ear can be stered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or h a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through al bone into the a. [0649[ 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 gacyclidine can be delivered from the oir of an external or internal implanted pumping system. [0650[ Formulations of the ion also can be administered to the ear by intratympanic ion into the middle ear, inner ear, or cochlea (e.g., US. Pat. No. 6,377,849 and Ser. No. 11/337,815). [0651[ Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the ic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered ly onto the round window membrane via transtympanic injection. In another ment, 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 bed herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae. [0652[ 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. In suppository forms of the compositions, a low- WO 75858 melting wax such as, but not limited to, a mixture of fatty acid ides, optionally in combination with cocoa butter is first melted. [0653[ Suppositories for rectal administration of the drug r as a solution, colloid, suspension or a complex) can be prepared by mixing the drug with a suitable non- ting 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 drug. Such materials include cocoa butter, inated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of hylene glycol. [0654[ In some embodiments, the compositions can be stered by transdermal patch. [0655[ Other modes of deliveries include using biodegradable or non- biodegradable scaffolds. [0656[ It is to be noted that concentrations and dosage values may also vary with the severity ofthe condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be ed 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. [0657[ Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, 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 drug 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. [0658[ Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, ike units, wafers, lyophilized matrix units, and the like. In a red embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly usefiil for their rapid disintegration, which also enables the rapid dissolution ofthe active compound. [0659[ On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. es of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid ition is a lyophilized powder. Such a dispersed lyophilized system ses 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 ing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound. [0660[ 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 the drug, so that the drug is located at the outer surface of the dual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more onal excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other ents used in ceutical coating compositions. [0661[ Also ed herein are kits. Typically, a kit includes one or more nds 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 above, and directions for use ofthe kit (e.g., instructions for treating a patient). In another embodiment, the kit can e 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 stered to a patient with one or more diseases or ions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease, and/or for promoting wound healing. [0662[ The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated, the selection of the appropriate dose is well within the dge of the skilled artisan.

Methods of Treatment [0663[ The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt y, 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. Non-limiting examples include one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease. In n embodiments, the compounds and compositions ed herein can be used for promoting wound healing. [0664[ In some embodiments, the methods r include administering to a patient in need of such treatment an ive amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent. [0665[ In some ments, the methods further include administering a pharmaceutical composition that includes a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and ally at least one other agent. [0666[ In some embodiments, the one or more diseases or conditions is a tendinopathy. In certain embodiments, the tendinopathy is tendinosis. In certain embodiments, the tendinopathy is tendinitis. In certain ments, the tendinopathy is tenosynovitis. [0667[ A tendon is a band of fibrous connective tissue that usually connects muscle to bone. Healthy tendons include el arrays oftype I collagen fibers closely packed er, but also include a small amount of elastin and of proteoglycans. Tendons can be slow to heal if injured, and sometimes do not regain their original th. Partial tears heal by the rapid production of disorganized II collagen, which is weaker than normal tendon.

