WO2019070742A1 - Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds - Google Patents

Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds Download PDF

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WO2019070742A1
WO2019070742A1 PCT/US2018/054006 US2018054006W WO2019070742A1 WO 2019070742 A1 WO2019070742 A1 WO 2019070742A1 US 2018054006 W US2018054006 W US 2018054006W WO 2019070742 A1 WO2019070742 A1 WO 2019070742A1
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compound
amino
triazol
pyridin
isopropyl
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PCT/US2018/054006
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French (fr)
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Martin W. Rowbottom
John. H. HUTCHINSON
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Sidecar Therapeutics, Inc.
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Publication of WO2019070742A1 publication Critical patent/WO2019070742A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Described herein are compounds that are apoptosis signal-regulating kinase 1 (ASKl) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASKl activity.
  • ASKl apoptosis signal-regulating kinase 1
  • ASKl a serine threonine kinase, activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • JNK c-Jun N-terminal kinase
  • p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • JNK c-Jun N-terminal kinase
  • p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx.
  • ASKl is implicated in the development and progression of fibrosis, cancer, diabetes, cardiovascular and
  • ASKl inhibitors and uses thereof.
  • the ASKl inhibitors described herein have the structure of Formula (I), or a pharmaceutically acceptable salt thereof.
  • described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • Ci-C 4 fluoroalkyl substituted or unsubstituted
  • Ci-C 4 deuteroalkyl or substituted or unsubstituted Ci-C 4 heteroalkyl
  • n 0, 1, or 2;
  • each R 1 is independently H, substituted or unsubstituted Ci-C 4 alkyl, substituted or
  • Ci-C 4 fluoroalkyl substituted or unsubstituted Ci-C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ;
  • r 0, 1, or 2;
  • L 1 is linker that is L 4 or -L 4 -X a -L 3 -;
  • L 2 is linker that is -L 4 -X a -L 4 -;
  • R 8 is H, Ci-C 6 alkyl, Ci-Cefluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 3 is Ci-C 6 alkylene
  • each L 4 is independently absent, or Ci-C 6 alkylene
  • R 7 is substituted or unsubstituted phenyl, substituted or unsubstituted C 3 - C 8 cycloalkyl, or a substituted or unsubstituted C 2 -C 8 heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 2 is H, Ci-C 6 alkyl, or Ci-C 6 deuteroalkyl
  • each R 3 is independently H, D, halogen, -CN, -OH, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 fluoroalkoxy, substituted or unsubstituted Ci-C 4 deuteroalkyl, or substituted or unsubstituted Ci-C 4 heteroalkyl; q is 0, 1, 2, or 3;
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • ring C is a 5-membered heteroaryl
  • each R 4 is independently selected from substituted or unsubstituted Ci-C 6 alkyl
  • Ci-C 6 fluoroalkyl substituted or unsubstituted Ci- C 6 fluoroalkyl, substituted or unsubstituted Ci- C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, substituted or unsubstituted Ci-C 6 alkyl,
  • Ci-Cefluoroalkyl substituted or unsubstituted Ci- C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ci 0 cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl; or two R 5 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.
  • the compound of Formula (I) has the following structure of Formula (II), or a pharmaceuticall acceptable salt, or solvate thereof:
  • X 1 is N or CR ;
  • n 0, 1, 2, or 3.
  • the compound of Formula (I) has the following structure of Formula (III), or a pharmaceutically acceptable salt, or solvate thereof:
  • X 1 is N or CR ;
  • X 2 is N or CR C ;
  • n 0, 1, 2, or 3.
  • the compound of Formula (I) has the following structure:
  • the compound of Formula (I) has the following structure:
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • described herein is a method of treating a disease or condition in a mammal that would benefit from the inhibition of apoptosis signal-regulating kinase 1 (ASK1) activity comprising administering to the mammal a compound, or pharmaceutically acceptable salt, or solvate thereof, as described herein.
  • ASK1 apoptosis signal-regulating kinase 1
  • the inhibition of ASK1 inactivates c-Jun N-terminal protein kinase, p38 MAP kinase, or a combination thereof.
  • the disease or condition is fibrosis, cancer, an autoimmune disease or condition, an inflammatory disease or condition, a cardiovascular disease or condition, a neurodegenerative disease or condition, or combinations thereof.
  • the disease or condition is fibrosis.
  • the fibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis or cutaneous fibrosis
  • described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
  • described herein is a method for the treatment or prevention of fibrosis in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the fibrosis is amenable to treatment with an ASK1 inhibitor.
  • the fibrosis is liver fibrosis.
  • the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is administered on a continuous daily dosing schedule.
  • any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • each agent is administered in any order, including simultaneously.
  • the mammal is a human.
  • compounds provided herein are administered to a human.
  • compounds provided herein are orally administered.
  • Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of ASK1, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition or reduction of the ASK1 activity, are provided.
  • MAPKs Mitogen-activated protein kinases
  • MAPK networks are critical for the transmission of extracellular signals into appropriate intracellular responses, such as, but not limited to cell growth, differentiation, inflammation, and apoptosis.
  • Prototypical MAPK activation employs a three-kinase core module consisting of a MAPK kinase kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase (MAP2K, MEK, or MKK) that in turn phosphorylates and dramatically increases the activity of one or more MAPK kinase kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase (MAP2K, MEK, or MKK) that in turn phosphorylates and dramatically increases the activity of one or more MAPK kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase (MAP2K, MEK, or MKK) that in turn phosphorylates and dramatically increases the activity of one or more MAPK kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase
  • Apoptosis signal-regulating kinase 1 is a member of the MAP3K family that activates the c-Jun N-terminal protein kinase (JNK) and p38 MAPK.
  • ASKl also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), is activated by a variety of stimuli including hyperglycaemia, transforming growth factor beta (TGF- ⁇ ), oxidative stress, reactive oxygen species (ROS), lipopolysaccharides (LPS), tumor necrosis factor alpha (T Fa), Fas ligand (FasL), endoplasmic reticulum (ER) stress, and increased intracellular calcium
  • TGF- ⁇ transforming growth factor beta
  • ROS reactive oxygen species
  • LPS lipopolysaccharides
  • T Fa tumor necrosis factor alpha
  • FasL Fas ligand
  • ER endoplasmic reticulum
  • ROS have been reported to be associated with increase of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS.
  • AGEs advanced glycation end-products
  • ASKl induces apoptosis, fibrosis and metabolic dysfunction by activating the p38 and JNKl pathways.
  • ASKl undergoes activation via autophosphorylation at Thr838 in response to these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which then phosphorylate and activates p38 and JNK MAPKs, respectively.
  • ASK2 is a related MAP3K that shares 45% sequence homology with ASKl .
  • ASK2 tissue distribution is restricted, in some cell types ASKl and ASK2 have been reported to interact and function together in a protein complex. In non-stressed conditions, ASKl is kept in an inactive state through binding to its repressor thioredoxin (Trx) and through association with AKT.
  • Trx repressor thioredoxin
  • ASKl protein can lead to apoptosis or other cellular responses depending on the cell type.
  • ASKl activation and signaling have been reported to play a role in a broad range of diseases including fibrosis, neurodegenerative, cardiovascular, inflammatory, autoimmunity, and metabolic disorders.
  • ASKl has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, liver and kidney.
  • Fibrosis is a wound-healing process in which there is excessive deposition of extracellular matrix (ECM).
  • ECM is composed of collagens, noncollagen glycoproteins, matrix bound growth factors, glycosaminoglycans, proteoglycans and matricellular proteins, which provide the scaffolding of both the normal and the fibrotic tissues.
  • glycoproteins e.g. cellular fibronectin, laminin, SPARC, osteonectin, tenascin and von Willebrand factor
  • glycosaminoglycans e.g.
  • perlecan perlecan, decorin, aggrecan, lumican and fibromodulin
  • HSCs hepatic stellate cells
  • Non-alcoholic steatotic hepatitis is an exemplary type of fibrosis implicating ASK1 activity.
  • Multiple pathways are involved in NASH-associated fibrosis including inflammasome-TLR activation and generation of the inflammatory cytokines, increased levels of hedgehog signalling, changes in lipid and glucose metabolism leading to oxidative stress, hepatocyte injury via apoptosis, cell death inducing inflammatory and pro-fibrogenic pathways in nonparenchymal cells and infiltrating immune cells.
  • ECM extracellular matrix
  • disclosed herein are methods of treating fibrosis with a compound disclosed herein.
  • Fibrosis refers to the accumulation of extracellular matrix
  • Fibrosis may refer to the development of fibrous connective tissue as a reparative response to injury or damage. Fibrosis may also refer to the connective tissue deposition that occurs as part of normal healing or to the excess tissue deposition that occurs as a pathological process.
  • a method of reducing fibrosis in a tissue comprising contacting a fibrotic cell or tissue with a compound disclosed herein, in an amount sufficient to decrease or inhibit the fibrosis.
  • the fibrosis includes a fibrotic condition.
  • the fibrosis comprises liver fibrosis, kidney fibrosis, lung fibrosis, cardiac fibrosis, peritoneal fibrosis, ocular fibrosis or cutaneous fibrosis.
  • the fibrosis comprises liver fibrosis.
  • the fibrosis comprises kidney fibrosis.
  • the fibrosis comprises cardiac fibrosis.
  • the fibrosis comprises lung fibrosis.
  • the fibrosis comprises peritoneal fibrosis.
  • the fibrosis comprises ocular fibrosis.
  • the fibrosis comprises cutaneous fibrosis.
  • reducing fibrosis, or treatment of a fibrotic condition includes reducing or inhibiting one or more of: formation or deposition of extracellular matrix proteins; the number of pro-fibrotic cell types (e.g., fibroblast or immune cell numbers); cellular collagen or hydroxyproline content within a fibrotic lesion; expression or activity of a fibrogenic protein; or reducing fibrosis associated with an inflammatory response.
  • the fibrotic condition is liver fibrosis.
  • Liver fibrosis refers to the scar tissue and nodules that replace liver tissue and disrupt liver function.
  • the scar tissue blocks the portal flow of blood through the organ therefore disturbing normal function. Damage to the hepatic parenchyma due to inflammation leads to activation of the stellate cell, which increases fibrosis through production of myofibroblasts and obstructs blood flow in the circulation.
  • Non-alcoholic fatty liver disease is a common liver disease characterized by fat accumulation in hepatocytes that is not linked to excessive alcohol intake and is correlated with obesity, insulin resistance, and cardiac diseases.
  • NAFLD is categorised into simple steatosis and non-alcoholic steatotic hepatitis (NASH), the latter of which can lead to hepatic fibrosis, hepatic cirrhosis, and liver cancer.
  • High fat diet (HFD) is used to induce hepatic steatosis in mouse models. HFD causes fat accumulation and fatty acid oxidation, which leads to ROS generation and subsequent hepatocyte dysfunction and cell death in the liver.
  • TNFa-deficient mice show reduced hepatic steatosis, indicating that proinflammatory cytokines including TNFa are required for liver injury.
  • TNFa-induced apoptosis of hepatocytes is mediated by ASKl -INK activation.
  • ASKl -deficient mice have reduced HFD-induced hepatic steatosis, fibrosis, and TGFp expression, which is responsible for hepatic fibrosis.
  • Olmesartan, an ATI blocker also improves HFD-induced hepatic steatosis by inhibiting ASKl .
  • olmesartan or ASKl deficiency can attenuate HFD-induced cardiac inflammation and fibrosis, and vascular endothelial dysfunction and remodelling.
  • the ASKl pathway has been shown to be activated in human NASH liver biopsies.
  • animals with established NASH Fl/2
  • a small molecule inhibitor of ASKl significantly reduced hepatic steatosis and fibrosis and significantly improved key metabolic parameters associated with NASH.
  • Treatment with a small molecule inhibitor of ASKl resulted in a significant reduction in body weight; decreased fasting blood glucose and insulin levels; reduction in plasma AST, ALT and cholesterol levels; a reduction in hepatic steatosis; a reduction in liver
  • hydroxyproline a reduction in alpha smooth muscle actin and p-P38 expression; a reduction in fibrillar collagen area and reduced synthesis of collagen.
  • ASK1 inhibition also reduced hepatic fibrosis, steatosis and insulin resistance and normalised fatty acid synthesis and lipid metabolism.
  • the fibrotic condition is a fibrotic condition of the lung.
  • Lung or pulmonary fibrosis refers to a number of conditions that cause interstitial lung damage, followed by accumulation of extracellular matrix constituents and eventually loss of lung elasticity and function. These conditions lead to symptoms such as persistent coughing, chest pain, difficulty breathing and fatigue. Lung fibrosis may occur as a secondary condition in various diseases.
  • the fibrotic condition is a fibrotic condition of the heart.
  • Cardiac fibrosis refers to the damage of the heart areas due to myocardial infarction or Davies' disease. Cardiac fibrosis can affect the valves in the heart as well as the muscles, which become stiff and less compliant. This can increase the risk of heart failure.
  • the fibrotic condition is a fibrotic condition of the kidney.
  • Kidney fibrosis refers to an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease.
  • the pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation.
  • Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial -mesenchymal transition, have been identified as the major ways for the generation of the matrix-producing cells in diseased conditions.
  • transforming growth factor-beta TGF- beta
  • TGF- beta transforming growth factor-beta
  • the fibrotic condition is a fibrotic condition of the skin.
  • the fibrotic condition is a fibrotic condition of the eye.
  • the fibrotic condition is a fibrotic condition of the
  • the fibrotic condition is a fibrotic condition of the bone marrow.
  • the fibrotic condition is idiopathic.
  • the fibrotic condition is associated with (e.g., is secondary to) a disease (e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and/or a connective disease); a toxin; an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarette smoking, a wound); a medical treatment (e.g., surgical incision, chemotherapy or radiation), or a combination thereof.
  • a method for the treatment or prevention of fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • disclosed herein is a method of improving lung function in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • the mammal has been diagnosed as having lung fibrosis.
  • a method of treating idopathic pulmonary fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • disclosed herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in a tissue of a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the tissue results in fibrosis.
  • a method for the treatment or prevention of scleroderma in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
  • a method for reducing undesired or abnormal dermal thickening in a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the dermal thickening is associated with scleroderma.
  • described herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in tissues of a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof.
  • the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the dermal tissues results in fibrosis.
  • described herein is a method of reducing hydroxyproline content in tissues of a mammal with fibrosis comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a
  • compounds described herein are used in the treatment of fibrosis associated with arthrofibrosis, Crohn's Disease, Dupuytren's contracture, keloids, myelofibrosis, Peyronie's disease, or scleroderma/systemic sclerosis.
  • anti-fibrotic strategies include (i) removing the injurious stimuli,
  • anti-fibrotic strategies in NASH include (a) removing the injurious stimuli, (b) suppressing or modulating hepatic inflammation, (c) protecting the liver, (d) downregulating stellate cell activation and (e) promoting matrix degradation.
  • Fibrosis such as hepatic fibrosis in NASH, is driven by multiple risk factors that may interact with each other via several inter-related mechanistic pathways. It is plausible that the injurious stimuli may be heterogenous, but the resultant response in laying down of collagen and worsening of fibrosis may be a common response. In some embodiments, multiple targets may be required to reverse or halt fibrosis. Removal of cause would be the most efficient way to improve fibrosis. This has been supported by observations seen with other chronic diseases, including hepatitis C and B.
  • Cardiovascular diseases include, but are not limited to,
  • compounds described herein are used in the treatement of diseases of the retina.
  • compounds described herein are used in the treatement of diseases of the spinal cord.
  • ASK1 plays a role in the pathogenesis of ventricular remodelling by promoting apoptosis or cardiomyocyte hypertrophy.
  • ASK1 is aldosterone- induced cardiac inflammation and fibrosis through induction of monocyte chemoattractant protein (MCP)-l and transforming growth factor (TGF)-pi expression, respectively.
  • MCP monocyte chemoattractant protein
  • TGF transforming growth factor
  • Neurodegenerative disorders include, but are not limited to, Huntington's disease (HD), spinobulbar muscular atrophy, spinocerebeller ataxia (SCA), Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Normal -tension glaucoma.
  • HD Huntington's disease
  • SCA spinobulbar muscular atrophy
  • SCA spinocerebeller ataxia
  • ALS Amyotrophic lateral sclerosis
  • Alzheimer's disease Parkinson's disease
  • Normal -tension glaucoma Normal glaucoma.
  • Inflammatory diseases include, but are not limited to, multiple sclerosis, rheumatoid arthritis.
  • compounds described herein are used in the treatment of respiratory diseases.
  • ASKl also plays a role in airway remodelling, an irreversible hypertrophic change that occurs in chronic bronchitis.
  • Leukotriene D4 has been suggested to activate ASKl and induce AP-1 activation in airway smooth muscle cells, leading to airway remodelling.
  • Respiratory diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthmas and acute lung injury.
  • COPD chronic obstructive pulmonary disease
  • asthmas and acute lung injury.
  • TNFa is one of the factors that aggravate insulin resistance.
  • TNFa induces ROS production in the mitochondria and activates INK via ASKl, which leads to insulin receptor substrate-1 (IRS-1) serine phosphorylation.
  • INK insulin receptor substrate-1
  • Such phosphorylation decreases tyrosine phosphorylation of IRS-1 resulting in insulin resistance and eventually causing type 2 diabetes.
  • compounds described herein are used in the treatement of liver injury.
  • Consumption of large quantities of acetaminophen a widely used analgesic and antipyretic agent, is known to cause liver injury.
  • acetaminophen a widely used analgesic and antipyretic agent
  • INK acetaminophen-induced, sustained activation of INK is suppressed and resistance to liver injury increased, indicating that the ASKl -INK pathway plays a critical role in acetaminophen-induced liver injury.
  • ASKl has also been reported to be involved in liver injury induced by troglitazone, a first- generation thiazolidinedione insulin sensitizer that has been linked to an unacceptable risk of liver injury in patients.
  • compounds described herein are used in the treatment of ageing.
  • ROS is thought to be one of the major causes of ageing.
  • long-lived mouse models such as Snell dwarf mice, Ames dwarf mice, and Klotho overexpressing mice, are known to be resistant to oxidative stress.
  • Mouse embryonic fibroblasts (MEFs) derived from Ames dwarf mice possess a larger amount of the Trx -bound form of ASKl and have less p38 activity than those derived from WT mice, suggesting that activity of the ASKl-p38 pathway is attenuated in Ames dwarf mice.
  • ROS-induced ASKl activity contributes to regulation of ageing-related cellular functions.
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are ASK1 inhibitors.
  • each R a is independently H, D, halogen, -CN, -OR 5 , substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 deuteroalkyl, or substituted or unsubstituted Ci-C 4 heteroalkyl; m is 0, 1, or 2;
  • each R 1 is independently H, substituted or unsubstituted Ci-C 4 alkyl, substituted or
  • Ci-C 4 fluoroalkyl substituted or unsubstituted Ci-C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ;
  • r 0, 1, or 2;
  • L 1 is linker that is L 4 or -L 4 -X a -L 3 -;
  • L 2 is linker that is -L 4 -X a -L 4 -;
  • R 8 is H, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, or Ci-C 6 deuteroalkyl;
  • L 3 is Ci-C 6 alkylene
  • each L 4 is independently absent, or Ci-C 6 alkylene
  • R 2 is H, Ci-C 6 alkyl, or Ci-C 6 deuteroalkyl
  • each R 3 is independently H, D, halogen, -CN, -OH, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 fluoroalkoxy, substituted or unsubstituted Ci-C 4 deuteroalkyl, or substituted or unsubstituted Ci-C 4 heteroalkyl; q is 0, 1, 2, or 3;
  • ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl
  • ring C is a 5-membered heteroaryl
  • each R 4 is independently selected from substituted or unsubstituted Ci-C 6 alkyl
  • Ci-Cefluoroalkyl substituted or unsubstituted Ci- C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -Ci 0 cycloalkyl, substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl;
  • each R 5 is independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 fluoroalkyl, substituted or unsubstituted Ci- C 6 deuteroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl; or two R 5 on the same N atom are taken together with the
  • substituents are selected from among a subset of the listed alternatives.
  • R 2 is H, or Ci-C 6 alkyl.
  • R 2 is H, or Ci-C 6 alkyl.
  • R 2 is H, -CH 3 , or -CH 2 CH 3 .
  • R 2 is H.
  • ring B is a 6-membered heteroaryl containing 1-3 N atoms or phenyl.
  • ring B is a pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or phenyl.
  • ring B is a pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or phenyl.
  • ring B is a pyridinyl, or phenyl.
  • ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
  • ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, thiadiazolyl, or furazanyl.
  • ring B is a 6-membered heteroaryl containing 1-3 N atoms or phenyl
  • ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
  • ring B is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • the groups are in a 1,3- relationship on ring B.
  • X 1 is N or CR ; n is 0, 1, 2, or
  • the compound of Formula (I) has the following structure of Formula (II), or a pharmaceuticall acceptable salt, or solvate thereof:
  • X 1 is N or CR ;
  • n 0, 1, 2, or 3.
  • ring B is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl;
  • ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • X 2 is N. In some embodiments, X 2 is CR C .
  • the compound of Formula (I) has the following structure of Formula (III), or a pharmaceuticall acceptable salt, or solvate thereof:
  • X 1 is N or CR ;
  • X 2 is N or CR C ;
  • n 0, 1, 2, or 3.
  • rin is a fused 5-membered heterocyle containing 1 carbonyl in the ring.
  • each R a is independently H, D, F, CI, Br, -CN, -OH, -OCH 3 , OCH 2 CH 3 , -OCF 3 , -OCH 2 CF 3; -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , - CH2CF 3 , -CD 3 , -OCD 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R a is independently H, D, F, CI, Br, -CN, -OH, -OCH 3 , - OCF 3 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CD 3 , and -OCD 3 .
  • each R 3 is independently H, D, F, CI, -CN, -OH, -CH 3 , - CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCH 3 , OCH 2 CH 3 , -OCF 3 , or -CD 3 .
  • q is 0 or 1.
  • each R 1 is independently H, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci- C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ; r is 0, 1, or 2; L 1 is linker that is L 3 or -L 4 -X a -L 3 -; L 2 is linker that is -L 4 -X a -L 4 -.
  • each R 1 is independently H, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci- C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ; r is 0, 1, or 2; L 1 is linker that is L 4 or -L 4 -X a -L 3 -; L 2 is linker that is -L 4 -X a -L 4 -. [00110] In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1. In some embodiments, r is 0.
  • each R 1 is independently H, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci- C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ;
  • L 1 is linker that is L 3 or -L 4 -X a -L 3 -;
  • L 2 is linker that is -L 4 -X a - L 4 -;
  • R 8 is H, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci-C 4 deuteroalkyl;
  • L 3 is Ci- C 6 alkylene; each L 4 is independently absent, or Ci-C 6 alkylene.
  • each R 1 is independently H, Ci-C alkyl, Ci-C fluoroalkyl, Ci- C 4 deuteroalkyl, -I ⁇ -R 6 or -L 2 -R 7 ;
  • L 1 is linker that is L 4 or -L 4 -X a -L 3 -;
  • L 2 is linker that is -L 4 -X a - L 4 -;
  • R 8 is H, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci-C 4 deuteroalkyl;
  • L 3 is Ci- C 6 alkylene; each L 4 is independently absent, or Ci-C 6 alkylene.
  • each R 1 is independently H, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, or substituted or unsubstituted Ci- C deuteroalkyl. In some embodiments, each R 1 is independently H, Ci-C alkyl, Ci-C fluoroalkyl, or Ci-C deuteroalkyl.
  • L 3 is Ci-C 4 alkylene.
  • L 3 is -CH 2 -, - CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • L 3 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • each L 4 is independently absent or Ci-C alkylene. In some embodiments, each L 4 is independently absent, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - , -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -. In some embodiments, each L 4 is independently absent, - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • X a is -NR 8 -, -
  • R 7 is substituted or unsubstituted phenyl, substituted or unsubstituted C3-C 6 cycloalkyl, or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R 7 is substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered or 6-membered C 2 - C 6 heterocycloalkyl, or substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl. In some embodiments, R 7 is substituted or unsubstituted phenyl, or substituted or unsubstituted 6-membered monocyclic heteroaryl.
  • the compound of Formula (I) has the following structure:
  • R c is as described in Table 1. In some embodiments, R c is as described in Table 2. In some embodiments, R c is as described in Table 1 or Table 2. In some embodiments,
  • R c is as described in Table 1 and
  • R c is as described in
  • the compound of Formula (I) has the following structure:
  • R c is as described in Table 1. In some embodiments, R c is as described in Table 2. In some embodiments, R c is as described in Table 1 or Table 2. In some embodiments,
  • R c is as described in Table 2 and
  • R c is as described
  • Table 1 or Table 2 is as described in Table 1 or Table 2.
  • provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
  • provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 2.
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use,
  • salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt- forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid.
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid;
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. In some embodiments, a compound described herein is prepared as a hydrochloride salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base.
  • the compound described herein is acidic and is reacted with a base.
