WO2012040499A2 - Metabolic inhibitors - Google Patents

Metabolic inhibitors Download PDF

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Publication number
WO2012040499A2
WO2012040499A2 PCT/US2011/052816 US2011052816W WO2012040499A2 WO 2012040499 A2 WO2012040499 A2 WO 2012040499A2 US 2011052816 W US2011052816 W US 2011052816W WO 2012040499 A2 WO2012040499 A2 WO 2012040499A2
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alkyl
hydroxy
halo
independently selected
group
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PCT/US2011/052816
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French (fr)
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WO2012040499A3 (en
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Enoch Kim
Bridget Cole
Paul Sweetnam
Eric Wong
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Surface Logix, Inc.
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Publication of WO2012040499A2 publication Critical patent/WO2012040499A2/en
Publication of WO2012040499A3 publication Critical patent/WO2012040499A3/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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention provides compounds useful for treating diseases, including neoplasias and metabolic disorders.
  • Compounds of the invention modulate AMPK activity.
  • the invention is based, at least in part, on the discovery of compounds that that modulate AMPK activity.
  • the compounds of the invention are useful for treating neoplastic diseases.
  • the compounds are useful for modulating metabolic diseases.
  • the compounds modulate AMPK activity by modulating other cellular components, including, but not limited to, GLUT1.
  • AMPK is a master energy regulator, affecting fundamental mechanisms of cellular metabolism. AMPK is activated in response to increases in the cellular AMP/ ATP ratio, for example in response to inhibition of ATP production or increased consumption. AMPK is activated by exercise and diet, and has been shown to mediate many of their benefits. It is a key component necessary for efficacy of metformin, thiazolidinediones, and resveratrol. AMPK has also been linked to growth and survival of cancer cells, and is thought to facilitate the activity of certain tumor suppressors.
  • GLUT1 is the primary glucose transporter found in muscle and adipose tissue. GLUT1 also provides a mechanism for increased metabolism necessary for sustained tumor growth.
  • Figure 1 shows activation of AMPK by compounds of the invention, compared to AICAR, a known activator of AMPK. AMPK activation is observed by detecting
  • Figure 2 shows selectivity of an AMPK activator of the invention.
  • Compound 48 demonstrated activity with respect to AMPK and three other targets ROCK2, CK2, and GLUTl .
  • Figure 3 shows that activation of AMPK by Compound 48 is specific for phosphorylation of Thrl72 and dose dependent.
  • Figure 4 shows that the ACC phosphorylation induced by Compound 48, which depends on AMPK activation, is also dose dependent.
  • Figure 5 shows dose dependent AMPK activation by Compound 48 in skeletal muscle cells.
  • Figure 6 shows dose dependent AMPK activation by Compound 48 in adipocytes
  • Figure 7 show that AMPK activation by Compound 48 in HT-1080 cells is rapid and reversible.
  • Figure 8 show that AMPK activation and ACC phosphorylation by Compound 48 in HT-1080 cells is rapid and reversible..
  • Figure 9 shows that tumor cells treated with Compound 48 demonstrated a significant increase in the [AMP]/[ATP] ratio, along with increased levels of AMP.
  • Figure 10 shows AMPK activation in a fibrosarcoma tumor line HT-1080 when treated with inhibitors of glucose uptake (Compound 48, AICAR), or a control (DMSO).
  • Figure 11 shows that in the presence of an AMPK phosphorylation inhibitor (an inhibitor of CAM kinase), inhibition of glucose transport increases phosphorylation of AMPK and ACC.
  • an AMPK phosphorylation inhibitor an inhibitor of CAM kinase
  • Figure 12 shows an increase in fatty acid oxidation in mice fed a high fat diet and supplemented with an activator of AMPK activity.
  • Figure 13 shows improvements in serum insulin, blood glucose, serum
  • Compound 48 in a mouse model of diabetes is a mouse model of diabetes.
  • Figure 14 shows improved levels of urinary protein excretion in a mouse model maintained on a high fat diet supplemented with Compound 48.
  • AMP kinase plays an important role in energy homeostasis. For example, AMPK phosphorylation is observed in physiological conditions of increased ATP consumption and/or where AMP concentrations are high.
  • the AMPK pathway involves several components, which for example, act to phorphorylate AMPK, or downstream from AMPK.
  • One such component is ACC, which is specifically phosphorylated in connection with AMPK activation.
  • the invention provides new compounds and methods for control of AMPK activation, either directly, or indirectly.
  • AMPK has also been implicated in growth and survival of cancer cells.
  • AMPK is phosphorylated and activated by the tumor suppressor LKB1, and functions in the phosphorylation and activation of tuberous sclerosis complex 2, another tumor suppressor.
  • the AMPK pathway is a target for treatment of metabolic disease, including, but not limited to insulin resistance and diabetes. Diabetes is characterized by abnormal glucose and lipid metabolism. Diabetes is generally classified into two categories. In insulin-dependent diabetes mellitus ("IDDM" or "type 1"), ⁇ -cells of the pancreas produce little or no insulin.
  • IDDM insulin-dependent diabetes mellitus
  • Non-insulin- dependent diabetes mellitus which is much more prevalent, is caused by a defect in insulin secretion and insulin resistance in cells that normally respond to diabetes.
  • type 2 diabetes is characterized by resistance to insulin action in skeletal muscle, liver, and fat. Insulin resistance occurs when insulin is unable to stimulate normal metabolic responses in those targets.
  • AMPK activation improves glucose and lipid levels in the blood. The effects of AMPK activation, for example using compounds of the invention, can be demonstrated in tissue culture, normal and insulin-resistant rodent models of diabetes, and in humans.
  • the compounds disclosed herein are used to treat of prevent neoplastic diseases.
  • the neoplasm may be cancer.
  • neoplasms and cancers to be treated or prevented include, without limitation, colon cancer, pancreatic cancer, lung cancer, breast cancer cervical cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, and uterine cancer.
  • the compounds disclosed herein are used to treat of prevent metabolic diseases and associated conditions. These include, but are not limited to, diabetes, insulin resistance, metabolic syndrome, atherosclerosis,
  • the compounds can be administered alone or in combination with other drugs normally used to treat such conditions.
  • a compound of Formula I is used in combination with metformin to treat type 2 diabetes.
  • the compounds can be observed to improve one or more of the following: ⁇ -cell mass, function, ⁇ -cell function, insulin sensitivity, muscle glucose uptake and utilization, and glycemic control.
  • the compounds can be used to improve lipid profile, decrease body weight, decrease percentage body fat, reduce blood pressure, cardiovascular disease (CVD). Further, the compounds reduce diabetes risk and CVD risk.
  • the AMPK pathway is well conserved, and is a target of major antidiabetic drugs, such as metformin and thiazolidinediones (TZDs).
  • Metformin is a biguanide drug and is thought to reduce gluconeogenesis in the liver.
  • TZDs are compounds that activate peroxisome proliferator-activated receptors (PPARs), which are involved in control of metabolism of carbohydrate, lipid, and protein.
  • PPARs peroxisome proliferator-activated receptors
  • Sulfonylureas are another class of drugs for diabetes management which act by increasing insulin release from the ⁇ -cells of the pancreas.
  • a- glucosidase inhibitors are oral drugs that prevent digestion of carbohydrates into simple sugars, and thus reduce the impact of carbohydrates on blood sugar. Accordingly, the invention provides methods of treatment of metabolic disease using compounds of the invention in combination with the aforementioned antidiabetic drugs.
  • Rho-kinase which is found in two forms, ROCK 1 (ROCKP; pi 60- ROCK) and ROCK 2 (ROCKa)inhibitors.
  • Rho kinase a serine/threonine kinase, serves as a target protein for small GTP -binding protein Rho. It serves as an important mediator of numerous cellular functions, including focal adhesions, motility, smooth muscle contraction, and cytokinesis.
  • ROCK plays an important role in Ca 2+ sensitization and the control of vascular tone. It modulates the level of phosphorylation of the myosin II light chain of myosin II, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca 2+ sensitization in smooth muscle contraction.
  • Preferred compounds are more efficient inhibitors of ROCK2 than of ROCK1.
  • ROCK-mediated pathway plays an important role in vascular smooth muscle contraction, cell adhesion, cell motility, and pathogenesis of atherosclerosis.
  • ROCK also suppress coronary
  • ROCK mediated pathways mediate numerous different cellular functions and ROCK inhibitors can be useful in treatments of patients in need thereof suffering from cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, central nervous system disorders such as neuronal degeneration and spinal cord injury, and in neoplasias where inhibition of Rho-kinase has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, asthma, regulation of intraoccular pressure, and bone resorption.
  • cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, central nervous system disorders such as neuronal degeneration and spinal cord injury, and in neoplasias where inhibition of Rho-kina
  • the invention provides compounds that inhibit a Rho kinase (ROCK).
  • ROCK Rho kinase
  • the compound is an inhibitor of ROCK2.
  • Certain compounds of the invention are inhibitors of GLUTl .
  • GLUTl is one of several transporters that facilitate transport of glucose and/or other molecules, and is the primary glucose transporter found in muscle and adipose tissue. Glucose transporters facilitate glucose uptake by tumors, in which they are frequently overexpressed. In particular, increased GLUTl expression has also been found to provide a mechanism for increased metabolism necessary for sustained tumor growth. Accordingly, compounds of the invention that inhibit GLUTl activity are used to treat cancer. Further, GLUTl expression is often observed in advanced tumors, which may be anoxic. Anoxia and GLUTl expression is associated with resistance to radiation and/or chemotherapy. Accordingly, compounds of the invention are used to treat anoxic tumors.
  • GLUTl inhibitors of the invention are compounds of Formulas I-V.
  • the GLUTl inhibitors also increase the anti-proliferative effects of non-targeted and targeted chemotherapeutic agents, including, but not limited to, paclitaxel, cisplatin, and gefitinib.
  • the compounds of the invention also restore chemosensitivity and radiation sensitivity to GLUTl -expressing tumors. Accordingly, compounds of the invention are use to treat neoplastic disease, particularly cancer, in
  • antineoplastic agents such as chemotherapeutics and/or radiation therapy.
  • compounds of the invention are used to reduce or block weight loss associated with disease.
  • weight loss is a complaint of half of cancer patients and indicates a poor prognosis.
  • Excessive glucose uptake and lactate production by tumor cells exacerbates weight loss.
  • the lactate produced by glycolysis induces the Cori cycle in liver and other tissues.
  • the Cori cycle is a metabolic pathway in which lactate produced by anaerobic glycolysis in muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate.
  • the Cori cycle converts lactate produced by anerobic glysolysis in tumors back to glucose. For every 2 ATP produced by glycolysis, 6 ATP molecules are consumed by gluconeogenesis.
  • ft 1 is selected from the group consisting of aryl, -(CH 2 ) NR 13 R 14 , -X-R 12 ,
  • NY01 222 5 2 89 vl independently selected from halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C6 alkenyl, Ci-C 6 alkoxy, C3-C7 cycloalkyl, -S0 2 -alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • X is selected from a covalent bond, O, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-O-(aryl),
  • R 16 and R 17 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -C 8 alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • NYOl 222 5 2 89 vl R 18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(C C 6 alkyl)-NR 16 R 17 , -(C C 6 alkyl)-0-(Ci-C 6 alkyl)-0- (Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoroalkyl;
  • x is selected from 1 to 6;
  • y is selected from 0 to 6;
  • z is selected from 2 to 6;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4.
  • R 3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH 2 ) «-NR 33 R 34 , -Y-R 32 , -0-(CH 2 ) «-C0 2 R 32 ,
  • R 33 and R 34 are independently selected from the group consisting of H, Ci-Cs alkyl, C 2 -Cs alkenyl, C 2 -C 8 alkynyl, -(C C 6 alkyl)-0-(Ci-C 6 alkyl), -(C C 6 alkyl)-NR 36 R 37 ,
  • R 33 and R 34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
  • NYOl 222 5 2 89 vl independently selected from halo, Ci-C 6 alkyl, C2-C6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 35 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl),
  • R 36 and R 37 independently selected from the group consisting of H, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • R 36 and R 37 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • R 38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 36 R 37 ,
  • R 4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH 2 ) «-NR 43 R 44 , -Z-R 42 , -0-(CH 2 ) fl -C0 2 R 42 ,
  • NYOl 222 5 2 89 vl R and R are independently selected from the group consisting of H, Ci-Cg alkyl, C2-C8 alkenyl, C 2 -C 8 alkynyl, -(C C 6 alkyl)-0-(Ci-C 6 alkyl), -(C C 6 alkyl)-NR 46 R 47 ,
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • Z is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 45 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl),
  • R 46 and R 47 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 46 R 47 ,
  • each a is independently selected from 0 to 6;
  • each b is independently selected from 0 to 6;
  • NYOl 222 5 2 89 vl each c is independently selected from 2 to 6;
  • R 5 is selected from the group consisting of H and Ci-C 6 alkyl
  • R 6 is selected from the group of formula (I A) and (IB):
  • Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • R 7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • m 0 to 2.
  • R 1 does not contain a charged group.
  • R 1 preferably does not contain an amine, a carboxyl, or other readily ionizable group.
  • the group of formula IA is selected from:
  • R la is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl
  • R 2a is selected from the group consisting of H and lower alkyl.
  • the group of formula IB is selected from:
  • R la is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R 2a is selected from the group consisting of H and lower alkyl.
  • R 1 , R 2 , R 3 , R 4 , n and m are as stated above for formula I.
  • R 1 , R 2 , R 3 , R 4 , n and m are as stated above for formula I.
  • R la is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R 1 , R 2 , R 3 , R 4 , n and m are as stated above for formula I.
  • substituent at R may preferrably have the structure:
  • R 1 is selected from the group consisting of aryl, -(CH 2 ) NR 13 R 14 , -X-R 12 ,
  • -(Ci-C 6 alkyl)-NR 16 R 17 aryl, -(C C 6 alkyl)-O-(aryl), aralkyl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, -S0 2 -alkyl, oxo, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-O-(aryl),
  • R 16 and R 17 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl)-0- (Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoroalkyl;
  • x is selected from 1 to 6;
  • y is selected from 0 to 6;
  • NYOl 22252 89 vl z is selected from 2 to 6;
  • each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • n is selected from 0 to 4.
  • R 3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH 2 ) « -NR 33 R 34 , -Y-R 32 , -0-(CH 2 ) « -C0 2 R 32 ,
  • R 33 and R 34 are independently selected from the group consisting of H, Ci-Cs alkyl, C 2 -Cs alkenyl, C 2 -C 8 alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 36 R 37 ,
  • R 33 and R 34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • Y is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 35 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl),
  • R 36 and R 37 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3
  • R 36 and R 37 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl,
  • R 4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH 2 ) « -NR 43 R 44 , -Z-R 42 , -0-(CH 2 ) fl -C0 2 R 42 ,
  • R 43 and R 44 are independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -C 8 alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 46 R 47 ,
  • R 43 and R 44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
  • R 3 and R 4 may be taken together to form a 5- or 6-membered ring
  • Z is selected from a covalent bond, O, NH, and Ci-C 6 alkyl
  • R 45 is selected from the group consisting of H, aryl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl),
  • R 46 and R 47 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 46 and R 47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
  • R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(C C 6 alkyl)-NR 46 R 47 ,
  • each a is independently selected from 0 to 6;
  • each b is independently selected from 0 to 6;
  • each c is independently selected from 2 to 6;
  • R 5 is selected from the group consisting of H and Ci-C 6 alkyl
  • R 6 is selected from the group of formula (I A) and (IB):
  • NYOl 222 5 2 89 vl Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • R 7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • m 0 to 2.
  • R 1 , R 2 , R 3 , R 4 ,and n are as stated above for formula X.
  • R 1 is selected from the group consisting of aryl, -(CH 2 ) NR 13 R 14 , -X-R 12 ,
  • -(Ci-C 6 alkyl)-NR 16 R 17 aryl, -(Ci-C 6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
  • NYOl 222 5 2 89 vl independently selected from halo, Ci-C 6 alkyl, C 2 -C6, alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, -S0 2 -alkyl, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-O-(aryl),
  • R 16 and R 17 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-NR 16 R 17 , -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl)-0- (Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoroalkyl;
  • x is selected from 1 to 6;
  • y is selected from 0 to 6;
  • z is selected from 2 to 6;
  • each R 9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • e is selected from 0 to 3;
  • NYOl 222 5 2 89 vl Ring A is a 5- or 6-membered ring which may comprise 0-3 ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
  • R" is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • Ring A of compound XV is a 5- or 6- membered aromatic ring which comprises 1-3 ring heteroatoms selected from N, O and S.
  • Ring A of compound XV may have the formula selected from:
  • R la is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R 2a is selected from the group consisting of H and lower alkyl.
  • R 1 is selected from the group consisting of aryl, -(CH 2 ) NR 13 R 14 , -X-R 12 ,
  • -(Ci-Ce alkyl)-NR 16 R 17 aryl, -(Ci-C 6 alkyl)-O-(aryl), aralkyl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 13 and R 14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, C 3 -C 7 cycloalkyl, -S0 2 -alkyl, oxo, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • X is selected from a covalent bond, O, and Ci-C 6 alkyl
  • R 15 is selected from the group consisting of H, Ci-C 8 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-O-(aryl),
  • R 16 and R 17 independently selected from the group consisting of H, Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -C 8 alkynyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7
  • R 16 and R 17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, oxo, hydroxy, cyano and C 1 -C 3 perfluoro alkyl;
  • R 18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C 6 alkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(C C 6 alkyl)-NR 16 R 17 , -(C C 6 alkyl)-0-(Ci-C 6 alkyl)-0- (Ci-C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C 6 alkoxy, hydroxy, cyano and C 1 -C 3 perfluoroalkyl;
  • x is selected from 1 to 6;
  • y is selected from 0 to 6;
  • z is selected from 2 to 6;
  • each R 9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
  • e is selected from 0 to 3;
  • Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
  • Q is selected from CH or N.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most preferred are nitrogen or oxygen.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to six carbons, and more preferably from one to four carbon atoms. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • cycloalkyl refers to saturated, carbocyclic groups having from 3 to 7 carbons in the ring.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may
  • NYOl 2225289 vl also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls and/or heterocyclic groups.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
  • phenanthridine acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycyclic group can be substituted with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
  • nitro means -N0 2 ;
  • halogen or “halo” designates -F, -CI, -Br or -I;
  • sulfhydryl means -SH;
  • hydroxyl means -OH; and
  • sulfonyl means -S0 2 -.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R, R' and R" each independently represent a group permitted by the rules of valence, preferably H, alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.
  • alkoxyl refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • lower alkoxy refers to an alkoxy group having from 1 to 6 carbon atoms.
  • oxo refers to an oxygen atom that has a double bond to a carbon.
  • each expression e.g. alkyl, m, n, R, R", R 2 , R 7 , R 9 , etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups examples include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved, or otherwise removed, to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group,
  • NY01 2225289 vl such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the general intermediate of formula (VII) may be prepared as illustrated in Scheme A.
  • anthralamide (2-aminobenzamide (I)) is coupled with an appropriately substituted acid chloride of formula (II) in the presence of a base such as pyridine to give the benzamide (III).
  • the reaction is run in an aprotic solvent such as chloroform (CHCI3) at a temperature of -20 to 50°C, preferably at room temperature for 1-24 hours, preferably for 6 hours.
  • the benzamide (III) may be formed by treatment of the anthralamide (2- aminobenzamide (I)) with the benzoic acid in the presence of a coupling agent.
  • Suitable coupling agents include N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide (DCC), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and bromotripyrrolidino phosphonium
  • the compound (IV) is aromatized to the chloroquinazoline (V) by treatment with thionyl chloride (SOCl 2 ) with catalytic dimethylformamide (DMF).
  • SOCl 2 thionyl chloride
  • DMF catalytic dimethylformamide
  • POCI3 phosphorous oxy trichloride
  • oxalyl chloride can be used instead of SOCl 2 to effect this transformation.
  • the protected indazole (VI) can be prepared as depicted in Scheme B.
  • 5-Nitro- indazole is appropriately protected via methods known to those skilled in the art, preferably with a tert-butoxy carbonyl group.
  • the nitro group is the reduced to the amino group via
  • reaction using a metal catalyst such as Pd/C in an inert solvent such as methanol (MeOH), 1 ,2 dimethoxethane (DME), ethanol (EtOH) or acetic acid (AcOH) or a combination of solvents preferably in a combination of MeOH and DME.
  • a metal catalyst such as Pd/C
  • an inert solvent such as methanol (MeOH), 1 ,2 dimethoxethane (DME), ethanol (EtOH) or acetic acid (AcOH) or a combination of solvents preferably in a combination of MeOH and DME.
  • MeOH methanol
  • DME 1 ,2 dimethoxethane
  • EtOH ethanol
  • AcOH acetic acid
  • the reaction can be carried out under balloon pressure or under a pressure of 20-50 pounds per square inch (p.s.i.).
  • the phenol (VII) is then alkylated with an electrophile of formula (X) in the presence of a base such as potassium carbonate (K 2 CO 3 ), potassium tert- butoxide (KO l Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3 to give the ether (XI).
  • a base such as potassium carbonate (K 2 CO 3 ), potassium tert- butoxide (KO l Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3
  • the reaction is run in an inert solvent such as DMF at a temperature of 20-100 °C, preferably at 30-40°C.
  • Additives such as sodium iodide (Nal) or potassium iodide (KI) may be optionally added to the reaction.
  • the compound of formula (XIII) can be treated with, preferably at room temperature, with a carboxylic acid of formula (XIV) in the presence of a coupling agent (e.g., PyBOP, PyBrOP, dicyclohexylcarbodiimide (DCC), l-(3'- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a solvent such as dichloromethane, chloroform, or dimethylformamide.
  • a coupling agent e.g., PyBOP, PyBrOP, dicyclohexylcarbodiimide (DCC), l-(3'- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid
  • the compound of formula (XVI) may be synthesized via treatment with an acid chloride of formula (XV) in the presence a tertiary amine base such as triethylamine or DMAP to give an amide of formula (XVI).
  • a tertiary amine base such as triethylamine or DMAP
  • the acid chlorides of formula (XV) are commercially available or can be prepared from carboxylic acids by procedures known to those skilled in the art. If necessary the indazole protecting group can be removed at this point to reveal the final compounds (XVII) via methods known to those skilled in the art.
  • Compounds of formula (XX) can be prepared by reacting the amines of formula (XIII) with a chloroformate of formula (XVI) in the presence of a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate in a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide or in a combination of such solvents.
  • a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate
  • a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide or in a combination of such solvents.
  • the reaction can be run at 0 to 60°C, though room temperature is preferred. If required the indazole protecting group may be removed to give compound of formula (XX) by methods known to those skilled in the art.
  • Ureas of formula (XXV) may be synthesized as depicted in Scheme F.
  • anilines of formula (XIII) may be treated with 4-nitrophenyl carbonochloridate followed by the sequential addition of an amine of formula
  • the reaction is run in an inert solvent such as THF, DMF or CH 2 CI 2 in the presence of an amine base such as Et 3 N, DIEA or NMO.
  • protecting groups e.g. indazole
  • the phenol (XXX) is then alkylated with an electrophile of formula (XXIX) in the presence of a base such as potassium carbonate (K 2 CO 3 ), potassium tert- butoxide (KO l Bu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K 2 CO 3 to give the ether (XXXI).
  • the reaction is run in an inert solvent such as DMF at a temperature of 20-100 °C, preferably at 85°C.
  • a coupling agent e.g., PyBOP, PyBrOP ® ,
  • DCC dicyclohexylcarbodiimide
  • EDC l-(3'-dimethylaminopropyl)-3-ethylcarbodiimide
  • PPAA 1-propanephosphonic acid cyclic anhydride
  • a suitable base e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)
  • a solvent such as dichloromethane, chloroform, or
  • the acid coupling partner may be esterified following the literature protocol utilizing benzyl bromide and sodium carbonate in DMF at room temperature. See Tetrahedron, 58, 2231 , 2002.
  • R 1 is a substituent selected from R 1 , or a precursor or protected group which may be converted to R 1 .
  • 2-Amino-5-bromobenzonitrile may be reduced using lM-borane-THF solution according the literature procedure to provide 2-(aminomethyl)-4-bromobenzenamine. See WO 2008/014822.
  • Ring A may be coupled to the product of Scheme M using a microwave promoted Suzuki conditions at 100 °C using PdCl 2 dppf as the catalyst and the Ring A-boronic acid or the corresponding boronate ester as the boronate coupling partner and cesium carbonate as the base.
  • the final compound may be obtained upon aqueous workup.
  • Reactive groups not involved in the above process steps can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley- Interscience) known to those of ordinary skill in the art.
  • Presently preferred protecting groups include methyl, benzyl, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, CBz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety.
  • the preferred protecting groups for the indazole moiety are BOC, CBz, trifluoroacetamide and benzyl.