Recurrence of injury in the d region of tendon is common. [0668[ Tendons which may be treated by the methods ofthe invention include any tendon of the human or mammalian body. Non-limiting examples of tendons include the patellar tendon, the anterior tibialis tendon, the Achilles , the hamstring tendon, the semitendinosus tendon, the gracilis tendon, the abductor tendon, the adductor tendon, the pinatus tendon, the infraspinatus tendon, the pularis tendon, the teres minor tendon, the flexor tendon, the rectus femoris tendon, the tibialis posterior tendon, and the quadriceps femoris tendon. [0669[ In some embodiments, the tendon is a tendon ofthe foot or ankle, e.g., the extensor hallucis longus, the flexor hallucis longus, the extensor digitorum longus, the or digitorum brevis, the peroneus longus, the peroneus brevis, the flexor hallucis brevis, the flexor digitorum longus, the posterior tibialis, the Achilles tendon, and the plantar fascia. [0670[ In some embodiments, the tendon is a tendon of the leg, e.g., the patellar tendon, the anterior tibialis tendon, the Achilles tendon, the hamstring tendon, the semitendinosus tendon, the gracilis tendon, the abductor , the adductor tendon, the flexor tendon, the rectus femoris tendon, the tibialis ior tendon, and the ceps femoris tendon. [0671[ In some embodiments, the tendon is a tendon of the er, e.g., the supraspinatus tendon, the pinatus tendon, the subscapularis tendon, and the teres minor tendon (rotator cuff complex). [0672[ In some embodiments, the tendon is a tendon ofthe elbow, e.g., the biceps tendon, the triceps tendon, the extensor carpi radialis brevis, the common extensor tendon, the extensor rum, the extensor digiti minimi, the extensor carpi ulnaris, the supinator, the common flexor tendon, the pronator teres, the flexor carpi radialis, the palmaris longus, the flexor carpi ulnaris and the digitorum superficialis. In some embodiments, the tendon is a tendon of the wrist. In some embodiments, the tendon of the wrist is selected from the group ting of biceps tendon, the triceps tendon, the extensor carpi radialis breVis, the common or , the extensor digitorum, the or digiti minimi, the extensor carpi ulnaris, the supinator, the common flexor tendon, the pronator teres, the flexor carpi radialis, the is longus, the flexor carpi ulnaris, the digitorum superficialis, the flexor pollicis breVis, the flexor pollicis longus, the abductor pollicis breVis, the abductor pollicis longus, the flexor digitorum profiindus, the flexor digitorum superficialis, the extensor pollicis breVis, and the extensor pollicis longus. In some embodiments, the tendon is a tendon of the hand. In some embodiments, the tendon ofthe hand is selected from the group consisting ofthe flexor pollicis breVis, the flexor pollicis longus, the abductor pollicis breVis, the abductor pollicis longus, the flexor digitorum profiJndus, the flexor digitorum superficialis, the extensor pollicis breVis, and the extensor is longus. [0673[ Non-limiting examples of tendinopathies include: claVicular or patellar tendinopathy, patellar tendonitis, medial tibial stress syndrome, Achilles tendinopathy, lateral epicondylitis or s elbow," medial epicondylitis or "golfer's elbow," plantar fasciitis, and r cuff tendinopathy. [0674[ In some embodiments, the tendinopathy is rotator cuff tendinopathy, e.g., supraspinatus tendinopathy, infraspinatus tendinopathy, subscapularis tendinopathy, and teres minor tendinopathy. [0675[ In some embodiments, the tendinopathy is lateral epicondylitis or "tennis elbow" at the extensor muscle group origin at the lateral humeral condyle insertion, principally in the extensor carpi radialis breVis (ECRB) tendon. In some embodiments, the tendinopathy is medial epicondylitis or r's elbow" at the interface between the or teres and flexor carpi radialis origin of the medial humeral condyle. [0676[ In some embodiments, the tendinopathy is ar tendinopathy. In some embodiments, the opathy is es opathy. In some embodiments, the tendinopathy is plantar fasciitis. In some embodiments, the opathy is medial plantar fasciitis. In some embodiments, the tendinopathy is lateral plantar fasciitis. [0677[ In some embodiments, the tendinopathy is tendinosis. In some embodiments, the tendinosis is selected from the group consisting of extensor hallucis longus tendinosis, flexor hallucis longus tendinosis, extensor digitorum longus tendinosis, extensor digitorum breVis tendinosis, peroneus longus tendinosis, us breVis tendinosis, flexor hallucis breVis osis, flexor digitorum longus tendinosis, posterior tibialis tendinosis, Achilles tendon tendinosis, and plantar fascia tendinosis. In some embodiments, the tendinosis is selected from the group consisting of patellar osis, the anterior tibialis tendinosis, the hamstring tendinosis, semitendinosus osis, gracilis tendinosis, abductor tendinosis, and adductor tendinosis. In some embodiments, the tendinosis is selected from the group consisting of flexor tendinosis, rectus femoris tendinosis, tibialis posterior tendinosis, and quadriceps femoris tendinosis. In some embodiments, the tendinosis is selected from the group ting of pinatus tendinosis, pinatus osis, subscapularis tendinosis, and teres minor tendinosis. [0678[ In some embodiments, the tendinosis is selected from the group ting of biceps tendinosis, triceps tendinosis, extensor carpi radialis breVis tendinosis, common extensor tendinosis, extensor digitorum tendinosis, extensor digiti minimi tendinosis, extensor carpi ulnaris tendinosis, supinator tendinosis, common flexor tendinosis, pronator teres osis, flexor carpi radialis tendinosis, palmaris longus tendinosis, flexor carpi ulnaris tendinosis and digitorum cialis tendinosis. In some ments, the tendinosis is selected from the group consisting of biceps tendinosis, triceps osis, extensor carpi radialis breVis tendinosis, common extensor tendinosis, extensor digitorum tendinosis, extensor digiti minimi tendinosis, extensor carpi ulnaris tendinosis, supinator tendinosis, common flexor tendinosis, pronator teres tendinosis, flexor carpi radialis tendinosis, palmaris longus tendinosis, flexor carpi ulnaris tendinosis, digitorum superficialis tendinosis, flexor pollicis breVis osis, flexor pollicis longus tendinosis, abductor pollicis breVis tendinosis, or pollicis longus tendinosis, flexor digitorum profiJndus tendinosis, flexor digitorum superficialis tendinosis, extensor pollicis breVis tendinosis, and extensor pollicis longus tendinosis. In some embodiments, the tendinosis is selected from the group consisting of flexor pollicis breVis osis, flexor is longus osis, abductor pollicis breVis tendinosis, abductor pollicis longus tendinosis, flexor rum profiJndus tendinosis, flexor digitorum superficialis tendinosis, extensor pollicis breVis tendinosis, and extensor pollicis longus tendinosis. [0679[ In some embodiments, the tendinopathy is tendinitis. In some embodiments, the itis is selected from the group ting of extensor hallucis longus tendinitis, flexor hallucis longus tendinitis, extensor digitorum longus tendinitis, extensor digitorum breVis tendinitis, peroneus longus tendinitis, peroneus breVis tendinitis, flexor hallucis breVis itis, flexor digitorum longus tendinitis, posterior tibialis tendinitis, Achilles tendon tendinitis, and plantar fascia tendinitis. In some embodiments, the tendinitis is selected from the group consisting of patellar tendinitis, the anterior tibialis tendinitis, the ing tendinitis, semitendinosus tendinitis, gracilis tendinitis, abductor itis, and adductor tendinitis. In some embodiments, the tendinitis is selected from the group consisting offlexor tendinitis, rectus femoris tendinitis, tibialis posterior tendinitis, and quadriceps femoris tendinitis. In some embodiments, the tendinitis is selected from the group consisting of supraspinatus tendinitis, infraspinatus tendinitis, pularis tendinitis, and teres minor tendinitis. [0680[ In some embodiments, the tendinitis is selected from the group consisting ofbiceps tendinitis, triceps tendinitis, extensor carpi radialis breVis tendinitis, common extensor tendinitis, extensor digitorum tendinitis, extensor digiti minimi itis, extensor carpi s tendinitis, supinator tendinitis, common flexor itis, pronator teres tendinitis, flexor carpi radialis tendinitis, palmaris longus itis, flexor carpi ulnaris tendinitis and rum superficialis tendinitis. In some embodiments, the tendinitis is selected from the group consisting of biceps tendinitis, triceps tendinitis, extensor carpi radialis brevis itis, common extensor tendinitis, extensor digitorum tendinitis, extensor digiti minimi tendinitis, extensor carpi ulnaris tendinitis, tor tendinitis, common flexor tendinitis, pronator teres tendinitis, flexor carpi radialis tendinitis, palmaris longus tendinitis, flexor carpi s tendinitis, digitorum superficialis tendinitis, flexor pollicis brevis tendinitis, flexor pollicis longus tendinitis, or pollicis brevis tendinitis, abductor pollicis longus tendinitis, flexor digitorum profiJndus tendinitis, flexor digitorum superficialis tendinitis, extensor pollicis brevis tendinitis, and extensor pollicis longus tendinitis. In some embodiments, the tendinitis is selected from the group consisting of flexor pollicis brevis tendinitis, flexor pollicis longus tendinitis, abductor pollicis brevis itis, abductor pollicis longus tendinitis, flexor digitorum profiJndus tendinitis, flexor digitorum superficialis tendinitis, extensor is brevis itis, calcific tendinitis, and extensor pollicis longus tendinitis. [0681[ In some embodiments, the tendinitis is caused by c overuse injuries oftendon failed healing. [0682[ In some embodiments, the injury or damage is localized very near the muscle-tendon junction (myotendinous junction). [0683[ In some embodiments, the tendinitis leads to scarring and fibrosis. [0684[ The methods of the invention may result in improvement in one or more of the following: decreasing pain of the affected joint or limb, decreasing stiffi1ess of the affected joint or limb, increasing mobility of the affected joint or limb, increasing th of the affected joint or limb, decreasing the rate of tendinopathy progression, decreasing inflammation, increasing the strength of the tendon, or improving the rate of tendon strength recovery. Various methods for ing effectiveness of the treatment include, but are not limited to: lities of the Arm, Shoulder and Hand Score (DASH), Visual Analog Score (VAS), and grip strength testing. [0685[ In some ments, the treatment results in increased strength of the tendon. In some ments, the treatment results in a more rapid rate of tendon strength recovery. In some embodiments, the treatment results in an increase in tendon strength of about %, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of administration ofa compound ofthe invention, as compared to baseline. [0686[ The methods of the invention may include preventive treatments. [0687[ In some embodiments, the administering is by direct injection to the affected site. In some embodiments, the direct injection is accomplished using the "peppering technique" with or without ultrasound guidance. The "peppering technique" is an injection method y after the needle is ed into the tender area, multiple small injections are performed by withdrawing, redirecting and reinserting the needle without emerging from the skin. [0688[ In some ments, the methods can further include administering one or more other therapeutic regimens and/or agents effective for treating a opathy, e.g., palliative care, with treatment focusing on anti-inflammatory measures, ing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), steroid injections, cortisone injections, platelet rich plasma (PRP) injections, physical therapy, shock wave y, low-level laser therapy (phototherapy), cell y, and sclerotherapy. [0689[ In some embodiments, the one or more es or conditions is psoriasis.

Non-limiting es include: psoriasis vulgaris (including nummular psoriasis and plaque psoriasis), generalized pustular psoriasis (including impetigo herpetiformis and von Zumbusch's disease), acrodermatitis continua, pustulosis palmaris et plantaris, guttate psoriasis, arthropathic psoriasis, other psoriasis (including inverse psoriasis). [0690[ In some embodiments, the one or more diseases or conditions is itis.