  • an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • the compounds provided herein are prepared as a sodium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • N-oxides if appropriate
  • crystalline forms also known as polymorphs
  • pharmaceutically acceptable salts of compounds described herein as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • compounds described herein are prepared as prodrugs.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
  • the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the "prodrug") but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxy alkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview,
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. [00147] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • arylhalide derivative 1-1 with (4H-[l,2,4]-triazol-3- yl)arylamine derivative I-l or (lH-imidazol-5-yl)arylamine derivative 1-2 (prepared as described in Schemes 5-8) in the presence of a base such as K 2 C0 3 , Cs 2 C0 3 , NaO l Bu, KO l Bu, or K 3 P0 4 and in the presence of a transition metal -derived catalyst such as Pd(OAc) 2 , Pd 2 (dba) 3 ,
  • Pd(dppf)Cl 2 or Pd[P( l Bu)] 2
  • a ligand such as XPhos, XantPhos, or BINAP
  • a suitable solvent such as 1,4-dioxane, tert- uOH, or toluene (or mixtures thereof) with heating
  • arylhalide derivative 1-1 with (4H-[l,2,4]-triazol-3-yl)arylamine derivative I-l or (lH-imidazol-5-yl)arylamine derivative 1-2 in the presence of a base such as Cs 2 C0 3 , NaO l Bu, or KO l Bu, and in the presence of a transition metal-derived catalyst such as Cul, or Copper(I) thiophene-2-carboxylate, and in the presence of a ligand such as L-proline, tram , -l,2-diaminocyclohexane, or N-methyl-2- (methylamino)ethylamine, and in a suitable solvent such as 1,4-dioxane, DMSO, DMF, or DMA (or mixtures thereof) with heating will afford 1-2 or 1-3, respectively.
  • a base such as Cs 2 C0 3 , NaO l Bu, or KO l Bu
  • (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 2-2 or (1H- imidazol-5-yl)arylamino derivatives 2-3 are synthesized as shown in Scheme 2.
  • Pd(dppf)Cl 2 or Pd[P( l Bu)] 2 and in the presence of a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P( l Bu) 3 , l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu, and in a suitable solvent such as 1,4-dioxane, tert- uOH, DME, THF, NMP, H 2 0, or toluene (or mixtures thereof) with heating will afford 2-2 or 2-3, respectively.
  • a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P( l Bu) 3 , l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu
  • a suitable solvent such as 1,4-
  • (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 3-8 are synthesized as shown in Scheme 3.
  • treatment of an aminoaryl derivative 3-4 with a haloamine derivative 3-5 in the presence of a base such as K 2 C0 3 , Cs 2 C0 3 ,
  • Pd(dppf)Cl 2 or Pd[P( l Bu)] 2 and in the presence of a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P( l Bu) 3 , l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu, and in a suitable solvent such as 1,4-dioxane, tert- uOH, DME, THF, NMP, or toluene (or mixtures thereof) with heating will afford 3-3.
  • a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P( l Bu) 3 , l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu
  • a suitable solvent such as 1,4-dioxane,
  • a arylhalide derivative 4-1 with an arylamine derivative 4-3 in the presence of a base such as K 2 C0 3 , Cs 2 C0 3 , NaO l Bu, KO l Bu, or K 3 P0 4 and in the presence of a transition metal-derived catalyst such as Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(dppf)Cl 2 , or Pd[P( l Bu)] 2 , and in the presence of a ligand such as XPhos, XantPhos, or BINAP, and in a suitable solvent such as 1,4-dioxane, tert-BuOH, THF, DMA, or toluene (or mixtures thereof) with heating, will afford 4-4.
  • a base such as K 2 C0 3 , Cs 2 C0 3 , NaO l Bu, KO l Bu, or K 3 P0 4
  • a transition metal-derived catalyst such as Pd(
  • (4H-[l,2,4]-triazol-3-yl)arylamine derivatives 1-1 are synthesized as shown in Scheme 5.
  • aryl-ester derivatives 5-1 can be converted to the corresponding hydrazides 5-2, via treatment of 5-1 with hydrazine in a suitable solvent such as MeOH or EtOH with heating. Hydrazide derivatives 5-2 upon heating with DMF-DMA can afford 5-3. Reaction of 5-3 with a primary amine (R C H 2 ) in the presence of HO Ac and in a suitable solvent such as MeCN with heating, will give 1-1.
  • the amino group of 6-1 may be protected with appropriate protecting groups (PG) to give 6-2.
  • PG protecting groups
  • (lH-imidazol-5-yl)arylamine derivatives 1-2 are synthesized as shown in Scheme 8.
  • arylamine derivative 8-1 treatment of arylamine derivative 8-1 with di-tert-butyl dicarbonate, in the presence of a suitable base such as TEA or Hunig's base, and in the presence of an activating agent such as DMAP, and in a suitable solvent such as THF, DCM, or tert- butanol, with or without heating, will afford 8-2.
  • a suitable base such as TEA or Hunig's base
  • an activating agent such as DMAP
  • a suitable solvent such as THF, DCM, or tert- butanol
  • aryl halide derivative 9-1 with hydrazine in a suitable solvent such as MeOH or EtOH with heating, will afford hydrazides 9-2.
  • Hydrazide derivatives 9-2 upon heating with DMF-DMA can afford 9-3.
  • Reaction of 9-3 with a primary amine (R C H 2 ) in the presence of HO Ac and in a suitable solvent such as MeCN with heating will give 1-3.
  • (4H-[l,2,4]-triazol-3-yl)aryl halide derivatives 1-3 are synthesized via a Sandmeyer reaction as shown in Scheme 10.
  • MY metal halide salt
  • a suitable solvent such as acetonitrile and water
  • (lH-imidazol-5-yl)aryl halide derivative 1-4 are synthesized via a Sandmeyer reaction as shown in Scheme 11.
  • MY metal halide salt
  • Ci-C x includes C 1 -C 2 , C 1 -C3 . . . Ci-C x .
  • a group designated as "C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, z ' so-propyl, /7-butyl, /so-butyl, sec-butyl, and t-butyl.
  • an "alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the "alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- C 10 alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., " 1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • an alkyl is a Ci-C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • alkylene refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkelene is a Ci-C 6 alkylene.
  • an alkylene is a Ci-C 4 alkylene.
  • Typical alkyl ene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -
  • Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkynyl group has the formula -C ⁇ C-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • Non-limiting examples of an alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 -C ⁇ CCH 2 CH 3 , - CH 2 C ⁇ CH.
  • alkoxy refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • aromatic refers to a planar ring having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl ("aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
  • pyridine e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • carbocyclic or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon.
  • at least one of the two rings of a bicyclic carbocycle is aromatic.
  • both rings of a bicyclic carbocycle are aromatic.
  • bicyclic carbocycles are fused, bridged or spirocyclic.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C6-C 10 aryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[l . l . l]pentyl.
  • a cycloalkyl is a C 3 -
  • Deuterocycloalkyl refers to a cycloalkyl group where 1 or more hydrogen atoms of a cycloalkyl are replaced with deuterium.
  • a deuterocycloalkyl is a C 3 - C 6 deuterocycloalkyl .
  • Fluorocycloalkyl refers to a cycloalkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluorcycloalkyl is a C 3 -C 6 fluoroalkyl.
  • halo or, alternatively, "halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoralkyl is a Ci-C 6 fluoroalkyl.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. - H-, - N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
  • thiomorpholinyl thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • the foregoing groups are either C-attached (or C-linked) or TV-attached where such is possible.
  • a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • bicyclic heterocycles are fused, bridged or spirocyclic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a Ci-C 9 heteroaryl.
  • monocyclic heteroaryl is a Ci-C5heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a Ce-Cgheteroaryl.
  • heterocycloalkyl or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 -
  • a heterocycloalkyl is a C 4 -Ci 0 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bicyclic heterocycloalkyls are fused, bridged or spirocyclic.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule.
  • Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an antagonist.
  • a modulator is a degrader.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • effective amount or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the term "subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the compounds described herein are formulated into
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes
  • injection or infusion including intraarterial, intracardiac, intradermal, intraduodenal,
  • compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non-systemic administration.
  • non-systemic administration includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10%) w/w, for instance from 1%> to 2% by weight of the formulation.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of ASK1 activity.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • therapeutic agents in certain embodiments, are administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.
  • Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and the ED 50 .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the pharmaceutical composition further comprises one or more anti-cancer agents.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
  • additional agent such as an additional therapeutically effective drug, an adjuvant or the like.
  • Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves.
  • the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • factors e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject.
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is administered in combination with chemotherapy, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Chemotherapy includes the use of anti-cancer agents.
  • the compound described herein, or a pharmaceutically acceptable salt thereof is administered or formulated in combination with one or more anti -cancer agents.
  • Step 2 (E)-A ⁇ -(6-((E)-2-((Dimethylamino)methylene)hydrazinecarbonyl)pyridin-2-yl)-N ⁇ V- dimethylformimidamide (A-3)
  • a stirred mixture of A-2 (23 g, 151 mmol) in DMF-DMA (200 mL) was heated at 110 °C for 24 h.
  • the mixture was cooled to rt then concentrated under reduced pressure.
  • the solid residue was re-suspended in EtOAc (150 mL) and stirred at 50 °C for 20 min.
  • the mixture was cooled to rt and Et 2 0 (100 mL) was added.
  • the solids were collected via filtration, washed with Et 2 0, and dried to afford compound A-3 (36.5 g, 92%) as a light yellow solid.
  • Step 1 (E)-5-(((2-Bromo-5-nitrophenyl)imino)methyl)-2,2-dimethyl-l,3-dioxane-4,6-dione (D-2)
  • Step 1 7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one trifluoroacetate (2)
  • Step 2 7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one hydrochloride (Compound 1-1)
  • Step 1 5-(((3-Bromophenyl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (3)
  • Step 2 l-Benzyl-5-bromoquinolin-4(lH)-one (4a) and l-benzyl-7-bromoquinolin-4(lH)- one (4b)
  • Step 3 l-Benzyl-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (5a) and l-benzyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (5b)
  • Step 4 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (6)
  • Step 5 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-30)
  • Step 1 5-Bromo-l-methylquinolin-4(lH)-one (2a) and 7-bromo-l-methylquinolin-4(lH)- one (2b)
  • Step 2 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinolin- 4(lH)-one (3a) and 7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l- methylquinolin-4(lH)-one (3b)
  • Step 3 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinolin- 4(lH)-one hydrochloride (Compound 1-31)
  • Step 2 Methyl 5-bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate (4a) and methyl 7- bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate (4b)
  • Step 3 Methyl 4-(benzyloxy)-5-bromoquinoline-2-carboxylate (5a) and methyl 4- (benzyloxy)-7-bromoquinoline-2-carboxylate (5b)
  • Step 4 Methyl 4-(benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinoline-2-carboxylate (6)
  • Step 5 Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate (7)
  • Step 6 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate sodium salt (Compound 1-212) [00279] To a stirred solution of compound 7 (75 mg, 0.185 mmol) in THF (3 mL) at 0 °C, was added aq. 0.2M NaOH (1 mL). The mixture stirred at rt for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified via trituration with Et 2 0/ «-pentane to afford compound 1-212 (45 mg, 72%) as a yellow solid. 1H NMR (400 MHz, DMSO-i3 ⁇ 4): ⁇ 13.90
  • Step 1 2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (2)
  • Step 2 2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-209)
  • Step 1 4-(Benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinoline- 2-carboxylic acid (2)
  • Step 2 4-(Benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N- (pyridin-2-yl)quinoline-2-carboxamide (3)
  • Step 3 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- l,4-dihydroquinoline-2-carboxamide (4)
  • Step 4 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- l,4-dihydroquinoline-2-carboxamide hydrochloride (Compound 1-234)
  • Step 2 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4- methoxybenzyl)isoindoline-l,3-dione (3)
  • Step 3 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione (4)
  • Step 4 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione hydrochloride (Compound 1-9)
  • Step 2 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindoline- 1,3-dione (3)
  • Step 3 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindoline- 1,3-dione hydrochloride (Compound 1-10)
  • Example 12 8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoquinolin-l 2H)-one hydrochloride (Compound 1-21)
  • Step 1 (R)-2-(3-(6-Bromopyridin-2-yl)-4H-l,2,4-triazol-4-yl)propan-l-ol (1)
  • Step 2 (R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (2)
  • Step 2 5-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (2)

Abstract

Described herein are ASK1 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASK1 activity.

Description

APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK 1) INHIBITOR COMPOUNDS
CROSS-REFERENCE
[0001] This application claims benefit of U.S. Provisional Patent Application No. 62/567,532 filed on October 3, 2017, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] Described herein are compounds that are apoptosis signal-regulating kinase 1 (ASKl) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASKl activity.
BACKGROUND OF THE INVENTION
[0003] ASKl, a serine threonine kinase, activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASKl is implicated in the development and progression of fibrosis, cancer, diabetes, cardiovascular and
neurodegenerative diseases.
SUMMARY OF THE INVENTION
[0004] In one aspect, described herein are ASKl inhibitors and uses thereof. In some embodiments, the ASKl inhibitors described herein have the structure of Formula (I), or a pharmaceutically acceptable salt thereof. In one aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
[0005] In one aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000002_0001
Formula (I)
wherein,
ring A is a fused 5-, 6-, 7-, or 8-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring or a fused 5-, 6-, 7-, or 8-membered heterocyle containing 1 or 2 carbonyl (C=0) in the ring; each Ra is independently H, D, halogen, -CN, -OR5, substituted or unsubstituted Ci-
C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted
Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl;
m is 0, 1, or 2;
each R1 is independently H, substituted or unsubstituted Ci-C4alkyl, substituted or
unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C4deuteroalkyl, -I^-R6 or -L2-R7;
r is 0, 1, or 2;
L1 is linker that is L4 or -L4-Xa-L3-;
L2 is linker that is -L4-Xa-L4-;
Xa is -NR8-, -C(=0)NR8-, -NR8C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR8-, -NR8S(=0)2-, -C(=0)-, -C(=0)0-, or -OC(=0)-;
R8 is H, Ci-C6alkyl, Ci-Cefluoroalkyl, or Ci-C6deuteroalkyl;
L3 is Ci-C6alkylene;
each L4 is independently absent, or Ci-C6alkylene;
R6 is H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -S(=0)2N(R5)2, -
NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, -N(R5)2, -C(=0)N(R5)2, -NR5C(=0)R4, -OC(=0)N(R5)2, -NR5C(=0)OR4, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6deuteroalkyl, Ci-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8cycloalkyl, or a substituted or unsubstituted C2- C8heterocycloalkyl or substituted or unsubstituted heteroaryl;
R7 is substituted or unsubstituted phenyl, substituted or unsubstituted C3- C8cycloalkyl, or a substituted or unsubstituted C2-C8heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2 is H, Ci-C6alkyl, or Ci-C6deuteroalkyl;
each R3 is independently H, D, halogen, -CN, -OH, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4alkoxy, substituted or unsubstituted Ci- C4fluoroalkyl, substituted or unsubstituted Ci-C4fluoroalkoxy, substituted or unsubstituted Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl; q is 0, 1, 2, or 3;
ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl;
each R is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, -NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, -NR5C(=0)R4, -C(=0)N(R5)2, -NR2C(=0)OR4, OC(=0)N(R5)2, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl; n is 0, 1, 2, 3, or 4;
ring C is a 5-membered heteroaryl;
each Rc is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, - R5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, - R5C(=0)R4, -C(=0)N(R5)2, OC(=0)N(R5)2, - R5C(=0)OR4, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6deuterocycloalkyl, substituted or unsubstituted C3-C6fluorocycloalkyl, or substituted or unsubstituted C2-C8heterocycloalkyl; p is 0, 1, 2, or 3;
each R4 is independently selected from substituted or unsubstituted Ci-C6alkyl,
substituted or unsubstituted Ci-C6fluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl;
each R5 is independently selected from H, substituted or unsubstituted Ci-C6alkyl,
substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ci0cycloalkyl, substituted or unsubstituted C2-Ci0heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl; or two R5 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.
[0006] In some embodiments, the compound of Formula (I) has the following structure of Formula (II), or a pharmaceuticall acceptable salt, or solvate thereof:
Figure imgf000004_0001
Formula (II)
wherein, X1 is N or CR ;
n is 0, 1, 2, or 3.
[0007] In some embodiments, the compound of Formula (I) has the following structure of Formula (III), or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000005_0001
Formula (III)
wherein,
X1 is N or CR ;
X2 is N or CRC; and
n is 0, 1, 2, or 3.
[0008] In some embodiments the compound of Formula (I) has the following structure:
Figure imgf000005_0002
or a pharmaceutically acceptable salt, or solvate thereof.
[0009] In some embodiments the compound of Formula (I) has the following structure:
Figure imgf000005_0003
or a pharmaceutically acceptable salt, or solvate thereof.
[0010] Any combination of the groups described above for the various variables is
contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[0011] In one aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
[0012] In one aspect, described herein is a method of treating a disease or condition in a mammal that would benefit from the inhibition of apoptosis signal-regulating kinase 1 (ASK1) activity comprising administering to the mammal a compound, or pharmaceutically acceptable salt, or solvate thereof, as described herein.
[0013] In some embodiments, the inhibition of ASK1 inactivates c-Jun N-terminal protein kinase, p38 MAP kinase, or a combination thereof.
[0014] In some embodiments, the disease or condition is fibrosis, cancer, an autoimmune disease or condition, an inflammatory disease or condition, a cardiovascular disease or condition, a neurodegenerative disease or condition, or combinations thereof.
[0015] In some embodiments, the disease or condition is fibrosis. In some embodiments, the fibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis or cutaneous fibrosis
[0016] In one aspect, described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
[0017] In one aspect, described herein is a method for the treatment or prevention of fibrosis in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof. In other embodiments, the fibrosis is amenable to treatment with an ASK1 inhibitor. In some embodiments, the fibrosis is liver fibrosis. In some embodiments, the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
[0018] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) adminstered non-systemically or locally to the mammal.
[0019] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.
[0020] In any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound described herein, or a pharmaceutically acceptable salt thereof. In various embodiments, each agent is administered in any order, including simultaneously.
[0021] In any of the embodiments disclosed herein, the mammal is a human.
[0022] In some embodiments, compounds provided herein are administered to a human.
[0023] In some embodiments, compounds provided herein are orally administered.
[0024] Articles of manufacture, which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of ASK1, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition or reduction of the ASK1 activity, are provided.
[0025] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Mitogen-activated protein kinases (MAPKs) are a highly conserved family of serine/threonine protein kinases involved in a variety of fundamental cellular processes such as proliferation, differentiation, motility, stress response, apoptosis, and survival. MAPK networks are critical for the transmission of extracellular signals into appropriate intracellular responses, such as, but not limited to cell growth, differentiation, inflammation, and apoptosis. Prototypical MAPK activation employs a three-kinase core module consisting of a MAPK kinase kinase (MAPKKK or MAP3K) that phosphorylates and activates a MAPK kinase (MAP2K, MEK, or MKK) that in turn phosphorylates and dramatically increases the activity of one or more
MAPKs.
[0027] Apoptosis signal-regulating kinase 1 (ASKl) is a member of the MAP3K family that activates the c-Jun N-terminal protein kinase (JNK) and p38 MAPK. ASKl, also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), is activated by a variety of stimuli including hyperglycaemia, transforming growth factor beta (TGF-β), oxidative stress, reactive oxygen species (ROS), lipopolysaccharides (LPS), tumor necrosis factor alpha (T Fa), Fas ligand (FasL), endoplasmic reticulum (ER) stress, and increased intracellular calcium
concentrations. ROS have been reported to be associated with increase of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. ASKl induces apoptosis, fibrosis and metabolic dysfunction by activating the p38 and JNKl pathways.
[0028] ASKl undergoes activation via autophosphorylation at Thr838 in response to these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which then phosphorylate and activates p38 and JNK MAPKs, respectively. ASK2 is a related MAP3K that shares 45% sequence homology with ASKl . Although ASK2 tissue distribution is restricted, in some cell types ASKl and ASK2 have been reported to interact and function together in a protein complex. In non-stressed conditions, ASKl is kept in an inactive state through binding to its repressor thioredoxin (Trx) and through association with AKT.
[0029] Phosphorylation of ASKl protein can lead to apoptosis or other cellular responses depending on the cell type. ASKl activation and signaling have been reported to play a role in a broad range of diseases including fibrosis, neurodegenerative, cardiovascular, inflammatory, autoimmunity, and metabolic disorders. In addition, ASKl has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, liver and kidney.
Fibrosis
[0030] Fibrosis is a wound-healing process in which there is excessive deposition of extracellular matrix (ECM). ECM is composed of collagens, noncollagen glycoproteins, matrix bound growth factors, glycosaminoglycans, proteoglycans and matricellular proteins, which provide the scaffolding of both the normal and the fibrotic tissues. However, as fibrosis develops, there are multiple changes in the specific contents of these, with a marked increase in total collagen content; an increase in glycoproteins (e.g. cellular fibronectin, laminin, SPARC, osteonectin, tenascin and von Willebrand factor) and glycosaminoglycans (e.g. perlecan, decorin, aggrecan, lumican and fibromodulin); both an increase in proteoglycans and a shift from heparan sulphate containing proteoglycans to those containing chondroitin and dermatan sulphates; and an increase in the fibril -forming collagens types I, III and V and in some nonfibril -forming collagens (types IV and VI). For example, with all of these changes occurring in the liver, there is a transition from the low-density basement membrane-like matrix in the subendothelial space that is found in the normal liver to the interstitial type which is associated with hepatocyte dysfunction and activation of the hepatic stellate cells (HSCs), which are the primary source of ECM in both the normal and fibrotic liver. During activation, HSCs transition from their normal quiescent state to proliferative, fibrogenic and contractile myofibroblasts.
[0031] Non-alcoholic steatotic hepatitis (NASH) is an exemplary type of fibrosis implicating ASK1 activity. Multiple pathways are involved in NASH-associated fibrosis including inflammasome-TLR activation and generation of the inflammatory cytokines, increased levels of hedgehog signalling, changes in lipid and glucose metabolism leading to oxidative stress, hepatocyte injury via apoptosis, cell death inducing inflammatory and pro-fibrogenic pathways in nonparenchymal cells and infiltrating immune cells. These processes lead to HSC activation which is the source of excessive deposition of extracellular matrix (ECM) in the parenchyma.
[0032] In some embodiments, disclosed herein are methods of treating fibrosis with a compound disclosed herein.
[0033] "Fibrosis," as used herein, refers to the accumulation of extracellular matrix
constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Fibrosis may refer to the development of fibrous connective tissue as a reparative response to injury or damage. Fibrosis may also refer to the connective tissue deposition that occurs as part of normal healing or to the excess tissue deposition that occurs as a pathological process.
[0034] In some embodiments, disclosed herein is a method of reducing fibrosis in a tissue comprising contacting a fibrotic cell or tissue with a compound disclosed herein, in an amount sufficient to decrease or inhibit the fibrosis. In some embodiments, the fibrosis includes a fibrotic condition.
[0035] In some embodiments, the fibrosis comprises liver fibrosis, kidney fibrosis, lung fibrosis, cardiac fibrosis, peritoneal fibrosis, ocular fibrosis or cutaneous fibrosis. In some embodiments, the fibrosis comprises liver fibrosis. In some embodiments, the fibrosis comprises kidney fibrosis. In some embodiments, the fibrosis comprises cardiac fibrosis. In some embodiments, the fibrosis comprises lung fibrosis. In some embodiments, the fibrosis comprises peritoneal fibrosis. In some embodiments, the fibrosis comprises ocular fibrosis. In some embodiments, the fibrosis comprises cutaneous fibrosis.
[0036] In some embodiments, reducing fibrosis, or treatment of a fibrotic condition, includes reducing or inhibiting one or more of: formation or deposition of extracellular matrix proteins; the number of pro-fibrotic cell types (e.g., fibroblast or immune cell numbers); cellular collagen or hydroxyproline content within a fibrotic lesion; expression or activity of a fibrogenic protein; or reducing fibrosis associated with an inflammatory response.
[0037] In some embodiments, the fibrotic condition is liver fibrosis. Liver fibrosis refers to the scar tissue and nodules that replace liver tissue and disrupt liver function. The scar tissue blocks the portal flow of blood through the organ therefore disturbing normal function. Damage to the hepatic parenchyma due to inflammation leads to activation of the stellate cell, which increases fibrosis through production of myofibroblasts and obstructs blood flow in the circulation.
Production of myofibroblasts accelerates the loss of liver function and can lead to death.
[0038] Non-alcoholic fatty liver disease (NAFLD) is a common liver disease characterized by fat accumulation in hepatocytes that is not linked to excessive alcohol intake and is correlated with obesity, insulin resistance, and cardiac diseases. NAFLD is categorised into simple steatosis and non-alcoholic steatotic hepatitis (NASH), the latter of which can lead to hepatic fibrosis, hepatic cirrhosis, and liver cancer. High fat diet (HFD) is used to induce hepatic steatosis in mouse models. HFD causes fat accumulation and fatty acid oxidation, which leads to ROS generation and subsequent hepatocyte dysfunction and cell death in the liver. TNFa-deficient mice show reduced hepatic steatosis, indicating that proinflammatory cytokines including TNFa are required for liver injury. TNFa-induced apoptosis of hepatocytes is mediated by ASKl -INK activation. ASKl -deficient mice have reduced HFD-induced hepatic steatosis, fibrosis, and TGFp expression, which is responsible for hepatic fibrosis. Olmesartan, an ATI blocker, also improves HFD-induced hepatic steatosis by inhibiting ASKl . Moreover, olmesartan or ASKl deficiency can attenuate HFD-induced cardiac inflammation and fibrosis, and vascular endothelial dysfunction and remodelling. These findings suggest that ASKl is involved in obesity-associated cardiovascular complications and hepatic steatosis.
[0039] The ASKl pathway has been shown to be activated in human NASH liver biopsies. In animals with established NASH (Fl/2), a small molecule inhibitor of ASKl significantly reduced hepatic steatosis and fibrosis and significantly improved key metabolic parameters associated with NASH. Treatment with a small molecule inhibitor of ASKl resulted in a significant reduction in body weight; decreased fasting blood glucose and insulin levels; reduction in plasma AST, ALT and cholesterol levels; a reduction in hepatic steatosis; a reduction in liver
hydroxyproline; a reduction in alpha smooth muscle actin and p-P38 expression; a reduction in fibrillar collagen area and reduced synthesis of collagen. ASK1 inhibition also reduced hepatic fibrosis, steatosis and insulin resistance and normalised fatty acid synthesis and lipid metabolism.
