Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

• 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.
• Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the mechanisms 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 identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families.
• the Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human.
• Members of the Wnt family of signaling molecules mediate many important short-and long-range patterning processes during invertebrate and vertebrate 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 ⁇ -catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl.
• misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers.
• 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 nervous system.
• Pathological activation of the Wnt pathway is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world. Activation of the Wnt pathway has also been extensively reported for hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias.
• inhibitors of the Wnt pathway can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as diabetic retinopathy, 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.
• 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 signaling pathways and other processes that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. 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.
• Tendinopathies are chronic disorders or injuries 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.
• dermatitis also known as eczema
• psoriasis Both dermatitis and psoriasis can cause serious physical and/or psychological suffering to the subject regardless of the location on the body that these conditions occur.
• WO 2013/040215 describes indazole-3-carboxamides having Formula (I) and their use as Wnt/B-catenin signalin pathway inhibitors.
• 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.
• One embodiment disclosed herein includes administering an indazole-3- carboxamide compound having the structure of Formula I:
• R 1 , R 2 and R 4 are independently selected from the group consisting of H, Ci-9 alkyl, halide, -N(R 10 ) 2 , -XR 10 , CN, -OCF 3 and -CF 3 ;
• R 3 is selected from the group consisting of carbocyclylR 6 , heterocyclylR 6 , arylR 6 and heteroarylR 6 ;
• R 5 is selected from the group consisting of -(Ci-9 alkyl) n carbocyclylR 7 , -(Ci-9 alkyl) n heterocyclylR 7 , -(Ci-9 alkyl) n arylR 7 and -(Ci- alkyl) n heteroarylR 7 ;
• each R 10 is independently selected from the group consisting of H, Ci -9 alkyl, -(Ci -9 alkyl) procurN(R 14 ) 2 , -(Ci- 9 alkyl) spaciouscarbocyclylR 8 , -(Ci- 9 alkyl) procurheterocyclylR 8 , -(Ci- 9 alkyl) procurarylR 8 and -(Ci-9 alkyl) n heteroarylR 8 ; each R 11 is independently selected from the group consisting of Ci- alkyl, -N(R 14 )2, - (Ci-9 alkyl) n carbocyclylR 8 , -(C1-9 alkyl) n heterocyclylR 8 , -(C1-9 alkyl) n arylR 8 and -(C1-9 alkyl) n heteroarylR 8 ;
• each R 12 is independently selected from the group consisting of H, Ci-9 alkyl, -(C1-9 alkyl) n N(R 14 )2, -(C1-9 alkyl) n carbocyclyl, -(C1-9 alkyl) n heterocyclyl, -(C1-9 alkyl) n aryl and -(C1-9 alkyl) n heteroaryl ;
• each R 13 is independently selected from the group consisting of Ci-9 alkyl, -N(R 14 )2, - (Ci-9 alkyl) n carbocyclyl, -(Ci-9 alkyl) n heterocyclyl, -(Ci-9 alkyl) n aryl and -(Ci-9 alkyl) n heteroaryl; each R 14 is independently selected from the group consisting of H, C 1 -3 alkyl, carbocyclyl and aryl;
• each X is selected from the group consisting of a bond, -O- and -S-;
• each n is 0 or 1.