Non-limiting examples include: atopic dermatitis, t dermatitis (e.g., allergic contact dermatitis, irritant contact dermatitis), stasis dermatitis, dermatitis that led up to steroid dermatitis, steroid-resistant dermatitis, dermatitis to which tacrolimus is not applicable, chronic dermatitis, erythroderma (e.g., erythroderma posteczematosa and erythroderma secondary to dermatoses, toxic erythroderma, infantile desquamative erythroderma, and paraneoplastic erythroderma), eczema, nummular eczema, dyshidrotic eczema, asteatotic eczema, seborrheic dermatitis, nsitization dermatitis, stasis dermatitis, urticaria, drug eruption, dermal vasculitis, prurigo, pruritus cutaneus, erythema (e.g. nodosum or multiforme), rosacea, rosacea- like dermatitis, lichen , photo-induced dermatitis, or follicular keratosis. In certain ments, the dermatitis is contact dermatitis, e.g., ic contact dermatitis, e.g., ing from direct skin contact with a substance such as poison ivy, poison oak, or poison sumac. [0691[ In some embodiments, the one or more diseases or ions is morphea. [0692[ In some embodiments, the one or more diseases or conditions is ichthyosis. [0693[ In some embodiments, the one or more diseases or conditions is Darier's disease. [0694[ In some embodiments, the methods can further include administering one or more other eutic regimens and/or agents effective in treating a skin disorder described herein, e.g., corticosteroids, immune modulators, vitamin D3 and its analogs, retinoic acids and their pharmaceutically active derivatives, or combinations thereof. Specific non-limiting examples of drugs include betamethasone dipropionate, clobetasol propionate, halobetasol propionate, diflorasone diacetate, amcinonide, desoximethasone, fluocinonide, halcinonide, mometasone fiiroate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, olone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, ortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone e, prednisone, Benadryl, tacrolimus, picrolimus, tene, isotretinoin, cyclosporin, anthralin, n D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, ol, 4-hydroxyestradiol, 2—hydroxyestradiol, 2- hydroxyestrone, 2—benzimidazolylthioacetamide-N-ethylbenzyl (KH7.102), an antibody, a nucleic acid, or combinations thereof. [0695[ In some embodiments, the one or more diseases or conditions is Raynaud's syndrome. [0696[ In some embodiments, the patient is a human. [0697[ In some embodiments, the compound of a (I) inhibits one or more proteins in the Wnt pathway. [0698[ In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins. [0699[ In some embodiments, the Wnt proteins are chosen from: WNTl, WNTZ, WNTZB, WNT3, WNT3A, WNT4, WNTSA, WNTSB, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNTlOA, , WNTl l, and WNT16. [0700[ In some embodiments, the compound of Formula (I) inhibits a kinase activity. [0701[ In some embodiments, the compound of a (I) inhibits one or more Wnt proteins.

Evaluation of Biological Activity [0702[ The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., 2005/009997. For example, the activity of a compound may be tested using one or more ofthe test methods ed below. [0703[ In another example, one may e in vitro assays for Wnt biological ty, e.g. stabilization of B-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of B-catenin, which can be ed, for example, by serial dilutions of a ate inhibitor composition. An exemplary assay for Wnt biological activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize B- 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 c for B-catenin. [0704[ In a fithher example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et a]. Cell (1997), 88(6), 6).

Example 8. [0705[ Another screening assay for Wnt activity is described as follows. er cell lines can be generated by stably transducing cells of cancer cell lines (e.g., colon cancer) with a lentiviral construct that e a Wnt-responsive promoter driving expression of the firefly luciferase gene. [0706[ Lentiviral constructs can be made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 promoter, is linked upstream of the firefly luciferase gene. The lentiviral constructs can also include a hygromycin resistance gene as a selectable marker. The SP5 promoter construct can be used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation of B-catenin. A control cell line can be generated using another iral construct containing the luciferase gene under the control of the SV40 promoter which does not require B-catenin for activation. [0707[ ed SW480 cells bearing a reporter construct can be distributed at approximately 10,000 cells per well into 96 well or 384 well plates. Compounds from a small molecule compound library can then be added to the wells in og dilutions using a ten micromolar top concentration. A series of control wells for each cell type receive only buffer and compound solvent. Twenty-four to forty hours after the addition of compound, reporter activity for luciferase can be assayed, for example, by on of the BrightGlo luminescence t (Promega) and the Victor3 plate reader (Perkin Elmer). Readings can be normalized to DMSO only treated cells, and normalized activities can then be used in the ECso ations.

Table 2 shows the activity of selected indazolecarboxamide s.

Table 2. ————-— -——-_ -_——-_ _l-——-_ -_——-_ “——-n- -I_—-_— 47 ——_ 01 N -—_ ——z-_~m_ ca N ——_ 79 -_ _=I=Iil_—— —-fi-_=I=Iil_ 172 “—— ——-E‘- 188 ““— Example 9. [0708[ entative compounds were screened using primary human mesenchymal stem cells (hMSCs) to determine their ability to induce te differentiation (process by which tendon is developed). [0709[ 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 ). Cells between passage 3 and 6 were used for the experiments. [0710[ Compound Screening: Each compound was dissolved in DMSO as a 10mM stock and used to prepare compound source plates. For the tenocyte differentiation assay, serial dilution (1:2, 10-point esponse curves from 10 uM to 19.5 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384- well black clear bottom assay plates (Greiner Bio-One) with riate DMSO backfill for a final DMSO concentration of 0.17%. hMSCs were plated at 3,000 cells/well in 70 uL/well co's modified Eagle's medium (DMEM, Life Technologies, Carlsbad, CA) with 1% Fetal Bovine Serum (FBS, Life Technologies). Bone Morphogenic Factor (BMP) and Fetal Growth Factor (FGF) (10 ng/ml each, Peprotech, Inc., Rocky Hill, NJ) were used as a positive- controls for differentiation while negative control wells were treated with 120 nL DMSO for normalization and calculating ECso . Cells were incubated at 37°C and 5% C02 for 4 days. Cells were fixed using 4% formaldehyde (Electron Microscopy Sciences), and stained with anti-Sclerasis (anti-SCXA) antibodies t, San Diego, CA) [Webb S., et.al., ic acid receptor signaling preserves tendon stem cell characteristics and prevents spontaneous differentiation in vitro, Stem Cell Research & Therapy 2016, 7:45] overnight at 4°C. The cells were washed with Phosphate Buffered Saline (PBS, Life Technologies) and incubated with anti-rabbit Alexa-flor 647 secondary antibodies (Life Technologies) and DAPI (Life Technologies) for 1 hour at room ature. Cells were washed using PBS, and imaged using the CellInsight CX5 (Life Technologies, 594/633nm filter). Number of cells positive for SCXA in each well was quantified using the sight CXS. Data was normalized to the average of 12 DMSO treated wells on the same plate using Dotmatics Studies module. The ized averages (fold change over DMSO) of 3 replicate wells for each compound tration were ated. Due to solubility limitations of some of the compounds, values for higher doses were manually corrected and curve fitting and EC50 determinations were performed using Dotmatics Studies. [0711[ EC50 for each compound is reported. Table 3 shows the measured activity for representative compounds of Formula I as described herein.

Table 3.

Comouna Example 10.