  • Compounds of Formula I-V are used to reduce or inhibit glucose uptake in cells or tissues via the GLUT1 transporter.
  • the compounds are particularly useful for limiting glucose availability and metabolism in cells that consume glucose at a high rate. More particularly, expression of hypoxia-regulated genes such as GLUT1 allows tumor cells to survive under hypoxic conditions of the tumor microenvironment, which leads to increased malignancy and likelihood of metastasis. Upregulation of GLUT1 in cancer cells allows increased glucose
  • GLUT1 inhibitors of the invention are cytotoxic in cancer cells, including cancer cells with mitochondrial defects and cancer cells in hypoxic environments. Accordingly, in one embodiment of the invention, neoplasias that express GLUT1 are treated by administering a therapeutically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. In another embodiment of the invention, hypoxic tumors are treated by administering a therapeutically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • Tumors to be treated include, but are not limited to, solid tumors, such as mammary tumors, brain tumors, squamous cell carcinoma, hypopharyngeal carcinoma, breast cancer, cervical carcinoma, ovarian carcinoma, pancreatic cancer, and the like.
  • the suitability of a neoplasm or tumor for treatment with a compound of the invention may be assessed by determining the level of expression of GLUT1 in the tumor.
  • the suitability of a neoplasm or tumor for treatment with a compound of the invention may be assessed by determining whether the neoplasm or tumor is hypoxic.
  • Hypoxia can be determined by testing a tumor directly or testing biopsy tissue.
  • hypoxia can be determined using polarographic needle electrode to meaure dissolved oxygen.
  • Hypoxia-inducible factor 1 (HIF-1) is known to induce the expression of several proteins linked to the maintenance of oxygen homeostasis, cellular energy metabolism, and tumor progression. Its a subunit (HIF-1 a) is stabilized under hypoxic conditions and is a suitable marker for hypoxia.
  • Other endogenous markers include HIF-regulated proteins, such as GLUT1 and carbonic anhydrase IX (CAIX). Such markers can be detected in biopsies using immunological methods. Also, nitroimadazoles such as poimonidazole can be injected prior to biopsy and detected by immunohistochemial methods.
  • glucose As a main energy source, though the glucose requirements of such normal tissues may be small compared to tumor tissue, and alternative energy sources or transporters may be available.
  • 2-DG at
  • compounds of the invention are used in an amount effective to limit glucose uptake by neoplastic cells, but non-toxic to normal cells that express GLUT1.
  • compound 48 has been administered to test animals without apparent adverse effects.
  • GLUT1 inhibitors of the invention may be coadministered with other compounds
  • antineoplastic agents including chemotherapeutic agents and radiation.
  • Anti-neoplastic agents can be grouped into a variety of classes including, for example, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, anti survival agents, biological response modifiers, anti- hormones, and anti-angiogenesis agents.
  • alkylating agents include, but are not limited to, cisplatin, cyclophosphamide, melphalan, and dacarbazine.
  • antimetabolites include, but are not limited to, doxorubicin, daunorubicin, and paclitaxel,
  • topoisomerase inhibitors are irinotecan (CPT-11), aminocamptothecin, camptothecin, DX-8951f, and topotecan (topoisomerase I) and etoposide (VP- 16) and teniposide (VM-26) (topoisomerase II).
  • the source of the radiation can be either external (e.g. , external beam radiation therapy - EBRT) or internal (i.e., brachytherapy - BT) to the patient being treated.
  • the dose of anti-neoplastic agent administered depends on numerous factors, including, for example, the type of agent, the type and severity tumor being treated and the route of administration of the agent. It should be emphasized, however, that the present invention is not limited to any particular dose.
  • a compound of Formula I-V is coadminstered with a drug that targets a cellular component or pathway.
  • a compound of Formula I-V is coadministered with an anti-angiogenic agent, for example a small molecule or biological molecule that targets a vascular endothelial growth factor (e.g., VEGF) or its receptor (e.g., VEGFR1, VEGFR2).
  • an anti-angiogenic agent for example a small molecule or biological molecule that targets a vascular endothelial growth factor (e.g., VEGF) or its receptor (e.g., VEGFR1, VEGFR2).
  • VEGF vascular endothelial growth factor
  • VEGFR1, VEGFR2 vascular endothelial growth factor 2
  • the compound is coadministered with an antagoinst of the human EGFR related family of receptor tyrosine kinases (HER1/EGFR
  • a compound of formula I-V is coadministered with a second agent that depletes cellular ATP.
  • a second agent that depletes cellular ATP.
  • it can be beneficial to restrict energy generation further, for example by coadministering a compound of the invention
  • a GLUT1 inhibitor of the invention may be coadministered with
  • the present invention also provides compounds and methods for preventing, treating, or ameliorating a neoplastic disease or condition in a patient in need thereof.
  • the present invention also provides compounds and methods for preventing, treating, or ameliorating a metabolic disease or condition in a patient in need thereof.
  • compounds are provided that are activators of AMPK.
  • the compounds include GLUT1 inhibitors as described above.
  • AMPK activators further include, but are not limited to, ROCK2 inhibitors and CK2 inhibitors.
  • the metabolic diseases are treated by administering a
  • Metabolic diseases or conditions include, without limitation, diabetes (type 1 and type 2), insulin resistance, metabolic syndrome, hyperinsulinemia, dyslipidemia, and hypercholesterolemia, obesity, hypertension, retinal degeneration, retinal detachment, Parkinson's disease, cardiovascular diseases including vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vascular disease in a subject.
  • the invention also provides for
  • second therapeutic agents for treatment of metabolic diseases such as diabetes and related conditions include biguanides (including, but not limited to metformin), which reduce hepatic glucose output and increase uptake of glucose by the periphery, insulin secretagogues (including but not limited to sulfonylureas and meglitinides) which trigger or enhance insulin release by pancreatic ⁇ -cells, and PPARy, PPARa, and PPARa/ ⁇ modulators (e.g., thiazolidinediones such as pioglitazone and rosiglitazone).
  • biguanides including, but not limited to metformin
  • insulin secretagogues including but not limited to sulfonylureas and meglitinides
  • PPARy, PPARa, and PPARa/ ⁇ modulators e.g., thiazolidinediones such as pioglitazone and rosiglitazone.
  • Additional second therapeutic agents include GLP1 receptor agonists, including but not limited to GLP1 analogs such as exendin-4 and liraglutide and agents that inhibit degradation of GLP1 by dipeptidyl peptidase-4 (DPP-4).
  • DPP-4 dipeptidyl peptidase-4
  • Vildagliptin and sitagliptin are non- limiting examples of DPP-4 inhibitors.
  • compounds of Formula I-V, X, XI, XV and XVI are coadministered with insulin replacement therapy.
  • compounds of I-V, X, XI, XV and XVI can be coadministered with statins and/or other lipid lowering drugs such as MTP inhibitors and LDLR upregulators, antihypertensive agents such as angiotensin antagonists, e.g., losartan, irbesartan, olmesartan, candesartan, and telmisartan, calcium channel antagonists, e.g.
  • statins and/or other lipid lowering drugs such as MTP inhibitors and LDLR upregulators
  • antihypertensive agents such as angiotensin antagonists, e.g., losartan, irbesartan, olmesartan, candesartan, and telmisartan
  • calcium channel antagonists e.g.
  • ACE inhibitors e.g., enalapril
  • ⁇ -andrenergic blockers e.g., atenolol, labetalol, and nebivolol.
  • a subject is prescribed a compound of the invention in combination with instructions to consume foods with a low glycemic index.
  • the compound of Formula I-V, X, XI, XV and XVI is administered before, during, or after another thereapy as well as any combination thereof, i.e., before and during, before and after, during and after, or before, during and after administering the second therapeutic agent.
  • a compound of the invention can be administered daily while extended release metformin is administered daily.
  • a compound of the invention is administered once daily and while exenatide is administered once weekly.
  • therapy with a compound of the invention can be commenced before, during, or after commencing therapy with another agent.
  • therapy with a comound of the invention can be introduced into a patient already receiving therapy with an insulin secretagogue.
  • Compounds the inhibit GLUT1 can be tested in vivo in animal models.
  • Animal models of diabetes and obesity include leptin deficient ob/ob mice (Jackson Laboratories; B6.V- Lep(ob)/J), leptin receptor deficient db/db mice, fatty Zucker rats, and the like. See, e.g., Sima A A F, Shafrir E. Animal Models in Diabetes: A Primer. Taylor and Francis, Publ Amsterdam, Netherlands, 2000). Such models may be used to test safety and efficacy of compounds of the invention, and to formulate appropriate dosages for use in humans.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • pharmaceutically acceptable carriers additives
  • the pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils,
  • NY01 2225289 vl such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mann
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • a basic functional group such as amino or alkylamino
  • “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al, supra).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium
  • antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like
  • metal chelating agents such as citric acid
  • EDTA ethylenediamine tetraacetic acid
  • sorbitol sorbitol
  • tartaric acid tartaric acid
  • phosphoric acid and the like.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active
  • NY01 2225289 vl ingredient preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Mass spectrometry was conducted by: SynPep Co., 6905 Sierra Ct. Dublin, CA 94568, or it was recorded on an LC-MS: Waters 2695 Separations Module with a Waters ZQ 2000 single quadrapole MS detector. Unless stated all mass spectrometry was run in ESI mode.
  • Analytical HPLC was run on an Agilent 1100 Series machine using an YMC ProC18 column (4.6x50 mm, 5 ⁇ particle size). Unless stated the method used was 5-95-10 which refers to a gradient of 5% of buffer A increased to 95% over 10 minutes with Buffer B. Buffer A is 0.1% TFA/H 2 0 and Buffer B is 0.0085% TFA/MeCN.
  • Preparative HPLC was performed on Waters Delta machine (600 and 515 Pumps ) using an YMC- Pack ProC18 (150 x 20 mm I.D.) column using a combination of Buffer A (0.1% TFA/H 2 O) and Buffer B (0.0085% TFA/MeCN) as the mobile phase.
  • NYOl 2225289 vl was added morpholine (8.7 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP ® were added. After stirring the solution for 15 minutes, 0.65 equivalents of morpholine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-l-morpholinoethanone. (13 mg, 0.027 mmol, 17 %).
  • NYOl 2225289 vl was added 2,2-dimethylpropan-l -amine (7.9 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP ® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2-dimethylpropan-l -amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-neopentylacetamide. (40 mg, 0.083 mmol, 59 %).
  • NYOl 2225289 vl layer was concentrated in vacuo.
  • the crude product was purified by preparative TLC (Si0 2 , 7 : 2.6 : 0.4 (CH 2 C1 2 : EtOAc : CH 3 OH) to give tert-butyl 5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.1 lOg). HPLC retention time 7.89 mins.

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Abstract

The invention provides compounds useful for treating diseases, including neoplasias and metabolic disorders. Compounds of the invention modulate GLUTl function and/or AMPK activity.

Description

METABOLIC INHIBITORS
FIELD OF THE INVENTION
[0001] The invention provides compounds useful for treating diseases, including neoplasias and metabolic disorders. Compounds of the invention modulate AMPK activity.
SUMMARY OF THE INVENTION
[0002] The invention is based, at least in part, on the discovery of compounds that that modulate AMPK activity. In one embodiment, the compounds of the invention are useful for treating neoplastic diseases. In another embodiment, the compounds are useful for modulating metabolic diseases. In certain embodiments, the compounds modulate AMPK activity by modulating other cellular components, including, but not limited to, GLUT1.
BACKGROUND OF THE INVENTION
[0003] AMPK is a master energy regulator, affecting fundamental mechanisms of cellular metabolism. AMPK is activated in response to increases in the cellular AMP/ ATP ratio, for example in response to inhibition of ATP production or increased consumption. AMPK is activated by exercise and diet, and has been shown to mediate many of their benefits. It is a key component necessary for efficacy of metformin, thiazolidinediones, and resveratrol. AMPK has also been linked to growth and survival of cancer cells, and is thought to facilitate the activity of certain tumor suppressors.
[0004] GLUT1 is the primary glucose transporter found in muscle and adipose tissue. GLUT1 also provides a mechanism for increased metabolism necessary for sustained tumor growth.
DESCRIPTION OF THE DRAWING
[0005] Figure 1 shows activation of AMPK by compounds of the invention, compared to AICAR, a known activator of AMPK. AMPK activation is observed by detecting
phosphorylation of threonine 172 using a specific antibody.
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NY01 2225289 vl [0006] Figure 2 shows selectivity of an AMPK activator of the invention. Compound 48 demonstrated activity with respect to AMPK and three other targets ROCK2, CK2, and GLUTl .
[0007] Figure 3 shows that activation of AMPK by Compound 48 is specific for phosphorylation of Thrl72 and dose dependent.
[0008] Figure 4 shows that the ACC phosphorylation induced by Compound 48, which depends on AMPK activation, is also dose dependent.
[0009] Figure 5 shows dose dependent AMPK activation by Compound 48 in skeletal muscle cells.
[0010] Figure 6 shows dose dependent AMPK activation by Compound 48 in adipocytes
[0011] Figure 7 show that AMPK activation by Compound 48 in HT-1080 cells is rapid and reversible.
[0012] Figure 8 show that AMPK activation and ACC phosphorylation by Compound 48 in HT-1080 cells is rapid and reversible..
[0013] Figure 9 shows that tumor cells treated with Compound 48 demonstrated a significant increase in the [AMP]/[ATP] ratio, along with increased levels of AMP.
[0014] Figure 10 shows AMPK activation in a fibrosarcoma tumor line HT-1080 when treated with inhibitors of glucose uptake (Compound 48, AICAR), or a control (DMSO).
[0015] Figure 11 shows that in the presence of an AMPK phosphorylation inhibitor (an inhibitor of CAM kinase), inhibition of glucose transport increases phosphorylation of AMPK and ACC.
[0016] Figure 12 shows an increase in fatty acid oxidation in mice fed a high fat diet and supplemented with an activator of AMPK activity.
[0017] Figure 13 shows improvements in serum insulin, blood glucose, serum
cholesterol, visceral fat, liver weight, and serum ALT resulting from adminsitration of
Compound 48 in a mouse model of diabetes.
[0018] Figure 14 shows improved levels of urinary protein excretion in a mouse model maintained on a high fat diet supplemented with Compound 48.
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NY01 2225289 vl DETAILED DESCRIPTION OF THE INVENTION
[0019] AMP kinase (AMPK) plays an important role in energy homeostasis. For example, AMPK phosphorylation is observed in physiological conditions of increased ATP consumption and/or where AMP concentrations are high. The AMPK pathway involves several components, which for example, act to phorphorylate AMPK, or downstream from AMPK. One such component is ACC, which is specifically phosphorylated in connection with AMPK activation. The invention provides new compounds and methods for control of AMPK activation, either directly, or indirectly.
[0020] AMPK has also been implicated in growth and survival of cancer cells. For example, AMPK is phosphorylated and activated by the tumor suppressor LKB1, and functions in the phosphorylation and activation of tuberous sclerosis complex 2, another tumor suppressor. The AMPK pathway is a target for treatment of metabolic disease, including, but not limited to insulin resistance and diabetes. Diabetes is characterized by abnormal glucose and lipid metabolism. Diabetes is generally classified into two categories. In insulin-dependent diabetes mellitus ("IDDM" or "type 1"), β-cells of the pancreas produce little or no insulin. Non-insulin- dependent diabetes mellitus ("NIDDM" or "type 2"), which is much more prevalent, is caused by a defect in insulin secretion and insulin resistance in cells that normally respond to diabetes. For example, type 2 diabetes is characterized by resistance to insulin action in skeletal muscle, liver, and fat. Insulin resistance occurs when insulin is unable to stimulate normal metabolic responses in those targets. AMPK activation improves glucose and lipid levels in the blood. The effects of AMPK activation, for example using compounds of the invention, can be demonstrated in tissue culture, normal and insulin-resistant rodent models of diabetes, and in humans.
[0021] According to the invention, in certain embodiments, the compounds disclosed herein are used to treat of prevent neoplastic diseases. The neoplasm may be cancer. Examples of neoplasms and cancers to be treated or prevented include, without limitation, colon cancer, pancreatic cancer, lung cancer, breast cancer cervical cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, and uterine cancer. In other embodiments, the compounds disclosed herein are used to treat of prevent metabolic diseases and associated conditions. These include, but are not limited to, diabetes, insulin resistance, metabolic syndrome, atherosclerosis,
3
NY01 2225289 vl hypertension, and Alzheimer's. The compounds can be administered alone or in combination with other drugs normally used to treat such conditions. For example, a compound of Formula I is used in combination with metformin to treat type 2 diabetes. The compounds can be observed to improve one or more of the following: β-cell mass, function, β-cell function, insulin sensitivity, muscle glucose uptake and utilization, and glycemic control. The compounds can be used to improve lipid profile, decrease body weight, decrease percentage body fat, reduce blood pressure, cardiovascular disease (CVD). Further, the compounds reduce diabetes risk and CVD risk.
[0022] The AMPK pathway is well conserved, and is a target of major antidiabetic drugs, such as metformin and thiazolidinediones (TZDs). Metformin is a biguanide drug and is thought to reduce gluconeogenesis in the liver. TZDs are compounds that activate peroxisome proliferator-activated receptors (PPARs), which are involved in control of metabolism of carbohydrate, lipid, and protein. Sulfonylureas are another class of drugs for diabetes management which act by increasing insulin release from the β-cells of the pancreas. Also, a- glucosidase inhibitors are oral drugs that prevent digestion of carbohydrates into simple sugars, and thus reduce the impact of carbohydrates on blood sugar. Accordingly, the invention provides methods of treatment of metabolic disease using compounds of the invention in combination with the aforementioned antidiabetic drugs.
[0023] Certain compounds of the invention are also inhibitors of Rho-kinase, which is found in two forms, ROCK 1 (ROCKP; pi 60- ROCK) and ROCK 2 (ROCKa)inhibitors. Rho kinase (ROCK), a serine/threonine kinase, serves as a target protein for small GTP -binding protein Rho. It serves as an important mediator of numerous cellular functions, including focal adhesions, motility, smooth muscle contraction, and cytokinesis. In smooth muscle, ROCK plays an important role in Ca2+ sensitization and the control of vascular tone. It modulates the level of phosphorylation of the myosin II light chain of myosin II, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca2+ sensitization in smooth muscle contraction.
[0024] Preferred compounds are more efficient inhibitors of ROCK2 than of ROCK1. ROCK-mediated pathway plays an important role in vascular smooth muscle contraction, cell adhesion, cell motility, and pathogenesis of atherosclerosis. ROCK also suppress coronary
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NY01 2225289 vl artery spasms. Long-term inhibition of ROCK is reported to block the development of coronary arteriosclerotic lesions. ROCK mediated pathways mediate numerous different cellular functions and ROCK inhibitors can be useful in treatments of patients in need thereof suffering from cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, penile erectile dysfunction, central nervous system disorders such as neuronal degeneration and spinal cord injury, and in neoplasias where inhibition of Rho-kinase has been shown to inhibit tumor cell growth and metastasis, angiogenesis, arterial thrombotic disorders such as platelet aggregation and leukocyte aggregation, asthma, regulation of intraoccular pressure, and bone resorption. Such treatment often relies on administering a therapeutic agent to a patient, wherein the therapeutic agent has a high specificity for a particular pathway or enzyme which is in need of regulation in the patient, by the therapeutic agent such as an enzyme inhibitor. Accordingly, the invention provides compounds that inhibit a Rho kinase (ROCK). Preferably the compound is an inhibitor of ROCK2.
[0025] Certain compounds of the invention are inhibitors of GLUTl . GLUTl is one of several transporters that facilitate transport of glucose and/or other molecules, and is the primary glucose transporter found in muscle and adipose tissue. Glucose transporters facilitate glucose uptake by tumors, in which they are frequently overexpressed. In particular, increased GLUTl expression has also been found to provide a mechanism for increased metabolism necessary for sustained tumor growth. Accordingly, compounds of the invention that inhibit GLUTl activity are used to treat cancer. Further, GLUTl expression is often observed in advanced tumors, which may be anoxic. Anoxia and GLUTl expression is associated with resistance to radiation and/or chemotherapy. Accordingly, compounds of the invention are used to treat anoxic tumors.
[0026] It has been found that in cancer lines that express GLUTl, incubation with GLUTl inhibitors of the invention inhibits proliferation by as much as 50% or more. GLUTl inhibitors of the invention are compounds of Formulas I-V. The GLUTl inhibitors also increase the anti-proliferative effects of non-targeted and targeted chemotherapeutic agents, including, but not limited to, paclitaxel, cisplatin, and gefitinib. The compounds of the invention also restore chemosensitivity and radiation sensitivity to GLUTl -expressing tumors. Accordingly, compounds of the invention are use to treat neoplastic disease, particularly cancer, in
combination with antineoplastic agents such as chemotherapeutics and/or radiation therapy.
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NY01 2225289 vl [0027] In certain embodiments, compounds of the invention are used to reduce or block weight loss associated with disease. For example, weight loss is a complaint of half of cancer patients and indicates a poor prognosis. Excessive glucose uptake and lactate production by tumor cells exacerbates weight loss. Not only is anaerobic glycolysis without respiration an inefficient route to ATP production, the lactate produced by glycolysis induces the Cori cycle in liver and other tissues. The Cori cycle is a metabolic pathway in which lactate produced by anaerobic glycolysis in muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate. Similarly, the Cori cycle converts lactate produced by anerobic glysolysis in tumors back to glucose. For every 2 ATP produced by glycolysis, 6 ATP molecules are consumed by gluconeogenesis.
[0028] Compounds useful according to the present invention include those having the formula I:
Figure imgf000007_0001
wherein:
ft1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) ,-C(=0)NR13R14, -0-(CH2VC02R12, -0-(CH2) ,-C(=0)NR13R14,
-0-(CH2) cycloalkyl, -(CH2) O-C(=0)-NR13R14, -NH-C(=0)-(CH2) NR13R14,
-NH-C(=0)-X-R15, -(CH2) S(=0)2NR13R14, -0-(CH2) S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) ,-NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-C(=0)NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents
6
NY01 2225289 vl independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, - (Ci-C6 alkyl)-NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(Ci-C6 alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
7
NYOl 2225289 vl R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR16R17, -(C C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4;
R3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR33R34, -Y-R32, -0-(CH2)«-C02R32,
-0-(CH2)fl-C(=0)NR33R34, -0-(CH2)iJ-heteroaryl, -0-(CH2)iJ-cycloalkyl,
-0-C(=0)-(CH2)«-NR33R34, -0-(CH2)c-NR33R34, -NH-C(=0)-(CH2)«-NR33R34,
-NH-C(=0)-Y-R35, -NH-C(=0)-(CH2)«-NR33R34;
R32 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR36R37, -(C C6 alkyl)-C(=0)NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R33 and R34 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-C(=0)NR36R37, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R33 and R34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
8
NYOl 2225289 vl independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
Y is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R35 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR36R37, -C02R38, -0-(CH2yC02R38, and -C(=0)NR36R37,
R36 and R37 independently selected from the group consisting of H, Ci-C8 alkyl, C2-C8 alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R36 and R37 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
R4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR43R44, -Z-R42, -0-(CH2)fl-C02R42,
-0-(CH2)fl-C(=0)NR43R44, -0-(CH2)iJ-heteroaryl, -0-(CH2)iJ-cycloalkyl,
-0-C(=0)-(CH2)iJ-NR43R44, -0-(CH2)c-NR43R44, -NH-C(=0)-(CH2)i2-NR43R44,
-NH-C(=0)-Z-R45, -NH-C(=0)-(CH2)«-NR43R44;
R42 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR46R47, -(C C6 alkyl)-C(=0)NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
9
NYOl 2225289 vl R and R are independently selected from the group consisting of H, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR46R47,
-(Ci-Ce alkyl)-C(=0)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R43 and R44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
Z is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R45 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR46R47, -C02R48, -0-(CH2yC02R48, and -C(=0)NR46R47;
R46 and R47 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R46 and R47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
each a is independently selected from 0 to 6;
each b is independently selected from 0 to 6;
10
NYOl 2225289 vl each c is independently selected from 2 to 6;
R5 is selected from the group consisting of H and Ci-C6 alkyl;
R6 is selected from the group of formula (I A) and (IB):
Figure imgf000012_0001
wherein
Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
m is 0 to 2.
[0029] In preferred embodiments of the invention in which GLUT1 activity is sought, R1 does not contain a charged group. In these embodiments, R1 preferably does not contain an amine, a carboxyl, or other readily ionizable group.
[0030] In certain embodiments of the invention, the group of formula IA is selected from:
Figure imgf000012_0002
11
NY01 2225289 vl
Figure imgf000013_0001
wherein the dotted line represents an optional double bond; Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
[0031] In certain embodiments of the invention, the group of formula IB is selected from:
Figure imgf000013_0002
wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
[0032] In a certain embodiments of the present invention, there is provided a compound of the formula II:
Figure imgf000013_0003
wherein R1, R2, R3, R4, R5, R7, Ring B, n and m are as stated above for formula I.