• R 1 , R 2 and R 4 are independently selected from the group consisting of H, C 1 -9 alkyl, halide, -N(R 10 ) 2 , -XR 10 , CN, -OCF3 and -CF 3 ;
• R 3 is selected from the group consisting of carbocyclylR 6 , heterocyclylR 6 , arylR 6 and heteroarylR 6 ;
• R 3 when R 3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole;
• R 5 is selected from the group consisting of -(C1-9 alkyl) n carbocyclylR 7 , -(C1-9 alkyl) n heterocyclylR 7 , -(C 1 -9 alkyl) n arylR 7 and -(Ci-9 alkyl) n heteroarylR 7 ;
• R 5 is not 4-pyridylR 7 when R 1 , R 2 and R 4 are 3 is selected from the group consisting of 3-pyridylR 6 , 4-pyridylR 6 , 2-pyridylR 6 , phenylR 6 ,
• R 5 is not -(CH2)(3-pyridyl)R 7 when R 1 , R 2 and R 4 are H
• R 3 is selected from the group consisting of 3-pyridylR 6 , 4-pyridylR 6 and thiazoleR 6 , and R 6 and R 7 are both H
• R 5 is not phenylR 7 when R 1 , R 2 and R 4 are H
• R 3 is 4-pyridylR 6 and R 6 and R 7 are both H
• R 3 is not 3-pyridylR 6 when R 1 , R 2 and R 4 are 5 is selected from the group consisting of phenylR 7
• R 3 is not oxazoleR 6 when R 1 , R 2 and R 4 are
• R 6 is H
• R 3 is not thiazole 6 when R 1 , R 2 and R 4 are
• R 5 is selected from the group consisting of and , and R 6 is H;
• each R 11 is independently selected from the group consisting of Ci-9 alkyl, -N(R 14 )2, - (Ci-9 alkyl) n carbocyclylR 8 , -(C1-9 alkyl) n heterocyclylR 8 , -(C1-9 alkyl) n arylR 8 and -(C1-9 alkyl) n heteroarylR 8 ;
• each R 12 is independently selected from the group consisting of H, C1-9 alkyl, -(C1-9 alkyl) n N(R 14 )2, -(C1-9 alkyl) n carbocyclyl, -(C1-9 alkyl) n heterocyclyl, -(C1-9 alkyl) n aryl and -(C1-9 alkyl) n heteroaryl ;
• each R 13 is independently selected from the group consisting of C1-9 alkyl, -N(R 14 )2, - (Ci-9 alkyl) n carbocyclyl, -(Ci-9 alkyl) n heterocyclyl, -(Ci-9alkyl) n aryl and -(Ci-9 alkyl) n heteroaryl; each R 14 is independently selected from the group consisting of H, C 1 -3 alkyl, carbocyclyl and aryl;
• each X is selected from the group consisting of a bond, -O- and -S-;
• each n is 0 or 1.
• Some embodiments include administering stereoisomers and pharmaceutically acceptable salts of a compound of general Formula (I).
• Some embodiments include administering pro-drugs of a compound of general Formula (I).
• Some embodiments include administering pharmaceutical compositions comprising a compound of general Formula (I) or in a pharmaceutically acceptable carrier, diluent, or excipient.
• the human colorectal cancer cell line (SW480) with constitutive activation 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 ⁇ .
• 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.
• FIG. 3 are images of the expression of SCXA, tenacinC, and tenomodulin in hMSCs treated with DMSO, bone morphogenic protein (BMP) and fibroblast growth factor (FGF), and compound 175 at 333 nM concentration.
• BMP bone morphogenic protein
• FGF fibroblast growth factor
• 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 10e 4 cells/well in a 96-well plate) were treated with DMSO (vehicle) or compound 175 at concentrations of 10, 3.5, 1, 0.5, 0.1, 0.035, 0.01, 0.005 ⁇ .
• 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 of the cytokines.
• Supernatants (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 ECso was calculated using Prism 5.
• Representative images indicate that exposure of the 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).
• FIG. 5 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, compound 175, and benzyl alcohol; and a rat Achilles tendon treated with a collagenase and compound 175.
• Tendinopathy in rats was induced by injecting collagenase (50 ⁇ , 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 mg/ml).
• 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
• Group 4 Collagenase-compound 175 with 0.5% Tween 80, without BA.
• FIG. 6 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 collagenase, compound 175, and benzyl alcohol; and a rat Achilles tendon treated with a collagenase and compound 175.
• Tendinopathy in rats was induced by injecting collagenase (50 ⁇ , 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 mg/ml).
• 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
• Group 4 Collagenase -compound 175 with 0.5% Tween 80, without BA.
• Blinded histology scoring of tendon injury and inflammation indicated that compound 175 with or without BA preservative significantly ameliorated collagenase-induced tendinopathy (**p ⁇ 0.01 and *p ⁇ 0.05 respectively) by student's t test.
• a total of 64 sections were scored for Group 1 and -96 sections each for Group 2-4.
• FIG. 7 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 ⁇ , 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 control or compound 175 (10 mg/ml). Blood was collected at various timepoints and plasma was analyzed for KC/GRO by ELISA.
• FIG. 8 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 collagenase, 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 induced by injecting collagenase (50 ⁇ , 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 10 mg/ml with 0.5% BA), Group 5 (Collagenase-compound 175 3 mg/ml with 0.5% Phx) and Group 6 (Collagenase- COMPOU D 175 10 mg/ml with 0.5% Phx).
• FIG. 9 is a plot of tendon histology scores 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 collagenase, 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 induced by injecting collagenase (50 ⁇ , 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 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).
• FIG. 10 is series of plots of plasma concentrations of KC/GRO in rats vs. the number of days elapsed after administration 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 ⁇ , 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 control or topical compound 175.
• FIG. 11 is a series of plots of compound 175 concentrations vs. time in Sprague-Dawley rat tendons, plasma, and skin after a topical application of 1 mg/mL compound 175 and benzyl alcohol, 10 mg/mL compound 175 and benzyl alcohol, and 10 mg/mL compound 175.