[0040] In some embodiments, the fibrotic condition is a fibrotic condition of the lung. Lung or pulmonary fibrosis refers to a number of conditions that cause interstitial lung damage, followed by accumulation of extracellular matrix constituents and eventually loss of lung elasticity and function. These conditions lead to symptoms such as persistent coughing, chest pain, difficulty breathing and fatigue. Lung fibrosis may occur as a secondary condition in various diseases.
[0041] In some embodiments, the fibrotic condition is a fibrotic condition of the heart. Cardiac fibrosis refers to the damage of the heart areas due to myocardial infarction or Davies' disease. Cardiac fibrosis can affect the valves in the heart as well as the muscles, which become stiff and less compliant. This can increase the risk of heart failure.
[0042] In some embodiments, the fibrotic condition is a fibrotic condition of the kidney.
Kidney fibrosis refers to an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease. The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial -mesenchymal transition, have been identified as the major ways for the generation of the matrix-producing cells in diseased conditions. Among many fibrogenic factors that regulate renal fibrotic process, transforming growth factor-beta (TGF- beta) is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated.
[0043] In some embodiments, the fibrotic condition is a fibrotic condition of the skin.
[0044] In some embodiments, the fibrotic condition is a fibrotic condition of the eye.
[0045] In some embodiments, the fibrotic condition is a fibrotic condition of the
gastrointestinal tract.
[0046] In some embodiments, the fibrotic condition is a fibrotic condition of the bone marrow.
[0047] In some embodiments, the fibrotic condition is idiopathic. In some embodiments, the fibrotic condition is associated with (e.g., is secondary to) a disease (e.g., an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and/or a connective disease); a toxin; an insult (e.g., an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), cigarette smoking, a wound); a medical treatment (e.g., surgical incision, chemotherapy or radiation), or a combination thereof. [0048] In some embodiments, disclosed herein is a method for the treatment or prevention of fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
[0049] In some embodiments, disclosed herein is a method of improving lung function in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof. In some embodiments, the mammal has been diagnosed as having lung fibrosis.
[0050] In some embodiments, disclosed herein is a method of treating idopathic pulmonary fibrosis in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
[0051] In some embodiments, disclosed herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in a tissue of a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof. In some embodiments, the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the tissue results in fibrosis.
[0052] In some embodiments, disclosed herein is a method for the treatment or prevention of scleroderma in a mammal comprising administering an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
[0053] In some embodiments, disclosed herein is a method for reducing undesired or abnormal dermal thickening in a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the dermal thickening is associated with scleroderma.
[0054] In some embodiments, described herein is a method of controlling an abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in tissues of a mammal comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the abnormal accumulation or activation of cells, fibronectin, collagen or increased fibroblast recruitment in the dermal tissues results in fibrosis. In some embodiments, described herein is a method of reducing hydroxyproline content in tissues of a mammal with fibrosis comprising administering to mammal in need thereof an ASK1 inhibitor described herein, or a
pharmaceutically acceptable salt thereof.
[0055] In some embodiments, compounds described herein are used in the treatment of fibrosis associated with arthrofibrosis, Crohn's Disease, Dupuytren's contracture, keloids, myelofibrosis, Peyronie's disease, or scleroderma/systemic sclerosis. [0056] In some embodiments, anti-fibrotic strategies include (i) removing the injurious stimuli,
(ii) suppressing or modulating inflammation, (iii) protecting the organ at risk of developing fibrosis, and (v) promoting matrix degradation. Some of these strategies have direct effect on fibrosis pathway, while others may have indirect effect. In some embodiments, anti-fibrotic strategies in NASH include (a) removing the injurious stimuli, (b) suppressing or modulating hepatic inflammation, (c) protecting the liver, (d) downregulating stellate cell activation and (e) promoting matrix degradation.
[0057] Fibrosis, such as hepatic fibrosis in NASH, is driven by multiple risk factors that may interact with each other via several inter-related mechanistic pathways. It is plausible that the injurious stimuli may be heterogenous, but the resultant response in laying down of collagen and worsening of fibrosis may be a common response. In some embodiments, multiple targets may be required to reverse or halt fibrosis. Removal of cause would be the most efficient way to improve fibrosis. This has been supported by observations seen with other chronic diseases, including hepatitis C and B.
[0058] In some embodiments, compounds described herein are used in the treatement of a cardiovascular disease. Cardiovascular diseases include, but are not limited to,
ischaemia/reperfusion injury, cardiac remodelling, and vascular endothelial dysfunction.
[0059] In some embodiments, compounds described herein are used in the treatement of diseases of the retina.
[0060] In some embodiments, compounds described herein are used in the treatement of diseases of the spinal cord.
[0061] During myocardial infarction, some cardiomyocytes undergo necrosis due to a shortage of oxygen and nutrition, which causes low cardiac output. To compensate for this loss of cardiac function, surviving cardiomyocytes undergo changes in size and location, which is referred to as cardiac hypertrophy. Sustained hypertension and diabetic cardiomyopathy can also induce cardiac hypertrophy. In ventricular hypertrophy, gene reprogramming and accumulation of extracellular matrix proteins are involved in ventricular fibrosis and remodelling. In some embodiments, ASK1 plays a role in the pathogenesis of ventricular remodelling by promoting apoptosis or cardiomyocyte hypertrophy. In some other embodiments, ASK1 is aldosterone- induced cardiac inflammation and fibrosis through induction of monocyte chemoattractant protein (MCP)-l and transforming growth factor (TGF)-pi expression, respectively.
[0062] In some embodiments, compounds described herein are used in the treatment of neurodegenerative disorders. Neurodegenerative disorders include, but are not limited to, Huntington's disease (HD), spinobulbar muscular atrophy, spinocerebeller ataxia (SCA), Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Normal -tension glaucoma.
[0063] In some embodiments, compounds described herein are used in the treatment of inflammatory diseases. Inflammatory diseases include, but are not limited to, multiple sclerosis, rheumatoid arthritis.
[0064] In some embodiments, compounds described herein are used in the treatment of respiratory diseases. ASKl also plays a role in airway remodelling, an irreversible hypertrophic change that occurs in chronic bronchitis. Leukotriene D4 has been suggested to activate ASKl and induce AP-1 activation in airway smooth muscle cells, leading to airway remodelling.
Respiratory diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthmas and acute lung injury.
[0065] In some embodiments, compounds described herein are used in the treatment of diabetes. TNFa is one of the factors that aggravate insulin resistance. In hepatocytes, TNFa induces ROS production in the mitochondria and activates INK via ASKl, which leads to insulin receptor substrate-1 (IRS-1) serine phosphorylation. Such phosphorylation decreases tyrosine phosphorylation of IRS-1 resulting in insulin resistance and eventually causing type 2 diabetes.
[0066] In some embodiments, compounds described herein are used in the treatement of liver injury. Consumption of large quantities of acetaminophen, a widely used analgesic and antipyretic agent, is known to cause liver injury. In ASKl -deficient mice, acetaminophen- induced, sustained activation of INK is suppressed and resistance to liver injury increased, indicating that the ASKl -INK pathway plays a critical role in acetaminophen-induced liver injury. ASKl has also been reported to be involved in liver injury induced by troglitazone, a first- generation thiazolidinedione insulin sensitizer that has been linked to an unacceptable risk of liver injury in patients.
[0067] In some embodiments, compounds described herein are used in the treatment of ageing. ROS is thought to be one of the major causes of ageing. Consistent with this notion, long-lived mouse models, such as Snell dwarf mice, Ames dwarf mice, and Klotho overexpressing mice, are known to be resistant to oxidative stress. Mouse embryonic fibroblasts (MEFs) derived from Ames dwarf mice possess a larger amount of the Trx -bound form of ASKl and have less p38 activity than those derived from WT mice, suggesting that activity of the ASKl-p38 pathway is attenuated in Ames dwarf mice. Also, in the livers of Klotho overexpressing mice, the activity of the ASKl-p38 pathway and the amount of Trx-bound ASKl are decreased and increased, respectively, whereas the opposite is observed in liver extracts from Klotho-deficient mice. In some embodiments, ROS-induced ASKl activity contributes to regulation of ageing-related cellular functions. Compounds
[0068] Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are ASK1 inhibitors.
[0069] In one aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000015_0001
Formula (I)
wherein,
ring A is a fused 5-, 6-, 7-, or 8-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring or a fused 5-, 6-, 7-, or 8-membered heterocyle containing 1 or 2 carbonyl (C=0) in the ring;
each Ra is independently H, D, halogen, -CN, -OR5, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl; m is 0, 1, or 2;
each R1 is independently H, substituted or unsubstituted Ci-C4alkyl, substituted or
unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C4deuteroalkyl, -I^-R6 or -L2-R7;
r is 0, 1, or 2;
L1 is linker that is L4 or -L4-Xa-L3-;
L2 is linker that is -L4-Xa-L4-;
Xa is - R8-, -C(=0) R8-, - R8C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2 R8-,
-NR8S(=0)2-, -C(=0)-, -C(=0)0-, or -OC(=0)-;
R8 is H, Ci-C6alkyl, Ci-C6fluoroalkyl, or Ci-C6deuteroalkyl;
L3 is Ci-C6alkylene;
each L4 is independently absent, or Ci-C6alkylene;
R6 is H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -S(=0)2N(R5)2, -
NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, -N(R5)2, -C(=0)N(R5)2, -NR5C(=0)R4, -OC(=0)N(R5)2, -NR5C(=0)OR4, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6deuteroalkyl, Ci-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8cycloalkyl, or a substituted or unsubstituted C2- C8heterocycloalkyl or substituted or unsubstituted heteroaryl; R7 is substituted or unsubstituted phenyl, substituted or unsubstituted C3-
C8cycloalkyl, or a substituted or unsubstituted C2-C8heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2 is H, Ci-C6alkyl, or Ci-C6deuteroalkyl;
each R3 is independently H, D, halogen, -CN, -OH, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4alkoxy, substituted or unsubstituted Ci- C4fluoroalkyl, substituted or unsubstituted Ci-C4fluoroalkoxy, substituted or unsubstituted Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl; q is 0, 1, 2, or 3;
ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl;
each R is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, -NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, -NR5C(=0)R4, -C(=0)N(R5)2, -NR2C(=0)OR4, OC(=0)N(R5)2, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- C6fluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl; n is 0, 1, 2, 3, or 4;
ring C is a 5-membered heteroaryl;
each Rc is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, -NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, -NR5C(=0)R4, -C(=0)N(R5)2, OC(=0)N(R5)2, -NR5C(=0)OR4, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- C6fluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6deuterocycloalkyl, substituted or unsubstituted C3-C6fluorocycloalkyl, or substituted or unsubstituted C2-C8heterocycloalkyl; p is 0, 1, 2, or 3;
each R4 is independently selected from substituted or unsubstituted Ci-C6alkyl,
substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ci0cycloalkyl, substituted or unsubstituted C2-Ci0heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl;
each R5 is independently selected from H, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci-C6fluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl; or two R5 on the same N atom are taken together with the
N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.
[0070] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, R2 is H, or Ci-C6alkyl. In other embodiments, R2 is H, or Ci-C6alkyl. In some other embodiments, R2 is H, -CH3, or -CH2CH3. In yet some other embodiments, R2 is H.
[0071] In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 N atoms or phenyl. In some embodiments, ring B is a pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or phenyl. In some embodiments, ring B is a pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or phenyl. In some embodiments, ring B is a pyridinyl, or phenyl.
[0072] In some embodiments, ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom. In some embodiments, ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl. In some embodiments, ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, thiadiazolyl, or furazanyl.
[0073] In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 N atoms or phenyl; ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
[0074] In some embodiments, ring B is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
Figure imgf000017_0001
[0075] In some embodiments, the groups are in a 1,3- relationship on ring B.
[0076] In some embodiments,
Figure imgf000017_0002
X1 is N or CR ; n is 0, 1, 2, or
3. [0077] In some embodiments,
[0078] In some embodiments,
[0079] In some embodiments,
Figure imgf000018_0001
is
[0080] In some embodiments, the compound of Formula (I) has the following structure of Formula (II), or a pharmaceuticall acceptable salt, or solvate thereof:
Figure imgf000018_0002
wherein,
X1 is N or CR ;
n is 0, 1, 2, or 3.
[0081] In some embodiments, ring B is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl; ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
Figure imgf000018_0003
Figure imgf000019_0001
 In
Figure imgf000020_0001
embodiments, X2 is N. In some embodiments, X2 is CRC.
[0085] In some embodiments, the compound of Formula (I) has the following structure of Formula (III), or a pharmaceuticall acceptable salt, or solvate thereof:
Figure imgf000020_0002
Formula (III)
wherein,
X1 is N or CR ;
X2 is N or CRC; and
n is 0, 1, 2, or 3.
[0086] In some embodiments, ring A is a fused 5-, 6-, 7-, or 8-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring. In some embodiments, ring A is a fused 5-, 6-, or 7- membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring. In some embodiments, ring A is a fused 5-, or 6-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring. In some embodiments, ring A is a fused 6-membered carbocycle containing 1 carbonyl (C=0) in the ring. In some embodiments, ring A is a fused 5-membered carbocycle containing 1 carbonyl (C=0) in the ring. In some embodiments, ring A contains 1 carbonyl (C=0) in the ring.
Figure imgf000021_0001
[0088] In some embodiments, ring A is a fused 5-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, and 0 or 1 O or S atoms in the ring. In some embodiments, rin is a fused 5-membered heterocyle containing 1 carbonyl in the ring.
Figure imgf000021_0002
Figure imgf000022_0001
21
Figure imgf000023_0001
[0094] In some embodiments, ring A is a fused 6-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, 0-2 O atoms, and 0-2 S atoms in the ring. In some embodiments, ring A is a fused 6-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, and 0 or 1 O atom or S atom in the ring. In some embodiments, ring A is a fused 6-membered heterocyle containing 1 carbonyl (C=0) in the ring. In some embodiments, ring A is a fused 6- membered heterocyle containing 1 carbonyl (C=0), and 1 N atom in the ring.
Figure imgf000023_0002
Figure imgf000024_0001

Figure imgf000025_0001

Figure imgf000026_0001
[0098] In some embodiments, ring A is a fused 7-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, 0-2 O atoms, and 0-2 S atoms in the ring. In some embodiments, ring A is a fused 7-membered heterocyle containing 1 carbonyl (C=0) in the ring.
Figure imgf000027_0001

Figure imgf000028_0001
[00102] In some embodiments
Figure imgf000029_0001
Figure imgf000029_0002
In some embodiments
Figure imgf000029_0003
[00104] In some embodiments, each Ra is independently H, D, F, CI, Br, -CN, -OH, -OCH3, OCH2CH3, -OCF3, -OCH2CF3; -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -CD3, -OCD3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[00105] In some embodiments, each Ra is independently H, D, F, CI, Br, -CN, -OH, -OCH3, - OCF3, -CH3, -CH2F, -CHF2, -CF3, -CD3, and -OCD3.
[00106] In some embodiments, each R3 is independently H, D, F, CI, -CN, -OH, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, OCH2CH3, -OCF3, or -CD3.
[00107] In some embodiments, q is 0 or 1.
[00108] In some embodiments, each R1 is independently H, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci- C4deuteroalkyl, -I^-R6 or -L2-R7; r is 0, 1, or 2; L1 is linker that is L3 or -L4-Xa-L3-; L2 is linker that is -L4-Xa-L4-.
[00109] In some embodiments, each R1 is independently H, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci- C4deuteroalkyl, -I^-R6 or -L2-R7; r is 0, 1, or 2; L1 is linker that is L4 or -L4-Xa-L3-; L2 is linker that is -L4-Xa-L4-. [00110] In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1. In some embodiments, r is 0.
[00111] In some embodiments, each R1 is independently H, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci- C4deuteroalkyl, -I^-R6 or -L2-R7; L1 is linker that is L3 or -L4-Xa-L3-; L2 is linker that is -L4-Xa- L4-; Xa is -C(=0) R8-; R8 is H, Ci-C4alkyl, Ci-C4fluoroalkyl, or Ci-C4deuteroalkyl; L3 is Ci- C6alkylene; each L4 is independently absent, or Ci-C6alkylene.
[00112] In some embodiments, each R1 is independently H, Ci-C alkyl, Ci-C fluoroalkyl, Ci- C4deuteroalkyl, -I^-R6 or -L2-R7; L1 is linker that is L4 or -L4-Xa-L3-; L2 is linker that is -L4-Xa- L4-; Xa is -C(=0) R8-; R8 is H, Ci-C4alkyl, Ci-C4fluoroalkyl, or Ci-C4deuteroalkyl; L3 is Ci- C6alkylene; each L4 is independently absent, or Ci-C6alkylene.
[00113] In some embodiments, R6 is H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, - R5S(=0)2R4, -C(=0)R4, -C02R5, -N(R5)2, -C(=0)N(R5)2, d-C6alkyl, Ci- Cefluoroalkyl, Ci-C6deuteroalkyl, Ci-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8cycloalkyl, or a substituted or unsubstituted C2- C8heterocycloalkyl or substituted or unsubstituted heteroaryl. In some embodiments, R6 is H, D, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -S(=0)2N(R5)2, -C(=0)R4, -C02R5, -N(R5)2, - C(=0)N(R5)2, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6deuteroalkyl, Ci-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8cycloalkyl, or a substituted or
unsubstituted C2-C8heterocycloalkyl or substituted or unsubstituted heteroaryl. In some embodiments, R6 is H, D, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -S(=0)2N(R5)2, -C(=0)R4, -C02R5, -N(R5)2, -C(=0)N(R5)2, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6deuteroalkyl, Ci- C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6cycloalkyl, or a substituted or unsubstituted 5-membered or 6-membered C2-C6heterocycloalkyl or substituted or unsubstituted 5-membered or 6-membered heteroaryl.
[00114] In some embodiments, each R1 is independently H, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, or substituted or unsubstituted Ci- C deuteroalkyl. In some embodiments, each R1 is independently H, Ci-C alkyl, Ci-C fluoroalkyl, or Ci-C deuteroalkyl.
[00115] In some embodiments, L3 is Ci-C4alkylene. In some embodiments, L3 is -CH2-, - CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.
[00116] In some embodiments, each L4 is independently absent or Ci-C alkylene. In some embodiments, each L4 is independently absent, -CH2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2- , -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, each L4 is independently absent, - CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. [00117] In some embodiments, Xa is - R8-, -C(=0) R8-, - R8C(=0)-, -0-, -S-, -S(=0)-, -
S(=0)2-, -S(=0)2 R8-, - R8S(=0)2-, or -C(=0)-. In some embodiments, Xa is -NR8-, -
C(=0)NR8-, -NR8C(=0)-, or -C(=0)-.
[00118] In some embodiments, R7 is substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6cycloalkyl, or a substituted or unsubstituted C2-C6heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R7 is substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered or 6-membered C2- C6heterocycloalkyl, or substituted or unsubstituted 5-membered or 6-membered monocyclic heteroaryl. In some embodiments, R7 is substituted or unsubstituted phenyl, or substituted or unsubstituted 6-membered monocyclic heteroaryl.
[00119] In some embodiments the compound of Formula (I) has the following structure:
Figure imgf000031_0001
or a pharmaceutically acceptable salt, or solvate thereof.
[00120] In some embodiments, Rc is as described in Table 1. In some embodiments, Rc is as described in Table 2. In some embodiments, Rc is as described in Table 1 or Table 2. In some
Figure imgf000031_0002
is as described in Table 1 or Table 2. In some embodiments, Rc is as described in Table 1 and
Figure imgf000031_0003
is as described in Table 1. In some embodiments, Rc is as described in
Table 1 or Table 2 and
Figure imgf000031_0004
is as described in Table 1 or Table 2. [00121] In some embodiments the compound of Formula (I) has the following structure:
Figure imgf000032_0001
[00122] or a pharmaceutically acceptable salt, or solvate thereof.
[00123] In some embodiments, Rc is as described in Table 1. In some embodiments, Rc is as described in Table 2. In some embodiments, Rc is as described in Table 1 or Table 2. In some
Figure imgf000032_0002
is as described in Table 1 or Table 2. In some embodiments, Rc is as described in Table 2 and
Figure imgf000032_0003
described in Table 2. In some embodiments, Rc is as described
Table 1 or Table 2 and
Figure imgf000032_0004
is as described in Table 1 or Table 2.