12
NY01 2225289 vl [0033] In a certain embodiments of the present invention, there is provided a compound of the formula III:
Figure imgf000014_0001
wherein R1, R2, R3, R4, n and m are as stated above for formula I.
[0034] In a certain embodiments of the present invention, there is provided a compound of the formula IV:
Figure imgf000014_0002
wherein R1, R2, R3, R4, n and m are as stated above for formula I.
[0035] In a certain embodiments of the present invention, there is provided a compound of the formula V:
Figure imgf000014_0003
13
NY01 2225289 vl wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R1, R2, R3, R4, n and m are as stated above for formula I.
[0036] In certain embodiments, substituent at R may preferrably have the structure:
Figure imgf000015_0001
[0037] Compounds useful according to the present invention include those having the formula X:
Figure imgf000015_0002
wherein:
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-0-(CH2) cycloalkyl, -(CH2) O-C(=0)-NR13R14, -NH-C(=0)-(CH2) NR13R14,
-NH-C(=0)-X-R15, -(CH2) S(=0)2NR13R14, -0-(CH2) S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) ,-NR13R14; -CHCH^-heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-C6 alkyl)-NR16R17, aryl, -(C C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to
14
NY01 2225289 vl 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(d-C6 alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
15
NYOl 2225289 vl z is selected from 2 to 6;
each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4;
R3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR33R34, -Y-R32, -0-(CH2)«-C02R32,
-0-(CH2)«-C(=0)NR33R34, -0-(CH2)e-heteroaiyl, -0-(CH2)e-cycloalkyl,
-0-C(=0)-(CH2)«-NR33R34, -0-(CH2)c-NR33R34, -NH-C(=0)-(CH2)«-NR33R34,
-NH-C(=0)-Y-R35, -NH-C(=0)-(CH2)«-NR33R34;
R32 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR36R37, -(Ci-C6 alkyl)-C(=0)NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R33 and R34 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-C(=0)NR36R37, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R33 and R34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
Y is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R35 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR36R37, -C02R38, -0-(CH2yC02R38, and -C(=0)NR36R37,
R36 and R37 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3
16
NYOl 2225289 vl heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R36 and R37 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl,
-(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
R4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR43R44, -Z-R42, -0-(CH2)fl-C02R42,
-0-(CH2)«-C(=0)NR43R44, -0-(CH2)iJ-heteroaryl, -0-(CH2)iJ-cycloalkyl,
-0-C(=0)-(CH2)iJ-NR43R44, -0-(CH2)c-NR43R44, -NH-C(=0)-(CH2)i2-NR43R44,
-NH-C(=0)-Z-R45, -NH-C(=0)-(CH2)«-NR43R44;
R42 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR46R47, -(C C6 alkyl)-C(=0)NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-C(=0)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R43 and R44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
17
NYOl 2225289 vl independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
alternatively, R3 and R4 may be taken together to form a 5- or 6-membered ring;
Z is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R45 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR46R47, -C02R48, -0-(CH2yC02R48, and -C(=0)NR46R47;
R46 and R47 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R46 and R47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
each a is independently selected from 0 to 6;
each b is independently selected from 0 to 6;
each c is independently selected from 2 to 6;
R5 is selected from the group consisting of H and Ci-C6 alkyl;
R6 is selected from the group of formula (I A) and (IB):
Figure imgf000019_0001
wherein
18
NYOl 2225289 vl Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
m is 0 to 2.
[0038] In a certain embodiments of the present invention, there is provided a compound of the formula XI:
Figure imgf000020_0001
wherein R1, R2, R3, R4,and n are as stated above for formula X.
[0039] In a certain embodiments of the present invention, there is provided a compound of the formula XII:
Figure imgf000020_0002
19
NY01 2225289 vl wherein R1, R2, and n are as stated above for formula X.
[0040] Compounds useful according to the present invention include those having the formula XV:
Figure imgf000021_0001
wherein
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-0-(CH2Vcycloalkyl, -(CH2) ,-0-C(=0)-NR13R14, -NH-C(=0)-(CH2) ,-NR13R14,
-NH-C(=0)-X-R15, -(CH2) S(=0)2NR13R14, -0-(CH2) S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-C(=0)NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-C6 alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(d-C6 alkyl), -(C C6 alkyl)-C(=0)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
20
NYOl 2225289 vl independently selected from halo, Ci-C6 alkyl, C2-C6, alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, oxo, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(d-C6 alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
e is selected from 0 to 3;
21
NYOl 2225289 vl Ring A is a 5- or 6-membered ring which may comprise 0-3 ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R" is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; and
is selected from 0 to 2.
[0041] In certain embodiments of the invention, the Ring A of compound XV is a 5- or 6- membered aromatic ring which comprises 1-3 ring heteroatoms selected from N, O and S. In certain embodiments Ring A of compound XV may have the formula selected from:
Figure imgf000023_0001
wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
[0042] Compounds useful according to the present invention include those having the formula XVI:
Figure imgf000023_0002
wherein
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2VC(=0)NR13R14, -0-(CH2VC02R12, -0-(CH2VC(=0)NR13R14,
22
NY01 2225289 vl -0-(CH2) cycloalkyl, -(CH2) O-C(=0)-NR1¾14, -NH-C(=0)-(CH2) NR1¾14, -NH-C(=0)-X-R15, -(CH2) ,-S(=0)2NR13R14, -0-(CH2) ,-S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, -(C C6 alkyl)-0-(C C6 alkyl)-0-(C C6 alkyl),
-(Ci-Ce alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-C8 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(Ci-Ce alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7
23
NYOl 2225289 vl cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR16R17, -(C C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
e is selected from 0 to 3;
Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
Q is selected from CH or N.
[0043] Compounds useful according to the present invention include those having the formula XVII:
Figure imgf000025_0001
24
NYOl 2225289 vl wherein R1, R9 and e are as stated above for formula XV.
[0044] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most preferred are nitrogen or oxygen.
[0045] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred
embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
[0046] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to six carbons, and more preferably from one to four carbon atoms. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
[0047] The term "cycloalkyl" refers to saturated, carbocyclic groups having from 3 to 7 carbons in the ring. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0048] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
[0049] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
[0050] The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may
25
NYOl 2225289 vl also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls and/or heterocyclic groups.
[0051] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
[0052] The terms "polycyclyl" or "polycyclic group" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycyclic group can be substituted with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
26
NY01 2225289 vl phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
[0053] As used herein, the term "nitro" means -N02; the term "halogen" or "halo" designates -F, -CI, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -S02-.
[0054] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
R R
_rJ _ ^R'
R"
or
wherein R, R' and R" each independently represent a group permitted by the rules of valence, preferably H, alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.
[0055] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term lower alkoxy refers to an alkoxy group having from 1 to 6 carbon atoms.
[0056] The term "oxo" as used herein refers to an oxygen atom that has a double bond to a carbon.
[0057] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
[0058] As used herein, the definition of each expression, e.g. alkyl, m, n, R, R", R2, R7, R9, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
27
NY01 2225289 vl [0059] It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
[0060] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
[0061] The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
[0062] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.
[0063] In addition, if, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved, or otherwise removed, to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group,
28
NY01 2225289 vl such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
[0064] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
[0065] The compounds of the invention may be prepared according to the following synthetic schemes:
Figure imgf000030_0001
Scheme A
[0066] The general intermediate of formula (VII) may be prepared as illustrated in Scheme A. As illustrated in Scheme A, anthralamide (2-aminobenzamide (I)) is coupled with an appropriately substituted acid chloride of formula (II) in the presence of a base such as pyridine to give the benzamide (III). The reaction is run in an aprotic solvent such as chloroform (CHCI3) at a temperature of -20 to 50°C, preferably at room temperature for 1-24 hours, preferably for 6 hours. Alternatively the benzamide (III) may be formed by treatment of the anthralamide (2- aminobenzamide (I)) with the benzoic acid in the presence of a coupling agent. Suitable coupling agents include N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide (DCC), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and bromotripyrrolidino phosphonium
29
NYOl 2225289 vl hexafluorophosphate (PyBroP ), benzotriazolel-lyl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (PyBOP®) with suitable additives if necessary which include 1- hydroxybenzotriazole (HOBt) and 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine.
[0067] Cyclodehydration of compound (III) is carried out under refluxing basic aqueous conditions using sodium hydroxide (NaOH) as base, though other bases such as potassium hydroxide (KOH) may also be used. The reaction of compound (III) is carried out at the reflux temperature of the mixture for about 1-24 hours, preferably about 4 hours. When X=OMe (compound VII) it may be necessary to exchange phenol protecting groups. This can be achieved via methods known to those skilled in the art.
[0068] The compound (IV) is aromatized to the chloroquinazoline (V) by treatment with thionyl chloride (SOCl2) with catalytic dimethylformamide (DMF). The reaction mixture is heated to reflux for 1-6 hours preferably 4 hours. Alternatively phosphorous oxy trichloride (POCI3) or oxalyl chloride can be used instead of SOCl2 to effect this transformation.
[0069] The chloroquinazoline is reacted with an appropriately protected 5 -amino indazole (VI) to give the amino quinazoline (VII). The reaction is carried out in z'so-propanol at 95°C for a reaction time of 30 minutes to 2 hours.
Figure imgf000031_0001
Scheme B
[0070] The protected indazole (VI) can be prepared as depicted in Scheme B. 5-Nitro- indazole is appropriately protected via methods known to those skilled in the art, preferably with a tert-butoxy carbonyl group. The nitro group is the reduced to the amino group via
hydrogenation using a metal catalyst such as Pd/C in an inert solvent such as methanol (MeOH), 1 ,2 dimethoxethane (DME), ethanol (EtOH) or acetic acid (AcOH) or a combination of solvents preferably in a combination of MeOH and DME. The reaction can be carried out under balloon pressure or under a pressure of 20-50 pounds per square inch (p.s.i.).
30
NYO l 2225289 vl X=OH
Figure imgf000032_0001
(VII), X=OH (XI) (XII)
Scheme C
[0071] Compounds of formula (XII) can be synthesized as depicted in scheme C.
Compound (VII) can undergo selective deprotection of the O-protecting group functionality to give compound (VII) where X=OH. This can be done by a variety of methods, which are well known to those skilled in the art. The phenol (VII) is then alkylated with an electrophile of formula (X) in the presence of a base such as potassium carbonate (K2CO3), potassium tert- butoxide (KOlBu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K2CO3 to give the ether (XI). The reaction is run in an inert solvent such as DMF at a temperature of 20-100 °C, preferably at 30-40°C. The electrophile (X) can be either a chloride (Y=C1), bromide, (Y=Br), iodide (Y=I) or other suitable leaving group though it is preferred to use a bromide. Additives such as sodium iodide (Nal) or potassium iodide (KI) may be optionally added to the reaction.
Figure imgf000032_0002
Scheme D
31
NYOl 2225289 vl [0072] Compounds of formula (XVII) may be synthesized as depicted in Scheme D. A compound of formula (VII) where X=N02, may be reduced to the anilino compound (XIII) via catalytic hydrogenation in an inert solvent or mixture of solvents such as EtOH, MeOH, THF or DME preferably a mixture of MeOH and DME. The transformation is effected by use of a metal catalyst such as palladium on carbon (Pd/C). The compound of formula (XIII) can be treated with, preferably at room temperature, with a carboxylic acid of formula (XIV) in the presence of a coupling agent (e.g., PyBOP, PyBrOP, dicyclohexylcarbodiimide (DCC), l-(3'- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a solvent such as dichloromethane, chloroform, or dimethylformamide. Optionally, agents such as HOBt maybe added to the reaction. Alternatively the compound of formula (XVI) may be synthesized via treatment with an acid chloride of formula (XV) in the presence a tertiary amine base such as triethylamine or DMAP to give an amide of formula (XVI). The acid chlorides of formula (XV) are commercially available or can be prepared from carboxylic acids by procedures known to those skilled in the art. If necessary the indazole protecting group can be removed at this point to reveal the final compounds (XVII) via methods known to those skilled in the art.
Figure imgf000033_0001
Scheme E
[0073] Compounds of formula (XX) can be prepared by reacting the amines of formula (XIII) with a chloroformate of formula (XVI) in the presence of a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate in a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide or in a combination of such solvents. The reaction can be run at 0 to 60°C, though room temperature is preferred. If required the indazole protecting group may be removed to give compound of formula (XX) by methods known to those skilled in the art.
32
NYO l 2225289 vl
Figure imgf000034_0001
Scheme F
[0074] Ureas of formula (XXV) may be synthesized as depicted in Scheme F. Treatment of an aniline of formula (XIII) with an isocyanate of formula (XXI) in an inert solvent such as CH2CI2 in the presence of an amine base such as Et3N, DIEA or NMO to give the urea of formula (XXIV) where Rs is a hydrogen. Alternatively, anilines of formula (XIII) may be treated with 4-nitrophenyl carbonochloridate followed by the sequential addition of an amine of formula
(XXII) . The reaction is run in an inert solvent such as THF, DMF or CH2CI2 in the presence of an amine base such as Et3N, DIEA or NMO. Another option of the synthesis of the ureas of formula (XXIV) is to treat the anilines of formula (XIII) with a carbamoyl chloride of formula
(XXIII) in the presence of a base such as Et3N, DIEA or NMO. If appropriate protecting groups (e.g. indazole) may be removed by methods known to those skilled in the art.
Figure imgf000034_0002
Scheme G
[0075] Carbamates of formula (XXVII) may be synthesized as depicted in Scheme G. Treatment of a phenol of formula (VII) where X=OH with an isocyanate of formula (XXII) in an inert solvent such as CH2CI2 in the presence of an amine base such as Et3N, DIEA or NMO.
33
NYOl 2225289 vl Alternatively, phenols of formula (VII) where X=OH) may be treated with 4-nitrophenyl carbonochloridate followed by the sequential addition of an amine of formula (XXII). The reaction is run in an inert solvent such as THF, DMF or CH2CI2 in the presence of an amine base such as Et3N, DIEA or NMO. Another option of the synthesis of the carbamates of formula (XXVI) is to treat the phenols of formula (VII) where X=OH) with a carbamoyl chloride of formula (XXIII) in the presence of a base such as Et3N, DIEA or NMO. If appropriate protecting groups (e.g. indazole) may be removed by methods known to those skilled in the art to give the final compounds (XXVII).
Figure imgf000035_0001
(XXXII)
Scheme H
[0076] Compounds of general formula (XXXIII) can be synthesized as depicted in Scheme H. Compound (VII) can undergo selective deprotection of the O-protecting group (Ri) functionality to give compound (XXX). This can be done by a variety of methods, which are well known to those skilled in the art. The phenol (XXX) is then alkylated with an electrophile of formula (XXIX) in the presence of a base such as potassium carbonate (K2CO3), potassium tert- butoxide (KOlBu), sodium hydride (NaH), sodium hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably K2CO3 to give the ether (XXXI). The reaction is run in an inert solvent such as DMF at a temperature of 20-100 °C, preferably at 85°C. The electrophile (XXIX) can be either a chloride (Y=C1), bromide, (Y=Br), iodide (Y=I) or other suitable leaving
34
NYOl 2225289 vl group though it is preferred to use a bromide. Additives such as sodium iodide (Nal) or potassium iodide (KI) may be optionally added to the reaction.
[0077] Deprotection of the indazole protecting group, which is well known by those skilled in the art, gives the desired compounds (XXXII).
[0078] Practitioners of the art will recognize that subsequent modification of R9 may be necessary and can be performed as depicted in scheme I-J.
Figure imgf000036_0001
Scheme I
[0079] In Scheme I the chloro compounds of formula (XXXI) where R9 is Z-Cl and Z is an appropriate linker is heated in the presence of an amine of formula (XXXIII) in a suitable solvent such as DMSO or DMF to give the amine containing compounds (XXXIV). Additives such as Nal or KI may be optionally added to the reaction. If appropriate protecting groups may be removed at this point by methods known to those skilled in the art.
Figure imgf000036_0002
Scheme J
[0080] In scheme J the acid compounds of formula (XXXI) where R9 is Z-C02H and Z is an appropriate linker is treated with an amine of formula (XXXIII) preferably at room
temperature, in the presence of a coupling agent (e.g., PyBOP, PyBrOP®,
dicyclohexylcarbodiimide (DCC), l-(3'-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a solvent such as dichloromethane, chloroform, or
35
NYOl 2225289 vl dimethylformamide to give the amides of formula (XXXVI). Optionally, agents such as HOBt maybe added to the reaction. If appropriate protecting groups may be removed at this point by methods known to those skilled in the art to give the product compounds of formula (XXXVII).
[0081] The compounds of the invention of formula XV, XVI and XVII may be prepared according to the following synthetic schemes:
Figure imgf000037_0001
Scheme K
[0082] The acid coupling partner may be esterified following the literature protocol utilizing benzyl bromide and sodium carbonate in DMF at room temperature. See Tetrahedron, 58, 2231 , 2002. R1 is a substituent selected from R1, or a precursor or protected group which may be converted to R1.
[0083]
Scheme L
[0084] 2-Amino-5-bromobenzonitrile may be reduced using lM-borane-THF solution according the literature procedure to provide 2-(aminomethyl)-4-bromobenzenamine. See WO 2008/014822.
Figure imgf000037_0003
Scheme M
36
NY01 2225289 vl [0085] The bis-amine product of Scheme L may then coupled with the product of Scheme K using EDC as a peptide coupling agent and DMAP as the base. The resultant crude product ma be treated with DDQ to provides the quinazoline ring structure.
Figure imgf000038_0001
dioxane:H20
Scheme N
[0086] Ring A may be coupled to the product of Scheme M using a microwave promoted Suzuki conditions at 100 °C using PdCl2dppf as the catalyst and the Ring A-boronic acid or the corresponding boronate ester as the boronate coupling partner and cesium carbonate as the base. The final compound may be obtained upon aqueous workup.
[0087] Practitioners of the art will also recognize that the order of certain steps in the above schemes may be altered. Further, certain conditions such as solvent, temperature, etc. may be adjusted as would be recognized by the ordinarily skilled practitioner.
[0088] Reactive groups not involved in the above process steps can be protected with standard protecting groups during the reactions and removed by standard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley- Interscience) known to those of ordinary skill in the art. Presently preferred protecting groups include methyl, benzyl, acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC, CBz, trifluoroacetamide and benzyl for the amino moiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety. The preferred protecting groups for the indazole moiety are BOC, CBz, trifluoroacetamide and benzyl.
[0089] Compounds of Formula I-V are used to reduce or inhibit glucose uptake in cells or tissues via the GLUT1 transporter. The compounds are particularly useful for limiting glucose availability and metabolism in cells that consume glucose at a high rate. More particularly, expression of hypoxia-regulated genes such as GLUT1 allows tumor cells to survive under hypoxic conditions of the tumor microenvironment, which leads to increased malignancy and likelihood of metastasis. Upregulation of GLUT1 in cancer cells allows increased glucose
37
NY01 2225289 vl uptake, which promotes glycolysis, as opposed to aerobic respiration, as an energy source. Even though less efficient per glucose molecule consumed, cells become dependent on glycolysis for ATP production. However, such cells are highly sensitive to inhibition of glycolysis.
[0090] GLUT1 inhibitors of the invention are cytotoxic in cancer cells, including cancer cells with mitochondrial defects and cancer cells in hypoxic environments. Accordingly, in one embodiment of the invention, neoplasias that express GLUT1 are treated by administering a therapeutically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. In another embodiment of the invention, hypoxic tumors are treated by administering a therapeutically effective amount of a compound of Formula I-V or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Tumors to be treated include, but are not limited to, solid tumors, such as mammary tumors, brain tumors, squamous cell carcinoma, hypopharyngeal carcinoma, breast cancer, cervical carcinoma, ovarian carcinoma, pancreatic cancer, and the like. In a further embodiment of the invention, the suitability of a neoplasm or tumor for treatment with a compound of the invention may be assessed by determining the level of expression of GLUT1 in the tumor. In yet another embodiment of the invention, the suitability of a neoplasm or tumor for treatment with a compound of the invention may be assessed by determining whether the neoplasm or tumor is hypoxic.
[0091] Hypoxia can be determined by testing a tumor directly or testing biopsy tissue. For example, hypoxia can be determined using polarographic needle electrode to meaure dissolved oxygen. Hypoxia-inducible factor 1 (HIF-1) is known to induce the expression of several proteins linked to the maintenance of oxygen homeostasis, cellular energy metabolism, and tumor progression. Its a subunit (HIF-1 a) is stabilized under hypoxic conditions and is a suitable marker for hypoxia. Other endogenous markers include HIF-regulated proteins, such as GLUT1 and carbonic anhydrase IX (CAIX). Such markers can be detected in biopsies using immunological methods. Also, nitroimadazoles such as poimonidazole can be injected prior to biopsy and detected by immunohistochemial methods.
[0092] Notably, certain normal tissues, particularly brain, use glucose as a main energy source, though the glucose requirements of such normal tissues may be small compared to tumor tissue, and alternative energy sources or transporters may be available. For example, 2-DG at
38
NY01 2225289 vl certain doses is considered safe. Thus, in certain embodiments, compounds of the invention are used in an amount effective to limit glucose uptake by neoplastic cells, but non-toxic to normal cells that express GLUT1. For example, compound 48 has been administered to test animals without apparent adverse effects.
[0093] GLUT1 inhibitors of the invention may be coadministered with other
antineoplastic agents, including chemotherapeutic agents and radiation. Anti-neoplastic agents can be grouped into a variety of classes including, for example, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, anti survival agents, biological response modifiers, anti- hormones, and anti-angiogenesis agents. Examples of alkylating agents include, but are not limited to, cisplatin, cyclophosphamide, melphalan, and dacarbazine. Examples of antimetabolites include, but are not limited to, doxorubicin, daunorubicin, and paclitaxel,
gemcitabine. Non-limiting examples of topoisomerase inhibitors are irinotecan (CPT-11), aminocamptothecin, camptothecin, DX-8951f, and topotecan (topoisomerase I) and etoposide (VP- 16) and teniposide (VM-26) (topoisomerase II). When the anti-neoplastic agent is radiation, the source of the radiation can be either external (e.g. , external beam radiation therapy - EBRT) or internal (i.e., brachytherapy - BT) to the patient being treated. The dose of anti-neoplastic agent administered depends on numerous factors, including, for example, the type of agent, the type and severity tumor being treated and the route of administration of the agent. It should be emphasized, however, that the present invention is not limited to any particular dose.
[0094] In an embodiment of the invention, a compound of Formula I-V is coadminstered with a drug that targets a cellular component or pathway. For example, a compound of Formula I-V is coadministered with an anti-angiogenic agent, for example a small molecule or biological molecule that targets a vascular endothelial growth factor (e.g., VEGF) or its receptor (e.g., VEGFR1, VEGFR2). In another embodiment, the compound is coadministered with an antagoinst of the human EGFR related family of receptor tyrosine kinases (HER1/EGFR
(epidermal growth factor receptor)/c-erbBl, HER2/c-erbB2, HER3/c-erbB3 and HER4/c-erbB4).
[0095] In an embodiment of the invention, a compound of formula I-V is coadministered with a second agent that depletes cellular ATP. In certain instances, it can be beneficial to restrict energy generation further, for example by coadministering a compound of the invention
39
NY01 2225289 vl with an ATP-depleting levels even further. Accordingly, a GLUT1 inhibitor of the invention may be coadministered with
[0096] The present invention also provides compounds and methods for preventing, treating, or ameliorating a neoplastic disease or condition in a patient in need thereof. The present invention also provides compounds and methods for preventing, treating, or ameliorating a metabolic disease or condition in a patient in need thereof. According to the invention, compounds are provided that are activators of AMPK. The compounds include GLUT1 inhibitors as described above. AMPK activators further include, but are not limited to, ROCK2 inhibitors and CK2 inhibitors. The metabolic diseases are treated by administering a
therapeutically effective amount of a compound of Formula I-V, X, XI, XV and XVI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Metabolic diseases or conditions include, without limitation, diabetes (type 1 and type 2), insulin resistance, metabolic syndrome, hyperinsulinemia, dyslipidemia, and hypercholesterolemia, obesity, hypertension, retinal degeneration, retinal detachment, Parkinson's disease, cardiovascular diseases including vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vascular disease in a subject.
[0097] For treatment of metabolic disease, the invention also provides for
coadministration of a compound of Formula I-V, X, XI, XV and XVI (or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate) to a subject in combination with a second therapeutic agent or other treatment.
[0098] For example, second therapeutic agents for treatment of metabolic diseases such as diabetes and related conditions include biguanides (including, but not limited to metformin), which reduce hepatic glucose output and increase uptake of glucose by the periphery, insulin secretagogues (including but not limited to sulfonylureas and meglitinides) which trigger or enhance insulin release by pancreatic β-cells, and PPARy, PPARa, and PPARa/γ modulators (e.g., thiazolidinediones such as pioglitazone and rosiglitazone).