• 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.
• alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl 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, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• Carbocyclyl means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
• Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxy
• 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 1 to about 3 carbons in the alkyl portion of the radical.
• amido means a H-CON- or alkyl-CON-, carbocyclyl- CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described.
• 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, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
• a preferred carbocyclic aryl is phenyl.
• 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., pyridine) 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.
• substituents e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
• heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-tf]pyrimidinyl, pyrrolo[2,3-6]pyridinyl, quinazolinyl,
• substitution on the aryl and heteroaryl rings is within the scope of certain embodiments.
• the radical is called substituted aryl or substituted heteroaryl.
• substituents Preferably one to three and more preferably one or two substituents occur on the aryl ring.
• preferred substituents include those commonly found in aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
• acyl means an H-CO- or alkyl-CO, carbocyclyl-CO, aryl-CO, heteroaryl-CO- or heterocyclyl-CO- group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described.
• Preferred acyls contain a lower alkyl.
• Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl.
• halo is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine.
• 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 fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length.
• haloalkylene means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
• heterocyclyl means a cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
• Heterocyclyls may be substituted 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 members.
• the heteroatom(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 heteroatoms selected from O, N, or S.
• heterocyclyl examples include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2- dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, ox
• substituted amino means an amino radical which is substituted by one or two alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, aryl, heteroaryl or heterocyclyl are defined as above.
• substituted 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.
• sulfonyl means an alkylSC , arylSC , heteroarylSC , carbocyclylSC , or heterocyclyl-SC group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.
• sulfamido means an alkyl-N-S(0) 2 N-, aryl-NS(0) 2 N-, heteroaryl-NS(0) 2 N-, carbocyclyl-NS(0) 2 N or heterocyclyl-NS(0) 2 N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
• sulfonamido means an alkyl-S(0) 2 N-, aryl-S(0) 2 N-, heteroaryl-S(0) 2 N-, carbocyclyl-S(0) 2 N- or heterocyclyl-S(0) 2 N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
• ureido means an alkyl-NCON-, aryl-NCON-, heteroaryl-NCON- , carbocyclyl-NCON- or heterocyclyl-NCON- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
• the compounds provided herein may encompass various stereochemical forms.
• the compounds also encompass diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
• 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.
• a "diagnostic” as used herein is a compound, 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.
• mamal is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes 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.
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes 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 incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g.
• pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds of the preferred embodiments and, which are not biologically or otherwise undesirable.
• the compounds of the preferred embodiments are capable of forming 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 include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein).
• Solidvate refers to the compound formed by the interaction of a solvent and a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
• 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.
• terapéuticaally effective amount or “pharmaceutically effective amount” is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound.
• “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula (I) in combination with one or more other agents that are effective to inhibit Wnt related 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 of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
• a therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. "Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
• Treatment refers to administering a pharmaceutical composition for therapeutic purposes.
• therapeutic treatment refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop.
• Morphea refers to a skin condition wherein discolored and/or hardened patches appear on the skin (e.g., one or more outer layers of the skin) resulting from excessive collagen deposition.
• Raynaud's syndrome refers to a disease in which certain parts of the body (e.g., fingers and/or toes) feel numb and/or cold in response to various stimuli (e.g., cold temperatures and/or stress) due to arterial narrowing.
• Darier's disease refers to an autosomal dominant disorder characterized by the appearance of dark crusty patches on the skin (e.g., keratotic papules, keratosis follicularis or dyskeratosis follicularis) that may contain pus.
• wound healing refers to a process by which skin and/or other bodily tissue repairs itself after experiencing, for example, damage and/or trauma.
• Ichthyosis refers to a group of genetic skin disorders characterized by the presence of dry, scaly, cracked, and/or flaky skin.
• Treating 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 of the tendon (e.g., acute, chronic, partial and/or complete rupture).
• 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
• tenosynovitis a tendinopathy of the outer lining of the tendon which occurs in certain tendons such as flexor tendons and the Achilles tendon.
• Symptoms of tendinopathy 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 stiffness; difficulty moving; weakness of the joint or muscles surrounding the tendon; redness of the skin near the tendon; swelling of the tendon and/or of tissue near the tendon; and/or crepitus.
• Tendinosis 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.
• Tendinitis refers to an inflammatory injury to the tendon, characterized by degeneration like that observed in tendinosis, but also accompanied by inflammation 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.