[00124] Any combination of the groups described above for the various variables is
contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[00125] Exemplary compounds described herein include the compounds described in the following Tables:
Table 1
Figure imgf000032_0005
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
[00126] Compounds in Table 1 are named:
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-1); 7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one
(Compound 1-2);
3,3-JD2-7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound
1-3);
3,3-/J2-7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-4);
3,3-Difluoro-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-5);
3,3-Difluoro-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l- one (Compound 1-6);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3,3-dimethylisoindolin-l-one (Compound 1-7);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3,3-trimethylisoindolin-l-one (Compound 1-8);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione (Compound 1-
9);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindoline- 1 ,3 -dione (Compound 1-10);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3-dihydro-lH-inden-l-one (Compound 1-11);
2,2-£>2-7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2,3 -dihydro- lH-inden- 1 -one (Compound 1-12);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)benzofuran-3(2H)-one (Compound 1-13);
2,2-£) 2-4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)benzofuran-3(2H)-one (Compound 1-14);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-lH-indazol-3(2H)-one (Compound 1-15);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)- 1 -methyl- lH-indazol-3 (2H)-one (Compound 1-16);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)- 1 ,2-dimethyl- lH-indazol-3 (2H)- one (Compound 1-17); 8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-3 ,4-dihydroisoquinolin- 1 (2H)-one
(Compound 1-18);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl )-2-methyl-3,4-dihydroisoquinolin- l(2H)-one (Compound 1-19);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)isoquinolin-l(2H)-one (Compound 1-20);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-2-methylisoquinolin- 1 (2H)-one (Compound 1-21);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)quinazolin-4(3H)-one (Compound 1-22);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-3-methylquinazolin-4(3H)-one (Compound 1-23);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)isoquinoline-l,3(2H,4H)-dione (Compound 1-24);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-2-methylisoquinoline- 1 ,3 (2H,4H)- dione (Compound 1-25);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)quinazoline-2,4(lH,3H)-dione (Compound 1-26);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-3 -m ethyl quinazoline-2,4( IH, 3H)- dione (Compound 1-27);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)- 1 -m ethyl quinazoline-2,4( ΙΗβΗ)- dione (Compound 1-28);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)- 1 ,3 -dimethyl quinazoline- 2,4(lH,3H)-dione (Compound 1-29);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)quinolin-4(lH)-one (Compound 1- 30);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)- 1 -m ethyl quinolin-4( lH)-one (Compound 1-31);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-2,3 -dihydroquinolin-4( lH)-one (Compound 1-32);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)- 1 -methyl-2,3 -dihydroquinolin- 4(lH)-one (Compound 1-33);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)-4H-chromen-4-one (Compound 1■ 34);
5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl amino)chroman-4-one (Compound 1-35); 3,3-/J2-5-((6-(4 sopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)chroman-4-one (Compound
1-36);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)thiochroman-4-one (Compound 1- 37);
5- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4H-thiochromen-4-one (Compound 1-38);
9-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (Compound 1-39);
9-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methyl-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (Compound 1-40);
6- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3,4-dihydrobenzo[f [l,4]oxazepin- 5(2H)-one (Compound 1-41);
6- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-methyl-3,4- dihydrobenzo[f [l,4]oxazepin-5(2H)-one (Compound 1-42);
7- ((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-43); 7-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-44); 7-((6-(4-(2,2,2-Trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-45);
7-((6-(4-(2-Fluoroethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-46);
7-((6-(4-(3 ,3 ,3 -Trifluoropropyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-47);
7-((6-(4-(2-Hydroxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-48);
7-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-49);
7-((6-(4-(2-Methoxyethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one
(Compound 1-50);
3-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-51);
(R)-7-((6-(4-( 1 -Fluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-52);
(,S)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-53); 7-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-54);
(R)-7-((6-(4-(l,l, l-Trifluoropropan-2-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l^ one (Compound 1-55);
(S)-7-((6-(4-(l , 1 , 1 -Trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 - one (Compound 1-56);
(R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-57);
(,S)-7-((6-(4-(l -Hydroxypropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-58);
7-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-59);
(R)-2-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-60);
(,S)-2-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-61);
7-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
62) ;
7-((6-(4-Cyclobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
63) ;
7-((6-(4-(Oxetan-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
64) ;
7-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-65);
7-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-66);
7-((6-(4-((lR,3R)-3-Hydroxycyclobutyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-67);
(l S,3S)-3-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-68);
(lR,3R)-3-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-69);
7-((6-(4-(Bicyclo[ 1.1.1 ]pentan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-70); 7-((6-(4-Cyclopentyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1 -
71);
7-((6-(4-((lR,2^-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-72);
7-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-73);
7-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-74);
7-((6-(4-((l,S',2)S)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-75);
(R)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 - one (Compound 1-76);
(,S)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-77);
7-((6-(4-((lR,2,S)-2-Hydroxycyclopentyl)-4H^
one (Compound 1-78);
7-((6-(4-((l^,2R)-2-Hydroxycyclopentyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-^ one (Compound 1-79);
7-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-80);
7-((6-(4-((l,S',2)S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-81);
(,S)-7-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-82);
(R)-7-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-83);
7-((6-(4-Cyclohexyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1 - 84);
7-((6-(4-((lR,2,S)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-85);
7-((6-(4-((l,S',2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-86);
7-((6-(4-((lR,2R)-2-fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-87); 7-((6-(4-((l,S',2)S)-2-fluorocyclohexyl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)isoindoli
(Compound 1-88);
(R)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-89);
(<S)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-90);
7-((6-(4-((lR,2S)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-91);
7-((6-(4-((lS,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-92);
7-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-93);
7-((6-(4-((l^,2^-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-94);
(,S)-7-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-95);
(R)-7-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-96);
7-((6-(4-(Tetrahydro-2H-pyran-4-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-97);
7-((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound
1- 98);
7-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one
(Compound 1-99);
2- Methyl-7-((6-(4-(2,2,2-trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-100);
7-((6-(4-(2-Fluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-101);
2-Methyl-7-((6-(4-(3,3,3-trifluoropropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-102);
7-((6-(4-(2-Hydroxyethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one (Compound 1-103);
7-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-104); 7-((6-(4-(2-Methoxyethyl)-4H- 1 ,2,44riazo
(Compound 1-105);
3-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-106);
(R)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-107);
(,S)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-108);
7-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-109);
(R)-2-Methyl-7-((6-(4-( 1, 1,1 -trifluoropropan-2-yl)-4H- l,2,4-triazol-3 -yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-110);
(5)-2-Methyl-7-((6-(4-(l , 1 , 1 -trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-111);
(R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-112);
(,S)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-113);
7-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-114);
(R)-2-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-115);
(,S)-2-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-116);
7-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-117);
7-((6-(4-Cyclobutyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one (Compound 1-118);
2-Methyl-7-((6-(4-(oxetan-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-119);
7-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin- 1-one (Compound 1-120);
7-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin- 1-one (Compound 1-121); 7-((6-(4-((lR,3R)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-122);
(l S,3S)-3-(3-(6 (2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-123);
(lR,3R)-3-(3-(6 (2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-124);
7-((6-(4-(Bicyclo[ 1.1.1 ]pentan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-125);
7-((6-(4-Cyclopentyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l -one (Compound 1-126);
7-((6-(4-((lR,25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-127);
7-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-128);
7-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-129);
7-((6-(4-((15',25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-130);
(R)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-131);
(lS>7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-132);
7-((6-(4-((lR,25)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-133);
7-((6-(4-((l^,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-134);
7-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-135);
7-((6-(4-((lS,25)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-136);
(^-2-Methyl-7 (6 4-(tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-137);
(R)-2-Methyl-7-((6-(4-(tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-138); 7-((6-(4-Cyclohexyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one
(Compound 1-139);
7-((6-(4-((lR,25)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-140);
7-((6-(4-((1^2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-141);
7-((6-(4-((lR,2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-142);
7-((6-(4-((l^,25)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-143);
(R)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-144);
(,S)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-145);
7-((6-(4-((lR,25)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-146);
7-((6-(4-((15',2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-147);
7-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-148);
7-((6-(4-((1^25)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-149);
(^-2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-150);
(R)-2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-151);
2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-152);
5-((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-153); 5-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 154);
5-((6-(4-(2,2,2-Trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-155);
5-((6-(4-(2-Fluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one
(Compound 1-156); 5-((6-(4-(3,3,3-Trifluoropropyl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one
(Compound 1-157);
5-((6-(4-(2-Hydroxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one
(Compound 1-158);
5-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinoHn-4(lH)- one (Compound 1-159);
5-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-160);
3-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-161);
(R)-5-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-162);
(S)-5-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-163);
5-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-164);
(R)-5-((6-(4-(l,l, l-Trifluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-165);
(S)-5-((6-(4-(l , 1 , 1 -Trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-166);
(R)-5-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-167);
(S)-5-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-168);
5-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-169);
(R)-2-(3 -(6-((4-Oxo- 1 ,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H- 1 ,2,4-triazol-4- yl)propanenitrile (Compound 1-170);
(,S)-2-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-171);
5-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-172);
5-((6-(4-Cyclobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 173); 5-((6-(4-(Oxetan-3-yl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound
1-174);
5-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-175);
5-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-176);
5-((6-(4-((lr,3r)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-177);
( 1 s,3 s)-3 -(3 -(6-((4-Oxo- 1 ,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H- 1 ,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-178);
(lR,3R)-3-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-179);
5-((6-(4-(Bicyclo[ 1.1.1 ]pentan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)quinolin-4( \H)- one (Compound 1-180);
5-((6-(4-Cyclopentyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-181);
5-((6-(4-((lR,25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-182);
5-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-183);
5-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-184);
5-((6-(4-((l^,2^-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH^ one (Compound 1-185);
(R)-5-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-186);
0S)-5-((6-(4-(2,2-Difluorocyclopentyl)-4^
one (Compound 1-187);
5-((6-(4-((lR,2,S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-188);
5-((6-(4-((l,S',2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-189);
5-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-190); 5-((6-(4-((lS,2S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-
4(lH)-one (Compound 1-191);
(,S)-5-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-ta
(Compound 1-192);
(R)-5-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-ta^
one (Compound 1-193);
5-((6-(4-Cyclohexyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 194);
5-((6-(4-((lR,2^-2-Fluorocyclohexyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-195);
5-((6-(4-((l£,2R)-2-Fluorocyclohexyty
one (Compound 1-196);
5-((6-(4-((lR,2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-y
one (Compound 1-197);
5-((6-(4-((l£,2.S)-2-Fluorocyclohe^
one (Compound 1-198);
(R)-5-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-199);
(,S)-5-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-ta^
one (Compound 1-200);
5-((6-(4-((lR,2S)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-201);
5-((6-(4-((lS,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-202);
5-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-203);
5-((6-(4-((lS,2S)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-204);
(S)-5-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-205);
(R)-5-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-206);
5-((6-(4-(Tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-207); 5-((6-(4-Isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-2-methylquinolin-4(lH)-one
(Compound 1-208);
2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-to
one (Compound 1-209);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(methoxymethyl)quinolin-4(lH)- one (Compound 1-210);
Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate (Compound 1-211);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4-dihydroquinoline-2- carboxylic acid (Compound 1-212);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4-dihydroquinoline-2- carboxamide (Compound 1-213);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N,N-dimethyl-4-oxo-l,4- dihydroquinoline-2-carboxamide (Compound 1-214);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(pyrrolidine-l-carbonyl)quinolin- 4(lH)-one (Compound 1-215);
(R)-2-(3-Fluoropyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-216);
(R)-2-(3-Hydroxypyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-217);
(R)-2-(3-Aminopyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-218);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(piperidine- 1 -carbonyl)quinolin- 4(lH)-one (Compound 1-219);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(morpholine-4- carbonyl)quinolin-4(lH)-one (Compound 1-220);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(piperazine-l-carbonyl)quinolin- 4(lH)-one (Compound 1-221);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methylpiperazine-l- carbonyl)quinolin-4(lH)-one (Compound 1-222);
N-(2-(Dimethylamino)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo- l,4-dihydroquinoline-2-carboxamide (Compound 1-223);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(2-(pyrrolidin- 1 -yl)ethyl)- l,4-dihydroquinoline-2-carboxamide (Compound 1-224); (R)-N-(2-(3 -Fluoropyrrolidin- 1 -yl)e
yl)amino)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-225);
(R)-N-(2-(3-Hydroxypyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,44riazol-3-yl)pyridi yl)amino)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-226);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-4-oxo- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-227);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(2-(piperazin-l-yl)ethyl)- l,4-dihydroquinoline-2-carboxamide (Compound 1-228);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin- 1 - yl)ethyl)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-229);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-phenyl- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-230);
N-Benzyl-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxamide (Compound 1-231);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroquinoline-l- carbonyl)quinolin-4(lH)-one (Compound 1-232);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroisoquinoline- 2-carbonyl)quinolin-4(lH)-one (Compound 1-233);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-234);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-3-yl)-l,4- dihydroquinoline-2-carboxamide (Compound 1-235);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-4-yl)- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-236);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methyl-4H-chromen-4-one (Compound 1-237);
2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4H-chromen-4- one (Compound 1-238);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(methoxymethyl)-4H-chromen-4- one (Compound 1-239);
Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxylate (Compound 1-240);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2-carboxylic acid (Compound 1-241); 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxamide (Compound 1-242);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)ami
2-carboxamide (Compound 1-243);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(pyrrolidine-l-carbonyl)-4H- chromen-4-one (Compound 1-244);
(R)-2-(3-Fluoropyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-245);
(R)-2-(3-Hydroxypyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-246);
(R)-2-(3-Aminopyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-247);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(piperidine- 1 -carbonyl)-4H- chromen-4-one (Chromone 1-248);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(morpholine-4-carbonyl)-4H- chromen-4-one (Compound 1-249);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(piperazine-l-carbonyl)-4H- chromen-4-one (Compound 1-250);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methylpiperazine-l-carbonyl)- 4H-chromen-4-one (Compound 1-251);
N-(2-(Dimethylamino)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo- 4H-chromene-2-carboxamide (Compound 1-252);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(2-(pyrrolidin- 1 -yl)ethyl)- 4H-chromene-2-carboxamide (Compound 1-253);
(R)-N-(2-(3-Fluoropyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-4H-chromene-2-carboxamide (Compound 1-254);
(R)-N-(2-(3-Hydroxypyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-4H-chromene-2-carboxamide (Compound 1-255);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-4-oxo-4H- chromene-2-carboxamide (Compound 1-256);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(2-(piperazin-l-yl)ethyl)- 4H-chromene-2-carboxamide (Compound 1-257);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin- 1 - yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 1-258); 5-((6-(4-Isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-phenyl-4H-chromene-2- carboxamide (Compound 1-259);
N-Benzyl-5-((6-(4-isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxamide (Compound 1-260);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-4H-chromen-4-one (Compound 1-261);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroisoquinoline- 2-carbonyl)-4H-chromen-4-one (Compound 1-262);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)-4H- chromene-2-carboxamide (Compound 1-263);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-3-yl)-4H- chromene-2-carboxamide (Compound 1-264);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-4-yl)-4H- chromene-2-carboxamide (Compound 1-265);
2-Ethyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-266);
2-Isopropyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-267);
2-Isobutyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-268);
2-(Cyclopropylmethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-269);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethyl)isoindolin-l- one (Compound 1-270);
2-(2-Hydroxyethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-271);
7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(2-methoxy ethyl )isoindolin- 1 - one (Compound 1-272);
2-(2-Aminoethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-273);
2-(2-(Dimethylamino)ethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-274);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-(pyrrolidin-l- yl)ethyl)isoindolin-l-one (Compound 1-275); (R)-2-(2 3-FluoropyiTolidin-l-yl)ethyl)-7-((6-(4-isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-276);
(R)-2-(2 3-Hydroxypyrrolidin-l-yl)ethyl)-7 (6 4-isopropyl-4H-l,2,44riazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-277);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-mo holinoethyl)isoindolin-l- one (Compound 1-278);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-(piperazin-l- yl)ethyl)isoindolin-l-one (Compound 1-279);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-(4-methylpiperazin-l- yl)ethyl)isoindolin-l-one (Compound 1-280);
N-(2-(7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2- yl)ethyl)acetamide (Compound 1-281);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(3- (methylsulfonyl)propyl)isoindolin-l-one (Compound 1-282);
Methyl 3-(7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2- yl)propanoate (Compound 1-283);
3-(7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2-yl)propanoic acid (Compound 1-284);
3-(7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2-yl)-2,2- dimethylpropanoic acid (Compound 1-285);
2-Benzyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-286);
7- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methoxybenzyl)isoindolin-l- one (Compound 1-287);
8- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methoxybenzyl)isoquinolin- l(2H)-one (Compound 1-288).
[00127] In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
Table 2
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
[00128] Compounds in Table 2 are named:
7-((3 -(4-Isopropyl-4H- 1 ,2,4-tri azol-3 -yl)phenyl)amino)isoindolin- 1 -one (Compound 2- 1 );
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-
2);
3 , 3 -Ζ¾-7-((3 -(4-Isopropyl -4H- 1 ,2,4-tri azol-3 -yl)phenyl)amino)i soindolin- 1 -one (Compound 2-3 ); 3,3-JD2-7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-4);
3 , 3 -Difluoro-7-((3 -(4-i sopropyl-4H- 1 ,2,4-tri azol-3 -yl)phenyl)amino)i soindolin- 1 -one
(Compound 2-5);
3,3-Difluoro-7-((3-(4-isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-6);
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-3,3-dimethylisoindolin-l-one
(Compound 2-7);
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3,3-trimethylisoindolin-l-one
(Compound 2-8);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)isoindoline-l,3-dione (Compound 2-9); 4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindoline-l,3-dione
(Compound 2-10);
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3-dihydro-lH-inden-l-one (Compound
2-11); 2,2-/J2-7-((3-(4 sopropyl-4H-l,2,44riazol-3-yl)phenyl)amino)-2,3-dihydro-lH-inden-l-one
(Compound 2-12);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl iamino)benzofuran-3(2H)-one (Compound 2-13);
2,2-Z)2-4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl iphenyl)amino)benzofuran-3(2H)-one
(Compound 2-14);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl iamino)-lH-indazol-3(2H)-one (Compound 2- 15);
4-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl lamino)- 1 -methyl - lH-indazol-3 (2H)-one
(Compound 2-16);
4- ((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-l,2-dimethyl-lH-indazol-3(2H)-one (Compound 2-17);
8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-3 ,4-dihydroisoquinolin- 1 (2H)-one (Compound 2-18);
8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-2-methyl-3,4-dihydroisoquinolin-l(2H)- one (Compound 2-19);
8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)isoquinolin-l(2H)-one (Compound 2-20); 8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-2-methylisoquinolin- 1 (2H)-one
(Compound 2-21);
5- ((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)quinazolin-4(3H)-one (Compound 2-22); 5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-3-methylquinazolin-4(3H)-one
(Compound 2-23);
8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)isoquinoline- 1 ,3 (2H,4H)-dione
(Compound 2-24);
8-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-2-methylisoquinoline-l,3(2H,4H)-dione (Compound 2-25);
5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)quinazoline-2,4(lH,3H)-dione
(Compound 2-26);
5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-3-methylquinazoline-2,4(lH,3H)-dione (Compound 2-27);
5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-l -methyl quinazoline-2,4(lH,3H)-dione (Compound 2-28);
5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)-l,3-dimethylquinazoline-2,4(lH,3H)- dione (Compound 2-29)
5-((3-(4-Isopropyl-4H-l 2,4-triazol-3-yl)phenyl iamino)quinolin-4(lH)-one (Compound 2-30); 5-((3-(4-Isopropyl-4H-l,2,4 riazol-3-yl)phenyl)amino)-l-methylquinolin-4(lH)-one (Compound
2-31);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3-dihydroquinolin-4(lH)-one
(Compound 2-32);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-l-methyl-2,3-dihydroquinolin-4(lH)-one (Compound 2-33);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4H-chromen-4-one (Compound 2-34); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)chroman-4-one (Compound 2-35);
3 ,3 -Z) 2-5-((3 -(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)amino)chroman-4-one (Compound 2-36); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)thiochroman-4-one (Compound 2-37);
5- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4H-thiochromen-4-one (Compound 2- 38);
9-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-l- one (Compound 2-39);
9-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methyl-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (Compound 2-40);
6- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-3,4-dihydrobenzo[f][l,4]oxazepin- 5(2H)-one (Compound 2-41);
6-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4-methyl-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 2-42).
[00129] In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 2.
[00130] Any combination of the groups described above for the various variables is
contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[00131] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
[00132] "Pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[00133] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt- forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
[00134] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid;
ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1,5-disulfonic acid;
naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p) and undecylenic acid. [00135] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. In some embodiments, a compound described herein is prepared as a hydrochloride salt.
[00136] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base. In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,
tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. In some embodiments, the compounds provided herein are prepared as a sodium salt.
[00137] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
[00138] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
[00139] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
[00140] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
[00141] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2H, 3H, 13C, 14C, 15N, 180, 170, 35 S, 18F, 36C1. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
[00142] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
[00143] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers,
Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. [00144] In some embodiments, compounds described herein are prepared as prodrugs. A
"prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the "prodrug") but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
[00145] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxy alkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview,
1985 and Method in Enzymology, Widder, K. et al, Ed.; Academic, 1985, vol. 42, p. 309-396;
Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and
Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.
[00146] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. [00147] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
[00148] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
Synthesis of Compounds
[00149] Compounds of Formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.
[00150] Unless otherwise indicated, conventional methods of mass spectroscopy, MR, UPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.
[00151] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Theodora W. Green and Peter G. M. Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons, Inc. (1999). The starting materials are available from commercial sources or are readily prepared.
[00152] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 1-2 or (1H- imidazol-5-yl)arylamino derivatives 1-3 are synthesized as shown in Scheme 1. Scheme 1
Figure imgf000092_0001
[00153] In some embodiments, treatment of arylhalide derivative 1-1 with (4H-[l,2,4]-triazol-3- yl)arylamine derivative I-l or (lH-imidazol-5-yl)arylamine derivative 1-2 (prepared as described in Schemes 5-8) in the presence of a base such as K2C03, Cs2C03, NaOlBu, KOlBu, or K3P04 and in the presence of a transition metal -derived catalyst such as Pd(OAc)2, Pd2(dba)3,
Pd(dppf)Cl2, or Pd[P(lBu)]2, and in the presence of a ligand such as XPhos, XantPhos, or BINAP, and in a suitable solvent such as 1,4-dioxane, tert- uOH, or toluene (or mixtures thereof) with heating will afford 1-2 or 1-3, respectively. Alternatively, treatment of arylhalide derivative 1-1 with (4H-[l,2,4]-triazol-3-yl)arylamine derivative I-l or (lH-imidazol-5-yl)arylamine derivative 1-2 in the presence of a base such as Cs2C03, NaOlBu, or KOlBu, and in the presence of a transition metal-derived catalyst such as Cul, or Copper(I) thiophene-2-carboxylate, and in the presence of a ligand such as L-proline, tram,-l,2-diaminocyclohexane, or N-methyl-2- (methylamino)ethylamine, and in a suitable solvent such as 1,4-dioxane, DMSO, DMF, or DMA (or mixtures thereof) with heating will afford 1-2 or 1-3, respectively.
[00154] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 2-2 or (1H- imidazol-5-yl)arylamino derivatives 2-3 are synthesized as shown in Scheme 2.
Scheme 2
Figure imgf000092_0002
2-2; X2 = N
2-3; X2 = CH [00155] In some embodiments, treatment of an aminoaryl derivative 2-1 with (4H-[ 1,2,4]- triazol-3-yl)aryl halide derivative 1-3 or (lH-imidazol-5-yl)aryl halide derivative 1-4 (prepared as described in Schemes 9-11) in the presence of a base such as K2C03, Cs2C03, NaOlBu, KOlBu, or K3P04 and in the presence of a transition metal derived catalyst such as Pd(OAc)2, Pd2(dba)3,
Pd(dppf)Cl2 or Pd[P(lBu)]2, and in the presence of a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P(lBu)3, l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu, and in a suitable solvent such as 1,4-dioxane, tert- uOH, DME, THF, NMP, H20, or toluene (or mixtures thereof) with heating will afford 2-2 or 2-3, respectively.
[00156] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 3-8 are synthesized as shown in Scheme 3.
Scheme 3
Figure imgf000093_0001
3-1 3-3
Figure imgf000093_0002
[00157] In some embodiments, treatment of arylhalide derivative 3-1 with an arylamine derivative 3-2 in the presence of a base such as K2C03, Cs2C03, NaOlBu, KOlBu, or K3P04 and in the presence of a transition metal-derived catalyst such as Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, or Pd[P(lBu)]2, and in the presence of a ligand such as XPhos, XantPhos, or BINAP, and in a suitable solvent such as 1,4-dioxane, tert-BuOH, THF, DMA, or toluene (or mixtures thereof) with heating, will afford 3-3. Alternatively, treatment of an aminoaryl derivative 3-4 with a haloamine derivative 3-5 in the presence of a base such as K2C03, Cs2C03, NaOlBu, KOlBu, or
K3P04 and in the presence of a transition metal derived catalyst such as Pd(OAc)2, Pd2(dba)3,
Pd(dppf)Cl2 or Pd[P(lBu)]2, and in the presence of a ligand such as XPhos, XantPhos, DavePhos, ruphos, BINAP, P(lBu)3, l,3-bis[2,6-diisopropylphenyl]imidazolium chloride, or CyPF-t-Bu, and in a suitable solvent such as 1,4-dioxane, tert- uOH, DME, THF, NMP, or toluene (or mixtures thereof) with heating will afford 3-3.
[00158] Treatment of 3-3 with hydrazine in a suitable solvent such as MeOH or EtOH with heating, will afford hydrazide derivative 3-6. Hydrazide derivative 3-6 upon heating with DMF- DMA can afford 3-7. Reaction of 3-7 with a primary amine (RCNH2) in the presence of HO Ac and in a suitable solvent such as MeCN with heating, will give (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 3-8.
[00159] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 4-5 are synthesized as shown in Scheme 4.
Scheme 4
Figure imgf000094_0001
4-1
= Br,
[00160] In some embodiments, treatment of a arylhalide derivative 4-1 with an arylamine derivative 4-3 (obtained via amine deprotection of 4-2, the synthesis of which is described in Scheme 7) in the presence of a base such as K2C03, Cs2C03, NaOlBu, KOlBu, or K3P04 and in the presence of a transition metal-derived catalyst such as Pd(OAc)2, Pd2(dba)3, Pd(dppf)Cl2, or Pd[P(lBu)]2, and in the presence of a ligand such as XPhos, XantPhos, or BINAP, and in a suitable solvent such as 1,4-dioxane, tert-BuOH, THF, DMA, or toluene (or mixtures thereof) with heating, will afford 4-4. Heating of 4-4 with a primary amine (RCNH2) in the presence of a suitable acid such as TFA or ?ara-toluenesulfonic acid, either neat or in a suitable solvent such as 1-butanol or xylene, will give (4H-[l,2,4]-triazol-3-yl)arylamino derivatives 4-5.
[00161] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamine derivatives 1-1 are synthesized as shown in Scheme 5.
Scheme 5
Figure imgf000095_0001
1-1
[00162] In some embodiments, aryl-ester derivatives 5-1 can be converted to the corresponding hydrazides 5-2, via treatment of 5-1 with hydrazine in a suitable solvent such as MeOH or EtOH with heating. Hydrazide derivatives 5-2 upon heating with DMF-DMA can afford 5-3. Reaction of 5-3 with a primary amine (RC H2) in the presence of HO Ac and in a suitable solvent such as MeCN with heating, will give 1-1.
[00163] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamine derivatives 1-1 are synthesized as shown in Scheme 6.
Scheme 6
Figure imgf000095_0002
1-1 6-4 [00164] In some embodiments, the amino group of 6-1 may be protected with appropriate protecting groups (PG) to give 6-2. Treatment of 6-2 with hydrazine in a suitable solvent such as
MeOH or EtOH with heating, will afford hydrazides 6-3. Heating of 6-3 with a primary amine
(RC H2) and a formamide of formula Rc HCHO, in the presence of a suitable acid such as TFA, and in a suitable solvent such as toluene, will give 6-4. Subsequent amine deprotection of 6-4 will afford 1-1.
[00165] In some embodiments, (4H-[l,2,4]-triazol-3-yl)arylamine derivatives 1-1 are synthesized as shown in Scheme 7.
Scheme 7
Figure imgf000096_0001
[00166] In some embodiments, treatment of hydrazide derivatives 7-1 (prepared as described in Scheme 6) with triethylorthoformate in the presence of /?ara-toluenesulfonic acid with heating, either neat or in a suitable solvent such as DMA, will give [l,2,4]-oxadiazol derivatives 7-2. Heating of 7-2 with a primary amine (RC H2) in the presence of a suitable acid such as TFA or /?ara-toluenesulfonic acid, either neat or in a suitable solvent such as 1-butanol or xylene, will give 7-3. Subsequent amine deprotection of 7-3 will afford 1-1.
[00167] In some embodiments, (lH-imidazol-5-yl)arylamine derivatives 1-2 are synthesized as shown in Scheme 8.
Schem
Figure imgf000097_0001
8-1 8-2 8-5
Figure imgf000097_0002
I-2
[00168] In some embodiments, treatment of arylamine derivative 8-1 with di-tert-butyl dicarbonate, in the presence of a suitable base such as TEA or Hunig's base, and in the presence of an activating agent such as DMAP, and in a suitable solvent such as THF, DCM, or tert- butanol, with or without heating, will afford 8-2. Treatment of imidazole derivative 8-3 with a suitable brominating agent such as l,3-dibromo-5,5-dimethyl-hydantoin, in a suitable solvent such as DCM, will give bromoimidazole derivative 8-4. Compound 8-4 upon treatment with n- butyl lithium at low temperature in a suitable solvent such as THF, followed by treatment with ZnBr2 at low to room temperature, followed by treatment with 8-2 in the presence of a palladium catalyst such as Pd[PPh3]4 at elevated temperature, will afford 8-5. Subsequent N-boc deprotection of 8-5 with TFA or HC1 will give 1-2.
[00169] In some embodiments, (4H-[l,2,4]-triazol-3-yl)aryl halide derivatives 1-3 are synthesized as shown in Scheme 9. Scheme 9
Figure imgf000098_0001
1-3
[00170] In some embodiments, the treatment of aryl halide derivative 9-1 with hydrazine in a suitable solvent such as MeOH or EtOH with heating, will afford hydrazides 9-2. Hydrazide derivatives 9-2 upon heating with DMF-DMA can afford 9-3. Reaction of 9-3 with a primary amine (RC H2) in the presence of HO Ac and in a suitable solvent such as MeCN with heating will give 1-3.