[0099] Additional second therapeutic agents include GLP1 receptor agonists, including but not limited to GLP1 analogs such as exendin-4 and liraglutide and agents that inhibit degradation of GLP1 by dipeptidyl peptidase-4 (DPP-4). Vildagliptin and sitagliptin are non- limiting examples of DPP-4 inhibitors.
40
NY01 2225289 vl [00100] In certain embodiments of the invention, compounds of Formula I-V, X, XI, XV and XVI are coadministered with insulin replacement therapy.
[00101] According to the invention, compounds of I-V, X, XI, XV and XVI can be coadministered with statins and/or other lipid lowering drugs such as MTP inhibitors and LDLR upregulators, antihypertensive agents such as angiotensin antagonists, e.g., losartan, irbesartan, olmesartan, candesartan, and telmisartan, calcium channel antagonists, e.g. lacidipine, ACE inhibitors, e.g., enalapril, and β-andrenergic blockers (β-b lockers), e.g., atenolol, labetalol, and nebivolol.
[0100] In another embodiment, a subject is prescribed a compound of the invention in combination with instructions to consume foods with a low glycemic index.
[0101] In a combination therapy, the compound of Formula I-V, X, XI, XV and XVI is administered before, during, or after another thereapy as well as any combination thereof, i.e., before and during, before and after, during and after, or before, during and after administering the second therapeutic agent. For example, a compound of the invention can be administered daily while extended release metformin is administered daily. In another example, a compound of the invention is administered once daily and while exenatide is administered once weekly. Also, therapy with a compound of the invention can be commenced before, during, or after commencing therapy with another agent. For example, therapy with a comound of the invention can be introduced into a patient already receiving therapy with an insulin secretagogue.
[0102] Compounds the inhibit GLUT1 can be tested in vivo in animal models. Animal models of diabetes and obesity include leptin deficient ob/ob mice (Jackson Laboratories; B6.V- Lep(ob)/J), leptin receptor deficient db/db mice, fatty Zucker rats, and the like. See, e.g., Sima A A F, Shafrir E. Animal Models in Diabetes: A Primer. Taylor and Francis, Publ Amsterdam, Netherlands, 2000). Such models may be used to test safety and efficacy of compounds of the invention, and to formulate appropriate dosages for use in humans.
[0103] In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical
41
NY01 2225289 vl compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
[0104] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment.
[0105] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
[0106] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils,
42
NY01 2225289 vl such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
[0107] As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term
"pharmaceutically-acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
[0108] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
[0109] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with
43
NY01 2225289 vl pharmaceutically-acceptable bases. The term "pharmaceutically-acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al, supra).
[0110] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0111] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium
metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0112] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active
44
NY01 2225289 vl ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
[0113] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
[0114] Throughout this application, various publications, reference texts, textbooks, technical manuals, patents, and patent applications have been referred to. The teachings and disclosures of these publications, patents, patent applications and other documents in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which the present invention pertains.
[0115] It is to be understood and expected that variations in the principles of invention herein disclosed may be made by one skilled in the art and it is intended that such modifications are to be included within the scope of the present invention. The following examples are illustrative of the invention, and should not be construed to limit the invention.
EXAMPLES
[0116] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
[0117] Abbreviations used in the following examples and preparations include:
Ac20 Acetic anhydride
AcOH Acetic acid
Bn Benzyl
Celite® Diatomaceous earth
1,2 DCE 1 ,2-Dichloroethane
d Doublet
45
NY01 2225289 vl dd Double Doublet
DIEA Di-isopropylethyl amine
DMAP 4-Dimethylamino Pyridine
DME 1,2 Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
EtOAc Ethyl Acetate
EtOH Ethyl Alcohol or Ethanol
Et20 Ethyl Ether
Et3N Triethylamine
g grams
HOBt 1-Hydroxybenzotriazole
HPLC High Pressure Liquid Chromatography
h Hour(s)
hr Hour(s)
m Multiplet
mins. Minutes
MeOH Methyl Alcohol or Methanol
min Minute(s)
mmol millimoles
mmole millimoles
MS Mass Spectrometry
NMR Nuclear Magnetic Resonance
o/n overnight
'PrOH Iso-propanol
PPAA 1-Propanephosphonic Acid Cyclic Anhydride
PyBOP® Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate q Quartet
RT (or rt) room temperature (about 20-25 ° C)
s Singlet
46 sat. Saturated
t Triplet
TBAF 7¾ra-Butyl Ammonium Fluoride
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
v/v volume/volume
wt/v weight/volume
[0118] Mass spectrometry was conducted by: SynPep Co., 6905 Sierra Ct. Dublin, CA 94568, or it was recorded on an LC-MS: Waters 2695 Separations Module with a Waters ZQ 2000 single quadrapole MS detector. Unless stated all mass spectrometry was run in ESI mode.
[0119] 1H NMR spectra were recorded on a Varian 400 MHz machine using Mercury software.
[0120] Analytical HPLC was run on an Agilent 1100 Series machine using an YMC ProC18 column (4.6x50 mm, 5μιη particle size). Unless stated the method used was 5-95-10 which refers to a gradient of 5% of buffer A increased to 95% over 10 minutes with Buffer B. Buffer A is 0.1% TFA/H20 and Buffer B is 0.0085% TFA/MeCN.
[0121] Preparative HPLC was performed on Waters Delta machine (600 and 515 Pumps ) using an YMC- Pack ProC18 (150 x 20 mm I.D.) column using a combination of Buffer A (0.1% TFA/H2O) and Buffer B (0.0085% TFA/MeCN) as the mobile phase.
[0122] Insofar as the synthesis of the following examples of compounds of the present invention is not explicitely described in such example, the synthesis is as described herein in general terms and the appropriate starting material can be easily selected for synthesizing the compound of the example.
47
NYOl 2225289 vl [0123] Example 1.
Figure imgf000049_0001
[0124] To a solution of anthranilamide (7.0 g, 51.41 mmole) in CHCI3 (260 mL) was added pyridine (8.13 g, 102.8 mmole, 8.28 mL) followed by slow addition of m-anisoyl chloride (9.20 g, 53.94 mmole, 7.35 mL). The reaction mixture was stirred at ambient temperature for 6 h and then concentrated in vacuo and subsequently dried under high vacuum for 4 h to give the product. (13.89g, mmol, 100%)
[0125] Example 2.
[0126] 2-(3-Methoxyphenyl)quinazolin-4(3H)-one
Figure imgf000049_0002
[0127] A solution of 2 N NaOH (250 mL) was added to the amide from example 1 (13.89 g, 51.41 mmole) and the reaction mixture was refluxed for 4 h. The reaction was cooled to ambient temperature and then adjusted to pH = 7 with 1 N HC1. The resulting solid was stirred at ambient temperature for 2 h and then filtered. The filtered solid was washed with water, ether and dried under high vacuum overnight. The crude product was also azeotroped from MeOH (IX) and toluene (2 X) and dried under high vacuum for several hours to give 2-(3- methoxyphenyl)quinazolin-4(3H)-one. (15.5 g, mmol, %)
[0128] Example 3.
[0129] 2-(3-Hydroxyphenyl)quinazolin-4(3H)-one
48
NYOl 2225289 vl
Figure imgf000050_0001
[0130] To 2-(3-methoxyphenyl)quinazolin-4(3H)-one (11.6 g, 45.98 mmole) was added of CH2CI2 (120 mL) and the mixture was cooled to -78 °C. Then, a 1 M solution of BBr3 in CH2C12 (60 mL, 60.0 mmol) was added drop wise and the reaction was stirred at -78 °C for 1 h and then ambient temperature for 3 h. The reaction was re-cooled to - 78 °C and cautiously quenched with MeOH (20 mL). The ice bath was removed and the system allowed to stir at ambient temperature for 0.5 h. The pH was adjusted to 7 with 10 % w/w NaHC03 solution. The solid was filtered, washed with ether, dried and then azeotroped from toluene (3 X) and dried under high vacuum overnight to give 2-(3-hydroxyphenyl)quinazolin-4(3H)-one. (11.0g, mmol, 100%).
[0131] Example 4.
[0132] 3-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate
Figure imgf000050_0002
[0133] To 2-(3-hydroxyphenyl)quinazolin-4(3H)-one (11.0g, 45.98 mmole) was added pyridine (16.06 mL, 15.71 g, 0.199 mmole) followed by addition of acetic anhydride (145 mL) and the reaction mixture was heated to 105 °C and stirred for 3.5 h. The reaction mixture was cooled to ambient temperature and then poured onto ice-water (800 mL) and stirred for 2 h. The solid was then filtered and washed with water, ethanol, ether and finally hexane and dried for several hours under high vacuum to give 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate. (8.4 g, mmol, 65 %).
[0134] Example 5.
[0135] 3-(4-Chloroquinazolin-2-yl)phenyl acetate
49
NYOl 2225289 vl
Figure imgf000051_0001
[0136] To 3 -(4-0X0-3, 4-dihydroquinazolin-2-yl)phenyl acetate was added thionyl chloride (100 mL) and DMF (2 mL) and the reaction was heated to reflux for 4 h. The flask was allowed to cool to RT and then concentrated in vacuo. The crude product was azeotroped with toluene (2 X 50 mL), taken up in CH2CI2 (300 mL) and washed with saturated NaHC03 (3 X 50 mL), water (1 X 50 mL) and brine (1 X 50 mL), dried with MgS04 and concentrated in vacuo to give 3-(4-chloroquinazolin-2-yl)phenyl acetate. (9.77 g, mmol, 100%).
[0137] Example 6.
[0138] terf-Butyl 5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate
Figure imgf000051_0002
[0139] 3-(4-Chloroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97mmole) was dissolved in isopropanol (290 mL) and fert-butyl 5 -amino- lH-indazole-1 -carboxylate (6.99 g, 29.97 mmole) was added. The solution was heated to 95 °C and stirred for 0.25 h. A gelatinous formation developed which was manually broken up and dissolution gradually occurred followed by formation of a yellow precipitate. The reaction was stirred for an additional 0.25 h, cooled to ambient temperature and filtered. The filtered solid was washed with ether and then dried under high vacuum overnight to give tert-butyl 5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-lH- indazole-1 -carboxylate. (14.58 g, mmol, 98 %)
50
NYOl 2225289 vl [0140] Example 7.
[0141] tert-Butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate
Figure imgf000052_0001
[0142] To a solution of give tert-butyl 5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (5.85 g, 11.8 mmole) in anhydrous MeOH (400 mL) was added 28 % (wt/v) NH4OH solution (6.50 mL). The reaction mixture was stirred at ambient temperature for 48 h. The crude product was filtered and washed with ether followed by hexane and dried under high vacuum overnight to give tert-butyl 5-(2-(3-hydroxyphenyl)-quinazolin-4-ylamino)-lH- indazole-l-carboxylate. (4.85g, mmol, 91 %).
[0143] Example 8
Figure imgf000052_0002
[0144] To a suspension of anthranilamide (24.0 g, 176.28 mmole) and 3-nitro benzoyl chloride (34.5 g, 186.3 mmole) CHCI3 (700 ml) was added pyridine (30 ml) drop wise at RT. The reaction mixture was stirred at ambient temperature for 8 h. The solvent was removed in vacuo and residue dried under high vacuum to give the product. (73 g, mmol, %)
[0145] Example 9.
[0146] 2-(3-Nitrophenyl)quinazolin-4(3H)-one
51
NYOl 2225289 vl
Figure imgf000053_0001
[0147] A suspension of amide from example 8 (estimated 176.3 mmole) was taken up in 2 N NaOH (800 mL) and was refluxed for 7h. The reaction mixture was cooled to ambient temperature and then pH adjusted to 7 with 3 N HCl. The suspension was stirred at RT for 2 h, filtered, and the filtered solid washed with water and dried under high vacuum to give 2-(3- nitrophenyl)quinazolin-4(3H)-one. (45 g, mmol, 96 % from anthranilamide).
[0148] Example 10.
[0149] 4-Chloro-2-(3-nitrophenyl)quinazoline
Figure imgf000053_0002
[0150] To a suspension of 2-(3-nitrophenyl)quinazolin-4(3H)-one (5.7 g, 21.32 mmole) in thionyl chloride (70 mL) was added of DMF (2 mL). The reaction mixture was refluxed for 4.5 h. The reaction was then concentrated in vacuo and residue suspended in a mixture of CH2CI2 (400 mL) and CHCI3 (500 mL). The organic layer was washed with water, saturated NaHCC"3, water, brine, dried with Na2S04 and concentrated in vacuo. The residue was dried under high vacuum to afford 4-chloro-2-(3-nitrophenyl)quinazoline as an off-white solid. (6.0 g, mmol, 97%).
[0151] Example 11.
[0152] terf-Butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate
52
NYOl 2225289 vl
Figure imgf000054_0001
[0153] A suspension of 4-chloro-2-(3-nitrophenyl)quinazoline (6.3 g, 21.9 mmole), tert- butyl 5-amino-lH-indazole-l-carboxylate (5.10 g, 21.9 mmole) in isopropanol (300 mL) was heated at 95 °C for 1.5 h. The suspension was filtered and the filtered solid was washed with isopropanol. The product was dried under high vacuum for several hours to give the desired product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. ( 8.3 g, mmol, 79%).
[0154] Example 12.
Figure imgf000054_0002
[0155] A suspension of product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (9.0 g, 18.65 mmole) in a mixture of DME / MeOH (300 mL / 100 mL) was hydrogenated in the presence of 10 % Pd / C (1.25 g) at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through
Celite™. The pad of Celite™ was washed with a 1 : 1 mixture of MeOH / CH2C12 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give tert- butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (8.8 g, mmol, %).
[0156] Example 13.
[0157] tert-butyl 5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate
53
NY01 2225289 vl
Figure imgf000055_0001
[0158] A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol),
PyBOP® (57 mg, 0.11 mmol), DIEA (38 pL, 0.22 mmol) in anhydrous CH2C12 (0.5 mL) was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert- butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (100 mg, 0.22 mmol) and anhydrous CH2C12 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2C12. Extracted with H20 (3x) and the organic layer was dried under Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1 : 1 EtOAc:Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert- butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate .( 123 mg, 0.20 mmol, 90%).
[0159] Example 14.
[0160] N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)ph
(methylamino)acetamide
Figure imgf000055_0002
[0161] To tert-butyl 5 -(2-(3 -(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4- ylamino)-l H-indazole- 1 -carboxylate (123 mg, 0.20 mmol) was added a solution of 1 : 1
TFA:CH2C12 (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo
54
NY01 2225289 vl and the residue was triturated with ethyl ether to afford 2-methoxyacetyl chloride N-(3-(4-(lH- indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(dimethylamino)acetamide. (95 mg, 0.22 mmol, 100%)
[0162] Example 15.
[0163] tert-butyl 5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin— 4-ylamino)-lH- indazole-l-carboxylate
[0164] A suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (100 mg, 22.0 mmol), 4-methoxyacetyl chloride (40 μΐ^, 0.44 mmol), Et3N(61 μΐ^, 0.44 mmol), in CH2CI2 (1 mL) was stirred at RT temperature for 30 minutes. The reaction was then concentrated in vacuo and residue was triturated with MeOH and drops of CH2CI2. The solid was filtered under high vacuum to afford tert-butyl 5-(2-(3-(2- methoxyacetamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (98mg, 85%)
[0165] Example 16.
[0166] N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide
Figure imgf000056_0002
[0167] To tert-butyl 5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (95 mg, 0.18 mmol) was added a solution of 1 : 1 TFA:CH2Ci2 (2 mL)
55
NYOl 2225289 vl and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid. Product was purified using prep HPLC (method 25-50_70mins) to afford 2-methoxyacetyl chloride N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenyl)-2-methoxyacetamide. (45 mg, 59%)
[0168] Example 17.
[0169] tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate
Figure imgf000057_0001
[0170] To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35
Figure imgf000057_0002
0.38 mmol) in CH2CI2 (1 mL) was added Et3N (53 uL, 0.38 mmol), and catalytic amount of DMAP. The reaction mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10: 1 CH2Cl2:MeOH). The product tert- butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate was isolate. (18 mg, 18%)
[0171] Example 18.
[0172] methyl 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2- oxoacetate
56
NYOl 2225289 vl
Figure imgf000058_0001
[0173] To tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (18 mg, 0.033 mmol) was added a solution of 1 : 1 TFA:CH2C12 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid to afford methyl 2-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate. (15mg, 100%).
[0174] Example 19.
[0175] tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)- -lH-indazole-l-carboxylate
Figure imgf000058_0002
[0176] A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (96
Figure imgf000058_0003
0.55 mmol) in CH2C12 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3- aminophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate () (100 mg, 0.22 mmol) and CH2C12 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture and stirred for 1.5 h. Added two more 0.5 equivalents of activated acid while stirring 1.5 hr between each addition. Diluted with more CH2C12 and extracted with H20 (3x). Organic layer was dried
57
NY01 2225289 vl under Na2S04 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-(2- morpholinoacetamido)phenyl)quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.
[0177] Example 20.
[0178] N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2- morpholinoacetamide
Figure imgf000059_0001
[0179] To tert-butyl 5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)- quinazolin-4-ylamino)-l H-indazole- 1 -carboxylate (100 mg, 0.16 mmol) was added a solution of 1 : 1 TFA:CH2C12 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35 90 mins) to afford N- (3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamide. (24mg, 38%)
[0180] Example 21.
[0181] tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)- -lH-indazole-l-carboxylate
Figure imgf000059_0002
[0182] To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-1 -carboxylate (1.0 g, 2.21 mmol) in EtOAc:THF:sat'd NaHC03 (110 mL: 30 mL: 50 mL) was added 2-chloroacetyl chloride (1 mL, 12.6 mmol) and stirred at RT for 2.5 hr. The
58
NY01 2225289 vl reaction mixture was stirred at RT for 1.5 h. Another addition of 2-chloroacetyl chloride (0.5 mL) was added and continued to stir for 2 h. Concentrated in vacuo to remove volatiles and residue was washed with 5% citric acid (2 x 50 mL), water (2 x 100 mL), and sat'd NaCl ( 1 x 50 mL). The organic layer was dried under Na2S04 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l- carboxylate. ( 1.02 g, 87%)
[0183] Example 22.
[0184] tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-
-lH-indazole-l-carboxylate
Figure imgf000060_0001
[0185] To a suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)-quinazolin-4- ylamino)-lH-indazole-l-carboxylate (1.0 g, 1.89 mmol) in DMF:THF (3 mL:4 mL) was added morpholine (1.8 mL, 20.6 mmol). The reaction mixture was stirred at RT for 2.5 h. The reaction mixture was concentrated in vacuo to remove volatiles. The residue was poured into ice-water and the resulting white solid was filtered and dried for several hours under high vacuum. The crude product re-crystallized using absolute EtOH to afford tert-butyl 5-(2-(3-(2- morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (830 mg,
75%)
[0186] Example 23.
[0187] N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2- morpholinoacetamide
59
NY01 2225289 vl
Figure imgf000061_0001
[0188] To tert-butyl 5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)- quinazolin-4-ylamino)-lH-indazole-l-carboxylate (805 mg, 1.39 mmol) was added a solution of 1 : 1 TFA:CH2C12 (10 mL) and stirred at RT for 3 h. Added an additional portion of TFA (1.5 mL) and stirred for another 2 h. The reaction mixture was diluted with ethyl ether (200 mL) and solid was filtered and dried for several hours under high vacuum to afford N-(3-(4-(lH-indazol- 5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamide. (917 mg, 100 %)
[0189] Example 24.
[0190] tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)- -lH-indazole-l-carboxylate
Figure imgf000061_0002
[0191] To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (100 mg, 0.22 mmol) and morpholine-4-carbonyl chloride (51 μί, 0.44 mmol,) in CH2C12 (2 mL) was added Et3N (61 μί, 0.44 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of morpholine-4- carbonyl chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added and continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (12: 1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(morpholine-4-
60
NY01 2225289 vl carboxamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate was isolated. (80 mg, 65%)
[0192] Example 25.
[0193] N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)morpholine-4- carboxamide
Figure imgf000062_0001
[0194] To tert-butyl 5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (25 mg, 0.044 mmol) was added a solution of 1 : 1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the product triturated with ethyl ether to afford N-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenyl)morpholine-4-carboxamide. (24 mg, 100% )
[0195] Example 26.
[0196] tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)- -lH-indazole-l-carboxylate
Figure imgf000062_0002
[0197] To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (75 mg, 0.17 mmol) and dimethylcarbamic chloride (30
Figure imgf000062_0003
0.33 mmol,) in CH2C12 (2 mL) was added Et3N (46 0.33 mmol) and catalytic amount of DMAP. The
61
NY01 2225289 vl reaction mixture was stirred at RT for 2 h after which 2 equivalents each of dimethylcarbamic chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added. Upon the addition of the third addition of the chloride and the Et3N the temperature was raised to 45° C. The reaction mixture was stirred for 48 h. Concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)-quinazolin-4-ylamino)-lH-indazole- 1-carboxylate was isolated. (62 mg, 70%)
[0198] Example 27.
[0199] 3-(3-(4-(lH-indaz -5-ylamino)quinazolin-2-yl)phenyl)-l,l-dimethylurea
Figure imgf000063_0001
[0200] To tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (50 mg, 0.10 mmol) was added a solution of 1 : 1 TFA:CH2C12 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether and the yellow solid was purified by prep HPLC (method 25-50 70 mins) to afford 3-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenyl)-l,l-dimethylurea. (36 mg, 86% )
[0201] Example 28.
[0202] tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-
-lH-indazole-l-carboxylate
62
NY01 2225289 vl
Figure imgf000064_0001
[0203] To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (150 mg, 0.33 mmol) and l-(isocyanatomethyl)benzene (162 μΐ^, 1.32 mmol,) in CH2CI2 (2 mL) was added Et3N (1.38 mL, 9.9 mmol). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The residue was triturated using MeOH and drops of CH2CI2 to afford tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate. (100 mg, 52%)
[0204] Example 29.
[0205] l-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea
Figure imgf000064_0002
[0206] To tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-lH-indazole- 1-carboxylate (30 mg, 0.051 mmol) was added a solution of 1 : 1 TFA:CH2Ci2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford l-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenyl)-3-benzylurea. (25 mg, 100 % )
[0207] Example 30.
[0208] tert- utyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-
-lH-indazole-l-carboxylate
63
NYOl 2225289 vl
Figure imgf000065_0001
[0209] A mixture of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (0.800g, 1.76 mmol), tert-butyl 2-bromoacetate (130 μί, 0.88 mmol) and K2C03 (0.972 g, 7.04 mmol) in DMF (35 mL) was heated at 80 °C for 2 h. Upon which additional tert-butyl 2-bromoacetate (130 μΐ,, 0.88 mmol) was added, heating at 80°C was continued for a further 1.5 h. The mixture was allowed to cool to RT and concentrated in vacuo. Diluted with CH2CI2 and extracted with water (3x). Dried under Na2S04 and concentrated in vacuo to give tert-Butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate. (0.950g, 1.68 mmol, 95%).
[0210] Example 31.
[0211] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
Figure imgf000065_0002
[0212] A solution of tert-butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)-quinazolin-4- ylamino)-lH-indazole-l-carboxylate was stirred in CH2C12 (2 mL) and TFA (2 mL) for lh. The volatiles were removed in vacuo and the residue was triturated with ethyl ether. The crude product was purified using prep HPLC (method 10-35_90mins) to afford to give 2-(3-(4-(lH- indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid. (0.43 mg, 0.10 mmol).
64
NYOl 2225289 vl [0213] Example 32.
[0214] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-
-N-isopropyl-N-methylacetamide
Figure imgf000066_0001
[0215] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (120 mg, 0.29 mmol), PyBOP® (150 mg, 0.29 mmol), DIEA (152 pL, 0.87 mmol) in CH2CI2 (5 mL) was stirred at RT for 10-15 minutes. To this solution of activated acid was added N-methylpropan-2-amine (30 μί, 0.29 mmol). The reaction mixture was stirred at RT for 3 h and concentrated in vacuo. The crude product was purified using prep HPLC (method 5-25- 50_80mins) and was further washed with ethyl ether and drops of CH2CI2 to afford 2-(3-(4-(lH- indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropyl-N-methylacetamide. ( 12mg, 0.025 mmol, 9 %).
[0216] Example 33.
[0217] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2- methoxyethyl)acetamide
Figure imgf000066_0002
[0218] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 pL, 0.72 mmol) in CH2CI2 :DMF (4 mL : 0.5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 2-methoxyethanamine (21 0.24 mmol) and the reaction mixture was stirred at RT
65
NYOl 2225289 vl for 3 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35_90mins) and was further washed with ethyl ether and drops of CH2C12 to afford 2-(3-(4- (lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide. ( 25mg, 0.053 mmol, 22 %).