Wnt Signaling inhibition [0712[ Cell Culture. SW480 cells (ATCC) were cultured in Dulbecco's modified Eagle's medium (DMEM, Fisher) with 1% aX (Life Technologies), 1% Penicillin-Streptomycin (Life Technologies), 150ug/ml Hygromycin (Life Technologies) with % fetal bovine serum (FBS) (Hyclone) at 37°C, 5% C02, [0713[ Wnt Reporter Assay. Human colorectal cancer cell line SW480, stably expressing the Wnt responsive promoter linked to luciferase gene, was plated overnight at 4 X 10e4 well in DMEM, high glucose, no glutamine, no phenol red (Life Technologies), 1% GlutamaX (Life Technologies), 1% Sodium Pyruvate (Life Technologies), 1% Penicillin- omycin (Life Technologies) with 1% Fetal Bovine Serum (Hyclone). Cells were then treated with DMSO (vehicle control) or COMPOUND 175 at 10 uM top tration and half a log dilution up to 10 concentrations (10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 and 0.0003 uM). Cells were incubated for 48 hours at 370C. 15 pl of -G10 (Bright-G10TM Luciferase Assay System, Promega) was added to the cells and luminescence was measured using the Cytation 3 plate reader (Biotek). Data was normalized using the DMSO control and inhibition profile and ECso was calculated using Prism 4 (GraphPad Software Inc, La Jolla, CA, USA).

Prism 4.0 was used to calculate the ECso ofthe Wnt reporter inhibition assay. [0714[ Exposure ofthe SW480 cells to compound 175 at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 and 0.0003 uM showed that compound 175 inhibited Wnt y activity in these cells in a dose-dependent manner with EC50 of ~ 152.9 nM (see FIG.

Example 11.

Tendon Differentiation [0715[ Cell Culture. Primary human mesenchymal stem cells , Lonza Inc) were cultured in MSCGMTM Mesenchymal Stem Cell Growth Medium, with 10% FBS (Lonza) 10% fetal bovine serum (FBS) ne) at 37°C, 5% C02,. hMSCs were used between passage 2 and 6 and were never allowed to reach confluence to maintain a naive state. [0716[ Tenocyte Differentiation Assay. For tenocyte differentiation, hMSCs were plated in 384-well plates at 1 X 104 cells/well in Dulbecco's modified Eagle's medium (DMEM, ThermoFisher) with 1% fetal bovine serum (FBS) (Hyclone). Cells were then treated with DMSO (vehicle control) or compound 175 at 750 nM top concentration and 2-fold dilution up to 8 concentrations (750, 333.3, 166.6, 83.3, 41.7, 21.7, 10.8and 5.8 nM) and incubated for 7 days at 37°C. A combination of BMP and FGF ml each, Peprotech, Inc.) was used as a ve control. At the end of 7 days, cells were fixed using 4 % methanol- free formaldehyde (Electron Microscopy es) for 10 min, washed with phosphate buffered saline (PBS) 3 times, perrneabilized with PBS containing 0.3% triton X-lOO (Sigma) for 5 min, blocked with PBST (PBS containing 0.3% triton X-lOO) with 3% bovine serum albumin (BSA, Sigma) for 1 h at room temperature, followed by incubation with primary antibodies in PBST + BSA overnight at 4°C. Cells were rinsed 3 times with PBS and incubated with hore- conjugated secondary antibody in PBST + BSA and DAPI for 1 h at room temperature and washed with PBS 3 times. Plates were imaged using a CX5 high-content imager (ThermoFisher) and the % of cells stained positive were determined using a cell scoring algorithm (ThermoFisher). Data was plotted and EC50 was calculated using Prism 5 (GraphPad Software Inc, La Jolla, CA, USA). Prism 5.0 was used to calculate the EC50 of the Tenocyte differentiation assay. [0717[ Exposure ofthe hMSCs to compound 175 at concentrations of 750, 333.3, 166.6, 83.3, 41.7, 21.7, 10.8and 5.8 nM showed that COMPOUND 175 induced the expression of SCXA, TenacinC and Tenomodulin, in a dose-dependent manner with an EC50 between 139- 189 nM (see FIGS. 2A-C and 3), indicating a differentiation ofhMSC into tenocytes.

Anti-inflammation [0718[ Cell Culture. THP-1 cells (Catalog # TIB-202, ATCC, as, VA) were cultured in Roswell Park Memorial Institute (RPMI) 1640 Medium (Catalog # 21870- 100, o, NY) with 1% L-glutamine, 1% HEPES, 1% Sodium Pyruvate, 2% Sodium Bicarbonate supplemented with 100 units/mL penicillin, 50 ug/mL streptomycin, 2- mercaptoethanol (0.05mM) [basal medium] and 10% fetal bovine serum og # 16140089, Life Technologies, ad, CA) at 37°C and 5% C02. [0719[ ne Production Assay. THP-1 cells were cultured in basal media with 1% FBS for 24 hours before the start of the assay. THP-1 cells were plated at 6 X 10e4 cells/well and treated with DMSO (vehicle control) or compound 175 at 10 uM highest test tration and 2 to 3.5-fold serial dilutions up to 8 concentrations (10, 3.5, 1, 0.5, 0.1, 0.035, 0.01, 0.005 uM). For the TNFa assay, 50 ng/mL of LPS was added to the wells after 2 hours to induce cytokine production, and cells were incubated for 5 hours at 37°C. For the IL6 assay, 500 ng/ml of LPS was added after 2 hours and cells were incubated for 22 hours at 37°C. Plates were spun in a centrifuge for 1 minute at 10,000 rpm and supematants were collected for ELISA. Supematants were diluted 1:1 for the TNFa assay and 1:4 for the IL6 assay using the assay medium. ELISA was performed using Human TNF-a ELISA MAXTM Deluxe og #430204, Biolegend, San Diego, CA) and Human IL-6 ELISA MAXTM Deluxe (Catalog # 430504, Biolegend, San Diego, CA) kits. Briefly, 96-well plates were coated with the appropriate capture dy overnight and washed to remove excess antibody. Blocking buffer was added and incubated for 1 hour to prevent non-specific g. Diluted supematants were incubated in the coated plates for 2 hours at room temperature. Following washes to remove unbound proteins, biotinylated detection antibody was added and incubated for 30 mins at room temperature, followed by washes to remove unbound excess antibody. Avidin-HRP was then added and incubated for 30 mins at room temperature. Following several washes to remove unbound avidin-HRP, the TMB substrate was added and the plates were read on the Cytation 3 plate reader (Biotek Inc., Winooski, VT) at an absorbance of 450 nm with correction at 570 nm. All samples were processed in triplicate. tion profile and EC50 was calculated using Prism 5 (GraphPad Software Inc, La Jolla, CA, USA). Prism 5.0 was used to calculate the EC50 of the TNFa and IL6 tion assays. [0720[ Exposure 1 cells to LPS induced the production ofboth TNFa and IL6. Compound 175 treatment inhibited the LPS-induced cytokine production in these cells in a dose-dependent manner with average EC50 ranging from 342 - 547 nM for TNFa and 356 - 629 nM for IL6 (see FIGS. 4A-B), with results generated from two independent assays and three replicates per assay.

Example 12.