[00171] In some embodiments, (4H-[l,2,4]-triazol-3-yl)aryl halide derivatives 1-3 are synthesized via a Sandmeyer reaction as shown in Scheme 10.
Scheme 10
Figure imgf000098_0002
[00172] In some embodiments, the treatment of arylamine derivative 1-1 with sodium nitrite and an acid such as HCl or HBr, in the presence of an appropriate metal halide salt (MY; where Y = CI, Br, or I) such as potassium halide, sodium halide, copper(I) halide, copper(II) halide, or zinc(II) halide salts, and in a suitable solvent such as acetonitrile and water, with or without heating, will afford 1-3.
[00173] In some embodiments, (lH-imidazol-5-yl)aryl halide derivative 1-4 are synthesized via a Sandmeyer reaction as shown in Scheme 11. Scheme 11
Figure imgf000099_0001
[00174] In some embodiments, the treatment of arylamine derivative 1-2 with sodium nitrite and an acid such as HC1 or HBr, in the presence of the appropriate metal halide salt (MY; where Y = CI, Br, or I) such as potassium halide, sodium halide, copper(I) halide, copper(II) halide, or zinc(II) halide salts, and in a suitable solvent such as acetonitrile and water, with or without heating, will afford 1-4.
[00175] In some embodiments, compounds are prepared as described in the Examples.
Certain Terminology
[00176] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including" as well as other forms, such as
"include", "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[00177] As used herein, Ci-Cx includes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, z'so-propyl, /7-butyl, /so-butyl, sec-butyl, and t-butyl.
[00178] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the "alkyl" group has 1 to 10 carbon atoms, i.e. a Ci- C10alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., " 1 to 10 carbon atoms" means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, an alkyl is a Ci-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
[00179] An "alkylene" group refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkelene is a Ci-C6alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkyl ene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -
CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.
[00180] "Deuteroalkyl" refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
[00181] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, wherein
[00182] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C=C-R2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkenyl group include - CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.
[00183] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3 -C≡CCH2CH3, - CH2C≡CH.
[00184] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.
[00185] The term "alkylamine" refers to the -N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
[00186] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
[00187] The term "carbocyclic" or "carbocycle" refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. In some embodiments, bicyclic carbocycles are fused, bridged or spirocyclic.
[00188] As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
[00189] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[l . l . l]pentyl. In some embodiments, a cycloalkyl is a C3-
C6cycloalkyl.
[00190] "Deuterocycloalkyl" refers to a cycloalkyl group where 1 or more hydrogen atoms of a cycloalkyl are replaced with deuterium. In one aspect, a deuterocycloalkyl is a C3- C6deuterocycloalkyl .
[00191] "Fluorocycloalkyl" refers to a cycloalkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluorcycloalkyl is a C3-C6fluoroalkyl.
[00192] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
[00193] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is a Ci-C6fluoroalkyl.
[00194] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. - H-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C6heteroalkyl.
[00195] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1.3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl,
3.4- dihydroisoquinolin-l (2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. In some embodiments, bicyclic heterocycles are fused, bridged or spirocyclic.
[00196] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls.
Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some
embodiments, heteroaryl is a Ci-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.
[00197] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some
embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,
imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-
Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Ci0heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. In some embodiments, bicyclic heterocycloalkyls are fused, bridged or spirocyclic.
[00198] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
[00199] The term "moiety" refers to a specific segment or functional group of a molecule.
Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[00200] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -N(Ry)2, -ORy, -SRy, -S(=0)Ry, -S(=0)2Ry, -C02Ry, -OC(=0)Rx, -C(=0)N(Ry)2, - RyC(=0)Rx, -OC(=0)N(Ry)2, - RyC(=0)N(Ry)2, - RyC(=0)ORx, - S(=0)2N(Ry)2, - RyS(=0)2Rx, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, heterocycloalkyl, aryl, and heteroaryl; each Rx is independently selected from alkyl, Ci-C6fluoroalkyl, deuteroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl and heteroaryl; each Ry is independently selected from H, alkyl, fluoroalkyl, deuteroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, benzyl and heteroaryl; or two R5 on the same N atom are taken together with the N atom to which they are attached to a N-containing heterocycle. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, - OH, -C02H, -C02alkyl, -C(=0)NH2, -C(=0)NH(alkyl), -C(=0)N(alkyl)2, -S(=0)2NH2, - S(=0)2NH(alkyl), -S(=0)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, - H2, - H(CH3), -N(CH3)2, -OH, -C02H, - C02(Ci-C4alkyl),
Figure imgf000104_0001
-
Figure imgf000104_0002
-S(=0)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=0)Ci-C4alkyl, and - S(=0)2C1-C4alkyl. In yet some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).
[00201] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
[00202] The term "modulate" as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
[00203] The term "modulator" as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is a degrader.
[00204] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
[00205] The terms "co-administration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00206] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.
[00207] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
[00208] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
[00209] The terms "kit" and "article of manufacture" are used as synonyms.
[00210] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
[00211] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
Pharmaceutical compositions
[00212] In some embodiments, the compounds described herein are formulated into
pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.
[00213] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a
pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes
(injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal,
intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular,
intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.
[00214] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[00215] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
[00216] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00217] Pharmaceutical compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00218] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[00219] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
[00220] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
[00221] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
[00222] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10%) w/w, for instance from 1%> to 2% by weight of the formulation.
[00223] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
[00224] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Methods of Dosing and Treatment Regimens
[00225] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of ASK1 activity.
Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
[00226] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic
applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
[00227] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
[00228] In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
[00229] In certain embodiments wherein a patient's status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
[00230] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
[00231] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
[00232] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[00233] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
[00234] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
[00235] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
[00236] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
[00237] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative
embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
[00238] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. In certain embodiments, the pharmaceutical composition further comprises one or more anti-cancer agents.
[00239] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
[00240] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
[00241] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
[00242] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen
encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
[00243] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
[00244] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
[00245] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
[00246] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
[00247] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with chemotherapy, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof. Chemotherapy includes the use of anti-cancer agents.
[00248] In one aspect, the compound described herein, or a pharmaceutically acceptable salt thereof, is administered or formulated in combination with one or more anti -cancer agents.
EXAMPLES
[00249] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Synthesis of Int-A
Figure imgf000114_0001
Step 1: 6-Aminopicolinohydrazide (A-2)
[00250] To a solution of 6-aminopicolinic acid methyl ester A-1 (25 g, 164 mmol) in MeOH (300 mL), was added hydrazine monohydrate (16.47 g, 329 mmol). The mixture was heated at 78 °C for 2 h. Additional hydrazine monohydrate (2.46 g, 50 mmol) and MeOH (100 mL) were added and the mixture stirred at 78 °C for a further 1 h. The mixture was cooled to rt then concentrated to approximately two-thirds volume. EtOAc (30 mL) and Et20 (100 mL) were added. The resulting precipitate was collected via filtration, washed with Et20, and dried, to afford compound A-2 (23 g, 92%) as an off-white solid. 1H MR (400 MHz, DMSO-i¾): δ 9.14 (s, 1H), 7.50 (m, 1H), 7.15 (m, 1H), 6.57 (m, 1H), 6.06 (s, 2H), 4.46 (s, 2H); LCMS Mass: 153.0 (M++l).
Step 2: (E)-A^-(6-((E)-2-((Dimethylamino)methylene)hydrazinecarbonyl)pyridin-2-yl)-N^V- dimethylformimidamide (A-3)
[00251] A stirred mixture of A-2 (23 g, 151 mmol) in DMF-DMA (200 mL) was heated at 110 °C for 24 h. The mixture was cooled to rt then concentrated under reduced pressure. The solid residue was re-suspended in EtOAc (150 mL) and stirred at 50 °C for 20 min. The mixture was cooled to rt and Et20 (100 mL) was added. The solids were collected via filtration, washed with Et20, and dried to afford compound A-3 (36.5 g, 92%) as a light yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 10.67 (s, 1H), 8.85 (s, 1H), 8.06 (s, 1H), 7.69 (m, 1H), 7.45 (m, 1H), 6.91 (m, 1H), 3.13 (s, 3H), 2.99 (s, 3H), 2.87 (s, 6H); LCMS Mass: 263.0 (M++l).
Step 3: 6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-amine (Int-A)
[00252] To a stirred solution of A-3 (36.5 g, 139 mmol) in a mixture of MeCN (184 mL) and HO Ac (46 mL), was added isopropyl amine (60 mL, 696 mmol). The mixture was heated at 100 °C for 16 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (180 mL) and the pH was adjusted to 8 with aq. 1M NaOH. The obtained precipitate was collected via filtration and dried to afford Int-A (18.1 g, 64%) as an off-white solid. 1H NMR (400 MHz, DMSO-i¾): δ 8.78 (s, 1H), 7.52 (m, 1H), 7.15 (m, 1H), 6.50 (m, 1H), 6.15 (s, 2H), 5.51 (m, 1H), 1.44 (m, 6H); LCMS Mass: 204.0 (M++l).
Synthesis of Int-B
Figure imgf000115_0001
A-3 Int-B
[00253] To a stirred solution of A-3 (500 mg, 1.91 mmol) (from Int-A, Step 2) in a mixture of MeCN (2.56 mL) and HO Ac (0.64 mL), was added (R)-2-aminopropan-l-ol (716 mg, 9.53 mmol). The mixture was heated at 100 °C for 16 h. The mixture was cooled to rt and
concentrated under reduced pressure. The residue was diluted with water (3 mL) and the pH was adjusted to 5 with aq. 1M NaOH. The obtained precipitate was collected via filtration and dried to afford Int-B (290 mg, 69%) as an off-white solid. 1H NMR (400 MHz, DMSO-i¾): δ 8.68 (s, 1H), 7.52 (m, 1H), 7.18 (m, 1H), 6.56 (m, 1H), 6.14 (s, 2H), 5.39 (m, 1H), 4.98 (m, 1H), 3.38 - 3.70 (m, 2H), 1.43 (m, 3H); LCMS Mass: 220.0 (M++l).
Synthesis of Int-C
Figure imgf000115_0002
C-1 C-2 Int-C Step 1: 6-Bromopicolinohydrazide (C-2)
[00254] To a stirred solution of methyl 6-bromopicolinate C-l (15 g, 69.4 mmol) in MeOH (90 mL) at rt, was added hydrazine hydrate (5.2 g, 104 mmol) and the mixture stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified via trituration with MTBE to afford compound C-2 (13.6 g, 91%) as white solid. 1H NMR (400 MHz, CDC13): δ 8.80 (br s, 1H), 8.12 (m, 1H), 7.72 (m, 1H), 7.63 (m, 1H), 4.08 (br s, 2H).
Step 2: (E)-N'-(6-Bromopicolinoyl)-N^V-dimethylformohydrazonamide (Int-C)
[00255] A solution of C-2 (7 g, 32.4 mmol) in DMF-DMA (9.6 g, 81 mmol) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford the crude product which was purified via trituration with Et20 to afford Int-C (6.2 g, 71%) as a yellow solid. LCMS Mass: 271.1 (M++l).
Synthesis of Int-D
Figure imgf000116_0001
Int-D
Step 1 : (E)-5-(((2-Bromo-5-nitrophenyl)imino)methyl)-2,2-dimethyl-l,3-dioxane-4,6-dione (D-2)
[00256] A stirred solution of 5-(methoxymethylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (7.3 g, 39.2 mmol) in CH(OCH3)3 (30 mL) was heated at 110 °C for 2 h. A suspension of 2-bromo-5- nitroaniline D-1 (5 g, 23.0 mmol) in CH(OCH3)3 (30 mL) was added and the reaction stirred at 110 °C for 16 h. The reaction mixture was cooled to rt, filtered, and the solid dried to afford D-2 (5.5 g 65%) as yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 11.57 (m, 1H), 8.91 (m, 1H), 8.72 (m, 1H), 7.99 - 8.07 (m, 2H), 1.71 (s, 6H); LCMS Mass: 368.9 (M+-l).
Step 2: 8-Bromo-5-nitroquinolin-4(lH)-one (D-3)
[00257] A stirred suspension of D-2 (1 g, 2.7 mmol) in diphenylether (14 mL) was heated in a microwave synthesizer at 200 °C for 1 h. The mixture was cooled to rt and diluted with petroleum ether. The precipitate that formed was collected via filtration and washed with DCM. The solid was dried to afford D-3 (400 mg, 55%) as a brown solid. 1H NMR (400 MHz, DMSO- d6): δ 11.55 (br s, 1H), 8.17 (m, 1H), 7.96 (m, 1H), 7.53 (m, 1H), 6.21 (m, 1H); LCMS Mass: 269.0 (M+-l).
Step 3: 5-Aminoquinolin-4(lH)-one (Int-D)
[00258] A solution of D-3 (2 g, 7.4 mmol) and 10% Pd/C (300 mg) in a 1 : 1 mixture of
EtOAc/EtOH (200 mL) was stirred under hydrogen (1 atmosphere pressure). The reaction heated at reflux for 16 h then cooled and the reaction filtered through Celite. The filtrate was
concentrated to afford Int-D (1.07 g, 91%) as a blue solid. 1H MR (400 MHz, DMSO-i¾): δ 11.98 (s, 1H), 7.86 (s, 1H), 7.30 (m, 1H), 6.66 (m, 1H), 6.46 (m, 1H), 6.04 (m, 1H); LCMS Mass: 161.1 (M++l).
Example 1: 7-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one h rochloride (Compound 1-1)
Figure imgf000117_0001
Int-A t-BuOH, Heat 2 Compound 1-1
Step 1: 7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one trifluoroacetate (2)
[00259] A stirred mixture of Int-A (200 mg, 0.984 mmol), 7-bromoisoindolin-l-one 1 (240 mg, 1.13 mmol), XPhos (47 mg, 0.098 mmol), Cs2C03 (800 mg, 2.46 mmol), and fert-butanol (7.8 mL) at rt, was purged with a stream of argon for 5 min. Pd2(dba)3 (90 mg, 0.098 mmol) was added and the vial was sealed and heated at 100 °C for 16 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was partitioned between DCM and water. The organic layer was separated and the aq layer re-extracted with additional DCM. The combined organic layers were dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified via reverse-phase preparative HPLC (X-Select CSH C18 250 χ 19 mm, 5μπι column; eluting with 10-90% MeCN/H20 containing 0.05% TFA, over 30 min) to afford compound 2 (52 mg, 12%) as a yellow solid. LCMS Mass: 335.0 (M++l).
Step 2: 7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one hydrochloride (Compound 1-1)
[00260] To a stirred solution of compound 2 (48 mg, 0.107 mmol) in DCM (5 mL) at rt, was added 2M HC1 in Et20 (107 μΕ, 0.214 mmol). The mixture was stirred at rt for 10 min. The mixture was concentrated under reduced pressure and the residue was purified via trituration with Et20 to afford compound 1-1 (40 mg, 100%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 10.00 (br s, 1H), 9.53 (s, 1H), 8.73 (s, 1H), 8.20 (m, 1H), 7.90 (m, 1H), 7.56 (m, 1H), 7.49 (m,
1H), 7.21 (m, 1H), 7.09 (m, 1H), 5.48 (m, 1H), 4.37 (s, 2H), 1.50 (m, 6H); LCMS Mass: 335.0
(M++l).
Example 2: 7-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin- 1-one hydrochloride (Compound -2)
Figure imgf000118_0001
Compound 1 -2
[00261] The title compound (1-2) was prepared from Int-A using the procedure described for Example 1, using 7-bromo-2-methyl-2,3-dihydro-lH-isoindol-l-one, and 1,4-dioxane as solvent in Step 1. 1H NMR (400 MHz, DMSO-i¾): δ 9.93 (s, 1H), 9.41 (s, 1H), 8.17 (m, 1H), 7.90 (m, 1H), 7.57 (m, 1H), 7.49 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 5.46 (m, 1H), 4.48 (s, 2H), 3.08 (s, 3H), 1.48 (m, 6H); LCMS Mass: 349.0 (M++l).
Example 3: (R)-7-^6-(4-(l-Hvdroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)- 2-methylisoindolin-l-one trifluoroacetate (Compound 1-112)
Figure imgf000118_0002
lnt_B t-BuOH, Heat Compound 1 -112
[00262] A stirred mixture of Int-B (83 mg, 0.378 mmol), 7-bromo-2-methyl-2,3-dihydro-lH- isoindol-l-one 1 (91 mg, 0.402 mmol), XPhos (33 mg, 0.068 mmol), Cs2C03 (305 mg, 0.938 mmol), and tert-butanol (4 mL) at rt, was purged with a stream of argon for 5 min. Pd2(dba)3 (35 mg, 0.038 mmol) was added and the vial was sealed and heated at 100 °C for 16 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was partitioned between DCM and water. The organic layer was separated and the aq layer re-extracted with additional DCM. The combined organic layers were dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified via reverse-phase preparative HPLC (X-Select CSH C18 250 19 mm, 5μιη column; eluting with 10-90% MeCN/H20 containing 0.05% TFA, over 30 min) to afford compound 1-112 (102 mg, 56%) as a yellow solid. 1H NMR (400 MHz,
DMSO-i¾): δ 9.94 (s, 1H), 9.18 (s, 1H), 8.25 (m, 1H), 7.89 (m, 1H), 7.44 - 7.58 (m, 2H), 7.16
(m, 1H), 7.09 (m, 1H), 5.43 (m, 1H), 4.46 (s, 2H), 3.60 - 3.65 (m, 2H), 3.08 (s, 3H), 1.48 (m,
3H); LCMS Mass: 365.0 (M++l).
Example 4: 5-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4flH)-one hydrochloride (Compound 1-30)
Figure imgf000119_0001
Step 1: 5-(((3-Bromophenyl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (3)
[00263] A stirred solution of Meldrum's acid 2 (6.26 g, 43.5 mmol) in triethyl orthoformate (30 mL) was heated at reflux for 1 h. The mixture was cooled to rt. 3-Bromoaniline 1 (5 g, 29.1 mmol) was added and the mixture heated at reflux for 2 h. The reaction mixture was cooled and the solid was collected via filtration. The solid was purified via trituration with Et20 to afford compound 3 (8 g, 84%) as a pale yellow solid. 1H NMR (400 MHz, CDC13): δ 11.20 (m, 1H), 8.60 (m, 1H), 7.39 - 7.46 (m, 2H), 7.31 (m, 1H), 7.21 (m, 1H), 1.76 (s, 6H); LCMS Mass: 325.1 (M++l).
Step 2: l-Benzyl-5-bromoquinolin-4(lH)-one (4a) and l-benzyl-7-bromoquinolin-4(lH)- one (4b)
[00264] A stirred mixture of compound 3 (5 g, 15.3 mmol) and diphenyl ether (30 mL) was refluxed under a nitrogen atmosphere for 1 h. The reaction mixture was cooled to rt. Hexane (100 mL) was added and the resulting solid was collected via filtration and dried to afford a mixture of 5-bromoquinolin-4(lH)-one and 7-bromoquinolin-4(lH)-one (2.5g) as a brown solid. The obtained mixture of 5-bromoquinolin-4(lH)-one and 7-bromoquinolin-4(lH)-one, was dissolved in DMF (30 mL) and cooled to 0 °C. K2C03 (5.5 g, 39.9 mmol) was added and the mixture stirred for 15 min. Benzyl bromide (3.41 g, 19.9 mmol) was added and the mixture was warmed to rt and stirred for a further 3 h. The mixture was diluted with water (100 mL) and EtOAc (100 mL). The organic layer was separated and washed with water, brine, then dried (Na2S04). The mixture was concentrated under reduced pressure and the residue purified (silica gel; eluting with
20% MeOH in EtOAc) to afford a mixture of compounds 4a and 4b (1.5 g, 36%) as a brown solid. LCMS Mass: 313.9 (M++l).
Step 3: l-Benzyl-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (5a) and l-benzyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (5b)
[00265] To a stirred solution of mixture of compounds 4a and 4b (1.5 g, 4.77 mmol) and Int-A (950 mg, 4.77 mmol) in t-BuOH (20 mL) at 0 °C under a nitrogen atmosphere, were added Pd2(dba)3 (430 mg, 0.47 mmol), XPhos (450 mg, 0.955 mmol), and Cs2C03 (4.6 g, 0.014 mmol). The reaction mixture was stirred at 110 °C for 6 h. The mixture was cooled to rt and diluted with DCM (200 mL) and water (200 mL). The organic layer was separated, dried (Na2S04), then concentrated under reduced pressure. The residue was purified (silica gel; eluting with 10-20% MeOH in EtOAc) to separately afford compound 5a (850 mg, 42%) and compound 5b (300 mg, 15%) both as a pale yellow solids.
[00266] Compound 5a: 1H MR (400 MHz, DMSO-i¾): δ 13.91 (s, 1H), 8.92 (s, 1H), 8.36 (m, 1H), 8.25 (m, 1H), 7.84 (m, 1H), 7.45 - 7.58 (m, 2H), 7.23 - 7.40 (m, 4H), 6.94 - 7.07 (m, 2H), 6.52 (m, 1H), 6.24 (m, 1H), 5.49 - 5.56 (m, 3H), 1.44 (m, 6H); LCMS Mass: 437.1 (M++l). Compound 5b: 1H NMR (400 MHz, DMSO-i¾) δ 9.64 (s, 1H), 8.89 (s, 1H), 8.08 (m, 2H), 7.76 (m, 1H), 7.66 (m, 1H), 7.56 (m, 1H), 7.45 (m, 1H), 7.18 - 7.34 (m, 3H), 7.01 - 7.14 (m, 2H), 6.91 (m, 1H), 6.04 (m, 1H), 5.37 (s, 2H), 5.30 (m, 1H), 1.38 (m, 6H); LCMS Mass: 437.1 (M++l).
Step 4: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (6)
[00267] To a stirred solution of compound 5a (700 mg, 0.16 mmol) in MeOH (20 mL), was added 20% Pd(OH)2/C (2.1 g). The mixture was stirred at rt under hydrogen (1 atmosphere pressure) for 16 h. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified via silica gel chromatography (eluting with 10% MeOH in DCM), followed by trituration with Et20/ «-pentane to afford compound 6 (310 mg, 52%) as a yellow solid. [00268] 1H MR (400 MHz, DMSO-i¾) δ 13.67 (s, 1H), 11.99 (br s, 1H), 8.94 (s, 1H), 8.29 (m,
1H), 7.90 (m, 1H), 7.83 (m, 1H), 7.46 - 7.56 (m, 2H), 6.97 - 7.07 (m, 2H), 6.09 (m, 1H), 5.51
(m, 1H), 1.48 (m, 6H); LCMS Mass: 347.0 (M++l).
Step 5: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-30)
[00269] To a stirred solution of compound 6 (150 mg, 0.43 mmol) in DCM (10 mL) at 0 °C, was added 4M HC1 in 1,4-dioxane (1.5 mL) and the mixture stirred for 30 min. The mixture was concentrated under reduced pressure and the residue purified via trituration with Et20/«-pentane to afford compound 1-30 (71 mg, 43%) as a yellow solid. 1H MR (400 MHz, DMSO-i¾) δ 13.74 (br s, 1H), 12.23 (m, 1H), 9.65 (s, 1H), 8.26 (m, 1H), 7.85 - 7.97 (m, 2H), 7.47 - 7.61 (m, 2H), 7.02 - 7.21 (m, 2H), 6.12 (m, 1H), 5.57 (m, 1H), 1.53 (m, 6H); LCMS Mass: 347.0 (M++l).
Example 5: 5-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinolin- -one hydrochloride (Compound 1-31)
Figure imgf000121_0001
Step 1: 5-Bromo-l-methylquinolin-4(lH)-one (2a) and 7-bromo-l-methylquinolin-4(lH)- one (2b)
[00270] A mixture of compound 1 (5 g, 15.3 mmol) (from Example 4, Step 1) and diphenyl ether (30 mL) was refluxed under a nitrogen atmosphere for 1 h. The mixture was cooled to rt then hexane (100 mL) was added. The obtained solid was collected via filtration and dried to afford a mixture of 5-bromoquinolin-4(lH)-one and 7-bromoquinolin-4(lH)-one (2.5 g) as a brown solid. The solid (2 g) was dissolved in DMF (20 mL) and cooled to 0 °C. NaH (524 mg of a 60% dispersion in mineral oil, 13.1 mmol) and iodomethane (0.83 mL, 13.3 mmol) were added slowly and the reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2S04), filtered, then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford a mixture of compound 2a and 2b (900 mg, 25%) as a brown solid. LCMS Mass: 239.1 (M++l).
Step 2: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinolin- 4(lH)-one (3a) and 7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l- methylquinolin-4(lH)-one (3b)
[00271] To a stirred solution of a mixture of compounds 2a and 2b (200 mg, 0.84 mmol) and compound Int-A (170 mg, 0.84 mmol) in t-BuOH (10 mL) at 0 °C and under a nitrogen atmosphere, was added Pd2(dba)3 (76 mg, 0.084 mmol), XPhos (80 mg, 0.16 mmol), and Cs2C03 (820 mg, 2.52 mmol) the reaction mixture was stirred at 110 °C for 6 h. The mixture was cooled to rt and diluted with DCM (100 mL) and water (100 mL). The organic layer was separated and dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 10-20% MeOH in EtOAc) to separately afford compound 3a (40 mg, 13%) and compound 3b (70 mg, 23%) as pale yellow solids. Compound 3a: 1H NMR (400 MHz, DMSO-i¾) : δ 13.93 (s, 1H), 8.93 (s, 1H), 8.40 (m, 1H), 8.02 (m, 1H), 7.84 (m, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 7.06 (m, 2H), 6.12 (m, 1H), 5.50 (m, 1H), 3.80 (s, 3H), 1.48 (m, 6H); LCMS Mass: 361.4 (M++l). Compound 3b: 1H NMR (400 MHz, DMSO-i¾) δ 9.97 (s, 1H), 8.87 (s, 1H), 8.05 (m, 1H), 7.74 - 7.92 (m, 3H), 7.60 (m, 1H), 7.48 (m, 1H), 7.13 (m, 1H), 5.92 (m, 1H), 4.87 (m, 1H), 3.70 (s, 3H), 1.37 (m, 6H); LCMS Mass: 361.4 (M++l).