[0219] Example 34.
[0220] 2-chloro-N-(2-(dimethylamino)ethyl)acetamide
Figure imgf000067_0001
[0221] A suspension of 2-chloroacetic acid (214 mg, 2.27 mmol), PyBOP® (1.18, 2.27 mmol), DIE A (1.18 mL, 6.81 mmol) in CH2C12 (1 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of Nl,Nl-dimethylethane-l,2-diamine (249 2.27 mmol) and CH2C12 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Diluted with more CH2C12 and extracted with H20 (3x). Organic layer was dried under Na2S04 and concentrated in vacuo to give the desired product 2-chloro-N-(2- (dimethylamino)ethyl)acetamide.
[0222] Example 35.
[0223] tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate
Figure imgf000067_0002
[0224] A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (120 mg, 0.26 mmol), isopropyl 2-chloroacetate (45 mL, 0.36 mmol), K2C03 (125 0.24 mmol), in DMF (5 mL) stirred at RT for 2 h. Concentrated in vacuo to
66
NY01 2225289 vl afford the crude tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate. (0.26 mmol).
[0225] Example 36.
[0226] isopropyl 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetate
Figure imgf000068_0001
[0227] To a suspension of tert-butyl 5-(2-(3-(2-isopropoxy-2- oxoethoxy)phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.26mmol) in 1,4-dioxane (0.5 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo residue was purified using prep HPLC (method 10-35_90mins) to afford isopropyl 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)acetate. (28 mg, 0.062 mmol, 24%).
[0228] Example 37.
[0229] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-l- morpholinoethanone
Figure imgf000068_0002
[0230] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol), PyBOP® (46 mg, 0.088 mmol), DIEA (28 pL, 0.16 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid
67
NYOl 2225289 vl was added morpholine (8.7 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of morpholine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-l-morpholinoethanone. (13 mg, 0.027 mmol, 17 %).
[0231] Example 38.
[0232] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide
Figure imgf000069_0001
[0233] To a solution of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2C12: DMF (2.0:0.1 mL), added DIEA ( 29 μΐ, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes,
methanamine was bubbled through the solution for 15minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by methanamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45 90 mins) to afford 2-(3-(4-(lH- indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide. (46 mg, 0.11 mmol, 68%).
[0234] Example 39.
[0235] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N- dimethylacetamide
68
NY01 2225289 vl
Figure imgf000070_0001
[0236] To a solution of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2C12: DMF (2.0:0.1 mL), added DIEA ( 29 μΐ, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes,
dimethylamine was bubbled through the solution for 15minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by dimethylamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45 90 mins) to afford 2-(3-(4-(lH- indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetamide (26 mg, 0.059 mmol, 37 %).
[0237] Example 40.
[0238] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- (cyclopropylmethyl)acetamide
Figure imgf000070_0002
[0239] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol), PyBOP® (46 mg, 0.088 mmol), DIEA (28 μΕ, 0.16 mmol) in dry CH2C12 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclopropylmethanamine (7.1 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes,
69
NY01 2225289 vl 0.65 equivalents of cyclopropylmethanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-(cyclopropylmethyl)-acetamide. (60 mg, 0.13 mmol, 81 %).
[0240] Example 41.
[0241] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-
N-(tetrahydro-2H-pyran-4-yl)acetamide
Figure imgf000071_0001
[0242] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μΐ., 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added tetrahydro-2H-pyran-4-amine hydrochloride (13 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro-2H-pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40 90 mins) to afford 2-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46 %).
[0243] Example 42.
[0244] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-
N-((R)-tetrahydrofuran-3-yl)acetamide
70
NYOl 2225289 vl
Figure imgf000072_0001
[0245] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate (24 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of (R)-tetrahydrofuran-3-aminium 4- methylbenzenesulfonate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15- 40 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-((R)- tetrahydrofuran-3-yl)acetamide. (41 mg, 0.085 mmol, 61 %).
[0246] Example 43.
[0247] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phe
-l-(piperidin-l-yl)ethanone
Figure imgf000072_0002
[0248] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added piperidine (7.7 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents
71
NYOl 2225289 vl of piperidine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-55 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-l-(piperidin-l-yl)ethanone. (29 mg, 0.061 mmol, 43 %).
[0249] Example 44.
[0250] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert- butylacetamide
Figure imgf000073_0001
[0251] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2-methylpropan-2-amine (6.7 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2-methylpropan-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-55 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-tert-butylacetamide. (36 mg, 0.061 mmol, 55 %).
[0252] Example 45.
[0253] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide
72
NYOl 2225289 vl
Figure imgf000074_0001
[0254] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added ethanamine hydrochloride (7.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of ethanamine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-ethylacetamide. (19 mg, 0.043 mmol, 31 %).
[0255] Example 46.
[0256] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- cyclobutylacetamide
Figure imgf000074_0002
[0257] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclobutanamine (6.5 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of cyclobutanamine were added and the mixture was stirred for an additional 30
73
NYOl 2225289 vl minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- cyclobutylacetamide. (36 mg, 0.077 mmol, 55%).
[0258] Example 47.
[0259] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- (cyanomethyl)acetamide
Figure imgf000075_0001
[0260] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added aminoacetonitrile monosulfate (14 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of aminoacetonitrile monosulfate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40 90 mins) to afford 2-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acetamide. (12 mg, 0.027 mmol, 19 %).
[0261] Example 48.
[0262] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phi
isopropylacetamide
74
NYOl 2225289 vl
Figure imgf000076_0001
[0263] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added propan-2-amine (5.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of propan-2-aminewere added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- isopropylacetamide. (40 mg, 0.086 mmol, 61 %).
[0264] Example 49.
[0265] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(R)-sec- butylacetamide
Figure imgf000076_0002
[0266] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-butan-2-amine (6.6 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of (R)-butan-2-amine were added and the mixture was stirred for an additional 30
75
NYOl 2225289 vl minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(R)-sec- butylacetamide. (34 mg, 0.073 mmol, 52 %).
[0267] Example 50.
[0268] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide
Figure imgf000077_0001
[0269] To a solution of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol) in dry CH2C12: DMF (2.0:0.1 mL), added DIEA ( 24 μί, 0.14 mmol) and PyBOP® (40 mg, 0.077 mmol). After stirring the mixture at RT for 15 minutes, ammonia was bubbled through the solution for 15minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by ammonia bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 10-35 90 mins) to afford2-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenoxy)acetamide. (27 mg, 0.066 mol, 47 %).
[0270] Example 51.
[0271] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2- trifluoroethyl)acetamide
Figure imgf000077_0002
76
NY01 2225289 vl [0272] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2,2,2-trifluoroethanamine (9.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2,2-trifluoroethanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-(2,2,2-trifluoroethyl)acetamide. (16 mg, 0.032 mmol, 23 %).
[0273] Example 52.
[0274] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phi
cyclohexylacetamide
Figure imgf000078_0001
[0275] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclohexanamine (9.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of cyclohexanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N- cyclohexylacetamide. (27 mg, 0.055 mmol, 39 %).
77
NYOl 2225289 vl [0276] Example 53.
[0277] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phe
N-(2-methylbut-3-yn-2-yl)acetamide
Figure imgf000079_0001
[0278] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2-methylbut-3-yn-2-amine (7.6 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2-methylbut-3-yn-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-(2-methylbut-3-yn-2-yl)acetamide. (22 mg, 0.046 mmol, 33 %).
[0279] Example 54.
[0280] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phi
neopentylacetamide
Figure imgf000079_0002
[0281] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid
78
NYOl 2225289 vl was added 2,2-dimethylpropan-l -amine (7.9 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2-dimethylpropan-l -amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-neopentylacetamide. (40 mg, 0.083 mmol, 59 %).
[0282] Example 55.
[0283] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2- ynyl)acetamide
[0284] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 pL, 0.14 mmol) in dry CH2CI2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added prop-2-yn-l -amine (5.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of prop-2-yn-l -amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-28 90 mins and 0-15 90 mins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2- yl)phenoxy)-N-(prop-2-ynyl)acetamide. (14 mg, 0.031 mmol, 22 %).
[0285] Example 56.
[0286] 2-Bromo-N-isopropylacetamide
0 I
H
79
NYOl 2225289 vl [0287] A solution of z'so-propyl amine (5.0 g, 7.20 mL, 84.6 mmole) in 63 mL of ethylene dichloride was cooled to -10 °C. To this was added a solution of a- bromoacetylbromide (8.53 g, 3.68 mL, 42.3 mmole) in 10.5 mL of ethylene dichloride. The reaction mixture was stirred for 10 mins. The z'so-propylammonium hydrobromide was filtered from the mixture and the filtrate then concentrated in vacuo to give 2-bromo-N- isopropylacetamide as a white solid. (5.30 g, 29.4 mmol 70 %).
[0288] Example 57.
[0289] terf-Butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate
Figure imgf000081_0001
[0290] A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2C03 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30 °C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2S04). The crude product was recrystallized from absolute EtOH (10 mL) to afford fert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.160 g, mmol, 45%).
[0291] Example 58.
[0292] 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phi
isopropylacetamide
Figure imgf000081_0002
80
NYOl 2225289 vl [0293] A solution of tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)- quinazolin-4-ylamino)-lH-indazole-l-carboxylate (4.30 g, 7.79 mmole) in TFA (20 mL) and CH2CI2 (20 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and to the crude residue was added ca. 50 mL Et20. The resulting bright yellow suspension was stirred for 15 minutes and filtered and dried giving 2-(3-(4-(lH-indazol-5- ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide trifluroacetate salt. (4.1 g, mmol, %).
[0294] Example 59.
[0295] 4,5-Dimethoxy-2-nitrobenzamide
Figure imgf000082_0001
[0296] To a suspension of 4,5-dimethoxy-2-nitrobenzoic acid (4.95g, 21.8 mmol) in anhydrous benzene (30 mL) was added SOCl2 (1.75 mL). The resulting mixture was heated at 75 °C for 3.5 h. The solvent was evaporated under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in anhydrous THF (30mL) and cooled to 0°C. To the cooled solution was added a saturated solution of ammonia in THF (ca. 50mL). A precipitate began to form and stirring was continued for 12 hours at RT. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 4,5-dimethoxy-2- nitrobenzamide which was used without further purification (6.0g). HPLC retention time 4.438 mins.
[0297] Example 60.
[0298] 2-Amino-4,5-dimethoxybenzamide
Figure imgf000082_0002
[0299] A suspension of 4,5-dimethoxy-2-nitrobenzamide (5.8g, 25.6mmol) in a 1 : 1 mixture of DME/MeOH (total volume 200 ml) and 10 % Pd / C (0.7 g) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction
81
NYOl 2225289 vl mixture filtered through Celite®. The pad of Celite® was washed with a 1 : 1 mixture of MeOH / CH2CI2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give 2-amino-4,5-dimethoxybenzamide. (5.0g, 25.5mmol, 99%). HPLC retention time 2.303 mins.
[0300] Example 61.
[0301] 4,5-Di-methoxy-2-(3-fluoro-4-(phenyl)phenyl)benzamide
Figure imgf000083_0001
[0302] To a solution of 2-amino-4,5-dimethoxybenzamide (3.1 g, 15.8 mmol) in CHCI3 (100 mL) was added acid chloride (3.41g, 15.8 mmol) as a solution in CHCI3 (40 mL) and pyridine (12 mL). The resulting mixture was stirred at RT for 16 h. The mixture was then heated at 55 °C for 2 h. The volatiles were removed in vacuo and the residue was triturated with water/lN HCl resulting in a solid which was washed with IN HCl and water. The solid was dried under vacuum and washed with CH2CI2 and dried under vacuum to give the desired product which was used directly in the next step (3.0g). HPLC retention time 8.33 mins.
[0303] Example 62.
[0304] 2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one
Figure imgf000083_0002
[0305] A suspension of the 4,5-Di-methoxy-2-(3-fluoro-4-(phenyl)phenyl)-benzamide (4.25g) in 2N NaOH (120 mL) was heated at 105 °C for 5h. The mixture was allowed to cool to
82
NYOl 2225289 vl RT. The mixture was neutralized with 6N HC1 with cooling. A solid separated out which was collected via filtration and washed with Et20 and hexane to give the desired product 2-(3-fluoro- 4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (4.00g, 10.6 mmol, 67% over two steps). HPLC retention time 7.9 mins.
[0306] Example 63.
[0307] 2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one
Figure imgf000084_0001
[0308] A mixture of 2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (3.83g, 10.2 mmol) and methionine (2.1g, 14.1 mmol) in methanesulfonic acid was heated 110 °C for 4h. Additional methionine (0.75g) was added and heating was continued for another 1.5 h. The mixture was allowed to cool to RT and was poured into ice-water (300 mL). A solid separated out, which was collected via filtration. The solid was suspended in sat. NaHC03 and the after the effervescence subsided the solid was again collected via filtration. The solid was washed with water and EtOH to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-6- hydroxy-7-methoxyquinazolin-4(3H)-one (3.2g, 8.83 mmol, 87%). HPLC retention time 7.06 mins.
[0309] Example 64.
[0310] 2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate
Figure imgf000084_0002
83
NY01 2225289 vl [0311] A mixture of 2-(3 -fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin- 4(3H)-one (3.2g, 8.83 mmol), Ac20 (40 mL) and pyridine (5 mL) was heated at 105 °C for 4 h. The mixture was poured onto ice-water (300 mL). The mixture was stirred for 1 h, upon which the solid which had formed was collected via filtration. The solid was washed with water and EtOH and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-7- methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate . MS 405.2 (M+l) HPLC retention time 8.23 mins.
[0312] Example 65.
[0313] 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate
Figure imgf000085_0001
[0314] A suspension of 2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4- dihydroquinazolin-6-yl acetate (3.0g, 7.42 mmol) in SOCl2 (60 mL) with DMF (1.4 mL) was heated at reflux for 5 h. the mixture was allowed to cool to RT and the volatiles were removed in vacuo. The residue was taken up in CHCI3 (300 mL) and washed with water (100 mL), sat. NaHC03 (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to give the desired product 4-chloro-2-(3-fluoro-4- (phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate (3.14g, 7.42 mmol, 100%). HPLC retention time 11.30 minutes (5-95-13 method).
[0315] Example 66.
[0316] tert-butyl 5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate
84
NYOl 2225289 vl
Figure imgf000086_0001
[0317] A mixture of 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate (3.14g, 7.42 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (1.85g, 7.93 mmol) in IPA (180 mL) was heated at 95 °C for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (Si02, CH2Cl2/MeOH) to give the desired compound tert-butyl 5-(6-acetoxy-2-(3-fluoro-4- (phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)- lH-indazole- 1 -carboxylate (2.70g, 4.36 mmol, 59%). MS 620.4 (M+l). HPLC retention time 8.10 mins (5-95-13 method).
[0318] Example 67.
[0319] tert-buty\ 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000086_0002
[0320] A mixture of tert-butyl 5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l -carboxylate (2.6g) and 28% NH4OH (2.8 mL) in MeOH (160 mL) was stirred at RT for 24 h. A solid separated out which was collected via filtration. The solid was triturated with hexane and dried under vacuum to give the desired
85
NY01 2225289 vl compound tert-butyl 5 -(2-(3 -fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.6g). MS 578.4 (M+1). HPLC retention time 7.66 mins.
[0321] Example 68.
[0322] teri-butyl 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000087_0001
[0323] A mixture of tert-butyl 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.61g, 1.06 mmol), l-bromo-2- chloro ethane (0.475g, 3.31 mmol) and K2C03 (0.533g, 3.86 mmol) in DMF (5 mL) was heated at 85 °C for 2.5 h. the mixture was allowed to cool to RT upon which, it was poured into water. A solid separated out which was collected via filtration and dried under vacuum. The residue was purified via preparative TLC (Si02, CH2Cl2:MeOH 9: 1) to give the desired compound tert-butyl 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-lH- indazole-l-carboxylate (0.37g, 0.578 mmol, 55%). MS 640.3 (M+1 CI isotope pattern).
[0324] Example 69.
[0325] 2-(3-fluoro-4-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(4- methylpiperazin-l-yl)ethoxy)quinazolin-4-amine
86
NY01 2225289 vl
Figure imgf000088_0001
[0326] A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.35g, 0.55 mmol) and 4-methyl piperazine in DMSO (1.5 mL) was heated at 85 °C for 3 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (Si02, CH2Cl2:MeOH 9: 1) to give the desired compound. The lower running spot was isolated and then taken up in CH2C12 (6 mL) and TFA (5 mL). The mixture was stirred for 2.5 h at RT. The volatiles were removed in vacuo to give a solid which was triturated with Et20, filtered and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-l- yl)ethoxy)quinazolin-4-amine (0.11 lg, 0.184 mmol, 33%). MS 604.5 (M+l). HPLC retention time 5.10 mins.
[0327] Example 70.
[0328] 6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-N-(lH-indazol-5- yl)-7-methoxyquinazolin-4-amine
Figure imgf000088_0002
[0329] To an ice-cold solution of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.26g, 0.55 mmol) in DMSO (3 mL)
87
NY01 2225289 vl was bubbled dimethylamine for 3-4 minutes. The mixture was heated at 85 °C for 2 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (Si02, CH2Cl2:MeOH 9: 1) to give the desired compound.
The purified compound was taken up in CH2C12 (5 mL) and TFA (5 mL). The mixture was stirred for 3 h at RT. The volatiles were removed in vacuo to give a solid which was dried under vacuum to give the desired product 6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)- N-(lH-indazol-5-yl)-7-methoxyquinazolin-4-amine (0.173g, 0.315mmol, 57%). MS 548.5 (M+). HPLC retention time 5.38 mins.
[0330] Example 71.
[0331] 2-(3-fluoro-4-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2- (pyrrolidin-l-yl)ethoxy)quinazolin-4-amine
Figure imgf000089_0001
[0332] A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.200g, 0.31 mmol) and pyrrolidine (0.385g, 5.41 mmol) in DMSO (1.5 mL) was heated at 75 °C for 1.5 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (Si02, CH2Cl2:MeOH 9: 1) to give the desired compound 2-(3-fluoro-4-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2- (pyrrolidin-l-yl)ethoxy)quinazolin-4-amine (0.15g, 0.261mmol, 84%). MS 575.4 (M+l) HPLC retention time 5.40 mins.
88
NY01 2225289 vl [0333] Example 72.
[0334] 4,5-Di-methoxy-2-(3-phenyl)pheny)benzamide
Figure imgf000090_0001
[0335] To a mixture of 2-amino-4,5-dimethoxybenzamide (8.42g, 38.86 mmole) and pyridine (11.64g, 147.4 mmole) in CHCI3 (180 mL) was added 3-phenylbenzoyl chloride (7.23g, 36.86 mmole) and the reaction was stirred at RT for 5 h. The volatiles were removed in vacuo and the product 2-(benzoylamino)-4,5-dimethoxybenzamide was used immediately without future purification. HPLC retention time 7.92 mins.
[0336] Example 73.
[0337] 2- [(3-phenyl)phenyl] -6,7-dimethoxyquinazolin-4(3H)-one
Figure imgf000090_0002
[0338] A mixture of 2 N NaOH (185 mL, 370 mmole) and 4,5-di-methoxy-2-(3- phenyl)pheny)benzamide (38.9 mmole) was stirred under reflux for 16 h. The mixture was cooled and then pH adjusted to 7 with 1 N HCl. The crude product was filtered from solution, and the cake was washed with ether, hexane and dried under vacuum to give 2-[(3- phenyl)phenyl]-6,7-dimethoxyquinazolin-4(3H)-one (9.97g, 27.82 mmole, 76 % over two steps). HPLC retention time 7.23 mins.
[0339] Example 74.
[0340] 2- [(3-phenyl)phenyl] -6-hydroxy-7-methoxyquiazolin-4(3H)-one
89
NYOl 2225289 vl
Figure imgf000091_0001
[0341] To a solution of 2-[(3-phenyl)phenyl]-6,7-dimethoxyquinazolin-4(3H)-one (9.97g, 27.8 mmole) in methanesulfonic acid (100 mL) was added L-methionine (5.00g, 33.49 mmoles) and the reaction was stirred at 100 °C for 24 h. The solution was cooled to RT and poured onto ice-water (800 mL) and the resulting precipitate was filtered and washed with water. To the crude product was added ethanol (400 mL) and the suspension was stirred at 60 °C for 1 h. The product was then filtered and the cake was washed with ether, hexane and dried under vacuum to afford 2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquiazolin-4(3H)-one (3.84g, 11.15 mmole, 40%). HPLC retention time 6.37 mins.
[0342] Example 75.
[0343] 2- [(3-phenyl)phenyl] -7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate
Figure imgf000091_0002
[0344] To a mixture of 2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquiazolin-4(3H)-one (3.40g, 9.87 mmole) in acetic anhydride (40 mL, 43.2g, 423.16 mmole) was added pyridine (4 mL, 3.91g, 49.46 mmole) and the reaction was stirred at 105 °C for 3 h. The suspension was cooled to RT and poured onto ice-water (800 mL) and stirred for 20 min. The crude product was filtered, washed with water and dried under vacuum to give 2-[(3-phenyl)phenyl]-7-methoxy-4- oxo-3,4-dihydroquinazolin-6-yl acetate (186-036, 3.6g, 9.32 mmole, 94%). HPLC retention time 7.81 mins.
[0345] Example 76.
[0346] 4-chloro-2- [(3-phenyl)phenyl] -7-methoxyquinazolin-6-yl acetate
90
NY01 2225289 vl
Figure imgf000092_0001
[0347] To a mixture of 2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6- yl acetate (3.6 g, 9.32 mmole) in SOCl2 (40 mL) was added DMF (1 mL) and the reaction was stirred at reflux for 16 h. The mixture was cooled to RT and then the volatiles were removed in vacuo. The crude product was dissolved in CHCI3 (300 mL) and washed with saturated NaHC03 solution (3x150 mL), water (2x150 mL) and brine (1 xl50 mL) and dried with Na2S04. The solution was concentrated in vacuo to yield 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin- 6-yl acetate (4.0g, 9.88 mmole). HPLC retention time 11.12 mins. (5-95-13 method).
[0348] Example 77.
[0349] tert-buty\ 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carb xylate
Figure imgf000092_0002
[0350] A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.00g, 9.88 mmole), tert-butyl 5-amino-lH-indazole-l-carboxylate (2.42g, 10.37 mmole) in iso- propanol (130 mL) was stirred at 95 °C for 2 h. The reaction was cooled to RT and the crude product was filtered and then washed with ether, z'so-propanol, and hexane and dried under vacuum to give tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)- lH-indazole-l-carboxylate ( 4.33g, 7.20 mmole, 77% over two steps). MS 602 (M+1). HPLC retention time 6.47 mins.
91
NYOl 2225289 vl [0351] Example 78.
[0352] 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-lH- indazole-l-carboxylate
Figure imgf000093_0001
[0353] To a mixture of tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (4.30g, 7.15 mmole) in CH3OH (300 mL) was added 28 % NH4OH, and the reaction was stirred at RT for 16 h. The solution was concentrated in vacuo and the resulting solid was triturated with toluene and then hexane, followed by filtration to give tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (4.40g, 7.87 mmole). MS 560 (M+1). HPLC retention time 7.62 mins.
[0354] Example 79.
[0355] tert-butyl 5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3-phenyl)phenyl]-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000093_0002
[0356] A mixture of tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate (l .Og, 1.79 mmole), tert-butylbromoacetate (0.174g, 0.132 mL, 0.895 mmole), potassium carbonate (0.99g, 7.16 mmole) in DMF (20 mL) was stirred at 80 °C for 2 h. Then, a second portion of tert-butylbromoacetate (0.174g, 0.132 mL, 0.895
92
NYOl 2225289 vl mmole) was added and the reaction for stirred for an additional 2 h at 80 °C. The mixture was cooled to RT and the volatiles were removed in vacuo. The crude product was partitioned between dichloromethane and water and the organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product tert- vXy\ 5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3- phenyl)phenyl] -7-methoxyquinazolin-4-y lamino)- 1 H-indazole- 1 -carboxylate was used immediately without further purification. MS 618 (M-'Bu+l). HPLC retention time 8.48 mins.
[0357] Example 80.
[0358] 2-(4-(lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6- yloxy)acetic acid
Figure imgf000094_0001
[0359] To tert-butyl 5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3-phenyl)phenyl]-7- methoxyquinazolin-4-ylamino)-l H-indazole- 1 -carboxylate (1.79 mmole) was added TFA (15 mL) at RT, and the solution was stirred for 2 h. The volatiles were removed in vacuo and the crude product was then triturated with ether, filtered and dried under vacuum to give 2-(4-(lH- indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yloxy) acetic acid (0.775g, 1.50 mmole, 84 % over 2 steps). MS 518 (M+l). HPLC retention time 5.95 mins.