Rat Tendinopathy Model 11) [0721[ Rat Model of enase-induced Tendonitis. Fifty (50 ul) of Collagenase Type IA (10 mg/ml in PBS, pH 7.4, approximately 469 units/mg) (Catalog #C5138, Sigma, St. Louis, MO) was injected into the Achilles tendon of both ankles near the osteotendinous on of male Sprague Dawley CD ®IGS rats (CRL, Inc.), using insulin syringes with 28.5 G needle. [0722[ Delivery of compound 175 by Topical Application. Rats were divided into 6 groups with 5 animals per group: Group 1 (sham injection); Group 2 (Collagenase- Vehicle); Group 3 (Collagenase- nd 175 10 mg/mL with 1% BA) and Group 4 (Collagenase—COMPOUND 175 10 mg/mL with 0.5% Tween 80). COMPOUND 175, formulated in 1% HPMC 1/20% PG/1% BA or 1% HPMC 40-0101/20% PG/0.5% Tween 80, or vehicle (1% HPMC 40-0101/20% PG/1% BA) was applied at a dose volume of uL/cm2 to cover a 2 cm2 dose area to the skin near the Achilles tendon region ofboth ankles ofthe collagenase-injected rats using an applicator and rubbed into the skin for 10 seconds. All rats were periodically observed for any pain, illnesses or abnormalities. At various time , blood was collected for plasma in m heparin coated tubes by saphenous vein bleeding. For histology, rats were euthanized using isoflurane, tendons were isolated (n=6 tendons/group), fixed in 10% ed formalin (Catalog # SF93-4, , Pittsburgh PA) and H & E histology ng was performed at a secondary site (Pacific Pathology, San Diego, CA). For biochemical analysis, tendons were isolated (n=4 tendons/group), flash frozen in liquid nitrogen and then stored at -80°C for subsequent biochemical analysis (not reported). [0723[ Histology Scoring of Tendons. There is biological variability in response to collagenase when injected directly into the tendons. This results in varying degrees of severity and location of inflammation as well as tendon degeneration (Urdzikova et al., Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat.

Biomed Eng Online. 2014 Apr 9, 13:42). Therefore, the entire tendon was isolated and placed in a tissue cassette and ed in paraffin. Five (5) um sections were generated and an average of 3 sections were fixed on one slide, with a minimum of eight (8) slides per tendon and subjected to Hematoxylin & Eosin (H&E) staining. Slides were Viewed under an upright light cope (EVOS AMEX-1200) at a 10X magnification and scored blinded using a 1-4 scoring system of severity: 1 - representing severe damage and 4 - representing normal tendon, for Linearity of the fiber structure, Shape of the tendon cells, Density of the tendon cells, Inflammation, and Hemorrhage for a total score of twenty (20) using a modification of that described previously (Urdzikova et al., 2014 - see Table 3). After the analysis was completed, the scorer was ded and scores for each criterion was annotated, totaled and total scores from each section were averaged together to generate a final score for each rat followed by averaging of scores for a given treatment group. [0724[ Biomarker Assays in Plasma. Following manufacturer’s instructions, KC/GRO plasma levels were ined using the KC/GRO Immunoassay kit (Catalog# 900- K57, ech, Rocky Hill, NJ). Briefly, 96-well plates were coated with the anti-rat KC/GRO capture antibody overnight and washed to remove excess antibody. Plasma samples were incubated in the coated plates for 2 hours at room ature. ing washes to remove unbound proteins, biotinylated anti-rat KC/GRO detection antibody was added and incubated for 30 mins at room temperature. Following washes to remove unbound excess antibody, avidin-HRP was added and incubated for 30 mins at room temperature. Following washes to remove unbound Avidin-HRP, the ABTS ate was added and the plates were read on the on 3 plate reader (Biotek Inc., Winooski, VT) at an absorbance of 525 nm with correction at 450 nm. All samples were processed in cate. [0725[ Data Analysis. For tendon scoring, each section was analyzed following a l-4 point scoring system as previously described (Urdzikova et al., 2014) with the exclusion of one variable, the Thickness of the epitenon, due to the difficulty in discerning the epitenon layer in histology sections. Table 4 below briefly summarizes the g system.

Table 4.

Score and Criteria 1 = no linear areas 2 = 20-50% linear Linearity of the fiber structure 3= > 50% linear 4 = linear (normal) 1 = predominantly round 2 = tely round Shape ofthe tendon cells 3 = ly oval 4 = linear normal 1 = sheets of cells 2 = moderate increase Density ofthe tendon cells 3 = slight increase 4 = sparse(normal) 1 = severe increase 2 = moderate increase Inflammation 3 = slight increase 4 = none 1 = predominant hemorrhage 2 = multiply areas in each field Hemorrhage 3 = sparse or patchy 4 = none [0726[ aHistology Scoring was modified by Samumed to exclude one variable, Thickness of the epitenon. [0727 [ In this study, a total of 64 sections were scored for Group 1 (sham injection group) and approximately 96 sections each for Group 2 (Collagenase-Vehicle), Group 3 (Collagenase-compound 175 with BA preservative) group and Group 4 (Collagenasecompound 175 without preservative). To determine tical significance between groups, student’s t-test was performed with p<0.05 considered as significant for histology scoring and biomarker assay. [0728[ Compound 175 Ameliorates Collagenase-Induced Tendinopathy.

Collagenase induced Tendonitis in rats recapitulates acute tendon injury in humans with inflammation resulting within a few hours (Urdzikova et al., 2014). Using an entional ch, topical formulation of compound 175 was administered 24 hours post collagenase injection into the Achilles tendon. The Collagenase-inj ected rats were dosed with vehicle alone or nd 175 (10 mg/mL) formulated with or without BA as a preservative for 21 consecutive days. Group 1 rats that received sham injections served as a control for no disease induction. [0729[ As shown in a significant presence of inflammatory cells was t in the Collagenase-vehicle group. Consequently, there was evidence of tendon degeneration and damage in the Collagenase-vehicle group compared to normal tendons found in the sham control group. Amelioration of inflammation as well as tendon degeneration by compound 175 is demonstrated in The histopathology ofthe tendon from the ent groups revealed tendons with decreased inflammation as well as improved structure of the fibers and tendon cells with respect to linearity, shape and density. This observation was fithher confirmed by blinded ogy scoring. As shown in upon topical treatment with compound 175, both compound 175 treatment groups demonstrated statistically significant ses in the tendon scores, achieving a score of 14.0 (:: 0.217) in Group 3 (Collagenase- compound 175 with BA) and a score of 12.2 (:: 0.284) in Group 4 (Collagenase-compound 175 without BA), compared to a score of 9.14 (:: 2.43) in Group 2 (Collagenase-vehicle), with a p- value of <0.01 and <0.05, respectively by student’s t test. [0730[ Compound 175 Reduces Plasma Biomarker KC/GRO in the enase-induced Tendon Injury Model. KC/GRO is an inflammatory biomarker reported to be associated with the development of itis. In this study, plasma concentrations of KC/GRO were investigated at various timepoints of the study. As shown in Table 4 and KC/GRO levels were elevated in the Group 2 (Collagenase-vehicle) on Days 5-21, ranging from 814 - 1483 pg/mL, while both the COMPOUND 175-treated groups, with or without BA, had lower levels of KC/GRO in plasma, g from 400 — 480 pg/mL and 347 - 451 pg/mL, respectively. Both nd eated groups (Groups 3 and 4) demonstrated a statistically significant decrease in plasma KC/GRO levels compared to Collagenase-vehicle control on Days 7 and 21 (p<0.05 by student's t test, Table 5). Overall, the decrease of a plasma biomarker of inflammation corroborates the ability of compound 175 to ameliorate tendonitis.

Table 5.