Step 3: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinolin- 4(lH)-one hydrochloride (Compound 1-31)
[00272] To a stirred solution of compound 3a (40 mg, 0.11 mmol) in DCM (10 mL) at 0 °C, was added 4M HC1 in 1,4-dioxane (0.4 mL). The mixture was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified via trituration with Et20/«- pentane to afford compound 1-31 (40 mg, 62%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-i4) : δ 13.97 (br s, 1H), 9.30 (br s, 1H), 8.39 (m, 1H), 8.03 (m, 1H), 7.89 (m, 1H), 7.63 (m, 1H), 7.56 (m, 1H), 7.10 (m, 2H), 6.13 (m, 1H), 5.52 (m, 1H), 4.27 (br s, 1H), 3.83 (s, 3H), 1.50 (m, 6H); LCMS Mass: 361.1 (M++l).
Example 6 : 5-((6-( 4-Isopropyl-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo- 1 ,4- dihydroquinoline-2-carboxylate sodium salt (Compound 1-212)
Figure imgf000123_0001
Figure imgf000123_0002
Pd/C
H2 (1 atmos)
MeOH, rt
Figure imgf000123_0003
Compound 1-212
Step 1: Dimethyl 2-((3-bromophenyl)amino)maleate (3)
[00273] To a stirred solution of 3-bromoaniline 1 (30 g, 0.175 mol) in EtOH (300 mL) at rt, was added dimethyl acetylenedicarboxylate 2 (32 g, 0.228 mol) and the mixture heated at 80 °C for 6 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in «-hexane) to afford compound 3 (25 g, 45%) as a pale green viscous liquid. 1H MR (400 MHz, DMSO-i¾): δ 9.54 (s, 1H), 7.19 - 7.25 (m, 3H), 6.88 (m, 1H), 5.41 (s, 1H), 3.68 (m, 6H); LCMS Mass: 313.8 (M++l).
Step 2: Methyl 5-bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate (4a) and methyl 7- bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate (4b)
[00274] A stirred mixture of compound 3 (7 g, 0.022 mol) and Eaton's reagent (21 mL) were heated at 60 °C for 5 h. The reaction mixture was cooled to 0 °C and sat. aq. NaHC03 was added. The obtained solid was collected via filtration and dried to afford a mixture of compounds 4a and 4b (5 g, 79%)) as an off-white solid, which was used without further purification. LCMS Mass: 281.8 (M++l).
Step 3: Methyl 4-(benzyloxy)-5-bromoquinoline-2-carboxylate (5a) and methyl 4- (benzyloxy)-7-bromoquinoline-2-carboxylate (5b)
[00275] To a stirred solution of a mixture of compounds 4a and 4b (1 g, 3.53 mmol) in DMF (10 mL) at 0 °C and under a nitrogen atmosphere, was added K2C03 (1.4 g, 10.6 mmol) and the mixture stirred for 15 minutes. Benzyl bromide (0.63 mL, 5.29 mmol) was added and the mixture stirred at rt for 2 h. The mixture was diluted with water (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with water, then brine, and then dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 5-
10% EtOAc in «-hexane) to separately afford compound 5a (300 mg, 23%) and compound 5b
(200 mg, 15%) as off-white solids.
[00276] Compound 5a: 1H NMR (400 MHz, DMSO-i¾): δ 8.10 (m, 1H), 7.97 (m, 1H), 7.71 (s, 1H), 7.60 - 7.69 (m, 3H), 7.41 - 7.48 (m, 2H), 7.36 (m, 1H), 5.50 (s, 2H), 3.95 (s, 3H); LCMS Mass: 372.1 (M++l). Compound 5b: 1H NMR (400 MHz, DMSO-i¾) : δ 8.33 (m, 1H), 8.16 (m, 1H), 7.83 (m, 1H), 7.71 (s, 1H), 7.56 - 7.61 (m, 2H), 7.36 - 7.50 (m, 3H), 5.51 (s, 2H), 3.96 (s, 3H); LCMS Mass: 372.1 (M++l).
Step 4: Methyl 4-(benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinoline-2-carboxylate (6)
[00277] To a stirred solution of compound 5a (2 g, 5.36 mmol) and Int-A (1.08 mg, 5.36 mmol) in 1,4-dioxane (40 mL) at rt and under a nitrogen atmosphere, were added Pd2(dba)3 (490 mg, 0.536 mmol), XPhos (255 mg, 0.536 mmol) and Cs2C03 (3.51 g, 10.7 mmol). The reaction mixture was stirred at 110 °C for 16 h. The mixture was cooled to rt and diluted with DCM (200 mL) and water (200 mL). The organic layer was separated, dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 2% MeOH in DCM) to afford compound 6 (280 mg, 10%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-i4) : δ 9.34 (s, 1H), 8.73 (s, 1H), 8.02 (m, 1H), 7.70 - 7.85 (m, 2H), 7.62 (s, 1H), 7.57 (m, 1H), 7.42 - 7.49 (m, 3H), 7.33 - 7.41 (m, 3H), 6.31 (m, 1H), 5.38 (s, 2H), 5.04 (m, 1H), 3.95 (s, 3H), 1.08 (m, 6H); LCMS Mass: 495.2 (M++l).
Step 5: Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate (7)
[00278] To a stirred solution of compound 6 (250 mg, 5.05 mmol) in MeOH (10 mL) at rt, was added 10% Pd/ C (50 mg) and the reaction mixture was stirred under H2 (1 atmosphere) for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified via silica gel (eluting with 10% MeOH in DCM) followed by trituration with Et20/ «-pentane to afford compound 7 (170 mg, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾) : δ 13.29 (s, 1H), 12.23 (s, 1H), 8.93 (s, 1H), 8.33 (m, 1H), 7.85 (m, 1H), 7.52 - 7.61 (m, 2H), 7.43 (m, 1H), 7.06 (m, 1H), 6.65 (m, 1H), 4.49 (m, 1H), 3.98 (s, 3H), 1.47 (m, 6H); LCMS Mass: 405.3 (M++l).
Step 6: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate sodium salt (Compound 1-212) [00279] To a stirred solution of compound 7 (75 mg, 0.185 mmol) in THF (3 mL) at 0 °C, was added aq. 0.2M NaOH (1 mL). The mixture stirred at rt for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified via trituration with Et20/ «-pentane to afford compound 1-212 (45 mg, 72%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 13.90
(s, 1H), 11.43 (br s, 1H), 8.92 (s, 1H), 8.23 (m, 1H), 7.81 (m, 1H), 7.49 (m, 1H), 7.39 - 7.47 (m,
2H), 6.99 (m, 1H), 6.47 (s, 1H), 5.53 (m, 1H), 1.48 (m, 6H); LCMS Mass: 391.0 (M++l).
Example 7: 2-fHvdroxymethyl)-5-^6-f4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- l)amino)quinolin-4(lH)-one hydrochloride (Compound 1-209)
Figure imgf000125_0001
Step 1 : 2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (2)
[00280] To a stirred solution of compound 1 (75 mg, 0.18 mmol) (from Example 6, Step 5) in a 1 : 1 mixture of MeOH and THF (5 mL) at 0 °C and under a nitrogen atmosphere, were added NaBH4 (13 mg, 0.36 mmol) and CaCl2 (40 mg, 0.36 mmol). The reaction mixture was warmed to rt and stirred for a further 3 h. The mixture was quenched with sat. aq. H4C1, then extracted with 10% MeOH in DCM (2 x 100 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified via trituration with Et20/ «-pentane to afford compound 2 (50 mg, 72%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 13.69 (s, 1H), 11.68 (s, 1H), 8.93 (s, 1H), 8.26 (m, 1H), 7.82 (m, 1H), 7.45 - 7.55 (m, 2H), 7.13 (m, 1H), 7.01 (m, 1H), 6.10 (s, 1H), 5.74 (m, 1H), 5.00 (m, 1H), 4.50 (m, 2H), 1.48 (m, 6H); LCMS Mass: 377.1 (M++l).
Step 2: 2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-209)
[00281] To a stirred solution of compound 2 (50 mg, 0.13 mmol) in DCM (2 mL) at 0 °C, was added 4M HCI in 1,4-dioxane (0.5 mL) and the mixture stirred at rt for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified via trituration with Et20/ n- pentane to afford compound 1-209 (40 mg, 74%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6): δ 13.72 (br s, 1H), 11.77 (s, 1H), 9.27 (s, 1H), 8.25 (m, 1H), 7.86 (m, 1H), 7.45 - 7.55 (m, 2H), 7.16 (m, 1H), 7.07 (m, 1H), 6.12 (m, 1H), 5.52 (m, 1H), 4.50 (s, 2H), 1.50 (m, 6H); LCMS Mass: 377.3 (M++l). Example 8: 5-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-fpyridin- -yl)-l,4-dihydroquinoline-2-carboxamide hydrochloride (Compound 1-234)
Figure imgf000126_0001
Step 1 : 4-(Benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinoline- 2-carboxylic acid (2)
[00282] To a stirred solution of compound 1 (350 mg, 0.708 mmol) (from Example 6, Step 4) in THF (15 mL) at 0 °C, was added LiOH.H20 (90 mg, 2.12 mmol) in H20 (3 mL) drop wise. The mixture was warmed to rt and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was acidified with sat. aq. citric acid solution. The obtained solids were collected via filtration and dried under vacuum to afford compound 2 (250 mg, 73%) as a yellow solid.
1H MR (400 MHz, DMSO-i¾): δ 9.35 (s, 1H), 8.73 (s, 1H), 8.01 (m, 1H), 7.72 - 7.87 (m, 2H), 7.62 (s, 1H), 7.57 (m, 1H), 7.41 - 7.50 (m, 3H), 7.34 - 7.40 (m, 3H), 6.32 (m, 1H), 5.39 (s, 2H), 5.04 (m, 1H), 1.07 (m, 6H); LCMS Mass: 481.3 (M++l).
Step 2: 4-(Benzyloxy)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N- (pyridin-2-yl)quinoline-2-carboxamide (3)
[00283] To a stirred solution of compound 2 (150 mg, 0.312 mmol) in DMF (5 mL) at rt, were added HATU (240 mg, 0.625 mmol) and DIPEA (0.17 mL, 0.937 mmol) and the mixture stirred at rt for 15 min. Pyridin-2-amine (1.08 mg, 5.36 mmol) was added and stirring was continued for 16 h. The mixture was poured into water (200 mL) and acidified with sat. aq. citric acid solution. The obtained solid was collected via filtration and was purified (silica gel; eluting with 2% MeOH in DCM) to afford compound 3 (84 mg, 48%) as a pale yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 10.63 (s, 1H), 9.39 (s, 1H), 8.74 (s, 1H), 8.44 (m, 1H), 8.32 (m, 1H), 8.06 (m, 1H), 7.89 - 7.99 (m, 2H), 7.78 - 7.86 (m, 2H), 7.61 (m, 1H), 7.45 - 7.50 (m, 3H), 7.35 - 7.42 (m, 3H), 7.25 (m, 1H), 6.35 (m, 1H), 5.46 (s, 2H), 5.08 (m, 1H), 1.09 (m, 6H); LCMS Mass: 557.4 (M++l). Step 3: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- l,4-dihydroquinoline-2-carboxamide (4)
[00284] To a stirred solution of compound 3 (140 mg, 0.251 mmol) in a 2: 1 mixture of
THF:MeOH (21 mL), was added 10% Pd/ C (50% wet, 60 mg). The reaction mixture was stirred under H2 (1 atmosphere) at rt for 24 h. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified (silica gel; eluting with 10% MeOH in DCM) to afford compound 4 (75 mg, 64%) as a pale yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 13.41 (s, 1H), 12.11 (s, 1H), 11.36 (s, 1H), 8.94 (s, 1H), 8.46 (m, 1H), 8.32 (m, 1H), 8.15 (m, 1H), 7.81 - 7.99 (m, 2H), 7.51 - 7.66 (m, 2H), 7.40 (m, 1H), 7.26 (m, 1H), 7.07 (m, 1H), 6.99 (s, 1H), 5.50 (m, 1H), 1.48 (m, 6H); LCMS Mass: 467.3 (M++l).
Step 4: 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- l,4-dihydroquinoline-2-carboxamide hydrochloride (Compound 1-234)
[00285] To a stirred solution of compound 4 (72 mg, 0.161 mmol) in a 2: 1 mixture of DCM and MeOH (7.5 mL) at 0 °C, was added 4M HCI in 1,4-dioxane (0.5 mL) and the mixture stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified via trituration with Et20/ «-pentane to afford compound 1-234 (46 mg, 59%) as an orange solid.
[00286] 1H MR (400 MHz, DMSO-i¾): δ 13.44 (s, 1H), 12.15 (s, 1H), 11.39 (s, 1H), 9.33 (s, 1H), 8.47 (m, 1H), 8.31 (m, 1H), 8.15 (m, 1H), 7.81 - 7.99 (m, 2H), 7.54 - 7.66 (m, 2H), 7.43 (m, 1H), 7.29 (m, 1H), 7.14 (m, 1H), 6.99 (s, 1H), 5.52 (m, 1H), 4.23 (br s, 1H), 1.51 (m, 6H); LCMS Mass: 467.1 (M++l).
Example 9: 4-^6-f4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3- dione hydrochloride (Compound 1-9)
Figure imgf000127_0001
Step 1: 4-Bromo-2-(4-methoxybenzyl)isoindoline-l,3-dione (2)
[00287] To a solution of 4-bromoisoindole-l,3-dione 1 (226 mg, 1.0 mmol) in DMF (8 mL) was added Cs2C03 (652 mg, 2.0 mmol). The mixture was cooled to 0-5 °C and PMB-Br (302 mg, 1.5 mmol) was added dropwise. The reaction was allowed to warm to rt and stirred for 16 h. The mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in hexanes) to afford compound 2 (208 mg, 74%) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 7.80 - 7.83 (m, 2H), 7.60 (m, 1H), 7.53 - 7.57 (m, 2H), 6.85 - 6.90 (m, 2H), 4.80 (s, 2H), 3.79 (s, 3H).
Step 2: 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4- methoxybenzyl)isoindoline-l,3-dione (3)
To a mixture of Int-A (102 mg, 0.5 mmol) and compound 2 (208 mg, 0.6 mmol) in 1,4-dioxane (8.0 mL) was added Pd2(dba)3 (24 mg, 0.025 mmol), xantphos (30 mg, 0.05 mmol) and K2C03 (138 mg, 1.0 mmol). The reaction mixture was heated at 100 °C under a N2 atmosphere for 16 h. The mixture was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers washed with water, brine, then dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 3% MeOH in DCM) to afford compound 3 (180 mg, 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 9.28 (s, 1H), 8.86 (s, 1H), 8.31(m, 1H), 7.88 (m, 1H), 7.74 (m, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.23 - 7.27 (m, 3H), 6.82 - 6.86 (m, 2H), 5.29 (m, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 1.31 (m, 6H).
Step 3: 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione (4)
[00288] To a solution of compound 3 (80 mg, 0.17 mmol) in DCM (3 mL) was added a mixture of TfOH/TFA (0.5/1.0 mL, 1 :2, v/v). The reaction mixture was stirred at rt for 5 h, then added dropwise to aq. sat. NaHC03. The aquous mixture was extracted with DCM and the combined organic layers dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by preparative silica gel TLC (eluting with 3% MeOH in DCM) to afford compound 4 (20 mg, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 11.30 (s, 1H), 9.24 (s, 1H), 8.90 (s, 1H), 8.37 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.25 (m, 1H), 5.34 (m, 1H), 1.36 - 1.38 (m, 6H); LCMS Mass: 349.2 (M++l).
Step 4: 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione hydrochloride (Compound 1-9)
[00289] To a solution of compound 4 (20 mg, 0.05 mmol) was added 4M HC1 in MeOH (4 mL). The mixture was stirred at rt for 1 h, then concentrated under reduce pressure to afford compound 1-9 (22 mg, 100%) as a solid. LCMS Mass: 349.2 (M++l). Example 10: 4-(Y6-( -Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindoline-l,3-dione hydrochloride (Compound 1-10)
Figure imgf000129_0001
Compound 1-10
Step 1: 4-Bromo-2-methylisoindoline-l,3-dione (2)
[00290] To a solution of 4-bromoisoindole-l,3-dione 1 (226 mg, 1.0 mmol) in MeCN (5 mL) was added CS2CO3 (652 mg, 2.0 mmol). The reaction mixture was stirred at rt for 15 min then cooled to 0-5 °C. lodomethane (0.2 mL, 3.0 mmol) added dropwise and the reaction mixture was allowed to warm to rt and stirred for a further 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, then dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in hexanes) to afford the compound 2 (220 mg, 92%) as a yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 7.97 (m, 1H), 7.86 (m, 1H), 7.70 (m, 1H), 3.03 (s, 3H).
Step 2: 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindoline- 1,3-dione (3)
[00291] To a mixture of Int-A (82 mg, 0.4 mmol) and compound 2 (120 mg, 0.5 mmol) in 1,4- dioxane (5.0 mL) was added Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and K2C03 (110 mg, 0.8 mmol). The reaction mixture was heated at 100 °C under a N2 atmosphere for 16 h. The mixture was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers washed with water, brine, then dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (eluting with 5% MeOH in DCM) to afford compound 3 (75 mg, 51%) as a yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 9.24 (s, 1H), 8.89 (s, 1H), 8.35 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 7.27 (m, 1H), 5.33 (m, 1H), 3.02 (s, 3H), 1.36 - 1.37 (m, 6H); LCMS Mass: 363.1 (M++l). Step 3: 4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindoline- 1,3-dione hydrochloride (Compound 1-10)
[00292] To a solution of compound 3 (70 mg, 0.19 mmol) was added 4M HC1 in MeOH (3 mL). The mixture was stirred at rt for 1 h, then concentrated under reduce pressure to afford compound 1-10 (76 mg, 100%) as a solid. 1H MR (400 MHz, DMSO-i¾): δ 9.41 (s, 1H), 9.35 (s, 1H), 8.32 (m, 1H), 7.94 (m, 1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 5.36 (m, 1H), 3.02 (s, 3H), 1.38 - 1.40 (m, 6H).
Example 11: 8- 6- 4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoquinolin-l 2H)- one hydrochloride (Compound 1-
Figure imgf000130_0001
Compound 1-20
[00293] The title compound (1-20) was prepared from 8-bromo-2H-isoquinolin-l-one using the procedure described for Example 9. 1H NMR (400 MHz, DMSO): δ 12.74 (s, 1H), 1 1.50 (m, 1H), 9.38 (s, 1H), 8.43 (m, 1H), 7.89 (m, 1H), 7.57 - 7.58 (m, 2H), 7.13 - 7.19 (m, 3H), 6.59 (m, 1H), 5.52 (m, 1H), 1.50 - 1.51 (m, 6H).
Example 12: 8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoquinolin-l 2H)-one hydrochloride (Compound 1-21)
Figure imgf000130_0002
Compound 1 -21
[00294] The title compound (1-21) was prepared from 8-bromo-2H-isoquinolin-l-one using the procedure described for Example 10. 1H NMR (400 MHz, DMSO-i¾): δ 12.74 (s, 1H), 9.68 (s, 1H), 8.46 (m, 1H), 7.91 (m, 1H), 7.58 - 7.61 (m, 2H), 7.51 (m, 1H), 7.19 (m, 1H), 7.15 (m, 1H), 6.65 (m, 1H), 5.54 (m, 1H), 3.53 (s, 3H), 1.51 - 1.53 (m, 6H).
Example 13: (R)-7-( ( 6-( 4-( l-Hydroxypropan-2-yn-4H-l,2,4-triazol-3-ynpyridin-2- yl)amino)isoindolin-l-one hydrochloride (Compound 1-57)
Figure imgf000131_0001
Step 1: (R)-2-(3-(6-Bromopyridin-2-yl)-4H-l,2,4-triazol-4-yl)propan-l-ol (1)
[00295] A mixture of (R)-(-)-2-amino-l-propanol (694 mg, 9.3 mmol), HOAc (666 mg, 11.1 mmol), and MeCN (15 mL) was stirred at rt for 30 min. Int-C (500 mg, 1.8 mmol) was added and the reaction was heated at 90 °C for 16 h. The reaction mixture was concentrated, diluted with water and the pH adjusted to 8 with aq. sat. NaHC03. The solid that precipitated was collected by filtration and dried to afford compound 1 (170 mg, 33%) as yellow solid. LCMS Mass: 283.1 (M++l).
Step 2: (R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (2)
[00296] To a solution of compound 1 (95 mg, 0.34 mmol) and 7-aminoisoindolin-l-one (50 mg, 0.34 mmol) in tert-BuOH (20 mL) was added K2C03 (95 mg, 0.68 mmol), Pd2(dba)3 (70 mg, 0.068 mmol), and Xantphos (95 mg, 0.16 mmol). The reaction mixture was heated at 100 °C under a N2 atmosphere for 12 h. The mixture was cooled to rt and filtered. Water was added to the filtrate and the mixture was repeatedly extracted with EtOAc. The combined organic layers were dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 0-10% MeOH in DCM) to afford compound 2 (20 mg, 17%) as yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 8.85 (s, 1H), 8.57 (m, 1H), 8.03 (m, 1H), 7.85 (m, 1H), 7.70 (s, 1H), 7.33 (m, 1H), 6.72 (m, 1H), 6.65 (m, 1H), 5.47 (m, 1H), 4.99 (s, 2H), 3.70 - 3.75 (m, 3H), 1.53 - 1.54 (m, 3H).
Step 3: (R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one hydrochloride (Compound 1-57)
[00297] A solution of compound 2 (20 mg, 0.057 mmol) in 4M HCI in MeOH (5 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford compound 1-57 (15 mg, 68%) a yellow solid. 1H NMR (400 MHz, DMSO-i¾): δ 9.43 (s, 1H), 8.63 (m, 1H), 8.08 (m, 1H), 7.88 (m, 1H), 7.31 - 7.35 (m, 2H), 6.74 (m, 1H), 6.66 (m, 1H), 5.59 (m, 1H), 5.00 (s, 2H), 3.78 (m, 2H), 3.57 (s, 1H), 1.56 - 1.58 (m, 3H); LCMS Mass: 351.1
(M++l).
Example 14: fRV2-Methyl-7- 6-f4-a,l,l-trifluoropropan-2-vn-4H-l,2,4-triazol-3- yl)pyridin-2-yl)amino)isoindolin- -one ( Compound 1-110)
Figure imgf000132_0001
Compound 1-110
[00298] The title compound (1-110) was prepared using the procedure described for Example 13, using (R)-2-amino-l, l, l-trifluoropropane hydrochloride in Step 1 and 7-amino-2-methyl-2,3- dihydro-lH-isoindol-l-one in Step 2. 1H MR (400 MHz, DMSO-i¾): δ 9.82 (s, 1H), 9.13 (s, 1H), 8.04 (m, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 7.17 (m, 1H), 7.13 (m, 1H), 6.66 (m, 1H), 4.47 (s, 2H), 3.08 (s, 3H), 1.81 - 1.82 (m, 3H); LCMS Mass: 403.1 (M++l).
Example 15 : 5-((6-( 4-( 2-Hydroxyethyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)amino)q uinolin-
4qH>one (Compound 1-158)
Figure imgf000132_0002
Compound 1-158
[00299] The title compound (1-158) was prepared using the procedure described for Example 16 Steps 1 and 2, using 2-aminoethanol in Step 1. 1H MR (400 MHz, DMSO-i¾): δ 13.58 (s, 1H), 12.04 (s, 1H), 8.61 (s, 1H), 8.17 (m, 1H), 7.90 (m, 1H), 7.83 (m, 1H), 7.53 - 7.59 (m, 2H), 7.00 - 7.04 (m, 2H), 6.08 (m, 1H), 4.98 (m, 1H), 4.60 (m, 2H), 3.66 (m, 2H); LCMS Mass: 349.1 (M++l).
Example 16 : 5-((6-(4-(2-Methoxyethyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2-yl)amino)q uinolin-
4(lH)-one hydrochloride (Compound 1-160)
Figure imgf000133_0001
Step 1: 2-Bromo-6-(4-(2-methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridine (1)
[00300] A solution of 2-methoxyethylamine (694 mg, 9.3 mmol) and HO Ac (666 mg, 11.1 mmol) in MeCN (15 mL) was stirred at rt for 30 min. Int-C (500 mg, 1.8 mmol) was added and the reaction stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and the pH adjusted to 8 with sat. aq. NaHC03. The precipitate which formed was collected via filtration and dried to afford compound 1 (150 mg, 29%) as colorless oil. LCMS Mass: 283.1 (M++l).