• tendinitis is referred to by the body part involved, such as Achilles tendinitis (affecting the Achilles tendon), or patellar tendinitis (also known as “jumper's knee,” affecting the patellar tendon), though there are certain exceptions, such as lateral epicondylitis (also known as “tennis elbow,” affecting the Extensor Carpi Radialis Brevis tendon).
• Symptoms can vary from aches or pains and local stiffness to a burning sensation surrounding the entire joint around the inflamed tendon.
• tendonitis is characterized by swelling, sometimes accompanied by heat and redness; there may also be visible knots surrounding the joint.
• the pain is usually worse during and after activity, and the tendon and j oint area can become suffer the following day as muscles tighten from the movement of the tendon.
• Psoriasis refers to an autoimmune disease in which skin cells build up and causes raised, red, scaly patches to appear on the skin.
• Dermatitis also known as eczema
• eczema refers to generic inflammation of the 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.
• Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drug thereof of Formula (I):
• R 1 , R 2 and R 4 are independently selected from the group consisting of H, Ci- alkyl, halide, -N(R 10 )2, -XR 10 , CN, -OCF3 and - CF 3 .
• R 3 is selected from the group consisting of carbocyclylR 6 , heterocyclylR 6 , arylR 6 and heteroarylR 6 .
• R 3 when R 3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole.
• R 5 is selected from the group consisting of -(Ci-9 alkyl) n carbocyclylR 7 , -(Ci- alkyl) n heterocyclylR 7 , -(Ci-9 alkyl) n arylR 7 and - (Ci-9 alkyl) n heteroarylR 7 .
• R 5 is not 4-pyridylR 7 when R 1 , R 2 and R 4 are H, R 3 is selected from the group consisting of 3-pyridylR 6 , 4-pyridyl 6 , 2-pyridylR 6 ,
• R 5 is not -(CH2)(3-pyridyl)R 7 when R 1 , R 2 and R 4 are H, R 3 is selected from the group consisting of 3-pyridylR 6 , 4-pyridylR 6 and thiazoleR 6 , and R 6 and R 7 are both H.
• R 5 is not phenylR 7 when R 1 , R 2 and R 4 are H, R 3 is 4-pyridylR 6 and R 6 and R 7 are both H.
• R 3 is not 3-pyridylR 6 when R 1 , R 2 and
• R is not oxazole R , R and 4 are H, R 5 is selected from the group consisting of an( j
• R 4 are H
• R 5 is selected from the group consisting of an
• R 6 is H.
• each R 10 is independently selected from the group consisting of H, C1-9 alkyl, -(C1-9 alkyl) n N(R 14 ) 2 , -(C1-9 alkyl) n carbocyclylR 8 , - (Ci-9 alkyl) n heterocyclylR 8 , -(C1-9 alkyl) n arylR 8 and -(Ci-9 alkyl) n heteroarylR 8 .
• each R 11 is independently selected from the group consisting of C1-9 alkyl, -N(R 14 ) 2 , -(C1-9 alkyl) n carbocyclylR 8 , -(C1-9 alkyl) n heterocyclylR 8 , -(C 1 -9 alkyl) n arylR 8 and -(Ci- 9 alkyl) n heteroarylR 8 .
• each R 12 is independently selected from the group consisting of H, C1-9 alkyl, -(C1-9 alkyl) n N(R 14 ) 2 , -(C1-9 alkyl) n carbocyclyl, -(Ci- 9 alkyl) n heterocyclyl, -(C1-9 alkyl) n aryl and -(Ci-9 alkyl) n heteroaryl.
• each R is independently selected from the group consisting of C1-9 alkyl, -N(R 14 )2, -(C1-9 alkyl) n carbocyclyl, -(C1-9 alkyl) n heterocyclyl, -(C 1 -9 alkyl) n aryl and -(Ci-9 alkyl) n heteroaryl.
• each R 14 is independently selected from the group consisting of H, C1-3 alkyl, carbocyclyl and aryl.
• each X is selected from the group consisting of a bond, -O- and -S-.
• each n is 0 or 1.
• X is O.
• R 1 , R 2 and R 4 are H.
• Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or ro-drug thereof of Formula (la):
• R 3 is selected from the group consisting of 3-pyridylR 6 , 5-pyrimidinylR 6 , and 4- pyridazinylR 6 ;
• R 5 is selected from the group consisting of -heteroarylR 7 ;
• R 6 is a substituent selected from the group consisting of -(Ci-2 alkyl)heterocyclylR 8 and -heterocyclylR 8 ;
• R 7 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, -NH 2 , -OCF3, -CF 3 , -CN, -OR 10 , -(C 1-2 alky l)heterocyclylR 9 , -heterocyclylR 9 , and
• R 8 is 1-2 substituents each independently selected from the group consisting of H, C 1 -3 alkyl, halide, and -OR 12 ;
• each R 9 is 1-2 substituents each independently selected from the group consisting of H, Ci-3 alkyl, halide, amino, -OCF3, -CF 3 , -CN, and -OR 12 ;
• R 10 is selected from the group consisting of H and C 1 -3 alkyl
• R 11 is Ci-3 alkyl
• each R 12 is independently selected from the group consisting of H and C1-3 alkyl.
• Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or ro-drug thereof of Formula (la):
• R 3 is 3-pyridylR 6 ;
• R 5 is selected from the group consisting of pyridylR 7 , -pyrimidinylR 7 , and - pyridazinylR 7 ;
• R 6 is -CH 2 heterocyclylR 8 ;
• R is 1-2 substituents each independently selected from the group consisting of H and halide.
• R 3 is selected from the group consisting of 3 -pyridylR 6 , 5 -pyrimidinylR 6 , and 4-pyridazinylR 6 ;
• R 5 is selected from the group consisting of -heteroarylR 7 .
• R 5 is selected from the group consisting of -piperazinylR 7 , -tetrahydropyranylR 7 , -piperidinylR 7 , pyrazolylR 7 , pyrimidinylR 7 , pyridazinylR 7 , benzo[ ⁇ f] [l,3]dioxolylR 7 , 2,3-dihydrobenzo[6] [l,4]dioxinylR 7 , pyrazinylR 7 , and 3 -pyridylR 7 .
• R 6 is a substituent selected from the group consisting of -(C 1-2 alky l)heterocyclylR 8 and -heterocyclylR 8 .
• R 7 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, -NH2, -OCF3, -CF3, - CN, -OR 10 , -(Ci- 2 alkyl)heterocyclylR 9 , -heterocyclylR 9 , and -SO2R 11 .
• R 8 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, and -OR 12 .
• each R 9 is 1-2 substituents each independently selected from the group consisting of H, C 1 -3 alkyl, halide, amino, -OCF 3 , -CF 3 , -CN, and -OR 12 .
• R 10 is selected from the group consisting of H and C 1 -3 alkyl.
• each R 10 is independently selected from the group consisting of H, C1-3 alkyl, -(C1-3 alkyl)N(R 14 ) 2 and -arylR 8 .
• R 11 is C1-3 alkyl.
• R 11 is each R 11 is independently selected from the group consisting of C1-3 alkyl, -N(R 14 ) 2 , -carbocyclylR 8 and -heterocyclylR 8 .
• each R 12 is independently selected from the group consisting of H and C1-3 alkyl.
• R 3 is selected from the group consisting of arylR 6 and heteroarylR 6 .
• R 3 when R 3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, lH-pyrrolo[2,3-c]pyridine and tetrazole.
• R 5 is selected from the group consisting of -carbocyclylR 7 , -heterocyclylR 7 , -arylR 7 , -heteroarylR 7 , and -(Ci- 2 alkyl)heteroarylR 7 .
• R 5 is not 4-pyridylR 7 when R 3 is selected from the group consisting of 3-pyridylR 6 , 4-pyridylR 6 , 2-pyridylR 6 , phenylR 6 ,
• thiazoleR imidazoleR , pyrimidineR , oxazoleR , an d , and R 6 and R 7 are both H.
• R 5 is not -(CH2)(3-pyridyl)R 7 when R 3 is selected from the group consisting of 3 -pyridylR 6 , 4-pyridylR 6 and thiazoleR 6 , and R 6 and R 7 are both H.
• R 5 is not phenylR 7 when R 3 is 4- pyridylR 6 and R 6 and R 7 are both H.
• Formula 3 is not 3-pyrid lR 6 when R 5 is selected from the group consisting of phenylR , , ,
• R is not oxazoleR when R is selected from the group consisting of an( j is H.
• each R 8 is 1-2 substituents each selected from the group consisting of H, Ci-3 alkyl, halide, amino, OCF3, -CF3 -CN and -OR 12 .
• each R 9 is 1-2 substituents each selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3 -CN and -OR 12 .
• each R 10 is independently selected from the group consisting of H, C1-3 alkyl, -(C1-3 alkyl)N(R 14 ) 2 and -arylR 8 .
• each R 11 is independently selected from the group consisting of C1-3 alkyl, -N(R 14 ) 2 , -carbocyclylR 8 and -heterocyclylR 8 .
• each R 12 is independently selected from the group consisting of H and C1-3 alkyl.