Plasma KC/GRO Concentration n 1 mL Groun 4 Day COmpound 175 Compound 175 Vehicle (10 mg/mL with (10 hout BA, (0 mg/mL) 0.5% BA With 0.5% Tween 80 —fl 2261 57.4 332 1 51.3 530 1 31.4 —- 5741106 521 1 23.9 637 1120 —- 3761156 6131614 5411569 I11651465 4601467 4101660 1463 1 266a 421 1 572* 451 1 76.6* —II 1356 1 367a 400 1 10.3 424 1 76.2 m614 1 924a 406 1 633* 347 1111* [0731[ 3Mean values were above quantitation limit (AQL>1000 pg/mL) and are reported as estimated. [0732[ * p<0.05 (student’s t test) in Compound 175-treated groups (Groups 3 and 4) as compared to Group 2 le) on Days 7 and 21. [0733[ Tendinopathy is an acute injury of the tendon that involves inflammation and tendon damage. If left untreated, repeated injury can lead to tendon ruptures and require surgery. The presence or absence of the preservative benzyl alcohol has no effect on the efficacy of compound 175. Treatment with compound 175 ameliorates tendinopathy as ed by blinded histological scoring of the . To fithher confirm this finding, it has shown that compound 175 also results in a decrease of an inflammatory plasma biomarker, KC/GRO.

Example 13.

Rat tendinopathy model 12) [0734[ Fifty (50 ul) of Collagenase Type IA (10 mg/ml in PBS, pH 7.4, approximately 469 units/mg) (Catalog #C5138, Sigma, St. Louis, MO) was injected into the es tendon of both ankles near the osteotendinous junction of male Sprague Dawley CD ®IGS rats (CRL, Inc.), using insulin syringes with 28.5 G needle. [0735[ Delivery of compound 175 by Topical ation. Rats were divided into 6 , with 6 animals per group except 8 s in Group 2: Group 1 (sham injection), Group 2 (Collagenase-Vehicle with 0.5% Phx), Group 3 (Collagenase-compound 175 3 mg/mL with 0.5% BA), Group 4 (Collagenase—compound 175 10 mg/mL with 0.5% BA), Group 5 (Collagenase— compound 175 3 mg/mL with 0.5% Phx) and Group 6 (Collagenase—compound 175 10 mg/mL with 0.5% Phx). COMPOUND 175, either at 3 or 10 mg/ml, prepared in either 1% HPMC 40-0101/20% PG/0.5% BA or 1% HPMC 40-0101/20% PG/0.5% Phx or vehicle (1% HPMC 1/20% PG/0.5% Phx) was applied at 30 uL/cm2 over a 2 cm2 area to the skin near the Achilles tendon region of both ankles of the collagenase-injected rats using an applicator, and rubbed into the skin for 10 seconds. All rats were periodically observed for any pain, illnesses or abnormalities. At various time points, blood was collected for plasma in lithium heparin coated tubes by saphenous vein bleeding. For histology, rats were euthanized using isoflurane, tendons were isolated (n=8 tendons/group), fixed in 10% buffered formalin (Catalog #SF93-4, , Pittsburgh, PA) and H & E ogy staining was performed at a secondary site (Pacific Pathology, San Diego, CA). For biochemical analysis, tendons were ed (n=4 tendons/group), flash frozen in liquid nitrogen and then stored at -80°C for subsequent biochemical analysis (not reported). Additionally, one (1) day after collagenase injection, 4 tendons were collected from Group 2 (vehicle) to e the induction of inflammation (not reported). [0736[ There is biological variability in response to collagenase when injected directly into the tendons. This results in varying degrees of severity and location of inflammation as well as tendon degeneration (Urdzikova et al., 2014). Therefore, the entire tendon was isolated and placed in a tissue cassette and embedded in paraffin. Five (5) um sections were generated with an average of 3 sections being fixed on one slide with a minimum of eight (8) slides per tendon and subjected to Hematoxylin & Eosin (H&E) staining. Slides were viewed under an upright light microscope (EVOS AMEX-1200) at a 10X magnification and scored blinded using a 1-4 scoring system of severity: 1- representing severe damage and 4 - representing normal tendon, for ity of the fiber structure, Shape of the tendon cells, Density of the tendon cells, Inflammation, and Hemorrhage for a total score of twenty (20) using a modification of that described previously kova et al., 2014 — see Table 3). After the analysis was completed, the scorer was unblinded and scores for each criterion was annotated, totaled and total scores from each section were ed er to generate a final score for each rat ed by averaging of scores for a given treatment group. [0737[ Biomarker Assays in Plasma. Following cturer’s ctions, KC/GRO plasma levels were determined using the KC/GRO Immunoassay kit (Cat# 900-K5 7, Peprotech, Rocky Hill, NJ). Briefly, l plates were coated with the anti-rat KC/GRO capture antibody overnight and washed to remove excess dy. Plasma samples were incubated in the coated plates for 2 hours at room temperature. Following washes to remove d proteins, biotinylated anti-rat KC/GRO detection antibody was added and incubated for 30 mins at room temperature. ing washes to remove unbound excess dy, avidin-HRP was added and incubated for 30 mins at room temperature. Following washes to remove unbound avidin-HRP, the ABTS substrate was added and the plates were read on the Cytation 3 plate reader (Biotek Inc., Winooski, VT) at an absorbance of 525 nm with correction at 450 nm. All samples were processed in triplicate. [0738[ Data Analysis. For tendon scoring, each section was ed following a 1-4 point scoring system as previously described (Urdzikova et al., 2014) with the exclusion of one variable, Thickness of the epitenon, due to difficulty in discerning the epitenon layer in the histology sections. Table 2 below briefly summarizes the scoring system. In this study, a total of 94 sections were scored for Group 1 (sham injection, l group) and between 92- 116 sections for Group 2 (Collagenase-Vehicle with 0.5%Phx), Group 3 (Collagenasecompound 175 3 mg/mL with 0.5% BA), Group 4 (Collagenase—compound 175 10 mg/mL with 0.5% BA), Group 5 (Collagenase—compound 175 3 mg/mL with 0.5% Phx) and Group 6 (Collagenase—compound 175 10 mg/mL with 0.5% Phx). [0739[ Compound 175 Ameliorates Collagenase-Induced Tendinopathy.

Collagenase-induced tendonitis in rats recapitulates acute tendon injury in humans with inflammation ing within a few hours (Urdzikova et al., 2014). Using an interventional WO 75858 approach, topical formulation of compound 175 was administered one day (~24 hours) after the injection of collagenase into the Achilles tendon. The collagenase-injected rats were dosed with vehicle alone (containing 0.5% PhX) or compound 175 (3 or 10 mg/mL) formulated with either 0.5% BA or 0.5% PhX as a preservative for twenty-one (21) consecutive days. Group 1 rats (sham injections) served as control animals for no disease induction. [0740[ As shown in a cant ce of inflammatory cells was evident in the Collagenase-vehicle group (Group 2). Consequently, there was evidence of tendon degeneration and damage in the enase-vehicle group ed to normal tendons found in the sham control group (Group 1). Amelioration of inflammation as well as tendon degeneration by compound 175 is demonstrated in The athology of the tendon from the compound 175-treated groups revealed tendons with sed inflammation as well as improved structure ofthe fibers and tendon cells with respect to linearity, shape and density.