Step 2: 5-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (2)
[00301] A suspension of compound 1 (100 mg, 0.35 mmol), Int-D (47 mg, 0.29 mmol), Pd2(dba)3 (13 mg, 0.01 mmol), Xantphos (16 mg, 0.02 mmol) and Cs2C03 (283 mg, 0.87 mmol) in 1,4-dioxane (5 mL) and 2 drops H20, was heated under a N2 atmosphere in a microwave synthesizer at 100 °C for 1 h. The reaction was cooled to rt and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 6% EtOH in DCM) to afford compound 2 (15 mg, 14%) as a yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 13.57 (s, 1H), 11.99 (s, 1H), 8.63 (s, 1H), 8.16 (m, 1H), 7.91 (m, 1H), 7.84 (m, 1H), 7.52 - 7.60 (m, 2H), 7.03 (m, 2H), 6.10 (m, 1H), 4.73 (m, 2H), 3.63 (m, 2H), 3.17 (s, 3H); LCMS Mass: 363.1 (M++l). Step 3: 5-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one hydrochloride (Compound 1-160)
[00302] To a solution of compound 2 (15 mg, 0.041 mmol) in MeOH (4 mL) at rt, was added dropwise 4M HC1 in MeOH (1 mL). The mixture was stirred at rt for 1 h then concentrated under reduced pressure to afford compound 1-160 (15 mg, 94%) as yellow solid. 1H MR (400 MHz, DMSO-i¾): δ 13.62 (s, 1H), 12.12 (s, 1H), 9.02 (s, 1H), 8.16 (m, 1H), 7.85 - 7.93 (m, 2H), 7.57 - 7.61 (m, 2H), 7.04 - 7.12 (m, 2H), 6.11 (m, 1H), 4.77 (m, 2H), 3.63 (m, 2H), 3.18 (s, 3H). Example 17: fRV5- 6-f4-a -Trifluoropropan-2-vn-4H-l,2,4-triazol-3-vnpyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-165)
Figure imgf000134_0001
Compound 1-165
[00303] The title compound (1-165) was prepared using the procedure described for Example 16, using (R)-2-amino-l, l, l-trifluoropropane hydrochloride in Step 1. 1H MR (400 MHz, DMSO-i4) : δ 13.63 (s, 1H), 12.28 (s, 1H), 9.15 (s, 1H), 8.08 (m, 1H), 7.87 - 7.90 (m, 2H), 7.65 (m, 1H), 7.53 (m, 1H), 7.06 - 7.10 (m, 2H), 6.70 (m, 1H), 6.10 (m, 1H), 1.84 - 1.86 (m, 3H).
Example 18: (R)-5-( ( 6-( 4-( l-Hvdroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-167)
Figure imgf000134_0002
Compound 1-167
[00304] The title compound (1-167) was prepared using the procedure described for Example 16, using (R)-(-)-2-amino-l-propanol in Step 1. 1H MR (400 MHz, DMSO-i¾) : δ 13.74 (s, 1H), 12.24 (s, 1H), 9.40 (s, 1H), 8.31 (m, 1H), 7.84 - 7.94 (m, 2H), 7.49 - 7.57 (m, 2H), 7.06 - 7.09 (m, 2H), 6.11 (m, 1H), 5.51 (m, 1H), 3.63 - 3.64 (m, 2H), 3.07 (m, 1H), 1.52 - 1.54 (m, 3H); LCMS Mass: 363.1 (M++l).
Example 19: (S)-5-((6-(4-(l-Hvdroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-168)
Figure imgf000134_0003
Compound 1-168
[00305] The title compound (1-168) was prepared using the procedure described for Example 16, using (5)-(+)-2-amino-l-propanol in Step 1. 1H MR (400 MHz, DMSO-i¾): δ 13.75 (s, 1H), 12.11 (s, 1H), 9.44 (s, 1H), 8.32 (m, 1H), 7.84 - 7.94 (m, 2H), 7.49 - 7.57 (m, 2H), 7.04 - 7.10 (m, 2H), 6.11 (m, 1H), 5.51 (m, 1H), 3.63 - 3.64 (m, 2H), 1.52 - 1.54 (m, 3H); LCMS Mass:
363.1 (M++l).
Example 20: 5-^6-f4-Cvclopentyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4flH)- one hydrochloride (Compound 1-
Figure imgf000135_0001
Compound 1-181
[00306] The title compound (1-181) was prepared using the procedure described for Example 16, using cyclopentylamine in Step 1. 1H MR (400 MHz, DMSO-i¾): δ 13.71 (s, 1H), 12.08 (m, 1H), 9.28 (s, 1H), 8.27 (m, 1H), 7.82 - 7.92 (m, 2H), 7.48 - 7.57 (m, 2H), 7.09 (m, 1H), 7.04 (m, 1H), 6.11 (m, 1H), 5.55 (m, 1H), 2.18 - 2.19 (m, 2H), 1.75 - 1.95 (m, 4H), 1.53 - 1.58 (s, 2H); LCMS Mass: 373.1 (M++l).
Example 21 : 5-((6-( 4-(( lR,2R)-2-Hvdroxycvclopentyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-190)
Figure imgf000135_0002
Compound 1-190
[00307] The title compound (1-190) was prepared using the procedure described for Example 16, using /ram,-(lR,2R)-2-aminocyclopentanol hydrochloride in Step 1. 1H MR (400 MHz, DMSO-i¾): δ 13.79 (br s, 1H), 12.38 (m, 1H), 9.77 (s, 1H), 8.39 (m, 1H), 7.84 - 7.97 (m, 2H), 7.53 - 7.57 (m, 2H), 7.10 - 7.15 (m, 2H), 6.14 (m, 1H), 5.39 (m, 1H), 4.33 (m, 1H), 2.34 (m, 1H), 1.92 - 2.03 (m, 2H), 1.79 (m, 1H), 1.64 (m, 1H), 1.45 (m, 1H); LCMS Mass: 389.2 (M++l)
Example 22 : 5-((6-( 4-( ( lS,2S)-2-Hvdroxycvclopentyl)-4H- 1 ,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-191)
Figure imgf000136_0001
Compound 1-191
[00308] The title compound (1-191) was prepared using the procedure described for Example 16, using /ra«5-(l^,25)-2-aminocyclopentanol hydrochloride in Step 1. 1H MR (400 MHz, DMSO-i4): δ 13.77 (br s, 1H), 12.38 (m, 1H), 9.83 (s, 1H), 8.39 (m, 1H), 7.84 - 7.97 (m, 2H), 7.53 - 7.57 (m, 2H), 7.10 - 7.15 (m, 2H), 6.14 (m, 1H), 5.37 (m, 1H), 4.33 (m, 1H), 2.34 (m, 1H), 1.92 - 2.03 (m, 2H), 1.79 (m, 1H), 1.64 (m, 1H), 1.45 (m, 1H); LCMS Mass: 389.2 (M++l)
Example 23 : 2-Benzyl-7-((6-( 4-isopropyl-4H- 1 ,2,4-triazol-3-yl)pyridin-2- yl)aniiiio)isoiiidoliii-l-oiie (Compound 1-286)
Figure imgf000136_0002
Step 1: 2-Benzyl-7-bromoisoindolin-l-one (2)
[00309] To a solution of 7-bromoisoindolin-l-one 1 (212 mg, 1.0 mmol) in MeCN (5.0 mL) was added CS2CO3 (652 mg, 2.0 mmol). The reaction mixture was stirred at rt for 15 min then cooled to 0-5 °C. Benzyl bromide (274 mg, 1.6 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in hexanes) to afford compound 2 (220 mg, 73%) as a yellow solid. 1H MR (400 MHz, CD3OD): δ 7.68 (m, 1H), 7.46 - 7.54 (m, 2H), 7.32 - 7.41 (m, 5H), 4.83 (s, 2H), 4.37 (s, 2H).
Step 2: 2-Benzyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-286)
[00310] To a mixture of Int-A (102 mg, 0.5 mmol) and compound 2 (190 mg, 0.6 mmol) in 1,4- dioxane (8.0 mL) was added Pd2(dba)3 (24 mg, 0.025 mmol), xantphos (30 mg, 0.05 mmol) and K2C03 (138 mg, 1.0 mmol). The reaction was stirred under a N2 atmosphere at 100 °C for 16 h. The reaction was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 2% MeOH in DCM) to afford compound 1-286 (107 mg, 50%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾) δ = 9.87 (s, 1H), 8.92 (s, 1H), 8.24 (m, 1H), 7.85 (m, 1H), 7.56 (m, 1H), 7.50 (m, 1H), 7.28 - 7.39 (m, 5H), 7.16 (m, 1H), 7.07 (m, 1H), 5.45 (m, 1H), 4.74 (s, 2H), 4.39 (s, 2H), 1.44 - 1.45 (m, 6H); LCMS Mass: 425.2 (M++l).
Example 24: 7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4- methoxybenzyQisoindolin-l-one (Compound 1-287)
Figure imgf000137_0001
Compound 1 -287
[00311] The title compound (1-287) was prepared using the procedure described for Example 23, using 4-(methoxy)benzyl bromide in Step 1. 1H NMR (400 MHz, DMSO-i¾): δ 9.88 (s, 1H), 8.92 (s, 1H), 8.25 (m, 1H), 7.85 (m, 1H), 7.50 - 7.60 (m, 2H), 7.23 - 7.27 (m, 2H), 7.17 (m, 1H), 7.07 (m, 1H), 6.90 - 6.95 (m, 2H), 5.54 (m, 1H), 4.66 (s, 2H), 4.35 (s, 2H), 3.73 (s, 3H), 1.43 - 1.45 (m, 6H); LCMS Mass: 455.2 (M++l).
Example 25: 8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4- methoxybenzyl)isoquinolin-l -one (Compound 1-288)
Figure imgf000137_0002
[00312] The title compound (1-288) was prepared from 8-bromo-2H-isoquinolin-l-one using the procedure described for Example 23, using 4-(methoxy)benzyl bromide in Step 1. 1H NMR (400 MHz, DMSO-i¾): δ 12.59 (s, 1H), 8.92 (s, 1H), 8.48 (m, 1H), 7.85 (m, 1H), 7.55 - 7.62 (m, 3H), 7.3 - 7.34 (m, 2H), 7.06 - 7.14 (m, 2H), 6.90 - 6.93 (m, 2H), 6.68 (m, 1H), 5.48 (m, 1H), 5.14 (s, 2H), 3.71 (s, 3H), 1.45 - 1.46 (m, 6H).
Example 26: (S)-5-((6-(4-(l,l,l-Trifluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one hydrochloride (Compound 1-166)
Figure imgf000138_0001
Compound 1-166
The title compound (1-166) was prepared using the procedure described for Example 16, using (5)-2-amino-l, l,l-trifluoropropane hydrochloride in Step 1. 1H MR (400 MHz, DMSO-i¾): δ 13.61 (s, 1H), 12.02 (br s, 1H), 9.15 (s, 1H), 8.08 (m, 1H), 7.87 - 7.92 (m, 2H), 7.66 (m, 1H), 7.53 (m, 1H), 7.03 - 7.10 (m, 2H), 6.70 (m, 1H), 6.11 (m, 1H), 1.80 - 1.86 (m, 3H). LCMS Mass: 401.1 (M++l).
Example A-l: Parenteral Pharmaceutical Composition
[00313] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection
Example A-2: Oral Solution
[00314] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
Example A-3: Oral Tablet
[00315] A tablet is prepared by mixing 20-50%) by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50%> by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
Example A-4: Oral Capsule
[00316] To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
[00317] In another embodiment, 10-500 mg of a compound described herein, or a
pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule
(hypromellose or hard gelatin) and the capsule is closed.
Example A-5: Topical Gel Composition
[00318] To prepare a pharmaceutical topical gel composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl celluose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
Biological Assays
Example B-l: Human ASK1 ADP-Glo Assay
[00319] The ability of test compounds to inhibit ASK1 kinase activity was determined using the luminescent ADP-Glo™ Kinase Assay and Myelin Basic Protein (MBP) as a substrate (Promega Corporation, Madison, WI). During the kinase reaction, ASK1 utilizes ATP and generates ADP. The remaining ATP is then depleted by addition of the ADP-Glo™ reagent which also terminates the reaction. Subsequent addition of the Kinase Detection Reagent converts the ADP that was produced during the kinase reaction to ATP, and this newly synthesized ATP is converted to light using the luciferase/luciferin reactions. The assay was performed according to the manufacturer's instructions. Briefly, purified, recombinant ASK1 (amino acids 649-946) (10-20 ng/well) was added to a 384-well, F bottom, small volume, HIbase, white plate (Greiner Bio-One, Monroe, North Carolina #784075) containing 1-2 μΙ_, 5X test compound or vehicle control (diluted 1 :20 from a 100% DMSO stock solution into IX Reaction Buffer A). The enzyme was allowed to pre- incubate with test compound from 15-120 min at 37 °C before the addition of the ATP/substrate mix (final concentrations of 50 μΜ ATP + 250 ng MBP in IX Reaction Buffer A). The mixture was then incubated at room temperature for 40 min before the addition of of ADP-Glo™ reagent and a second 40 minute room temperature incubation. Following the addition of the Kinase Detection Reagent, the plate was incubated for an additional 40 min at room temperature before reading luminescence on a FlexStation 3 (Molecular Devices, Sunnyvale, CA). Maximum activity was determined from wells treated with vehicle and was set to 100% and background activity was determined from wells containing no enzyme and this was set to 0%. Percent inhibition was calculated relative to the controls and the data graphed in Collaborative Drug Discovery (CDD) Vault (Burlingame, CA). Table 3
Figure imgf000140_0001
<300nM; B is 300nM to ΙΟΟΟηΜ; C is >1000nM
Example B-2: LPS-induced RAW264.7 TNF-g Release Assay
[00320] LPS activates ASKl and stimulates the release of T F-α from the mouse macrophage cell line, RAW264.7. The ability of test compounds to inhibit intracellular ASKl kinase activity was determined by measuring the release of TNF-a from LPS stimulated RAW264.7 cells after treatment with test compound. RAW264.7 cells were cultured in complete growth media (DMEM + 10% fetal bovine serum + 1% penicillin/streptomycin solution), harvested the day before the assay and resuspended to a concentration of 2-3 x 105 cells/mL in complete growth media. 100 μΐ. of the cell suspension was plated into each well of a 96-well tissue culture treated plate and cultured overnight at 37°C and 5% C02. On the day of the assay, the media was removed from the plate by dumping and gently tapping the plate on blotter paper. IX test compound (diluted 1 :250 from a 100% DMSO stock solution into DMEM containing 1% fetal bovine serum and 10 mM Hepes, pH 7.4) or vehicle was added to each well and incubated at 37°C, 5% C02 for 15 minutes. LPS E. Coli serotype 055 :B5 (5 μΐ^ of a 5 μg/mL solution in DMEM containing 1% fetal bovine serum and 10 mM Hepes, pH 7.4) or vehicle was added to each well and the plate incubated at 37°C, 5% C02 for 6 hours. At the end of the 6 hour incubation, 200 μΐ. of the supernatant was removed and a 1 :4 dilution of the supernatant was assayed for TNF-a concentrations using a commercially available ELISA kit according to the manufacturer's instructions (R&D Systems, Minneapolis, MN). Maximum activity was determined from wells treated with test compound vehicle and LPS and was set to 100% and background activity was determined from wells treated with test compound vehicle and LPS vehicle and this was set to 0%. Percent inhibition was calculated relative to the controls and the data graphed in Collaborative Drug Discovery (CDD) Vault (Burlingame, CA).
Example B-2: Mouse APAP-induced Hepatotoxicity Assay.
[00321] Acetominophen (APAP) overdose causes hepatotoxicity that is mediated through ASK1. Mice (C57B1/6) are fasted overnight (8-16 hrs) and administered test compound orally, intraperitoneally, intravenously or subcutaneously 0.5-24 hours prior to APAP. Mice are then injected intraperitoneally with 100-400 mg/kg APAP. Six to 24 hrs later, animals are
anesthetized with 3-4% isoflurane and blood collected via cardiac puncture into serum separator tubes. Blood is allowed to sit at room temperature for ~1 hour then centrifuged at 12,000 rpm for 10 minutes at 4°C to prepare serum. Liver enzymes, such as alanine aminotransferase (ALT), are measured using a clinical chemistry analyzer. Compounds 1-1, 1-2, and 1-30 (dosed
prophylactically at 30 mg/kg p.o.) were efficacious in this model. In addition, compound 1 -1 dosed prophylactically at 10 or 3 mg/kg p.o. was efficacious in this model.
Example B-3: Mouse LPS-induced TNFq Release Pharmacodynamic Assay.
[00322] The administration of lipopolysaccharide (LPS) induces the release of TNFa through the activation of ASK1. Mice (C57B1/6, Balb/c, C3H) are administered test compound orally, intraperitoneally, intravenously or subcutaneously 1-24 hours prior to LPS. Mice are then injected intraperitoneally with 0.3 mg/kg LPS (Salmonella typhosd) and ninety minutes later, animals are anesthetized with 3-4% isoflurane and blood collected via cardiac puncture into serum separator tubes. Blood is allowed to sit at room temperature for ~1 hour then centrifuged at 12,000 rpm for 10 minutes at 4°C to prepare serum. T Fa concentrations in serum are measured using a commercially available ELISA.
Example B-4: Rat/Mouse CCh Model of Liver Fibrosis
[00323] Liver fibrosis is induced in mice (Balb/c or C57B1/6) by intraperitoneal administration of CCU (0.5-2 ml/kg body weight) diluted in corn oil twice weekly for 4-8 weeks or by oral administration two-three times weekly using an escalating dose protocol (Popov et al. 2011 Gastroenetrology; 140(5): 1642-1652.). Liver fibrosis is induced in rats by either intraperitoneal administration (1-2.5 ml/kg) or by oral administration in oil (mineral, olive or corn) twice weekly for 6-12 weeks. Inhibitors are delivered orally, intraperitoneally, intravenously or subcutaneously 1 day to 1 hour prior to the initial CC14 dosing (prophylactic dosing) or 1-4 weeks after the initial CCI4 dosing (therapeutic dosing). At the end of the study, mice are sacrificed by opening the chest cavity under isoflurane, blood is drawn via cardiac puncture into EDTA vacutainer tubes and the liver is harvested. Part of the liver is fixed in 10% neutral buffered formalin for subsequent histopathological analysis of inflammation and fibrosis by H&E and Picrosirius red staining. The remaining tissue is snap frozen at -80 °C for subsequent hydroxyproline analysis of total collagen content and fibrotic gene expression.
Example B-5: Thioacetamide (TAA) model of Liver Fibrosis in mouse
[00324] Liver fibrosis is induced in Balb/c or C57B1/6 mice by intraperitoneal injection of thioacetamide (TAA) at doses ranging from 100-400 mg/kg 3x/week. Doses of TAA are either constant throughout the study period (100-200 mg/kg) or escalate from 100 mg/kg to 400 mg/kg every 2 weeks to increase tolerance to the TAA treatment. Inhibitors are administered orally, intraperitoneally, intravenously or subcutaneously given prophylactically (starting prior to TAA administration) or therapeutically (3-6 weeks after initiation of TAA administration). Liver fibrosis is studied 8-12 weeks after initiation of TAA. At the end of the study, blood is drawn via cardiac puncture into EDTA vacutainer tubes in mice under isoflurane anesthesia and
subsequently sacrificed by cervical dislocation. The liver is then harvested and part of the liver is fixed in 10% neutral buffered formalin for subsequent histopathological analysis of inflammation and fibrosis by H&E and picrosirius red staining. The remaining tissue is snap frozen at -80°C for subsequent hydroxyproline analysis of total collagen content or mRNA analyses. Serum is collected for analysis of liver biochemistries (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin) as a measure of liver function. Example B-6: Mouse model of NASH induced through a choline deficient, amino-acid defined (CDAA) diet supplemented with high fat content
[00325] Liver fibrosis is induced by feeding C57B1/6 mice a choline-deficient L-amino acid- defined high-fat diet (CDAA-HFD) containing 60% kcal% fat and 0.1% methionine (Research Diets C/N A06071302) starting at 6 weeks of age. Once on diet for 4-6 weeks of age, mice are screened for and those with abnormally elevated bilirubin levels are excluded. Remaining mice are assigned to groups and dosing initiated. Inhibitors are administered orally, intraperitoneally, intravenously or subcutaneously at 30-100 mg/kg/day for an additional 8-12 weeks. At the end of the study, blood is drawn via cardiac puncture into EDTA vacutainer tubes in mice under isoflurane anesthesia and subsequently sacrificed by cervical dislocation. The liver is then harvested and part of the liver is fixed in 10% neutral buffered formalin for subsequent histopathological analysis of inflammation and fibrosis by H&E, tnchrome and/or Picrosirius red staining. The remaining tissue is snap frozen at -80°C for subsequent hydroxyproline analysis of total collagen content, total cholesterol, liver triglyceride and/or mRNA analyses.
[00326] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I), or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000144_0001
Formula (I)
wherein,
ring A is a fused 5-, 6-, 7-, or 8-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring or a fused 5-, 6-, 7-, or 8-membered heterocyle containing 1 or 2 carbonyl (C=0) in the ring;
each Ra is independently H, D, halogen, -CN, -OR5, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl; m is 0, 1, or 2;
each R1 is independently H, substituted or unsubstituted Ci-C4alkyl, substituted or
unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C4deuteroalkyl, -L^R6 or -L2-R7;
r is 0, 1, or 2;
L1 is linker that is L4 or -L4-Xa-L3-;
L2 is linker that is -L4-Xa-L4-;
Xa is -NR8-, -C(=0)NR8-, -NR8C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR8-,
-NR8S(=0)2-, -C(=0)-, -C(=0)0-, or -OC(=0)-;
R8 is H, Ci-C6alkyl, Ci-Cefluoroalkyl, or Ci-C6deuteroalkyl;
L3 is Ci-C6alkylene;
each L4 is independently absent, or Ci-C6alkylene;
R6 is H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -S(=0)2N(R5)2, -
NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, -N(R5)2, -C(=0)N(R5)2, -NR5C(=0)R4, -OC(=0)N(R5)2, -NR5C(=0)OR4, Ci-C6alkyl, Ci-C6fluoroalkyl, Ci-C6deuteroalkyl, Ci-C6heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8cycloalkyl, or a substituted or unsubstituted C2- C8heterocycloalkyl or substituted or unsubstituted heteroaryl; R7 is substituted or unsubstituted phenyl, substituted or unsubstituted C3-
C8cycloalkyl, or a substituted or unsubstituted C2-C8heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2 is H, Ci-C6alkyl, or Ci-C6deuteroalkyl;
each R3 is independently H, D, halogen, -CN, -OH, substituted or unsubstituted Ci- C4alkyl, substituted or unsubstituted Ci-C4alkoxy, substituted or unsubstituted Ci- C4fluoroalkyl, substituted or unsubstituted Ci-C4fluoroalkoxy, substituted or unsubstituted Ci-C4deuteroalkyl, or substituted or unsubstituted Ci-C4heteroalkyl; q is 0, 1, 2, or 3;
ring B is a 6-membered heteroaryl, phenyl, or a 5-membered heteroaryl;
each R is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, -NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, -NR5C(=0)R4, -C(=0)N(R5)2, -NR2C(=0)OR4, OC(=0)N(R5)2, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- C6fluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, or substituted or unsubstituted C3-C6cycloalkyl; n is 0, 1, 2, 3, or 4;
ring C is a 5-membered heteroaryl;
each Rc is independently H, D, halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, - S(=0)2N(R5)2, -NR5S(=0)2R4, -C(=0)R4, -OC(=0)R4, -C02R5, -OC02R4, - N(R5)2, -NR5C(=0)R4, -C(=0)N(R5)2, OC(=0)N(R5)2, -NR5C(=0)OR4, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci- C6fluoroalkyl, substituted or unsubstituted Ci-C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6deuterocycloalkyl, substituted or unsubstituted C3-C6fluorocycloalkyl, or substituted or unsubstituted C2-C8heterocycloalkyl; p is 0, 1, 2, or 3;
each R4 is independently selected from substituted or unsubstituted Ci-C6alkyl,
substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ci0cycloalkyl, substituted or unsubstituted C2-Ci0heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl;
each R5 is independently selected from H, substituted or unsubstituted Ci-C6alkyl, substituted or unsubstituted Ci-C6fluoroalkyl, substituted or unsubstituted Ci- C6deuteroalkyl, substituted or unsubstituted Ci-C6heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroaryl; or two R5 on the same N atom are taken together with the
N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.
The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
R2 is H.
The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
ring B is a 6-membered heteroaryl containing 1-3 N atoms or phenyl;
ring C is a 5-membered heteroaryl containing 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms, or a 5-membered heteroaryl containing 0-4 N atoms and 1 O or S atom.
The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
ring B is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl;
ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
the groups
Figure imgf000146_0001
are in a 1,3- relationship on ring B.
The compound of claim 5, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000146_0002
X1 is N or CR ;
n is 0, 1, 2, or 3.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, or solvate thereof wherein:
Figure imgf000147_0001
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000147_0002
The compound of any one of claims 1-6, wherein the compound of Formula (I) has the following structure of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000147_0003
wherein,
X1 is N or CR ;
n is 0, 1, 2, or 3.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
ring B is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl;
ring C is triazolyl, imidazolyl, pyrazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, or solvate thereof wherein:
Figure imgf000147_0004
Figure imgf000148_0001
The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, or lvate thereof, wherein:
Figure imgf000148_0002
The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000149_0001
X2 is N or CRC.
The compound of claim 1, wherein the compound of Formula (I) has the following structure of Formula (III) or a pharmaceutically acceptable salt, or solvate thereof:
Figure imgf000149_0002
Formula (III)
wherein,
X1 is N or CR ;
X2 is N or CRC; and
n is 0, 1, 2, or 3.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
ring A is a fused 5-, 6-, 7-, or 8-membered carbocycle containing 1 or 2 carbonyl (C=0) in the ring.