[0360] Example 81.
[0361] 2-(4-(lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6- yloxy)-l-(4-methylpiperazin-l-yl)ethanone
93
NY01 2225289 vl
Figure imgf000095_0001
[0362] To a mixture of 2-(4-(lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-6-yloxy)acetic acid (0.25g, 0.48 mmole) in DMF (1 mL) / CH2CI2 (7 mL) was added PyBOP® (0.25g, 0.48 mmole), and DIEA (0.186g, 0.251 mL, 1.44 mmole). The mixture was then stirred for 15 minutes and 1-methylpiperazine (0.048g, 0.053 mL, 0.48 mmole) was added and the reaction was stirred at RT for 3 h. The volatiles were then removed in vacuo. Upon adding CH2CI2, the crude product precipitated and was subsequently filtered. The cake was washed with ether, hexane, CH3OH, CH2CI2 and finally hexane. The crude product was purified by reverse phase HPLC (25 to 55 % CH3CN / H20, 90 minute run time) to yield 2-(4- (lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yloxy)-l-(4- methylpiperazin-l-yl)ethanone (0.015g, 5%). MS 600 (M+l). HPLC retention time 5.22 mins.
[0363] Example 82.
[0364] tert-butyl 5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000095_0002
[0365] A mixture of fert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate (0.055 g, 0.098 mmole), 2-bromoethyl methyl ether (0.03 lg, 0.021 mL, 0.226 mmole), K2C03 (0.036g, 0.26 mmole), and DMF (2.5 mL) was stirred at 85 °C for 3.5 h. The mixture was poured onto ice-water (200 mL) and the crude product was filtered. The product was then dissolved in ether and was washed with water and the organic
94
NYOl 2225289 vl layer was concentrated in vacuo. The crude product was purified by preparative TLC (Si02, 7 : 2.6 : 0.4 (CH2C12 : EtOAc : CH3OH) to give tert-butyl 5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.1 lOg). HPLC retention time 7.89 mins.
[0366] Example 83.
[0367] 2-[(3-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-amin
Figure imgf000096_0001
[0368] TFA (4 mL) was added to tert-butyl 5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.1 lOg, mmole) and the reaction was stirred at RT for 2 h. The solution was concentrated in vacuo and then azeotroped from hexane (I X) The crude product was triturated with ether and filtered, dried under vacuum to give 2-[(3-(phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-methoxyethoxy)quinazolin- 4-amine (0.024g, 0.046 mmole, 47 % over 2 steps). MS 518.4 (M+1). HPLC retention time 6.47 mins.
[0369] Example 84.
[0370] terf-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate
95
NYOl 2225289 vl
Figure imgf000097_0001
[0371] A mixture of tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate (1.5 g, 2.68 mmole), l-bromo-2-chloroethane (1.32g, 0.76 mL, 9.17 mmole), K2C03 (1.55g, 11.21 mmole), and DMF (15 mL) was stirred at 85 °C for 2.5 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2C12 and CH3OH and the solution was concentrated in vacuo to give tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate (1.55g, 2.49mmol, 93 %). HPLC retention time 8.22 mins.
[0372] Example 85.
[0373] 6-(2-(dimethylamino)ethoxy)-N-(lH-indazol-5-yl)-7-methoxy-2-(3- (phenyl)phenyl)quinazoli -4-amine
Figure imgf000097_0002
[0374] A solution of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.25g, 0.40 mmole) in DMSO (3 mL) was cooled to 0 °C. To this was added dimethylamine gas (bubbled into solution for 15 minutes) and the reaction was slowly heated to 85 °C and stirred for 2 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2C12 and CH3OH and the solution was concentrated in vacuo. The residue was
96
NY01 2225289 vl purified via preparative TLC (Si02, 10% CH2C12 / CH3OH). To the crude product was added TFA (5 mL) and the reaction was stirred at RT for 1 h. The solution was concentrated in vacuo and the residue was triturated with ether, filtered and dried under vacuum to give 6-(2- (dimethylamino)ethoxy)-N-( 1 H-indazol-5 -yl)-7-methoxy-2-(3 -(phenyl) phenyl)quinazolin-4- amine (0.096g, 0.18 mmole, 45 % over 2 steps). MS 531 (M+l). HPLC retention time 5.18 mms.
[0375] Example 86.
[0376] 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-l- yl)ethoxy)quinazolin-4-amine
Figure imgf000098_0001
[0377] To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.25g, 0.040 mmole) in DMSO (2 mL) was added pyrrolidine (0.143g, 0.16 mL, 2.00 mmole) and the reaction was stirred at 85 °C for 4 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2C12 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (Si02, 10% CH2C12 / CH3OH) to give 2- [(3 -phenyl)phenyl)-N-(l H-indazol-5 -yl)-7-methoxy-6-(2-(pyrrolidin- l-yl)ethoxy)quinazolin-4- amine (0.042g, 0.075 mmole, 19 %). MS 557 (M+l). HPLC retention time 5.34 mins.
[0378] Example 87.
[0379] 2-((2-(4-(lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin- 6-yloxy)ethyl)(methyl)amino)-N,N-dimethylacetamide
97
NYOl 2225289 vl
Figure imgf000099_0001
[0380] To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.25g, 0.40 mmole) in DMSO (2 mL) was added N,N-dimethyl-2-(methylamino)acetamide (0.232g, 2.00 mmole) and the reaction was stirred at 85 °C for 4 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2CI2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (Si02, 10% CH2C12 / CH3OH). To the product was added TFA (4 mL) and the reaction was stirred at RT for 2 h. The solution was concentrated in vacuo and the residue was triturated with ether, filtered and dried under vacuum to give 2-((2-(4-(lH-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-6-yloxy) ethyl)(methyl)amino)-N,N-dimethylacetamide (0.178g, 0.30 mmole, 74 %). MS 602.6 (M+l). HPLC retention time 5.24 mins.
[0381] Example 88.
[0382] tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-l- yl)ethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000099_0002
[0383] To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.30g, 0.44 mmole) in DMSO (2 mL) was added 1-methylpiperazine (0.903g, 1.00 mL, 9.02 mmole) and the reaction was stirred at 85 °C for 3 h. The mixture was poured onto ice-water (100 mL) and the crude product was
98
NYOl 2225289 vl filtered. The product was then dissolved in a mixture of CH2CI2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (Si02, 10% CH2C12 / CH3OH-with 0.1% NH4OH) to give tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4- methylpiperazin-l-yl)ethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate which was taken on to the next step. HPLC retention time 6.00 mins.
[0384] Example 89.
[0385] 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(4- methylpiperazin-l-yl)ethoxy)quinazolin-4-amine
Figure imgf000100_0001
[0386] TFA (4 mL) was added to 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4- methylpiperazin-l-yl)ethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate and the reaction was stirred at RT for 1.5 h. The solution was concentrated in vacuo and the crude product was triturated with ether and filtered, dried under vacuum to give 2-[(3-phenyl)phenyl)-N-(lH- indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-l-yl)ethoxy)quinazolin-4-amine
(0.166g, 0.283 mmole, 64 % over two steps). MS 586.4 (M+1). HPLC retention time 5.06 mins.
[0387] Example 90.
[0388] 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2- morpholinoethoxy)quinazolin-4-amine
Figure imgf000100_0002
99
NYOl 2225289 vl [0389] To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.25g, 0.40 mmole) in DMSO (2 mL) was added morpholine (1.32g, 1.33 mL, 15.2 mmole) and the reaction was stirred at 85 °C for 48 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2CI2 and CH3OH and the solution was
concentrated in vacuo. The residue was purified via preparative TLC (Si02, 10% CH2C12 / CH3OH) to give 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2- morpholinoethoxy)quinazolin-4-amine (0.131g, 0.20 mmole, 50 %). MS 572.2 (M+). HPLC retention time 5.27 mins.
[0390] Example 91.
[0391] tert-butyl 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-l,4-diazepan-l- yl)ethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000101_0001
[0392] A mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.25g, 0.402 mmole), l-methyl-1,4- diazepane (0.23g, 0.25 mL, 2.00 mmoles) in DMSO was stirred at 85 °C for 2.5 h. The suspension was poured onto ice-water, filtered and re-dissolved in a mixture of CH2C12 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (Si02, 10% CH2C12 / CH3OH-with 0.1% NH4OH) to give tert-butyl 5-(2-[(3- phenyl)phenyl)-7-methoxy-6-(2-(4-methy 1- 1 ,4-diazepan- 1 -yl)ethoxy)quinazolin-4-ylamino)- 1 H- indazole-l-carboxylate which taken on directly to the next step. HPLC retention time 5.96 mins.
100
NYOl 2225289 vl [0393] Example 92.
[0394] 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-l,4- diazepan-l-yl)ethoxy)quinazolin-4-amine
Figure imgf000102_0001
[0395] To a solution of 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-l,4-diazepan- l-yl)ethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate in CH2CI2 (2 mL) was added HC1 as a 4.0 M solution in 1,4 dioxane (8 mL) and the reaction was stirred at RT for 5 h. The volatiles were removed in vacuo and the crude product was washed with hexane and dried under vacuum to yield 2-[(3-phenyl)phenyl)-N-(lH-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-l,4- diazepan-l-yl)ethoxy)quinazolin-4-amine (0.063g, 0.105 mmole, 26 % over 2 steps.). MS 600.4 (M+l). HPLC retention time 5.01 mins.
[0396] Example 93.
[0397] 5-Methoxy-2-nitrobenzamide
Figure imgf000102_0002
[0398] To a suspension of 5-methoxy-2-nitrobenzoic acid (7.5 g, 38.0 mmol) in anhydrous benzene (50 mL), was added thionyl chloride (3.8 mL, 52.05 mmol) followed by the addition of anhydrous DMF (0.4 mL). The resulting reaction mixture was refluxed for 5 h, upon which the volatiles were removed in vacuo. The residue was dissolved in anhydrous THF (60 mL) and added to an ice-cold saturated solution of ammonia in THF (60 mL). The resulting heterogeneous reaction mixture was allowed to warm room temperature and stirring was continued at RT for 48 h. The s volatiles were removed in vacuo and the residue was used without further purification for next step. HPLC retention time 3.29 mins.
101
NYOl 2225289 vl [0399] Example 94.
5-Methoxy-2-aminobenzamide
Figure imgf000103_0001
[0401] To a suspension of 5-methoxy-2-nitrobenzamide (38.0 mmol) in methanol (150 mL), was added 10% Pd-C (1.2 g) under an atmosphere of argon followed by addition of ammonium formate (18.0 g, 285.4 mmole). T resulting reaction mixture was refluxed for 2.5 h, upon which, the mixture was allowed to cool to RT and was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue was washed with water to give a solid (4.74g). The filtrate, was extracted with ethyl acetate (2x300 mL), dried (Na2S04), filtered, concentrated in vacuo and combined with the previous solid. The resulting solid was dried under vacuum to give 5-methoxy-2-aminobenzamide (4.74 g, 35.7 mmol, 94%). HPLC retention time 3.16 mins.
[0402] Example 95.
[0403] 5-Methoxy-2-(3-nitrophenyl)aminobenzamide
Figure imgf000103_0002
[0404] To a suspension of 2-amino-5-methoxybenzamide (2.42g, 14.6 mmol) and pyridine (6 mL) in CHCI3 (120 mL) was added 3-nitrobenzoyl chloride (3.0g, 16.1 mmol). The resulting mixture was stirred at RT for 6 h. The volatiles were removed in vacuo and the resultant solid was washed with Et20 to give the 5-Methoxy-2-(3-nitrobenzoyl)aminobenzamide (6.15g) which was taken directly on to the next step. HPLC retention time 6.58 mins.
102
NYOl 2225289 vl [0405] Example 96.
[0406] 6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
Figure imgf000104_0001
[0407] A suspension of the amide from the previous step (6.0g) in 3N NaOH (160 mL) was heated at 100°C fro 9 h. The mixture was allowed to cool to RT and stirring was continued overnight at RT. The mixture was neutralized with 6N HCl to pH 7. A solid precipitated out and was collected via filtration and dried under vacuum to give the desired product 6-methoxy-2-(3- nitrophenyl)quinazolin-4(3H)-one (4.0g, 13.5 mmol, 95%). HPLC retention time 6.721 min.
[0408] Example 97.
[0409] 6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
Figure imgf000104_0002
[0410] To a suspension of 6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.90g, 13.1 mmol), in CH2C12 (30 mL) cooled to -78 °C under an atmosphere of N2 was added BBr3 as a 1.0M solution in CH2C12 (20 mL, 20.0 mmol). The resulting mixture was stirred at -78 °C for 1 h, then allowed to warm to RT upon which it was stirred for a further 3 h. The mixture was re- cooled to -78 °C and stirred overnight. The reaction was quenched by the addition of EtOH (60 mL) and allowed to warm to RT. Stirring was continued for 1 h at RT, upon which a precipitate formed. Sat. NaHC03 solution was added and the yellow solid was collected via filtration and washed with Et20 and EtOH and dried under vacuum to give 6-hydroxy-2-(3- nitrophenyl)quinazolin-4(3H)-one (2.96g, 10.5 mmol, 80%). HPLC retention time 5.588 min.
103
NY01 2225289 vl [0411] Example 98.
[0412] 2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate
Figure imgf000105_0001
[0413] A mixture of 6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.92g,
10.3mmol) Ac20 (30 mL) and pyridine (4 mL) was heated at 105 °C for 4h.. The mixture was allowed to cool to RT and was poured into ice-water (300mL). The resulting slurry was stirred for 2-3 h at RT, then the solid was collected via filtration, washed with water, EtOH and Et20 and dried under vacuum to give the product 2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.35g, 10.3 mmol, 100%). HPLC retention time 6.559 min.
[0414] Example 99.
[0415] 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate
Figure imgf000105_0002
[0416] A suspension of 2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.30g, lO. lmmol) in SOCl2 (65 mL) was added DMF (2 mL). The mixture was refluxed for 2.5 h, upon which the volatiles were removed in vacuo. The residue was taken up in CHC13 (450 mL) and washed with sat NaHC03 (200 ml) and water (200 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to give the product 4-chloro-2-(3- nitrophenyl)quinazolin-6-yl acetate (3.53g, 10.3 mmol). HPLC retention time 9.748 min.
[0417] Example 100.
[0418] tert-butyl 5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-indazole- 1-carboxylate
104
NYOl 2225289 vl
Figure imgf000106_0001
[0419] A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.63g, 4.74 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (1.16g, 4.28 mmol) in IPA (80 mL) were heated at 95 °C for 5h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et20 to give the product tert-butyl 5-(6-acetoxy-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (2.14g, 3.96mmol, 84%). HPLC retention time 9.649 min.
[0420] Example 101.
[0421] tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-lH-indazole- 1-carboxylate
Figure imgf000106_0002
[0422] A mixture of tert-butyl 5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-lH- indazole-l-carboxylate (0.84g, 1.55mmol) in MeOH (200 mL) was added 10% Pd/C under an atmosphere of N2. The mixture was stirred under an atmosphere of H2 (balloon pressure) for 48 h at RT. The mixture was filtered through a pad of Celite® washing with MeOH. The volatiles were removed in vacuo to give tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (0.81 lg, 1.59 mmol). HPLC retention time 5.51 min.
105
NY01 2225289 vl [0423] Example 102.
[0424] tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-lH- indazole-l-carboxylate
Figure imgf000107_0001
[0425] A mixture of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (0.570g, 1.12 mmol), butryl chloride (0.18g, 1.69 mmol), and DIEA (0.65g, 5.03 mmol) in CH2CI2 (20 mL) was stirred at RT for 7 h. the volatiles were removed in vacuo and the residue was triturated with water. The resultant solid was collected by filtration, washed with water and dried under vacuum.
[0426] The residue was taken up in MeOH (50 mL) and 28% NH4OH (0.9 mL) was added. The mixture was stirred at RT for 24 h. The volatiles were removed in vacuo and the residue was triturated with MeOH/Et20 to give the product tert-butyl 5-(2-(3- butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate (0.354g, 0.657mmol, 59%). HPLC retention time 6.342 min.
[0427] Example 103.
[0428] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2- yl)phenyl)butyramide
Figure imgf000107_0002
[0429] To a mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4- ylamino)-! H-indazole- 1 -carboxylate (0.107g, 0.199 mmol), 2-chloro-N,N-dimethylethanamine
106
NYOl 2225289 vl hydrochloride (0.065g, 0.451 mmol), K2C03 (0.065g, 0.451 mmol) in DMF (1.2 mL) was heated at 70 °C for 2.5 h. The mixture was allowed to cool to RT upon which, the mixture was diluted with CH2C12 (75 mL), washed with water (10 mL), dried (Na2S04), filtered and concentrated in vacuo.
[0430] The material was taken up in CH2C12 (2 mL) and TFA (3 mL) was added. The mixture was stirred at RT for 3 h. The volatiles were removed in vacuo and the residue was triturated with Et20 and dried under vacuum to give the desired product N-(3-(4-(lH-indazol-5- ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl)phenyl) butyramide (0.037g, 72.6μιηο1, 36%). MS 510.4 (M+l). HPLC retention time 5.16 min.
[0431] Example 104.
[0432] N-(3-(4-(lH-indazol-5-ylamino)-6-(3-(dimethylamino)propoxy)quinazolin-2- yl)phenyl)butyramide
Figure imgf000108_0001
[0433] To a mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.106g, 0.197 mmol), 3-chloro-N,N-dimethylpropan-l- amine (0.081g, 0.451 mmol), K2C03 (0.065g, 0.512 mmol) in DMF (1.2 mL) was heated at 70 °C for 2.5 h. The mixture was allowed to cool to RT upon which, the mixture was diluted with CH2C12 (75 mL), washed with water (10 mL), dried (Na2S04), filtered and concentrated in vacuo. The material was purified by preparative TLC (Si02, CH2Cl2:MeOH 9: 1).
[0434] The purified material was taken up in CH2C12 (2 mL) and TFA (3 mL) was added. The mixture was stirred at RT for 3 h. The volatiles were removed in vacuo and the residue was triturated with Et20 and dried under vacuum to give the desired product N-(3-(4-(lH-indazol-5- ylamino)-6-(3 -(dimethy lamino)propoxy)quinazolin-2-yl)phenyl) butyramide (0.057g,
0.109mmol, 55%). MS 524.6 (M+l). HPLC retention time.
107
NY01 2225289 vl [0435] Example 105.
[0436] 4,5-Dimethoxy-2-(3-nitrophenyl)aminobenzamide
Figure imgf000109_0001
[0437] To a suspension of 2-amino-4,5-dimethoxybenzamide (5.05 g, 25.7 mmole) and 3-nitro benzoyl chloride (5.2 g, 28.0 mmole) CHCI3 (120 ml) was added pyridine (50 ml) drop wise at RT. The reaction mixture was stirred at RT for 24 h. The solvent was removed in vacuo and residue was triturated with Et20, filtered and dried under high vacuum to give 4, 5- dimethoxy-2-(3-nitrophenyl)aminobenzamide, which was used directly in the next step.
[0438] Example 106.
[0439] 6,7-Dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
Figure imgf000109_0002
[0440] A suspension of 4, 5-dimethoxy-2-(3-nitrophenyl)aminobenzamide (9.5g) was taken up in 2 N NaOH (200 mL) and was refluxed for 8 h. The reaction mixture was cooled to RT and left to stand overnight. The pH adjusted to 7 with 3 N HCl and the mixture was filtered. The filtered solid washed with water and dried under high vacuum to give 6,7-dimethoxy-2-(3- nitrophenyl)quinazolin-4(3H)-one. (6.2g, 18.9mmol, 74% over two steps) HPLC retention time 6.15 mins.
[0441] Example 107.
[0442] 6-Hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
108
NYOl 2225289 vl
Figure imgf000110_0001
[0443] A mixture of 6,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (5.72g, 17.5 mmol) and L-methionine (3.1g, 20.7mmol) in methanesulfonic acid (40 mL) was heated at 100 °C for 4.5 h. An additional aliquot of L-methionine (0.45g, 1.36mmol) and methanesulfonic acid (10 mL) were added and the mixture was heated for a further 2 h. The mixture was allowed to cool to RT, poured into ice water (ca. 500 mL) and was neutralized with sat. NaHC03 solution. A solid separated out which was collected by filtration and dried under vacuum to give the desired 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one. (7.3g). HPLC retention time 5.486 min.
[0444] Example 108.
[0445] Benzyl 3-(benzyloxy)-4-methoxybenzoate
Figure imgf000110_0002
[0446] To an ice cold mixture of isovanillic acid 1 (4.3 g, 25.5 mmol) and K2C03 (10.5 g, 0.152 mol) in anhydrous DMF (40 mL) was added benzyl bromide (8.7g, 6.05 mL, 51.1 mmol). The resulting reaction mixture stirred at RT overnight. An additional aliquot of benzyl bromide was added (1.0 ml) and stirring was continued for 1.5 h. The reaction mixture was poured into brine (100 mL) and the solid was collected via filtration, washed with water and dried under high vacuum to give benzyl 3-(benzyloxy)-4-methoxybenzoate as a white solid (7.99g, 23.0 mmol, 90%).
[0447] Example 109.
[0448] Benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate
109
NY01 2225289 vl
Figure imgf000111_0001
[0449] To a solution of benzyl 3-(benzyloxy)-4-methoxybenzoate (6.32g, 18.1 mmol) in Ac20 (62 mL) cooled to -10 °C under an atmosphere of N2 was added fuming HNO3 (1.5 mL, 37.1 mmol) in one portion. Stirring was continued at -10 °C for 10 minutes, then at RT for 3 hours. The reaction mixture was carefully poured into ice-water and the pH adjusted to ca. pH=5 with 5N NaOH, sat. NaHC03 and 0.5 NaOH. The mixture was extracted with CH2C12 (3x200 mL). The combined organics were dried (Na2S04), filtered and concentrated in vacuo. The residue was azeotroped with heptane to give benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate as red colored oil (6.55g, 16.7 mmol, 93%).
[0450] Example 110.
[0451] 5-(Benzyloxy)-4-methoxy-2-nitrobenzoic acid
Figure imgf000111_0002
[0452] To a solution of benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (1.4g, 3.56 mmol) in EtOH (10 mL) was added IN NaOH (4.27 mL, 4.27 mmol). The mixture was stirred at RT for lh, upon which an additional aliquot of NaOH (4.27 mL, 4.27 mmol) was added. Stirring was continued at RT overnight. The mixture was diluted with water (20 mL) and washed with CH2C12 (2x25 mL). The aqueous layer was acidified to pH=2 with 0.5 N HCl and extracted with EtOAc (3 x50 mL). The combined organics were dried (Na2S04), filtered and concentrated in vacuo to give 5-(benzyloxy)-4-methoxy-2-nitrobenzoic acid (1.02g, 3.37 mmol, 94%).
[0453] Example 111.
[0454] 4-Methoxy-5-benzyloxy-2-nitrobenzamide
110
NY01 2225289 vl
Figure imgf000112_0001
[0455] To a suspension of 4-methoxy-5-benzyloxy-2-nitrobenzoic acid (10.0 g, 33.3 mmol) in anhydrous THF (100 mL) was added oxalyl chloride (4.90 mL, 56.2 mmol) followed by one drop of anhydrous DMF. The mixture was stirred at RT for 16 h, upon which the mixture was poured into water (300 mL) and ammonium hydroxide (50 mL). A solid was separated out, which was collected by filtration and dried under vacuo. The solid was taken up in re fluxing methanol (500 mL) and the insoluble solid was collected via filtration and dried under vacuum to give 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.50g, 21.5 mmol, 65 %). HPLC retention time 6.154 min.
[0456] Example 112.
[0457] 4-Methoxy-5-benzyloxy-2-aminobenzamide
Figure imgf000112_0002
[0458] A mixture of 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.60 g, 21.9 mmol) and iron powder (8.14 g, 0.146 mol) in acetic acid/methanol (80 mL/80mL) was heated at 85+ 5°C for 1.5 h. The reaction mixture was allowed to cool to RT and the iron was removed by filtration, and volatiles were removed in vacuo. The residue was taken up in sat. sodium bicarbonate and the mixture was extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with water (1x150 mL), brine (1x150 mL), dried (Na2S04), filtered and concentrated in vacuo to give 4-methoxy-5-benzyloxy-2-aminobenzamide (5.2 g, 19.1 mmol, 87%). MS 273.2. (M+). HPLC retention time 4.585 min.
[0459] Example 113.
[0460] 4-Methoxy-5-benzyloxy-2-(3-nitrobenzoylamino)benzamide
111
NY01 2225289 vl
Figure imgf000113_0001
[0461] To a suspension of 6-methoxy-7-benzyloxy-2-aminobenzamide (4.86 g, 17.9 mmol) and pyridine (10 mL) in chloroform (600 mL), was added 3-nitrobenzoyl chloride (3.60 g, 19.4 mmol) slowly. The resulting reaction mixture was stirred at room temperature for 24 h, upon which the volatiles were removed under reduced pressure, and resulting residue was dried under vacuum. The residue upon trituration with Et20 gave a light yellow colored solid in quantitative yield (Note: Possesses some pyridine. HCl). HPLC retention time 8.384 min.