• each R 14 is independently selected from the group consisting of H, C 1 -3 alkyl and carbocyclyl.
• halide is fluorine
• R 3 is -arylR 6 .
• R 3 is -heteroarylR 6 .
• R 5 is -arylR 7 .
• R 5 is -heteroarylR 7 .
• R 5 is -heterocyclylR 7 .
• R 3 is -heteroarylR 6 and R 5 is -heteroarylR 7 .
• R 3 is -phenylR 6 and R 5 is -heteroarylR 7 .
• R 3 is -heteroarylR 6 and R 5 is -phenylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is -CH 2 -3-pyridylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is -pyridazinylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is -pyrazinylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is - pyrimidinylR 7 .
• R 3 is -3-pyridylR 6 and R 5 is benzo[ ⁇ f][l,3]dioxolyl.
• R 3 is -3-pyridylR 6 and R 5 is 2,3-dihydrobenzo[6][l,4]dioxinyl.
• the aryl is phenyl
• the heteroaryl is benzo[tf][l,3]dioxolyl.
• the heteroaryl is 2,3-dihydrobenzo[6][l,4]dioxinyl.
• R 6 is a heterocyclyl.
• the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl.
• R 6 is morpholinyl.
• R 6 is piperazinyl.
• R 6 is piperidinyl.
• R 6 is pyrrolidinyl.
• R 7 is a heterocyclyl.
• the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl.
• R 7 is morpholinyl.
• R 7 is piperazinyl.
• R 7 is piperidinyl.
• R 7 is pyrrolidinyl.
• R 7 is azetidinyl.
• R 10 is a carbocyclyl.
• the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 10 is cyclopropyl.
• R 10 is cyclobutyl.
• R 10 is cyclopentyl.
• R 10 is cyclohexyl.
• R 11 is a heterocyclyl.
• the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl.
• R 11 is mo ⁇ holinyl.
• R 11 is piperazinyl.
• R 11 is piperidinyl.
• R 11 is pyrrolidinyl.
• R 11 is azetidinyl.
• R 11 is a carbocyclyl.
• the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 11 is cyclopropyl.
• R 11 is cyclobutyl.
• R 11 is cyclopentyl.
• R 11 is cyclohexyl.
• R 12 is a carbocyclyl.
• the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 12 is cyclopropyl.
• R 12 is cyclobutyl.
• R 12 is cyclopentyl.
• R 12 is cyclohexyl.
• R 13 is a heterocyclyl.
• the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl.
• R 13 is morpholinyl.
• R 13 is piperazinyl.
• R 13 is piperidinyl.
• R 13 is pyrrolidinyl.
• R 13 is azetidinyl.
• R 13 is a carbocyclyl.
• the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• R 13 is cyclopropyl.
• R 13 is cyclobutyl.
• R 13 is cyclopentyl.
• R 13 is cyclohexyl.
• R 6 is one substituent.
• R 6 is 1-2 substituents.
• R 6 is 1-3 substituents.
• R 6 is 1-4 substituents.
• R 6 is H.
• R 6 is one substituent and the substituent is a halide.
• R 6 is one substituent and the substituent is -Nth.
• R 6 is one substituent and the substituent is -OCF3.
• R 6 is one substituent and the substituent is -OCH3.
• R 6 is one substituent and the substituent is -CF3.
• R 6 is one substituent and the substituent is -heterocyclylR 8 .
• R 6 is one substituent and the substituent is -(CtyheterocyclylR 8 .
• R 6 is one substituent and the substituent is -(CtypyrrolidinylR 8 .
• R 6 is one substituent and the substituent is -(CtypyrrolidinylR 8 where R 8 is two substituents and both substituents are halides.
• R 6 is one substituent and the substituent is -(CtypiperidinylR 8 .
• R 6 is one substituent and the substituent is -(CtyphenylR 8 .
• R 6 is one substituent and the substituent is - phenoxyR 8 .
• nts of Formula I or Formula la, R 6 is one substituent
• R 6 is one substituent and the substituent is -N(R 10 ) 2 .
• R 6 is one substituent and the substituent is -N(R 10 ) 2 where each R 10 is independently selected from C 1 -3 alkyl.
• R 6 is one substituent and the substituent is -(CH 2 )N(R 10 ) 2 .
• R 6 is one substituent and the substituent is -(CH2)N(R 10 )2 where each R 10 is independently selected from C1-3 alkyl.
• R 6 is one substituent and the substituent is -N(R 10 )SO 2 R u .
• R 6 is two substituents and the substituents are fluorine and -(Ci- alkyl) n heterocyclylR 8 .