16. The compound of claim 15, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000149_0003
17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or solvate thereof, wherein: ring A is a fused 5-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, and 0 or 1 O or S atoms in the ring.
The compound of claim 17, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000150_0001
The compound of claim 17, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000150_0002
20. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
ring A is a fused 6-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, 0-2 O atoms, and 0-2 S atoms in the ring.
Figure imgf000151_0001
22. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
ring A is a fused 7-membered heterocyle containing 1 or 2 carbonyl (C=0), 0-2 N atoms, 0-2 O atoms, and 0-2 S atoms in the ring.
23. The compound of claim 22, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Figure imgf000152_0001
151
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
each Ra is independently H, D, F, CI, Br, -CN, -OH, -OCH3, OCH2CH3, -OCF3, -
OCH2CF3; -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CD3, -OCD3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
each Ra is independently H, D, F, CI, Br, -CN, -OH, -OCH3, -OCF3, -CH3, -CH2F, -CHF2, -CF3, -CD3, and -OCD3.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
each R3 is independently H, D, F, CI, -CN, -OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, - OCH3, OCH2CH3, -OCF3, or -CD3.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
q is 0 or 1.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, or
solvate thereof, wherein:
each R1 is independently H, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4deuteroalkyl, -I^-R6 or - L2-R7;
L1 is linker that is L4 or -L4-Xa-L3-;
L2 is linker that is -L4-Xa-L4-;
Xa is -C(=0)NR8-;
R8 is H, Ci-C4alkyl, Ci-C4fluoroalkyl, or Ci-C4deuteroalkyl;
L3 is Ci-C6alkylene;
each L4 is independently absent, or Ci-C6alkylene.
29. The compound of claim 1, wherein the compound is:
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-1); 7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one
(Compound 1-2);
3,3-JD2-7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound
1-3);
3,3-JD2-7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-4); 3,3-Difluoro-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-5);
3,3-Difluoro-7-((6-(4-isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l- one (Compound 1-6);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3,3-dimethylisoindolin-l-one (Compound 1-7);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3,3-trimethylisoindolin-l-one (Compound 1-8);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindoline-l,3-dione (Compound 1-
9);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindoline- 1 ,3 -dione (Compound 1-10);
7- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3-dihydro-lH-inden-l-one (Compound 1-11);
2,2-£>2-7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2,3 -dihydro- lH-inden- 1 -one (Compound 1-12);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)benzofuran-3(2H)-one (Compound 1-13);
2,2-£) 2-4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)benzofuran-3(2H)-one (Compound 1-14);
4-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-lH-indazol-3(2H)-one (Compound 1-15);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)- 1 -methyl- lH-indazol-3 (2H)-one (Compound 1-16);
4-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)- 1 ,2-dimethyl- lH-indazol-3 (2H)- one (Compound 1-17);
8- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3,4-dihydroisoquinolin-l(2H)-one (Compound 1-18);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methyl-3,4-dihydroisoquinolin- l(2H)-one (Compound 1-19);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoquinolin-l(2H)-one (Compound 1-20);
8-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoquinolin- 1 (2H)-one (Compound 1-21); 5-((6-(4-Isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)quinazolin-4(3H)-one (Compound
1-22);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3-methylquinazolin-4(3H)-one (Compound 1-23);
8-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoquinoline-l,3(2H,4H)-dione (Compound 1-24);
8- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyrid
dione (Compound 1-25);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinazoline-2,4(lH,3H)-dione (Compound 1-26);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3-methylquinazoline-2,4(lH,3H)- dione (Compound 1-27);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-methylquinazoline-2,4(lH,3H)- dione (Compound 1-28);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l,3-dimethylquinazoline- 2,4(lH,3H)-dione (Compound 1-29);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 30);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l -methyl quinolin-4(lH)-one (Compound 1-31);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3-dihydroquinolin-4(lH)-one (Compound 1-32);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)- 1 -methyl-2,3 -dihydroquinolin- 4(lH)-one (Compound 1-33);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4H-chromen-4-one (Compound 1- 34);
5-((6-(4-isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)chroman-4-one (Compound 1-35); 3,3-JD2-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)chroman-4-one (Compound 1-36);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)thiochroman-4-one (Compound 1- 37);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4H-thiochromen-4-one (Compound 1-38);
9- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (Compound 1-39); 9-((6-(4 sopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-2-methyl-2,3,4,54etrahydro-lH- benzo[c]azepin-l-one (Compound 1-40);
6-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-3,4-dihydrobenzo[f [l,4]oxazepin- 5(2H)-one (Compound 1-41);
6- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-methyl-3,4- dihydrobenzo[f [l,4]oxazepin-5(2H)-one (Compound 1-42);
7- ((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-43); 7-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-44); 7-((6-(4-(2,2,2-Trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-45);
7-((6-(4-(2-Fluoroethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-46);
7-((6-(4-(3 ,3 ,3 -Trifluoropropyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-47);
7-((6-(4-(2-Hydroxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-48);
7-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-49);
7-((6-(4-(2-Methoxyethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one
(Compound 1-50);
3-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-51);
(R)-7-((6-(4-( 1 -Fluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-52);
(,S)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-53);
7-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-54);
(R)-7-((6-(4-(l,l, l-Trifluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-55);
(,S)-7-((6-(4-(l , 1 , 1 -Trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 - one (Compound 1-56);
(R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-57); (,S)-7-((6-(4-(l -Hydroxypropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one
(Compound 1-58);
7-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-59);
(R)-2-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-60);
(,S)-2-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4-yl)propanenitrile (Compound 1-61);
7-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
62) ;
7-((6-(4-Cyclobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
63) ;
7-((6-(4-(Oxetan-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-
64) ;
7-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-65);
7-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-66);
7-((6-(4-((lr,3r)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-67);
(ls,3s)-3-(3-(6-((3-Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-68);
( 1 r,3r)-3 -(3 -(6-((3 -Oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H- 1 ,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-69);
7-((6-(4-(Bicyclo[ 1.1.1 ]pentan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-70);
7-((6-(4-Cyclopentyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1 -
71);
7-((6-(4-((lR,25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-72);
7-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-73);
7-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-74); 7-((6-(4-((l,S',2)S)-2-Fluorocyclopentyl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)isoindoli one (Compound 1-75);
(R)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 - one (Compound 1-76);
(,S)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-77);
7-((6-(4-((lR,2^-2-Hydroxycyclopentyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l^ one (Compound 1-78);
7-((6-(4-((l^,2R)-2-Hydroxycyclopentyl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l^ one (Compound 1-79);
7-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-80);
7-((6-(4-((l,S',2)S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-81);
(,S)-7-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-82);
(R)-7-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-83);
7-((6-(4-Cyclohexyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1 - 84);
7-((6-(4-((lR,2,S)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-85);
7-((6-(4-((l,S',2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-86);
7-((6-(4-((lR,2R)-2-fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-87);
7-((6-(4-((l,S',2)S)-2-fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-88);
(R)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-89);
(<S)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-90);
7-((6-(4-((lR,2^-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-91); 7-((6-(4-((lS,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-92);
7-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-93);
7-((6-(4-((l^,2^-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-94);
(,S)-7-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-95);
(R)-7-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-96);
7-((6-(4-(Tetrahydro-2H-pyran-4-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)isoindolin- 1 -one (Compound 1-97);
7-((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound
1- 98);
7-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one
(Compound 1-99);
2- Methyl-7-((6-(4-(2,2,2-trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-100);
7-((6-(4-(2-Fluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-101);
2- Methyl-7-((6-(4-(3,3,3-trifluoropropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-102);
7-((6-(4-(2-Hydroxyethyl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one (Compound 1-103);
7-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-104);
7-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-105);
3- (3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-106);
(R)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-107);
(,S)-7-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-108); 7-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-109);
(R)-2-Methyl-7-((6-(4-( 1, 1,1 -trifluoropropan-2-yl)-4H- l,2,4-triazol-3 -yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-110);
(5)-2-Methyl-7-((6-(4-(l , 1 , 1 -trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-111);
(R)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-112);
(,S)-7-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-113);
7-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-114);
(R)-2-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-115);
(,S)-2-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-116);
7-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-117);
7-((6-(4-Cyclobutyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-methylisoindolin- 1 -one (Compound 1-118);
2-Methyl-7-((6-(4-(oxetan-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-119);
7-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin- 1-one (Compound 1-120);
7-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin- 1-one (Compound 1-121);
7-((6-(4-((lr,3r)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin- 1-one (Compound 1-122);
(ls,3s)-3-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-123);
(lr,3r)-3-(3-(6-((2-Methyl-3-oxoisoindolin-4-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-124);
7-((6-(4-(Bicyclo[l .1. l]pentan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin- 1-one (Compound 1-125); 7-((6-(4-Cyclopentyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one
(Compound 1-126);
7-((6-(4-((lR,25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-127);
7-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-128);
7-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-129);
7-((6-(4-((15',25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-130);
(R)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-131);
(S)-7-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-132);
7-((6-(4-((lR,25)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-133);
7-((6-(4-((15',2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-134);
7-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-135);
7-((6-(4-((1^25)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-136);
(^-2-Methyl-7-((6-(4-(tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-137);
(R)-2-Methyl-7-((6-(4-(tetrahydrofuran-3-yl)-4 /-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-138);
7-((6-(4-Cyclohexyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylisoindolin-l-one (Compound 1-139);
7-((6-(4-((lR,25)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-140);
7-((6-(4-((lS,2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-141);
7-((6-(4-((lR,2R)-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-142); 7-((6-(4-((l^,2^-2-Fluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-143);
(R)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-144);
(,S)-7-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-145);
7-((6-(4-((lR,2^-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-146);
7-((6-(4-((15',2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-147);
7-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-148);
7-((6-(4-((1^25)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2- methylisoindolin-l-one (Compound 1-149);
(^-2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-150);
(R)-2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-151);
2-Methyl-7-((6-(4-(tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-152);
5-((6-(4-Ethyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-153); 5-((6-(4-Isobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 154);
5-((6-(4-(2,2,2-Trifluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-155);
5-((6-(4-(2-Fluoroethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one
(Compound 1-156);
5-((6-(4-(3,3,3-Trifluoropropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-157);
5-((6-(4-(2-Hydroxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-158);
5-((6-(4-(2-Hydroxy-2-methylpropyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-159);
5-((6-(4-(2-Methoxyethyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-160); 3-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-161);
(R)-5-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-162);
(,S)-5-((6-(4-(l-Fluoropropan-2-yl)-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-163);
5-((6-(4-(l,3-Difluoropropan-2-yl)-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-164);
(R)-5-((6-(4-(l,l, l-Trifluoropropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-165);
(S)-5-((6-(4-(l , 1 , 1 -Trifluoropropan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-166);
(R)-5-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-167);
(S)-5-((6-(4-(l-Hydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-168);
5-((6-(4-(l,3-Dihydroxypropan-2-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-169);
(R)-2-(3 -(6-((4-Oxo- 1 ,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H- 1 ,2,4-triazol-4- yl)propanenitrile (Compound 1-170);
(,S)-2-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)propanenitrile (Compound 1-171);
5-((6-(4-Cyclopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-172);
5-((6-(4-Cyclobutyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 173);
5-((6-(4-(Oxetan-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-174);
5-((6-(4-(3,3-Difluorocyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-175);
5-((6-(4-((ls,3s)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-176);
5-((6-(4-((lr,3r)-3-Hydroxycyclobutyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-177); ( 1 s,3 s)-3 -(3 -(6-((4-Oxo- 1 ,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H- 1 ,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-178);
(lr,3r)-3-(3-(6-((4-Oxo-l,4-dihydroquinolin-5-yl)amino)pyridin-2-yl)-4H-l,2,4-triazol-4- yl)cyclobutanecarbonitrile (Compound 1-179);
5-((6-(4-(Bicyclo[ 1.1.1 ]pentan-2-yl)-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)quinolin-4( 1H> one (Compound 1-180);
5-((6-(4-Cyclopentyl-4H-l,2,44riazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1-181);
5-((6-(4-((lR,25)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-182);
5-((6-(4-((l^,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-183);
5-((6-(4-((lR,2R)-2-Fluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-184);
5-((6-(4-((l£,2.S)-2-Fluorocyclopenty^^
one (Compound 1-185);
(R)-5-((6-(4-(2,2-Difluorocyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-186);
(S)-5-((6-(4-(2,2-Difluorocyclope^
one (Compound 1-187);
5-((6-(4-((lR,2S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-188);
5-((6-(4-((lS,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-189);
5-((6-(4-((lR,2R)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-190);
5-((6-(4-((lS,2S)-2-Hydroxycyclopentyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-191);
(,S)-5-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-on (Compound 1-192);
(R)-5-((6-(4-(Tetrahydrofuran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-193);
5-((6-(4-Cyclohexyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)-one (Compound 1- 194); 5-((6-(4-((lR,2,S)-2-Fluorocyclohexyl)-4^
one (Compound 1-195);
5-((6-(4-((l£,2R)-2-Fluorocyclohexy^
one (Compound 1-196);
5-((6-(4-((lR,2R)-2-Fluorocyclohexyl)-4H^^
one (Compound 1-197);
5-((6-(4-((l£,2.S)-2-Fluorocyclohe^
one (Compound 1-198);
(R)-5-((6-(4-(2,2-Difluorocyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-199);
(,S)-5-((6-(4-(2,2-Difluorocyclohexy^
one (Compound 1-200);
5-((6-(4-((lR,2S)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-201);
5-((6-(4-((lS,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-202);
5-((6-(4-((lR,2R)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-203);
5-((6-(4-((lS,2S)-2-Hydroxycyclohexyl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-204);
(S)-5-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-205);
(R)-5-((6-(4-(Tetrahydro-2H-pyran-3-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin- 4(lH)-one (Compound 1-206);
5-((6-(4-(Tetrahydro-2H-pyran-4-yl)-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-207);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methylquinolin-4(lH)-one (Compound 1-208);
2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)quinolin-4(lH)- one (Compound 1-209);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(methoxymethyl)quinolin-4(lH)- one (Compound 1-210);
Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxylate (Compound 1-211); 5-((6-(4-Isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4-dihydroquinoline-2- carboxylic acid (Compound 1-212);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4-dihydroquinoline-2- carboxamide (Compound 1-213);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N,N-dimethyl-4-oxo-l,4- dihydroquinoline-2-carboxamide (Compound 1-214);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(pyrrolidine-l-carbonyl)quinolin- 4(lH)-one (Compound 1-215);
(R)-2-(3-Fluoropyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-216);
(R)-2-(3-Hydroxypyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-217);
(R)-2-(3-Aminopyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)quinolin-4(lH)-one (Compound 1-218);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(piperidine- 1 -carbonyl)quinolin- 4(lH)-one (Compound 1-219);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(morpholine-4- carbonyl)quinolin-4(lH)-one (Compound 1-220);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(piperazine-l-carbonyl)quinolin- 4(lH)-one (Compound 1-221);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methylpiperazine-l- carbonyl)quinolin-4(lH)-one (Compound 1-222);
N-(2-(Dimethylamino)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo- l,4-dihydroquinoline-2-carboxamide (Compound 1-223);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(2-(pyrrolidin- 1 -yl)ethyl)- l,4-dihydroquinoline-2-carboxamide (Compound 1-224);
(R)-N-(2-(3-Fluoropyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-225);
(R)-N-(2-(3-Hydroxypyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-226);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-4-oxo- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-227);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(2-(piperazin-l-yl)ethyl)- l,4-dihydroquinoline-2-carboxamide (Compound 1-228); 5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin- 1 - yl)ethyl)-4-oxo-l,4-dihydroquinoline-2-carboxamide (Compound 1-229);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-phenyl- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-230);
N-Benzyl-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-l,4- dihydroquinoline-2-carboxamide (Compound 1-231);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroquinoline-l- carbonyl)quinolin-4(lH)-one (Compound 1-232);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroisoquinoline- 2-carbonyl)quinolin-4(lH)-one (Compound 1-233);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-234);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-3-yl)-l,4- dihydroquinoline-2-carboxamide (Compound 1-235);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-4-yl)- 1 ,4- dihydroquinoline-2-carboxamide (Compound 1-236);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-methyl-4H-chromen-4-one (Compound 1-237);
2-(Hydroxymethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4H-chromen-4- one (Compound 1-238);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(methoxymethyl)-4H-chromen-4- one (Compound 1-239);
Methyl 5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxylate (Compound 1-240);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2-carboxylic acid (Compound 1-241);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxamide (Compound 1-242);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N,N-dimethyl-4-oxo-4H-chromene- 2-carboxamide (Compound 1-243);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(pyrrolidine-l-carbonyl)-4H- chromen-4-one (Compound 1-244);
(R)-2-(3-Fluoropyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-245); (R)-2-(3-Hydroxypyrrolidine-l-carbonyl)-5-((6-(4 sopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-246);
(R)-2-(3-Aminopyrrolidine-l-carbonyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4H-chromen-4-one (Compound 1-247);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(piperidine- 1 -carbonyl)-4H- chromen-4-one (Chromone 1-248);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(morpholine-4-carbonyl)-4H- chromen-4-one (Compound 1-249);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(piperazine-l-carbonyl)-4H- chromen-4-one (Compound 1-250);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methylpiperazine-l-carbonyl)- 4H-chromen-4-one (Compound 1-251);
N-(2-(Dimethylamino)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo- 4H-chromene-2-carboxamide (Compound 1-252);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-4-oxo-N-(2-(pyrrolidin- 1 -yl)ethyl)- 4H-chromene-2-carboxamide (Compound 1-253);
(R)-N-(2-(3-Fluoropyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-4H-chromene-2-carboxamide (Compound 1-254);
(R)-N-(2-(3-Hydroxypyrrolidin-l-yl)ethyl)-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)-4-oxo-4H-chromene-2-carboxamide (Compound 1-255);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-4-oxo-4H- chromene-2-carboxamide (Compound 1-256);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(2-(piperazin-l-yl)ethyl)- 4H-chromene-2-carboxamide (Compound 1-257);
5-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin- 1 - yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 1-258);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-phenyl-4H-chromene-2- carboxamide (Compound 1-259);
N-Benzyl-5-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-4H-chromene-2- carboxamide (Compound 1-260);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-4H-chromen-4-one (Compound 1-261);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(l,2,3,4-tetrahydroisoquinoline- 2-carbonyl)-4H-chromen-4-one (Compound 1-262); 5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-2-yl)-4H- chromene-2-carboxamide (Compound 1-263);
5-((6-(4-Isopropyl-4H-l,2,4 riazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-3-yl)-4H- chromene-2-carboxamide (Compound 1-264);
5-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-4-oxo-N-(pyridin-4-yl)-4H- chromene-2-carboxamide (Compound 1-265);
2-Ethyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-266);
2-Isopropyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-267);
2-Isobutyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-268);
2-(Cyclopropylmethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-269);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethyl)isoindolin-l- one (Compound 1-270);
2-(2-Hydroxyethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l- one (Compound 1-271);
7-((6-(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)amino)-2-(2-methoxy ethyl )isoindolin- 1 - one (Compound 1-272);
2-(2-Aminoethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one (Compound 1-273);
2-(2-(Dimethylamino)ethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-274);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-(pyrrolidin-l- yl)ethyl)isoindolin-l-one (Compound 1-275);
(R)-2-(2-(3-FluoropyiTolidin-l-yl)ethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-276);
(R)-2-(2-(3-Hydroxypyrrolidin-l-yl)ethyl)-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2- yl)amino)isoindolin-l-one (Compound 1-277);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-mo holinoethyl)isoindolin-l- one (Compound 1-278);
7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(2-(piperazin-l- yl)ethyl)isoindolin-l-one (Compound 1-279); 7-((6-(4-Isopropyl-4H-l,2,4-tri azol-3 -yl)pyridin-2-yl)amino)-2-(2-(4-methylpiperazin-l- yl)ethyl)isoindolin-l-one (Compound 1-280);
N-(2-(7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2- yl)ethyl)acetamide (Compound 1-281);
7-((6-(4-Isopropyl-4H-l,2,4-tri azol-3 -yl)pyridin-2 -yl)amino)-2-(3 - (methyl sulfonyl)propyl)isoindolin-l -one (Compound 1-282);
Methyl 3-(7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2- yl)propanoate (Compound 1-283);
3-(7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2-yl)propanoic acid (Compound 1-284);
3- (7-((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-l-oxoisoindolin-2-yl)-2,2- dimethylpropanoic acid (Compound 1-285);
2-Benzyl-7-((6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)isoindolin-l-one
(Compound 1-286);
7- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methoxybenzyl)isoindolin-l- one (Compound 1-287);
8- ((6-(4-Isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)amino)-2-(4-methoxybenzyl)isoquinolin- l(2H)-one (Compound 1-288);
7-((3 -(4-Isopropyl-4H- 1 ,2,4-tri azol-3 -yl)phenyl)amino)isoindolin- 1 -one (Compound 2- 1 );
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-
2);
3 , 3 -D2-7-((3 -(4-Isopropyl AH- 1 ,2,4-tri azol-3 -yl)phenyl)amino)i soindolin- 1 -one (Compound 2-3 ); 3,3-JD2-7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-4);
3 , 3 -Difluoro-7-((3 -(4-i sopropyl-4H- 1 ,2,4-tri azol-3 -yl)phenyl)amino)i soindolin- 1 -one
(Compound 2-5);
3,3-Difluoro-7-((3-(4-isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindolin-l-one (Compound 2-6);
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-3,3-dimethylisoindolin-l-one
(Compound 2-7);
7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3,3-trimethylisoindolin-l-one
(Compound 2-8);
4- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)isoindoline-l,3-dione (Compound 2-9); 4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methylisoindoline-l,3-dione
(Compound 2-10); 7- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-2, 3 -dihydro- lH-inden- 1 -one (Compound
2-11);
2,2-D2-7-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl phenyl)amino)-2,3 -dihydro- lH-inden- 1 -one (Compound 2-12);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)benzofuran-3(2H)-one (Compound 2-13); 2,2-D2-4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl phenyl)amino)benzofuran-3(2H)-one
(Compound 2-14);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)- lH-indazol-3(2H)-one (Compound 2- 15);
4-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)- 1 -methyl - lH-indazol-3 (2H)-one
(Compound 2-16);
4- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)- l,2-dimethyl-lH-indazol-3(2H)-one (Compound 2-17);
8- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-3 ,4-dihydroisoquinolin- 1 (2H)-one (Compound 2-18);
8-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-2-methyl-3,4-dihydroisoquinolin-l(2H)- one (Compound 2-19);
8-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)isoquinolin-l(2H)-one (Compound 2-20); 8-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-2-methylisoquinolin- 1 (2H)-one
(Compound 2-21);
5- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)quinazolin-4(3H)-one (Compound 2-22); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-3-methylquinazolin-4(3H)-one
(Compound 2-23);
8-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)isoquinoline- 1 ,3 (2H,4H)-dione
(Compound 2-24);
8-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-2-methylisoquinoline-l,3(2H,4H)-dione (Compound 2-25);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)quinazoline-2,4(lH,3H)-dione
(Compound 2-26);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-3-methylquinazoline-2,4(lH,3H)-dione (Compound 2-27);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-l -methyl quinazoline-2,4(lH,3H)-dione (Compound 2-28);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl amino)-l,3-dimethylquinazoline-2,4(lH,3H)- dione (Compound 2-29); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)quinolin-4(lH)-one (Compound 2-30);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-l-methylquinolin-4(lH)-one (Compound
2-31);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3-dihydroquinolin-4(lH)-one
(Compound 2-32);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-l-methyl-2,3-dihydroquinolin-4(lH)-one (Compound 2-33);
5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4H-chromen-4-one (Compound 2-34); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)chroman-4-one (Compound 2-35);
3 ,3 -Z) 2-5-((3 -(4-Isopropyl-4H- 1 ,2,4-triazol-3 -yl)phenyl)amino)chroman-4-one (Compound 2-36); 5-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)thiochroman-4-one (Compound 2-37);
5- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4H-thiochromen-4-one (Compound 2- 38);
9-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-l- one (Compound 2-39);
9-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-2-methyl-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (Compound 2-40);
6- ((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-3,4-dihydrobenzo[f][l,4]oxazepin- 5(2H)-one (Compound 2-41);
6-((3-(4-Isopropyl-4H-l,2,4-triazol-3-yl)phenyl)amino)-4-methyl-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 2-42);
or a pharmaceutically acceptable salt, or solvate thereof.
30. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, or solvate thereof, of any one of claims 1-29, and at least one pharmaceutically acceptable excipient.
31. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal
administration, or ophthalmic administration.
32. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
33. A method of treating a disease or condition in a mammal that would benefit from the inhibition of apoptosis signal-regulating kinase 1 (ASK1) activity comprising administering to the mammal a compound, or pharmaceutically acceptable salt, or solvate thereof, of any one of claims 1-29.
34. The method of claim 33, wherein the inhibition of ASKl inactivates c-Jun N-terminal protein kinase, p38 MAP kinase, or a combination thereof.
35. The method of any one of claim 33 or claim 34, wherein disease or condition is fibrosis, cancer, an autoimmune disease or condition, an inflammatory disease or condition, a cardiovascular disease or condition, a neurodegenerative disease or condition, or combination thereof.
36. The method of any one of claims 33-35, wherein the disease or condition is fibrosis.
37. The method of claim 36, wherein the fibrosis comprises lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, peritoneal fibrosis or cutaneous fibrosis.
PCT/US2018/054006 2017-10-03 2018-10-02 Apoptosis signal-regulating kinase 1 (ask 1) inhibitor compounds WO2019070742A1 (en)

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