[0462] Example 114.
[0463] 6-(Benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
Figure imgf000113_0002
[0464] A suspension of 4-methoxy-5-benzyloxy-2-(3-nitrobenzoylamino) benzamide (8.00 g, possesses some pyridine.HCl) in 4N NaOH (200 mL) was heated at 100+5°C for 10 h. The reaction mixture was allowed to cool to room temperature and pH was adjusted to 7 - 7.5 with 6 N HCl. A solid separated out, which was collected by filtration, washed with water (100 mL) and dried under vacuum to give 6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin- 4(3H)-one (3.22g, 7.99 mmol, 47% over two steps). MS 404 (M+1) HPLC retention time 8.026 mm.
[0465] Example 115.
[0466] 6-Hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
112
NY01 2225289 vl
Figure imgf000114_0001
[0467] To a suspension of 6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)- one (3.21 g, 7.95 mmol) in trifluoroacetic acid (45 mL) was heated at 75+5 °C for 2.5 h. The volatiles were removed in vacuo and residue was taken up with sat. NaHC03 solution. A light yellow colored solid separated out, which was collected via filtration. The solid was washed with water and dried under vacuum to give 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)- one (2.38g, 7.60 mmol, 96%). HPLC retention time 5.486 min.
[0468] Example 116.
[0469] 7-Methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate
Figure imgf000114_0002
[0470] A mixture of 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.3g, 7.34mmol), Ac20 (40mL) and pyridine (4 mL) were heated at 105 °C for 3.5 h. The reaction mixture was allowed to cool and poured into ice-water (ca. 300 mL) and the resulting slurry was stirred for 2 h. The solid was collected by filtration and washed with water, EtOH and Et20 and dried under high vacuum to give 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate. (2.6g, 7.31 mmol, 99%). HPLC retention time 6.24 min.
[0471] Example 117.
[0472] 4-Chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate
Figure imgf000114_0003
113
NY01 2225289 vl [0473] A mixture of the 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (1.70g, 4.79 mmol), thionyl chloride (30 mL) and anhydrous DMF (0.6 mL) were refluxed for 2.5 h. The volatiles were removed in vacuo and the residue dissolved in CH2CL2 (500 mL) and was washed with water, sat. NaHC03, water and brine, dried (Na2S04), filtered and concentrated in vacuo to 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate. (1.6g, 4.23 mmol, 88%). HPLC retention time 9.75 min.
[0474] Example 118.
[0475] tert-Butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate
Figure imgf000115_0001
[0476] A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.60g, 4.23 mmol) and tert-butyl 5-amino-lH-indazole-l-carboxylate (l .Og, 4.28 mmol) were refluxed in anhydrous z'so-propanol (60mL) for 5 h. The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with Et20 to give tert-butyl 5-(6- acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (2.2g, 4.23mmol, 100%). HPLC retention time = 7.75 mins.
[0477] Example 119.
[0478] tert-Butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate
Figure imgf000115_0002
114
NY01 2225289 vl [0479] To a suspension of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)- quinazolin-4-ylamino)-lH-indazole-l-carboxylate (1.150g, 2.01mmol) in MeOH (100 mL) was added 28% aq. NH4OH solution (0.7 mL). The mixture was stirred at RT for 20 h. The solid was collected via filtration and dried under vacuum to give tert-butyl 5-(6-hydroxy-7-methoxy-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. (0.800g, 1.51mmol, 75%). HPLC retention time 6.57 mins.
[0480] Example 120.
[0481] tert-buty\ 5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000116_0001
[0482] A mixture of tert-Butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.70g, 1.32 mmol), 4-(3-chloropropyl)morpholine (0.32g, 1.96 mmol) and K2C03 (1.33g, 9.62 mmol) in DMF (lOmL) was heated at 80°C for 2.5 h. The mixture was allowed to cool to RT and the volatiles were removed in vacuo. The crude product was purified by column chromatography (Si02, CH2C12 97:3 to 94:6 to 90: 10) to give the desired compound tert-butyl 5 -(7-methoxy-6-(3 -morpholinopropoxy)-2-(3 -nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate. HPLC retention time (5.76 min).
[0483] Example 121.
[0484] tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
115
NYOl 2225289 vl
Figure imgf000117_0001
[0485] To a mixture of 5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.215 g) in MeOH (60mL) was added Pd/C (0.2 lg) and NH4C02 (0.2 lg). The mixture was heated at 60 °C for 40 mins, upon which an additional portion of NH4C02 (0.095g) was added, heating was continued for a further 20 minutes. The mixture was filtered to remove the Pd/C and the filtrate was concentrated under reduced pressure. The residue was taken up in CH2C12 (300 mL) wand was washed with water and brine. The mixture was dried (Na2S04) and the volatiles removed in vacuo. The material was combined with an identical experiment using 0.2g and the residue was subjected to preparative TLC (Si02, CH2C12: MeOH 9: 1) to give the desired product tert-butyl 5-(2-(3-aminophenyl)-7- methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate. HPLC retention time 4.67 mins.
[0486] Example 122.
[0487] N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-2-yl)phenyl)butyramide
Figure imgf000117_0002
[0488] To a solution of tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.076g, 0.121 mmol) in CH2C12 (4mL), DIEA (0.040g, 0.30 mmol) and butryl chloride (0.026g) were added were added.
116
NYOl 2225289 vl The resulting mixture was stirred at RT for 2.5h. The volatiles were removed in vacuo and the residue was taken up in CH2C12 (15 mL), washed with NaHC03 solution, water and brine, dried (Na2S04) and filtered.
[0489] The residue was taken up in CH2C12 (3 mL) and TFA (3 mL) was added. The mixture was stirred at RT for 2.5 h. The volatiles were removed in vacuo and the residue was washed with Et20 and hexane. The solid was dried under vacuum to give the desired product N- (3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin -2-yl)phenyl) butyramide (0.066g, O. l lOmmol, 91%). MS 596.3 (M+l). HPLC retention time 4.60 mins.
[0490] Example 123.
[0491 ] 5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)- lH-indazole-l-carboxylate
Figure imgf000118_0001
[0492] To a mixture of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.40g, 0.70 mmol) in MeOH (lOOmL) was added Pd/C (0.15g) under an atmosphere of N2. The mixture was then stirred under an atmosphere of H2 (balloon pressure) for 48h at RT. The mixture was filtered through a pad of Celite® washing with MeOH. The filtrate was concentrated in vacuo to give the desired product tert-butyl 5-(6- acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate.
(0.23g, 0.43mmol, 61%). HPLC retention time 5.748 mins.
[0493] Example 124.
[0494] terf-Butyl 5-(6-acetoxy-2-(3-butyramidophenyl)-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate
117
NY01 2225289 vl
Figure imgf000119_0001
[0495] To a solution of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate (2.51 g, 4.65 mmol) and DIEA (3.08 mL, 17.7 mmol) in dichloromethane (60 mL) was added butryl chloride (0.72 g, 6.76 mmol). The resulting reaction mixture was stirred at room temperature for 84 h upon which a solid separated out. The solid was collected by filtration and dried under vacuum (1.32 g). The filtrate was concentrated in vacuo and upon trituration with water gave an additional product (1.0g). Combination of the two solids gave tert-butyl 5 -(6-acetoxy-2-(3 -butyramidophenyl)-7-methoxyquinazolin-4-ylamino)- 1 H- indazole-l-carboxylate (2.32g, 3.80 mmol, 82%). HPLC retention time 7.079 min.
[0496] Example 125.
[0497] tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4- ylamino)-lH-indazole-l-carboxyla
Figure imgf000119_0002
[0498] To a mixture of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin- 4-ylamino)-lH-indazole-l-carboxylate (0.205g, 0.38 mmol) in CH2CI2 (lOmL) was added DIEA (0.180g, 1.4 mmol) and butryl chloride (0.055g, 0.52 mmol) respectively. The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and taken up in CH2CI2 (60 mL), the organic layer was washed with water and brine, dried (Na2S04), filtered and concentrated in vacuo.
118
NYOl 2225289 vl [0499] The residue was taken up in MeOH (40mL) and 28% NH4OH (0.25 mL) was added to the mixture. The mixture was stirred at RT for 24 h. The volatiles were removed in vacuo and the residue was triturated with Et20 to give tert-butyl 5-(2-(3-butyramidophenyl)-6- hydroxy-7-methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.130g, 0.24mmol, 63%). HPLC retention time 6.49 min.
[0500] Example 126.
[0501] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7- methoxyquinazolin-2-yl)phenyl)butyramide
Figure imgf000120_0001
[0502] To a mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.102g, 0.168 mmol), 2-chloro-N,N- dimethylethanamine hydrochloride (0.053g, 0.37 mmol) and K2CO3 (0.090g, 0.65 mmol) in DMF (2.5 mL) was heated at 85 °C for 3 h. The mixture was allowed to cool to RT and was concentrated in vacuo. The residue was subjected to preparative TLC (Si02, CH2C12 9: 1).
[0503] After isolation, the product was immediately taken up CH2C12 (1 mL) and TFA (2 mL) was added. The mixture was stirred at RT for 3.5 h, the volatiles were removed in vacuo and the residue was triturated with Et20 and dried under vacuum to give the desired product N- (3-(4-(lH-indazol-5-ylamino)-6-(2-(dimethylamino) ethoxy)-7-methoxy quinazolin-2- yl)phenyl)butyramide. MS 540.5 (M+l). (HPLC retention time 4.55 mins.
[0504] Example 127.
[0505] terf-Butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
119
NYOl 2225289 vl
Figure imgf000121_0001
[0506] A mixture of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.475g, 0.898mmol), 2-chloro-N,N-dimethylethanamine (0.28g, 1.94 mmol) and K2C03 (1.18g, 2.54 mmol) in DMF (8 mL) was heated at 85°C for 3 h. The volatiles were removed in vacuo and the residue was taken up in CHCl3/MeOH. The solid was removed via filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si02, CHCl3/MeOH 93:7 then 90: 10) to give tert-butyl 5-(6-(2- (dimethylamino)ethoxy)-7-methoxy-2-(3 -nitrophenyl)quinazolin-4-ylamino)- 1 H-indazole- 1 - carboxylate. (0.087g, 0.145 mmol, 16%). MS 600.4 (M+l).
[0507] Example 128.
[0508] terf-Butyl 5-(2-(3-aminophenyl)-6-(2-(dimethylamino)ethoxy)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000121_0002
[0509] A mixture of tert-butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3- nitrophenyl)quinazolin-4-ylamino)-l H-indazole- 1 -carboxylate (0.085g, 0.142mmol) and 10 % Pd / C (0. lOOg) in MeOH (20 ml) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was heated at 55 °C for 1 h. The reaction mixture filtered through Celite® washing with MeOH. The filtrate was concentrated in vacuo to give tert-butyl 5-(2-(3- aminophenyl)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-4-ylamino)- 1 H-indazole- 1 - carboxylate. (0.065g, 0.128mmol, 90%). HPLC retention time 3.42 mins.
120
NY01 2225289 vl [0510] Example 129.
2-Methoxyethyl 4-methoxy-3-(2-methoxyethoxy)benzoate
Figure imgf000122_0001
[0512] To a mixture of 3-hydroxy-4-methoxy benzoic acid (9.6g, 57.1 mmol) in DMF (110 mL) cooled to 0°C under an atmosphere of N2 was added K2C03 slowly. The mixture was stirred for 30 minutes upon which 2-bromoethyl methyl ether (10.7 mL, 114.2 mmol) was added slowly. The mixture was stirred at RT for 1 h and then at 80 °C for 12 hours, upon which another portion of 2-bromoethyl methyl ether (8.0 mL, 85.7 mmol) was added. Heating was continued for 2 h., upon which TLC indicated complete reaction. The reaction mixture was allowed to cool to RT and poured into ice-water. The mixture was extracted with EtOAc:hexane (4: 1 v/v, 3x300 mL). The combined extracts were washed with brine (lx 300 mL), dried (Na2S04), filtered and concentrated in vacuo to give 2-methoxy ethyl 4-methoxy-3-(2-methoxyethoxy)benzoate as a dark colored oil. (15.05g, 52.9mmol, 93%). MS 307.3 (M+Na). HPLC retention time 5.80 mins.
[0513] Example 130.
[0514] 2-Methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate
Figure imgf000122_0002
[0515] To a solution of 2-methoxy ethyl 4-methoxy-3-(2-methoxyethoxy)benzoate (15.05g, 52.9 mmol) in AcOH (54 mL) under an atmosphere of N2 was added cone. HN03 (13.5 mL) in one portion. The reaction was stirred at RT for 72 h. The mixture was poured into ice- water (ca. 800mL) and extracted with EtOAc (2x400 mL). The combined organics were washed with water (2x 200 mL) and brine (lx 200 mL), dried (Na2S04) and cone, in vacuo. The residue was azeotroped with heptane (2x300 mL) to remove residual AcOH giving 2-methoxy ethyl 4- methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a dark colored oil. (15.5g, 47.1mmol, 89%). HPLC retention time 6.24 mins.
121
NY01 2225289 vl [0516] Example 131.
4-Methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic acid
Figure imgf000123_0001
[0518] To a solution of 2-methoxy ethyl 4-methoxy-5-(2-methoxyethoxy)-2- nitrobenzoate (5.0g, 15.2 mmol) in EtOH (40mL) was added 2N NaOH (40mL, 76.0 mmol, 5 eq.). The mixture was stirred at RT for 12 h. The mixture was diluted with water (100 mL) and washed with CH2C12 (1x100 mL). The aqueous layer was acidified to pH=l using IN HCl (A solid began to precipitate, this was dissolved by the addition of EtOAc). The aqueous mixture was extracted with EtOAc (2x200 mL). The combined organics were washed with brine (lxlOOmL), dried (Na2S04), filtered and concentrated in vacuo to give 4-methoxy-5-(2- methoxyethoxy)-2-nitrobenzoic acid as an off white solid (3.55g, 12.4 mmol, 86%). HPLC retention time 4.94 mins.
[0519] Example 132.
[0520] 4-Methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide
Figure imgf000123_0002
[0521] To a solution of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic acid (3.35g, 12.4mmol) under an atmosphere of N2 in anhydrous THF (50 mL) was added oxalyl chloride (2.25 mL, 1.7 eq. 25.5 mmol) and two drops of DMF. The mixture was stirred at RT for 30 minutes, upon which two more drops of DMF were added and stirring at RT was continued for 1 h. Tic and HPLC analysis indicated complete formation of the acid chloride intermediate and the mixture was concentrated in vacuo to give the acid chloride intermediate as a yellow solid. The solid was dissolved in anhydrous THF (50 mL) and to this solution was added a saturated solution of NH3 in THF (15 mL) via a cannula. A precipitate began to form and stirring was continued at RT for 12 h. The mixture was concentrated in vacuo to give 4-methoxy-5-(2-
122
NY01 2225289 vl methoxyethoxy)-2-nitrobenzamide as an off-white solid. (4.5g, contains some NH4C1, the mixture was taken on directly to the next step). HPLC retention time 8.55 mins.
[0522] Example 133.
[0523] 2-Amino-4-methoxy-5-(2-methoxyethoxy)benzamide
Figure imgf000124_0001
[0524] A mixture of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide (4.5g, contains some NH4CI) and 10% Pd/C (ca. 0.5g) in DME (200mL) and MeOH (200mL) was
hydrogenated under a balloon of ¾ at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to give 2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide as an off white solid (2.8g, 11.6 mmol). HPLC retention time 2.80 mins.
[0525] Example 134.
[0526] 4-Methoxy-5-(2-methoxyethoxy)-(3-nitrophenyl)aminobenzamide
Figure imgf000124_0002
[0527] To a mixture of 2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide (1.78g, 7.40 mmol) and pyridine (2.40 mL, 29.6 mmol) in CHCI3 (40 mL) was added 3-nitrobenzoyl chloride (1.44g, 7.8 mmol). The mixture was stirred at RT for 2.5 h upon which the mixture was concentrated in vacuo to give the desired product, which was used directly in the next step without purification.
[0528] Example 135.
[0529] 7-Methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one
123
NYOl 2225289 vl
Figure imgf000125_0001
[0530] The crude product from the previous step (7.4 mmol theoretically) was taken up in 2N NaOH (40 mL) and refluxed for 4 h. the mixture was allowed to cool to RT and neutralized to pH=7 with 6 and 1 N HC1. Upon neutralization a precipitate appeared which was collected via filtration and washed with Et20. The solid was azeotroped with toluene (2x5 OmL) to remove any residual water and dried under high vacuum to give 7-methoxy-6-(2- methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one as an off white solid (2.60g, 7.00 mmol, 95% over two steps). HPLC retention time 6.2 mins.
[0531] Example 136.
[0532] 4-Chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline
Figure imgf000125_0002
[0533] To a suspension of 7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazolin-4(3H)-one (1.65g, 4.46 mmol) in anhydrous THF (30mL) was added oxalyl chloride (1.3 mL, 14.7 mmol) and 2 drops of DMF. The mixture was refluxed for 2 h, upon which the mixture was concentrated in vacuo, taken up in CHCI3 (100 mL) and washed with sat. NaHC03 (3x 50 mL), water (2x50 mL) and brine (1x50 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to give 4-chloro-7-methoxy-6-(2- methoxyethoxy)-2-(3-nitrophenyl)quinazoline (1.18g, 3.03 mmol, 68%). HPLC retention time 9.55 mins.
[0534] Example 137.
[0535] terf-Butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4- ylamino)-lH-indazole-l-carboxylate
124
NYOl 2225289 vl
Figure imgf000126_0001
[0536] A mixture of 4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazoline (0.500g,1.28 mmol) and 5-amino-lH-indazole-l-carboxylate (0.314g, 1.34mmol) in iso-propanol (30 mL) was heated at 95°C for 30 minutes and at 95 °C for 8 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The cake was washed with iso-propanol and Et20, triturated with CH2C12 and EtOAc and dried in vacuo to give tert-Butyl 5 -(7-methoxy-6-(2-methoxyethoxy)-2-(3 -nitrophenyl)quinazolin-4-ylamino)- 1 H- indazole-l-carboxylate (0.560g, 0.955 mmol, 71%). MS 587 (M+1). HPLC retention time 7.21 mins.
[0537] Example 138.
[0538] terf-Butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin- 4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000126_0002
[0539] A mixture of fert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3- nitrophenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.560g, 0.95 mmol) and 10% Pd/C (ca. O.lg) in DME (lOOmL) and MeOH (lOOmL) was hydrogenated under a balloon of H2 at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to
125
NY01 2225289 vl give tert-butyl 5 -(2-(3 -aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)- lH-indazole-l-carboxylate as an off white solid (0.5 lOg, 0.92 mmol, 97%). HPLC retention time 5.62 mins.
[0540] Example 139.
[0541] 2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)- one
Figure imgf000127_0001
[0542] To mixture of 2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide (2.20g, 9.16 mmol) and 3-(benzyloxy)benzoyl chloride (2.50 g, 10.1 mmol) in CHCI3 (50 mL) was added pyridine 2.9 mL). The mixture was stirred at RT for 3 h, upon which the volatiles were removed in vacuo.
[0543] The residue was taken up in 2N NaOH (60 mL) and heated at reflux overnight. The mixture was allowed to cool to RT, upon which it was neutralized with IN HCl to pH=7. The mixture was allowed to stand for 2 h upon which the precipitate was collected via filtration. The solid was dried under high vacuum to give 2-(3-(benzyloxy)-phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4(3H)-one (3.28g, 7.58 mmol, 83%). MS 433 (M+l). HPLC retention time 7.41 mins.
[0544] Example 140.
[0545] 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline
Figure imgf000127_0002
126
NYOl 2225289 vl [0546] To a suspension of 2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4(3H)-one (3.28g, 7.58 mmol) in CH2CI2 (lOOmL) was added oxalyl chloride (2.20 mL, 24.8 mmol) and 2 drops of DMF. The mixture was stirred at RT for 6 h. An additional aliquot of oxalyl chloride (1.20 mL, 13.5 mmol) was added. Stirring was continued at RT overnight, upon which the mixture was concentrated in vacuo, taken up in CHCI3 (100 mL) and washed with sat. NaHC03 (3x 50 mL), water (2x50 mL) and brine (1x50 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to give 2-(3-(benzyloxy)phenyl)-4- chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.52g, 3.37 mmol, 45%). MS 451 (M+1 CI isotope pattern). HPLC retention time 10.84 mins. (10-95-13 method).
[0547] Example 141.
[0548] tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000128_0001
[0549] A mixture of 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2- methoxyethoxy)quinazoline (1.55g, 3.44 mmol) and tert-butyl 5-amino-lH-indazole-l- carboxylate (0.842g, 3.61 mmol) in iso-propanol (100 mL) was heated at 95 °C for 2h, upon which the an additional aliquot of tert-butyl 5-amino-lH-indazole-l-carboxylate (O.lOOg, 0.43 mmol) was added. Stirring was continued at 95 °C for a further 3 h upon which a third aliquot of tert-butyl 5-amino-lH-indazole-l-carboxylate (0.050g, 0.22 mmol) was added. Stirring was continued at 95 °C for a further 1 h upon which the mixture was allowed to cool to RT and the precipitate was collected via filtration. The solid was washed with iso-propanol and dried under vacuum to give tert- vXy\ 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-
127
NYOl 2225289 vl methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (2.35g, 3.44 mmol, 100%). MS 648 (M+l). HPLC retention time 7.79 mins.
[0550] Example 142.
[0551] tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000129_0001
[0552] A suspension of tert-butyl 5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (2.70g, 4.17 mmol) in MeOH (400 mL) and DME (200 mL) was added Pd/C (10%, wet, 0.500g) under an atmosphere of N2. The N2 was exchanged for H2 and the mixture was stirred under an atmosphere of H2 (balloon pressure) overnight. The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (2.25g, 4.04 mmol, 97 %). MS 558 (M+l). HPLC retention time 6.44 mins.
[0553] Example 143.
[0554] ieri-buty\ 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7-methoxy-6-(2- methoxyethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate
128
NY01 2225289 vl
Figure imgf000130_0001
[0555] To a solution of tert-Butyl 5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2- methoxyethoxy) quinazolin-4-ylamino)-lH-indazole-l -carboxylate (0.400g, 0.72 mmol) and 2- chloro-N-isopropylacetamide (0.107g, 0.79 mmol) in DMF (16 mL) was added K2CO3 (0.297g, 1.44 mmol). The mixture was heated at 80 °C for 72 h. The mixture was concentrated in vacuo and taken on directly into the next step. HPLC retention time 6.76mins.
[0556] Example 144.
[0557] 2-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2- yl)phenoxy)-N-isopropylacetamide
Figure imgf000130_0002
[0558] The crude tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7- methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate from the previous step was taken up in CH2CI2 (2 mL) and TFA (5 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and a portion of the residue was purified by preparative HPLC (10-35-90, 10-30-90, 0-15-90, 5-20-90 and 20-40-90 methods) to give 2-(3- (4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin-2-yl)phenoxy)-N- isopropylacetamide (0.039g, 68.4 μιηοΐ). MS 557 (M+l). HPLC retention time 5.48 mins.
129
NYOl 2225289 vl [0559] Example 145.
[0560] tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-lH- indazole-l-carboxylate
Figure imgf000131_0001
[0561] To a solution of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)- lH-indazole-l-carboxylate (0.57 g, 1.12 mmol) and DIEA (0.65 g, 5.03 mmol) in
dichloromethane (20 mL) was added butryl chloride (0.180 g, 1.69 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure and the residue was triturated with water causing formation of a precipitate. The solid was collected via filtration and dried under vacuum. The solid was suspended in anhydrous methanol (50 mL) and 28% ammonium hydroxide (0.9 mL) was added. The resulting reaction mixture was stirred at room temperature for 24 h. The volatiles were removed under reduced pressure and the residue upon trituration with ether gave tert-butyl 5-(2-(3- butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.354 g, 0.66 mmol, 59% over two steps). HPLC retention time 6.342 min.
[0562] Example 146.
[0563] tert-buty\ 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)quinazolin-4- ylamino)-lH-indazole-l-carboxylate
Figure imgf000131_0002
130
NY01 2225289 vl [0564] To a mixture of 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-lH- indazole-l-carboxylate (1.50 g, 2.79 mmol) and potassium carbonate (1.64 g, 11.8 mmol) in anhydrous DMF (5 mL) was added l-bromo-2-chloroethane (1.6 g, 11.2 mmol) The subsequent mixture was heated at 85°C for 4 h, upon which it was allowed to cool to RT and it was poured onto ice-water. A solid was precipitated out, which collected via filtration and dried under vacuum. The solid was purified via silica gel column chromatography to give tert-butyl 5-(2-(3- butyramidophenyl)-6-(2-chloroethoxy)-quinazolin-4-ylamino)- 1 H-indazole- 1 -carboxylate (0.94g, 1.56 mmol, 60%). HPLC retention time 7.479.