• R 6 is two substituents and the substituents are fluorine and -heterocyclylR 8 .
• R 6 is two substituents and the substituents are fluorine and -(Ci-2 alkyl)heterocyclylR 8 .
• R 6 is one substituent
• R 7 is one substituent.
• R 7 is 1-2 substituents.
• R 7 is 1-3 substituents.
• R 7 is 1-4 substituents.
• R 7 is one substituent and the substituent is a halide.
• R 7 is one substituent and the substituent is -Nth.
• R 7 is one substituent and the substituent is -OH.
• R 7 is one substituent and the substituent is -CF 3 .
• R 7 is one substituent and the substituent is -CN.
• R 7 is one substituent and the substituent is -XR 10 where X is O and R 10 is C1-3 alkyl.
• R 7 is one substituent and the substituent is -OR 10 and R 10 is C1-3 alkyl.
• R 7 is one substituent and the substituent is -phenylR 9 .
• R 7 is one substituent and the substituent is -(CH 2 )N(R 10 ) 2 .
• R 7 is one substituent and the substituent is -(CH2)N(R 10 )2 where each R 10 is independently selected from C1-3 alkyl.
• R 7 is one substituent and the substituent is -(CtyheterocyclylR 9 .
• R 7 is one substituent and the substituent is -(CtypyrrolidinylR 9 .
• R 7 is one substituent and the substituent is -heterocyclylR 9 .
• R 7 is one substituent and the substituent is - phenoxyR 9 .
• R 7 is one substituent and the substituent is -(CH 2 )phenylR 9 .
• R 7 is one substituent and the substituent is -phenylR 9 .
• R 7 is one substituent and the substituent is -N(R 10 ) 2 .
• R 7 is one substituent and the substituent is -SO2R 11 .
• R 7 is one substituent and the substituent is -SO2R 11 ; and R 11 is C1-3 alkyl.
• R 7 is two substituents and the substituents are C1-3 alkyl and -heterocyclylR 9 .
• R 7 is one substituent
• R is one substituent.
• R 8 is 1-2 substituents.
• R 8 is 1-3 substituents.
• R 8 is 1-4 substituents.
• R 8 is H.
• R 8 is one substituent and the substituent is C1-3 alkyl.
• R 8 is one substituent and the substituent is -OH.
• R 8 is one substituent and the substituent is a halide.
• R 8 is two substituents and the substituents are halides.
• R 8 is three substituents and the substituents are halides.
• R 9 is one substituent.
• R 9 is 1-2 substituents. [0233] In some embodiments of Formula I, R 9 is 1-3 substituents.
• R 9 is 1-4 substituents.
• R 9 is H.
• R 9 is one substituent and the substituent is C1-3 alkyl.
• R 9 is one substituent and the substituent is -OH.
• R 9 is one substituent and the substituent is a halide.
• R 9 is two substituents and the substituents are halides.
• R 8 is a -C1-3 alkyl.
• the -C 1 -3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.
• R 8 is methyl.
• R 8 is ethyl.
• R 10 is a -C 1 -3 alkyl.
• the -C 1 -3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl.
• R 10 is methyl.
• R 10 is ethyl.
• R 10 is n-propyl.
• R 10 is iso-propyl.
• R 11 is a -C1-3 alkyl.
• the -C1-3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl.
• R 11 is methyl.
• R 11 is ethyl.
• R 11 is n-propyl.
• R 11 is iso-propyl.
• R 14 is a -C1-3 alkyl.
• the -C1-3 alkyl can be selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl.
• R 14 is methyl.
• R 14 is ethyl.
• R 14 is n-propyl.
• R 14 is iso-propyl.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)N(R 10 )2; and
• R 7 is one substituent consisting of -CF3; and each R 10 is -C1-3 alkyl.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(Ci- 2 alkyl)heterocyclylR 8 ;
• R 7 and R 8 are both H; and the heterocycle is a 5 -member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(Ci-2 alkyl)heterocyclylR 8 ;
• R 7 and R 8 are both H; and the heterocycle is a 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of CN;
• R 8 is H; and the heterocycle is a 5 -member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of CN;
• R 8 is H; and the heterocycle is a 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of CF3;
• R 8 is H; and the heterocycle is a 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of -heterocyclylR 8 ;
• each R 8 is H; and the heterocycles are independently selected from a 5 or 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)N(R 10 )2; and
• R 7 is one substituent consisting of -CN; and each R 10 is -C 1 -3 alkyl.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)N(R 10 )2; and
• R 7 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 8 is H; each R 10 is -C1-3 alkyl; and the heterocycle is a 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of -heterocyclylR 8 ;
• each R 8 is one substituent independently selected from H and -OH; and the heterocycles are independently selected from a 5 or 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 11 is -heterocyclylR 8 ;
• each R 8 is H; and the heterocycles are independently selected from a 5 or 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of -heterocyclylR 8 ;
• each R 8 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.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 11 is -NHR 10 ;
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is one substituent consisting of -SO2R 11 ;
• R 8 is H;
• R 11 is -C1-3 alkyl; and the heterocycle is a 6-member ring.