This observation was further confirmed by blinded Histology scoring. As shown in upon topical treatment with compound 175, all four (4) compound 175-treated groups demonstrated statistically significant increases in the tendon scores, achieving a score of 14.5 (:: 1.15) in Group 3 (Collagenase-compound 175 3 mg/mL with 0.5% BA), a score of 14.8 (:: 0.968) in Group 4 (Collagenase—compound 175 10 mg/mL with 0.5% BA), a score of 15.1 (:: 0.506) in Group 5 (Collagenase—compound 175 3 mg/mL with 0.5% PhX) and a score of 13.2 (:: 0.855) in Group 6 (Collagenase—compound 175 10 mg/mL with 0.5% PhX), compared to a score of 8.57 (:: 0.672) in Group 2 (Collagenase-vehicle), with p-values of <0.001 (Groups 3, 4 and 5) and <0.01 (Group 6) versus Group 2, by student’s t test. [0741[ Compound 175 s Plasma Biomarker KC/GRO in the Collagenase-induced Tendon Injury Model. KC/GRO is an inflammatory biomarker reported to be associated with the development of tendonitis. In this study, plasma concentrations of KC/GRO were investigated at various ints of the study. As shown in Table 5 and , KC/GRO levels were elevated in Group 2 (Collagenase-vehicle with 0.5% PhX) on Days 5-21, ranging from 488 - 778 pg/mL, while all four compound 175-treated groups had decreased levels of KC/GRO in plasma, ranging from 150-561 pg/mL. Compound 175 at both 3 and 10 mg/mL dose concentrations, with either BA or PhX as preservative (Groups 3-6), demonstrated a tically significant decrease in plasma KC/GRO levels compared to vehicle control (Group 2) on Days 5, 7 and 21 5, by student's t test) as indicated in Table 6.

Overall, the decrease of a plasma biomarker of inflammation corroborates the ability of compound 175 to ameliorate itis.

Table 6.

Plasma KC/GRO Concentration n 1 mL) Comuound 175-Treated Grou n s 05% Phx 219 i 94.9 254 i 60.6 450 i 53.1 375 i 44.4 451 i 50.2 405 i 42.1 778 i 56-9 328 i 37-1” 708 i 95.5 299 i 539* 704 i 170 265 i 20.8 488 i 98.8 342 i 39.7 [0742[ * p<0.05 nt’s t test) on Day 7 (Group 6) and on Day 21 (Group 3) compared to Group 2 (Vehicle) on Days 7 and 21. [0743[ ** p<0.01 (student’s t test) on Day 5 compound 175-treated groups (Groups 4, 5 and 6) compared to Group 2 (Vehicle). [0744[ Tendinopathy is an acute injury of the tendon that es inflammation and tendon damage. If left ted, repeated injury can lead to tendon ruptures and require surgery. Both doses of compound 175 (3 and 10 mg/ml with either BA or Phx preservatives) were efficacious in the rat tendonitis model. Based on the foregoing results, neither preservative, BA or PhX, appeared to e the efficacy of compound 175. The results demonstrate that treatment with compound 175 ameliorated tendinopathy as assessed by blinded histological g of the tendon. To fithher confirm this finding, it has been shown that compound 175 also s in a decrease of an inflammatory plasma biomarker, KC/GRO.

Example 14.

Pharmacokinetics [0745[ Thirty (30) na'1've male Sprague Dawley rats were divided into three dose groups (Groups 1-3, 10 animals/group). compound 175 was formulated in 1% hydroxypropyl methylcellulose (HPMC) 40-0101/20% propylene glycol at 1 or 10 mg/mL containing 1% benzyl alcohol (BA) as preservative s 1 and 2) or at 10 mg/mL containing 0.5% Tween 80 (used in earlier rat studies) without BA preservative (Group 3). The compound 175 formulation was d once topically to each ankle of the hind leg of each animal at 60 uL volume (30 uL/cm2 X 2 cm2) over the area ofthe Achilles tendon. The study design is presented in Table 7 below.

Table 7.

Left and Ri_ht Hind limba Dose per Total Dose Group N/Sex ° ' Unit Area Volume _ 10/M _ _ 10/M _ /M preseervativ [0746[ a Topical application to left and right ankles of the hind limbs over the area ofthe Achilles tendon [0747[ 1’ Compound 175 topical formulations: 1% HPMC 40-0101/20% propylene glycol containing 1% benzyl alcohol (BA) as preservative (Groups 1 and 2), and without BA preservative but with 0.5% Tween 80 (Group 3). [0748[ Blood Sample Collection. Blood samples (~05 mL) were collected via cardiac puncture, into tubes containing KzEDTA as anticoagulant, at l, 2, 4, 7 and 24 hours post-dose from 2 animals per timepoint (n=2). Plasma was harvested and frozen at -80°C for bioanalysis. [0749[ Tissue Sample Collection. The Achilles s from both ankles were collected following euthanasia at l, 2, 4, 7 and 24 hours post-dose from 2 animals per int (n=4) from all . Skin tissue samples were collected from the dose-site at 7 and 24 hours post-dose from 2 animals per timepoint (n=4) in Group 2. Tissues were frozen at -80°C for bioanalysis. Blood and tissue tion schedule is outlined in Table 8 below.

Table 8.

Tendon Blood Collectioln Collection ) Collection Timepoints (h) T' ' lmepomts Timepoints (11)]; 1,2,4,7and24 1,2,4,7and24 [0750[ NS: No samples collected. [0751[ 1) n=2/timepoint/group for blood collection. [0752[ 1’ mepoint/group for tendon and skin tion (2 animals per timepoint X 2 ankles). [0753[ Experimental Procedures. Skin tissue samples were processed using the following ures: 1) Weigh tissue and homogenize using cryoPrep (Covaris), 2) Add 9X volume of AcetonitrilezMethanol (70:30) and vorteX for one hour, 3)Aliquot 100 uL of tissue homogenate into 96 microtube polypropylene plate, 4) Add 10 uL ing standard to each standard, 5) Add 10 uL anol in all samples and blanks, 6) Add 10 uL ofinternal standard (IS) to all tubes except blanks, 7) Spin in centrifiige at 3000 rpm for 10 minutes, and 8) Transfer 100 uL of supernatant into 96-well plate containing 150 uL of water. Cap and vorteX for LC/MS/MS analysis. [0754[ Bioanalytical and Pharmacokinetic is. The chromatograms of the samples were integrated and calibrated using Analyst 1.6.2 (AB ScieX, Redwood City, CA).

Linear sion with UK2 weighting and internal standardization was used for standard calibration, with an acceptance criterion of::30% ofnominal standard concentration. The lower limit of quantitation (LLOQ) was 2.00 ng/mL (plasma), 6.00 ng/g (tendon) and 25 .0 ng/g (skin).

Pharmacokinetic parameters were estimated by noncompartmental analysis from individual concentration versus time profiles using Pheonix WinNonlin version 6.3 (Certara, Inc., Princeton, NJ). The time to maximum concentration (tmax) and the maximum concentration (Cmax) were determined based on measured plasma and tissue concentrations. The area under the curve (AUCmast) was calculated using the linear trapezoidal rule. [0755[ ic re. Systemic exposure to nd 175 was low compared to tendon and skin tissues after a single topical administration of a 1 or 10 mg/mL formulation, with either BA or Tween 80. Plasma exposure in Groups 1 and 2 (1 and 10 mg/mL formulation containing BA) were: 1.30 and 10.6 ng/mL Cmax and 0.650 and 36.1 h-ng/mL AUC(0-last), respectively, showing a dose-proportional increase in Cmax and r than dose-proportional increase in total exposure (AUC(0-last)). Exposure in Group 3 (10 mg/mL formulation without BA but ning Tween 80) was 1.94 ng/mL Cmax and 6.79 h-ng/mL AUC(0-last), which was ~0.2x of Group 2 (10 mg/mL with BA). [0756[ Tendon Exposure. Compound 175 es tendon re in Groups 1 and 2 (1 and 10 mg/mL formulation containing BA) was 519 and 1930 ng/g Cmax and 2164 and 7270 h-ng/g AUC(o-1ast), respectively, indicating a less than dose-proportional increase in exposure: 3.4x increase in AUC(o-1ast) for a 10x dose-increment. Group 3 (10 mg/mL without BA) tendon exposure was 7053 ng/g Cmax and 28077 h-ng/g AUC(o-1ast), Which was ~4x of Group 2 (10 mg/mL with BA). Tendon to plasma ratios (AUC(o-1ast)) were 3329 and 202 in Groups 1 and 2 (1 and 10 mg/mL formulations containing BA) and 4135 in Group 3 (10 mg/mL without BA). [0757 [ Skin concentrations in Group 2 (10 mg/mL containing BA) were reported as estimated as all values were above quantitation limit (AQL>25000 ng/g). Mean skin concentrations at 7 and 24 hours post-dose were ~208600 and 113375 ng/g, y 1000x tendon concentrations at these timepoints. Plasma, Tendon and Skin PK parameters are presented below in Table 9 and tration-time profiles are displayed in .

Table 9.

Tissue tmax (h) 0.650 IBM—_- 36-1 1% BA 1930 7270 m—208600 NC NC "-M6.79 4135 ative 7053 28077 [0758[ Total dose volume = 60 uL/ankle ofhind limb, n=2 (plasma), n=4 (tendon, skin, 2). [0759[ NC = not calculated due to lack of sufficient timepoints for AUC calculation. [0760[ 1) Above quantitation limit (AQL>25000 ng/g) - value ed as estimated. [0761[ Systemic exposure to compound 175 in rats after a single topical administration was low in all dose groups compared to tendon exposure, with tendon to plasma ratios ranging from 202 to 4135 across groups. A dose dependent increase in plasma and tendon exposure was seen n the l and 10 mg/mL formulations ning BA. While the 10 mg/mL formulation without BA (containing Tween 80) showed lower ic exposures (0.2x) compared to the formulation containing BA, the tendon exposure was 4 fold higher than the 10 mg/mL formulation containing BA. [0762[ The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, ted elements or method steps.

Claims (17)

WHAT IS CLAIMED IS:

1. A method of treating of one or more diseases or conditions independently selected from the group consisting ofa tendinopathy, dermatitis, psoriasis, a, ichthyosis, Raynaud's syndrome, and Darier's disease, the method comprising stering to a subject (e.g., a subject in need thereof) a compound or pharmaceutically acceptable salt thereof having the structure of Formula 1: o / R4 NH R2 N wherein: R1, R2 and R4 are independently selected from the group consisting of H, C1.9 alkyl, halide, —N(R10)2, —XR10, CN, —OCF3 and —CF3, R3 is selected from the group consisting of carbocyclle6, heterocyclle6, arle6 and heteroarle6, R5 is selected from the group consisting of -(C1-9 alkyl)ncarbocyclle7, -(C1-9 nheterocyclle7, -(C1_9 alkyl)narle7 and -(C1_9 alkyl)nheteroarle7, each R6 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1_9 narle8, -(C1_9 alkyl)nheteroarle8, -C(=O)R11, - N(R10)C(=O)R“, -(C1_9 alkyl)nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR“ and -SOzR11, each R7 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclle9, -(C1-9 alkyl)nheterocyclle9, -(C1_9 alkyl)narle9, -(C1_9 alkyl)nheteroarle9, -C(=O)R11, - N(R10)C(=O)R“, -(C1_9 alkyl)nN(R10)2, -(C1_9 nN(R10)SOZR11 and , each R8 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, OCF3, -CF3 -CN, -XR12, R13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, - (C1_9 alkyl)nN(R12)SOZR13 and -SOle3, each R9 is 1-5 substituents each ed from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3 -CN, -XR12, -C(=O)Rl3, -N(R12)C(=O)R13, -(C1.9alkyl)nN(R12)2, - (C1_9 alkyl)nN(R12)SOZR13 and -SOle3, each R10 is independently selected from the group consisting of H, C1_9 alkyl, -(C1_9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, -(C1_9 narle8 and -(C1_9 alkyl)nheteroarle8, each R11 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, - (C1.9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle8, -(C1-9 alkyl)narle8 and -(C1-9 alkyl)nheteroarle8, each R12 is independently selected from the group consisting of H, C1.9 alkyl, -(C1-9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl, each R13 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, - (C1.9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl, each R14 is ndently selected from the group ting of H, C1_3 alkyl, carbocyclyl and aryl, each X is selected from the group consisting of a bond, and -S-, and eachnis Oor l.

2. The method of claim 1, wherein R1, R2 and R4 are H.

3. The method of claim 2, wherein R3 is dle6.

4. The method of claim 2, wherein R3 is 5-pyrimidinle6.

5. The method of claim 2, wherein R3 is 4-pyridazinle6.

6. The method of claim 3, wherein R6 is one substituent and is -N(R9)C(=O)R10.

7. The method of claim 3, wherein R6 is one tuent and is — (CH2)heterocyclle8.

8. The method of claim 7, wherein the R6 heterocyclyl is independently selected from the group consisting of azetidinleS, pyrrolidinleS, piperidinle8, piperazinleS, and morpholinleS.

9. The method of claim 2, wherein R5 is 3-pyridle7.

10. The method of claim 3, wherein R5 is 3-pyridle7.

11. The method of claim 2, wherein R5 is 5-pyrimidinle7.

12. The method of claim 2, wherein R5 is 4-pyridazinle7.

13. The method of claim 9, wherein R7 is one substituent and is selected from the group consisting of halide, -OCF3, -CF3, -(C1_9 alkyl)nN(R10)2, -(C1_9 nN(R10)SOZR11 and - N(R1°)C(=0)R“.

14. The method of claim 10, wherein R7 is one tuent and is selected from the group consisting of halide, -OCF3, -CF3, -(C1_9 nN(R10)2, -(C1_9 alkyl)nN(R10)SOZR11 and - N(R10)C(=0)R“.

15. The method of claim 9, n R7 is one substituent and is selected from the group consisting of -OR10 and -C(=O)R11 where R11 is -N(R10)2, and each R10 is independently selected from the group consisting of H, methyl and -(C1-9 alkyl)ncarbocyclle8 where n is 0 and each R8 is l-2 substituents independently ed from H or halide.

16. The method of claim 10, wherein R7 is one substituent and is selected from the group ting of -OR10 and -C(=O)R11 where R11 is -N(R10)2, and each R10 is independently ed from the group consisting of H, methyl and -(C1-9 alkyl)ncarbocyclle8 where n is 0 and each R8 is 1-2 substituents independently selected from H or halide.

17. The method of claim 1, the compound having a structure selected from the group consisting of: WO 75858 WO 75858 Q Q (:1 R" \ka KI vim d WO 75858 0N3 0 4—) /