• R 3 is -3-pyridylR 6 and R 5 is -3-pyridylR 7 ;
• R 6 is one substituent consisting of -(C1-2 alkyl)heterocyclylR 8 ;
• R 7 is H;
• R 8 is 1-4 substituents independently selected from H and F with the proviso that at least one substituent is fluorine; and the heterocycle is a 5-member ring.
• nuclear magnetic resonance spectra were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 3 ⁇ 4 or Avance TM DRX500, 500 MHz for 3 ⁇ 4) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 3 ⁇ 4). 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, triplet of doublets; m, multiplet.
• DIPEA diisopropylethylamine
• HATU 2-(lH-7-azabenzotriazol-l-yl)-l, l,3,3-tetramethyluronium
• H2SO4 sulfuric acid
• K3PO4 potassium phosphate
• LAH lithium aluminum hydride
• MgS04 magnesium sulfate
• NaBH(OAc)3 sodium triacetoxyborohydride
• NaHCC sodium bicarbonate
• NaHS03 sodium bisulfite
• NaHS04 sodium bisulfate
• PdChidppf l, l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride
• Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
• PPTS pyridinium p-toluenesulfonate
• Tr-Cl trityl chloride or triphenylmethyl chloride
• Scheme 1 describes a method for preparation of indazole-3-carboxamide derivatives (I) by first forming the Weinreb amide (III) of a lH-indazole-3-carboxylic acid (II).
• the Weinreb amide (III) is reacted with (bis(trifluoroacetoxy)iodo)benzene to produce the 5- iodo-lH-indazole-3-carboxylic acid (IV) followed by ⁇ protection of the indazole nitrogen.
• the Weinreb amide of protected indazole V is reduced to aldehyde VI followed by reaction with bis(pinacolato)diboron to give the pinacol ester (VII).
• Scheme 2 describes an alternative method for preparation of indazole-3- carboxamide derivatives (I) 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.
• 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 indazole -3 -carboxamide derivatives (I).
• Scheme 3 describes another alternative method for preparation of indazole- 3-carboxamide derivatives (I) by bromination of the indazole 5-position followed by either Route 1 : esterification to form ester XII, then trityl protection of the indazole nitrogen and then finally hydrolyzed of the ester to acid XVII; or Route 2: trityl protection of the indazole nitrogen directly to acid XVII.
• the acid is coupled with a variety of amines to produce amide XVIII which is then coupled with a variety of boronic acids (Route 3) to give XIX.
• XVIII can be converted to the boronate ester and then couple to a variety of bromides (Route 4) to yield XIX.
• Route 4 a variety of bromides
• Final deprotection of the indazole nitrogen yields the desired indazole-3-carboxamide derivatives (I).
• the vessel was sealed, and the reaction was heated to 130°C for 5 h in a microwave reactor.
• the solvent was decanted away from the solid material and concentrated to a residue.
• the residue was purified by silica gel chromatography using a 40 g Thomson normal -phase silica gel cartridge (100% CHC1 3 ⁇ 3:97 MeOH[7N NH 3 ]:CHC1 3 ) to afford 5-((dimethylamino)methyl)-N-(4- methoxybenzyl)pyridin-3 -amine (LVI) (0.68 g, 2.49 mmol, 42% yield) as a yellow solid.
• 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-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole-3-carboxamide (CXIII) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0°C until the reaction was completed, approximately 30 min. The reaction was quenched by the slow addition of EtOAc at 0°C, and the whole mixture was poured into 0.4 N aqueous NaHSO/t.
• HATU (0.190 g, 0.5 mmol) was added to a solution of 5 -(5 -(3,3- dimethylureido)pyridin-3-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylic acid (CXXIV) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol) in DMF stirred at room temperature under argon. After stirring 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.
• CXXIV 5 -(5 -(3,3- dimethylureido)pyridin-3-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylic acid
• HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-3-carboxylic 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-amino-2-trifluoromethyl pyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon.
• CXXVII 5-amino-2-trifluoromethyl pyridine
• 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 vacuum. The residue was treated with water, sonicated briefly and the solids formed were filtered.

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