[0565] Example 147.
[0566] N-(3-(4-(lH-Indazol-5-ylamino)-6-(2-(pyrrolidin-l-yl)ethoxy)-quinazolin-2- yl)phenyl)butyramide
Figure imgf000132_0001
[0567] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2- chloroethoxy)quinazolin-4-ylamino)-l H-indazole- 1 -carboxylate (0.170g,0.282 mmol) in DMSO (2 mL) was added pyrrolidine (0.5 mL). The subsequent mixture was heated at 80 °C for 1.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH 8: 1).
[0568] The purified solid was taken up in HC1 (4M in 1,4 dioxane, 2 mL) and stirred at RT for 2 h. The volatiles were removed in vacuo to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2- (pyrrolidin-l-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide di-hydrochloride salt (0.120g, 0.198 mmol, 70% over two steps). MS 536 (M+l). HPLC retention time 4.61 mins.
131
NY01 2225289 vl [0569] Example 148.
[0570] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(piperidin-l-yl)ethoxy)-quinazolin-2- yl)phenyl)butyramide
Figure imgf000133_0001
[0571] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2- chloroethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.174g, 0.290 mmol) in DMSO (1.5 mL) was added piperidine (0.5 mL). The subsequent mixture was heated at 80 °C for 1.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH 8: 1).
[0572] The purified solid was taken up in HC1 (4M in 1 ,4 dioxane, 2 mL) and stirred at RT for 2 h. The volatiles were removed in vacuo to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2- (piperidin-l-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide di-hydrochloride salt (0.085g, 0.137 mmol, 47% over two steps). MS 550 (M+l). HPLC retention time 4.67 mins.
[0573] Example 149.
[0574] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2- yl)phenyl)butyramide
132
NY01 2225289 vl
Figure imgf000134_0001
[0575] A mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.167g, 0.31 mmol), l-bromo-2-methoxyethane (0.118g, 0.85 mmol) and K2C03 (0.172g, 1.25 mmol) in DMF (2 mL) was heated at 80 °C for 2.5 h. The mixture was allowed to cool to RT, upon which it was poured into water. A precipitate formed which was collected via filtration, dried under vacuum and purified via preparative TLC (Si02, CH2Cl2:MeOH 95:5).
[0576] The purified solid was taken up in HC1 (4M in 1,4 dioxane, 30 mL) and stirred at RT for 4.5 h. The volatiles were removed in vacuo and the residue was triturated with Et20 to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2-methoxyethoxy) quinazolin-2-yl)phenyl) butyramide hydrochloride (0.091g, 0.171mmol, 55% over two steps). MS 497 (M+1). HPLC retention time 5.547 mins.
[0577] Example 150.
[0578] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-((2- methoxyethyl)(methyl)amino)ethoxy)quinazolin-2-yl)phenyl)butyramide
Figure imgf000134_0002
133
NY01 2225289 vl [0579] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)- quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.150g, 0.250 mmol) in DMSO (2 mL) was added 2-methoxy-N-methylethanamine (0.5 mL). The subsequent mixture was heated at 75 °C for 1.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH 8: 1). Two compounds were isolated and combined.
[0580] The combined compounds were taken up in CH2C12 (2mL) and HC1 (4M in 1 ,4 dioxane, 25 mL) and stirred at RT for 7 h. The volatiles were removed in vacuo and the residue was washed with CH2C12 and Et20. The solid was dried under vacuum to give N-(3-(4-(lH- indazol-5-ylamino)-6-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-quinazolin-2- yl)phenyl)butyramide di-hydrochloride salt (0.1 OOg, 0.160 mmol, 64% over two steps). MS 554 (M+l). HPLC retention time 4.52 mins.
[0581] Example 151.
[0582] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(4-methylpiperazin-l-yl)ethoxy)- quinazolin-2-yl)phenyl)butyramide
Figure imgf000135_0001
[0583] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2- chloroethoxy)quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.150g, 0.250 mmol) in DMSO (2 mL) was added 1-methylpiperazine (0.5 mL). The subsequent mixture was heated at 85 °C for 2 h upon which an additional aliquot of 1-methylpiperazine (0.2 mL). Heating at 85 °C was continued for a further 1.5 h, upon which the mixture was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried
134
NY01 2225289 vl under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH:NH4OH 9: 1 :0.1) to give two compounds.
[0584] The combined compounds were taken up in CH2C12 (2mL) TFA (4mL) was added. The resulting mixture was stirred at RT for 4 h, upon which the volatiles were removed in vacuo. The residue was neutralized with sat. NaHC03 and extracted with THF (3x25 mL). The combined organics were washed with brine (1x20 mL), dried (Na2S04) and purified by preparative TLC (Si02, CH2Cl2:MeOH:NH4OH 9: 1 :0.1). The purified compound was taken up in CH2C12 (2 mL) and HC1 (4M in 1,4 dioxane, 10 mL) and was stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was triturated with Et20, filtered and dried under vacuum to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(4-methylpiperazin-l-yl)ethoxy)quinazolin-2- yl)phenyl)butyramide di-hydrochloride salt (0.067g, 0.105 mmol, 42% over two steps). MS 565 (M+l). HPLC retention time 4.30 mins.
[0585] Example 152.
[0586] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-l-yl)ethoxy)- quinazolin-2-yl)phenyl)butyramide
Figure imgf000136_0001
[0587] A mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4- ylamino)-lH-indazole-l-carboxylate (0.120g, 0.186 mmol), l-(2-bromoethyl)pyrrolidin-2-one (0.25 g, 1.31 mmol) and K2C03 (0.415g, 3.0 mmol) in DMF (1.5 mL) was heated at 75 °C for 5 h. The mixture was allowed to cool to RT, upon which it was poured into water. A precipitate formed which was collected via filtration, dried under vacuum and purified via preparative TLC (Si02, CH2Cl2:MeOH 95:5).
135
NYOl 2225289 vl [0588] The purified solid was taken up in HC1 (4M in 1,4 dioxane, 30 mL) and stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was washed with CH2C12 to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-l-yl)ethoxy)quinazolin-2- yl)phenyl)butyramide hydrochloride (0.025g, 0.043mmol, 23% over two steps). MS 550 (M+1). HPLC retention time 5.30 mins.
[0589] Example 153.
[0590] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(3-hydroxypyrrolidin-l-yl)ethoxy)- quinazolin-2-yl)phenyl)butyramide
Figure imgf000137_0001
[0591] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)- quinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.143 g, 0.240 mmol) in DMSO (1.5 mL) was added pyrrolidin-3-ol (0.5 mL). The subsequent mixture was heated at 75 °C for 1.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH NH4OH 9: 1 :0.1).
[0592] The purified solid was taken up in MeOH/CH2Cl2 (3 mL 1 : 1) and HC1 (4M in 1 ,4 dioxane, 2 mL) was added. The mixture was stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was washed with CH2C12 to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2-(3- hydroxypyrrolidin-l-yl)ethoxy)quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt (0.095g, 0.153 mmol, 64% over two steps). MS 552 (M+1). HPLC retention time 4.389 mins.
136
NY01 2225289 vl [0593] Example 154.
[0594] N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-l- yl)ethoxy)quinazolin-2-yl)phenyl)butyramide
Figure imgf000138_0001
[0595] A mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.200 g, 0.35 mmol), 2-(2- oxopyrrolidin-l-yl)ethyl methanesulfonate (0.300 g, 1.48 mmol) and K2CO3 (0.4 lOg, 2.97 mmol) in DMF (3 mL) was heated at 75 °C for 5 h. The mixture was allowed to cool to RT, upon which it was poured into water 50-80 mL). A precipitate formed which was collected via filtration, dried under vacuum and purified via preparative TLC (Si02, CH2Cl2:MeOH 95:5).
[0596] The purified solid was taken up in CH2Cl2/MeOH (3 mL 1 : 1 ) and HC1 (4M in 1 ,4 dioxane, 30 mL) was added. The mixture was stirred at RT for 5 h. The volatiles were removed in vacuo to give N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-l- yl)ethoxy)quinazolin-2-yl)phenyl)butyramide hydrochloride (0.108, 0.176 mmol, 50% over two steps). MS 580 (M+l). HPLC retention time 5.523 mins.
[0597] Example 155.
[0598] N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin- 2-yl)phenyl)butyramide
137
NYOl 2225289 vl
Figure imgf000139_0001
[0599] A mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.176g, 0.31 mmol), l-bromo-2- methoxyethane (0.120g, 0.86 mmol) and K2C03 (0.120 g, 2.8 mmol) in DMSO (1.5 mL) was heated at 75 °C for 1.5 h. The mixture was allowed to cool to RT, upon which it was poured into water. A precipitate formed which was collected via filtration and dried under vacuum.
[0600] The solid was taken up CH2C12 (8 mL) and HC1 (4M in 1 ,4 dioxane, 18 mL) was added. The subsequent mixture was stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was triturated with Et20 to give N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6- (2-methoxyethoxy)quinazolin-2-yl)phenyl) butyramide hydrochloride (0.09g, 0.160 mmol, 52 % over two steps). MS 527 (M+l). HPLC retention time 5.71 mins.
[0601] Example 156.
[0602] tei-i-Butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate
Figure imgf000139_0002
[0603] To a mixture of tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxy-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.855 g, 1.50 mmol) and potassium carbonate (0.950g, 6.87 mmol) in anhydrous DMF (8 mL) was added, l-bromo-2-chloroethane (0.89 g, 6.20 mmol) and resulting reaction mixture was stirred at 85°C for 3.5 h. The mixture was
138
NY01 2225289 vl allowed to cool to room temperature upon which, it was poured into ice-water. A solid was precipitated out, which was collected via filtration and dried under vacuum to give tert-butyl 5- (2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamino)-lH-indazole-l- carboxylate (0.864g, 1.37 mmol, 91%). HPLC retention time 7.694 min.
[0604] Example 157.
[0605] N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-l- yl)ethoxy)quinazolin-2-yl)phenyl)butyramide
Figure imgf000140_0001
[0606] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.170g, 0.299 mmol) in DMSO (2 mL) was added 1-methylpiperazine (0.5 mL). The subsequent mixture was heated at 85 °C for 2.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH:NH4OH 9: 1 :0.1). The purified compound was taken up in CH2C12 (2mL) and HC1 (4M in 1,4 dioxane, 10 mL) and stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was triturated with Et20, filtered and dried under vacuum to give N-(3-(4-(lH-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-l- yl)ethoxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt (0.085g, 0.128 mmol, 43% over two steps). MS 595 (M+l). HPLC retention time 4.337 mins.
[0607] Example 158.
[0608] N-(3-(4-(lH-indazol-5-ylamino)-6-(2-((S)-3-(dimethylamino)pyrrolidin-l- yl)ethoxy)-7-methoxyquinazolin-2-yl)phenyl)butyramide
139
NY01 2225289 vl
Figure imgf000141_0001
[0609] To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7- methoxyquinazolin-4-ylamino)-lH-indazole-l-carboxylate (0.180g, 0.300 mmol) in DMSO (2 mL) was added (S)-N,N-dimethylpyrrolidin-3-amine (0.5 mL). The subsequent mixture was heated at 80 °C for 1.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (Si02, CH2Cl2:MeOH:NH4OH 9: 1 :0.1).
[0610] The purified solid was taken up in HC1 (4M in 1,4 dioxane, 2 mL) and stirred at RT for 2 h. The volatiles were removed in vacuo to give N-(3-(4-(lH-indazol-5-ylamino)-6-(2- ((S)-3 -(dimethylamino)pyrrolidin- 1 -yl)ethoxy)-7-methoxyquinazolin-2-yl) phenyl) butyramide di-hydrochloride salt (0.090g, 0.132 mmol, 44% over two steps). MS 609 (M+l). HPLC retention time 4.30 mins.
[0611] Example 159
Figure imgf000141_0002
140
NY01 2225289 vl [0612] Example 160.
H
Figure imgf000142_0001
[0613] Example 161.
Figure imgf000142_0002
[0614] Example 162.
Figure imgf000142_0003
[0615] Example 163.
Figure imgf000142_0004
141
225289 vl [0616] Example 164.
H
Figure imgf000143_0001
[0617] Example 165.
H
Figure imgf000143_0002
[0618] Example 166.
H
Figure imgf000143_0003
[0619] Exampl 167.
Figure imgf000143_0004
142
225289 vl [0620] Example 168.
Figure imgf000144_0001
[0621] Example 169.
Figure imgf000144_0002
[0622] Example 170.
Figure imgf000144_0003
[0623] Example 171.
Figure imgf000144_0004
14301 2225289 vl [0624] Example 172.
Figure imgf000145_0001
[0625] Example 173.
Figure imgf000145_0002
[0626] Example 174.
Figure imgf000145_0003
[0627] Example 175.
Figure imgf000145_0004
144 2225289 vl [0628] Example 176.
H
Figure imgf000146_0001
[0629] Example 177.
H
Figure imgf000146_0002
[0630] Example 178.
H
Figure imgf000146_0003
[0631] Example 179.
H
Figure imgf000146_0004
225289 vl [0632] Example 180.
[0633] Example 181.
Figure imgf000147_0001
[0634] Example 182.
Figure imgf000147_0002
[0635] Example 183.
Figure imgf000147_0003
[0636] Example 184.
Figure imgf000147_0004
[0637] Example 185.
[0638] Example 186.
Figure imgf000147_0005
146225289 vl [0639] Example 187.
[0640] Example 188.
[0641] Example 189.
[0642] Example 190.
[0643] Example 191.
[0644] Example 192.
[0645] Example 193.
Figure imgf000148_0001
147225289 vl [0646] Example 194.
[0647] Example 195.
[0648] Example 196.
[0649] Example 197.
[0650] Example 198.
[0651] Example 199.
Figure imgf000149_0001
148225289 vl [0652] Example 200.
[0653] Example 201.
[0654] Example 202.
[0655] Example 203.
[0656] Example 204.
[0657] Example 205.
[0658] Example 206.
Figure imgf000150_0001
149225289 vl [0659] Example 207.
[0660] Example 208.
[0661] Example 209.
[0662] Example 210.
[0663] Example 211.
[0664] Example 212.
Figure imgf000151_0001
225289 vl [0665] Example 213.
Figure imgf000152_0001
Figure imgf000152_0002
Tetrahedron, 58, 2231, 2002 2. Pd/C/¾ 5A5
Figure imgf000152_0003
Dioxane:H20 (4:l)
Figure imgf000152_0004
151
2225289 vl [0666] The acid coupling partner 3-(2-methoxy-2-oxoethoxy)benzoic acid {A} was synthesized via a protection / de-protection protocol as follows. Commercially available 3- hydroxybenzoic acid was esterified following the literature protocol utilizing benzyl bromide and sodium carbonate in DMF at room temperature. See Tetrahedron, 58, 2231, 2002. The resulting phenol was then alkylated using methyl-2-bromoacetate in the presence of potassium carbonate in DMF at 80 °C. The benzyl protecting group was then removed via hydrogenation using palladium carbon conditions using the parr apparatus to provide 3-(2-methoxy-2- oxoethoxy)benzoic acid compound {A} .
[0667] Commercially available 2-amino-5-bromobenzonitrile was reduced using 1M- borane-THF solution according the literature procedure to provide 2-(aminomethyl)-4- bromobenzenamine. See WO 2008/014822. The bis-amine was then coupled with 3-(2- methoxy-2-oxoethoxy)benzoic acid compound {A} using EDC as a peptide coupling agent and DMAP as the base. The resultant crude product was then cyclized using phosphorous oxychloride to provide methyl 2-(3-(6-bromo-3,4-dihydroquinazolin-2-yl)phenoxy)acetate. Oxidation using DDQ provides the required quinazoline ring scaffold IN methyl 2-(3-(6- bromoquinazolin-2-yl)phenoxy)acetate {B} . The methyl ester in the phenoxy side chain of {B} was converted to the isopropyl amide by a series of hydrolysis (utilizing IN NaOH), followed by peptide coupling reaction (with isopropylamine as the nucleophile). The final compound was assembled via a Microwave promoted Suzuki conditions at 100 °C using PdCl2 dppf as the catalyst and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l- carboxylate as the boronate coupling partner and cesium carbonate as the base. Under the microwave conditions the Boc protecting group is removed and the final compound 2-(3-(6-(lH- pyrazol-4-yl)quinazolin-2-yl)phenoxy)-N-isopropylacetamide is obtained upon aqueous workup and ISCO purification.
HPLC: 6.2 mins (95 5 10 min method, YMC column)
LCMS: ESI (388.0, M+) 6.10 mins (95 5 10 min method, YMC column).
[0668] Example 214.
Figure imgf000153_0001
152
NY01 2225289 vl W
[0669] Example 215.
[0670] Example 216.
[0671] Example 217.
[0672] Example 218.
[0673] Example 219.
[0674] Example 220.
[0675] Example 221.
[0676] Example 222.
Figure imgf000154_0001
1531 2225289 vl [0677] Example 223.
[0678] Example 224.
[0679] Example 225.
[0680] Example 226.
[0681] Example 227.
[0682] Example 228.
[0683] Example 229.
[0684] Example 230.
Figure imgf000155_0001
225289 vl [0685] Example 231.
[0686] Example 232.
[0687] Example 233.
[0688] Example 234.
[0689] Example 235.
[0690] Example 236.
[0691] Example 237.
[0692] Example 238.
Figure imgf000156_0001
155225289 vl [0693] Example 239.
[0694] Example 240.
[0695] Example 241.
[0696] Example 242.
[0697] Example 243.
[0698] Example 244.
Figure imgf000157_0001
The following compounds were prepared according to the method of Example
[0699] Example 245. N-isopropyl-2-(3-(6-(pyridin-4-yl)quinazolin-2- yl)phenoxy)acetamide
156
NY01 2225289 vl
Figure imgf000158_0001
[0700] N-isopropyl-2-(3-(6-(pyridin-4-yl)quinazolin-2-yl)phenoxy)acetamide was synthesized following the representative Suzuki procedure above utilizing 2-(3-(6- bromoquinazolin-2-yl)phenoxy)-N-isopropylacetamide as the aryl bromide and pyridin-4- ylboronic acid as the boronic acid coupling partner.
HPLC retention time: 4.2 mins (95% pure @254nm).
LCMS: ES+ 399.2 (M+l).
[0701] Example 246. N-isopropyl-2-(3-(6-(pyridin-3-yl)quinazolin-2- yl)phenoxy)acetamide
Figure imgf000158_0002
[0702] N-isopropyl-2-(3 -(6-(pyridin-3 -yl)quinazolin-2-yl)phenoxy)acetamide was synthesized following the representative Suzuki procedure above utilizing 2-(3-(6- bromoquinazolin-2-yl)phenoxy)-N-isopropylacetamide as the aryl bromide and pyridin-3- ylboronic acid as the boronic acid coupling reagent.
HPLC retention time: 5.4 mins (95% pure @254nm).
LCMS: ES+ 399.2 (M+l).
[0703] Example 247. N-(l-methylpiperidin-4-yl)-2-(3-(6-(pyridin-4-yl)quinazolin-2- yl)phenoxy)acetamide
Figure imgf000158_0003
157
NY01 2225289 vl [0704] N-(l-methylpiperidin-4-yl)-2-(3-(6-(pyridin-4-yl)quinazolin-2- yl)phenoxy)acetamide was synthesized following the representative Suzuki procedure above utilizing 2-(3-(6-bromoquinazolin-2-yl)phenoxy)-N-(l-methylpiperidin-4-yl)acetamide as the aryl bromide and pyridin-3-ylboronic acid as the boronic acid coupling reagent.
HPLC retention time: 2.9 mins (95% pure @254nm).
LCMS: ES+ : 454.2 (M+l).
[0705] Example 248. N-q-methvlpiperidin-4-vl)-2-(3-(6-(pvridin-3-vl)quinazolin-2- yl)phenoxy)acetamide
Figure imgf000159_0001
[0706] N-(l-methylpiperidin-4-yl)-2-(3-(6-(pyridin-3-yl)quinazolin-2- yl)phenoxy)acetamide was synthesized following the representative Suzuki procedure above utilizing 2-(3-(6-bromoquinazolin-2-yl)phenoxy)-N-(l-methylpiperidin-4-yl)acetamide as the aryl bromide and pyridin-3-ylboronic acid as the boronic acid coupling reagent.
HPLC retention time: 3.3 mins (95% pure @254nm).
LCMS: ES+ : 454.2 (M+l).
[0707] Table 1 summarizes AMPK activation, CK2 inhibition, ROCK2 inhibition, and GLUT1 inhibition activities for the compounds exemplified above.
Figure imgf000159_0002
158
NY01 2225289 vl Table 1. - Activities
Ex. AMPK CK2 ROCK2 GLUT1 activation inhibition inhibition inhibition
48 + + + +
189 + - -
190 + +
191 +
192 + +
193 + +
194 + + +
195 +
196 + +
197 + - + +
198 + - -
199 + +/- +
200 + + +
201 + + +
202 + + +
203 + + -
204 + + +
205 + + + -
206 + -
207 + -
208 + + +
209 + - - +
210 + - - +
211 + - -
212 + - -
213 + - -
214 + +
215 + - +
216 + - Table 1. - Activities
Ex. AMPK CK2 ROCK2 GLUT1 activation inhibition inhibition inhibition
217 + -
218 + -
219 + -
220 + -
221 -
222
223 + -
224 + -
225 + -
226
227
228 +
229 + +
230 + -
231 -
232 +/- -
233 + -
234 + -
235 - -
236 - -
237 + -
238 + -
239 + -
240 - -
241 + -
242 + -
243 - - [0708] Cell culture: HT1080 cells (human fibrosarcoma line, ATCC #CCL-121) were grown in a Growth Media containing MEM media (ATCC #30-2003) with 1 g/1 glucose, 10% fetal bovine serum (Gibco/Invitrogen #16140) and 1% penicillin- streptomycin (Gibco/Invitrogen #15070). To plate the cells for assays, the cells growing in T 175 plates were washed with D- PBS (Gibco/Invitrogen #14040), trypsinized for 5-10 minutes at 37°C with TrypLE
(Gibco/Invitrogen #12604) and suspended at 250,000 cells/ml with Growth Media. 200 μΐ of the cells were transferred to each well of a 96 well tissue culture treated microtiter plate (Becton Dickinson #353072 for glucose consumption and Perkin Elmer #6005181 for 2-deoxyglucose transport) and the cells were incubated at 37°C overnight.
[0709] Glucose Consumption Assay: The media in the microtiter wells was replaced with 240 μΐ of Growth Media with compounds plus 0.2% DMSO or just 0.2% DMSO and the cells were incubated for various time points (20 hours for routine screening). 10 μΐ of the supernatant was removed for glucose determination using a glucose assay kit (Sigma- Aldrich #GAHK20).
[0710] [3H]-2-Deoxyglucose Uptake Assay: [3H]-2-Deoxy-D-glucose uptake was measured in an Assay Buffer containing glucose free DMEM (Gibco/Invitrogen #11966) with 1 mM Na pyruvate (Gibco/Invitrogen #11360), 1% fetal bovine serum (ATCC #30-2020) and 25 mM HEPES (Gibco/Invitrogen). The wells were first washed with 280 μΐ D-PBS
(Gibco/Invitrogen 14040) and 245 μΐ/well of Assay Buffer containing varying concentrations of compounds and 0.2%> DMSO was added. The cells were incubated at room temperature for 30 minutes and 5 μΐ/well of 25 μθ/ιηΐ [3H]-2-deoxy-D-glucose (Perkin Elmer #NET32800) in Assay Buffer with 1.25 mM cold 2-deoxy-D-glucose (Sigma Aldrich #D6134) was added. After a 60 minute incubation, the assay was stopped by aspirating the media and washing each well twice with 280 μΐ D-PBS. 50 μΐ of EchoLume scintillation fluid (MP Biomedicals #882470) was added to each well and the plate was counted in a Perkin Elmer Microbeta Jet.
[0711] Example 249.
[0712] Compounds of the invention were tested in studies of Rho kinase inhibition (ROCKl and ROCK2), 2-deoxy-D-glucose uptake, glucose consumption, AMPK activation (phosphorylation), and ACC phosphorylation.
161
NY01 2225289 vl 2-DG Glucose
ROCK2
% inhib consumption
ROCK1 ROCK2 % inhib
Example @ % inhib @ 10μΜ pAMPK pACC
IC50 IC50 @
500 nM HT1080 cells
500 nM
C6 cells Assay 1 Assay 2
180 0.06 19% 18 12
181 .43 57 50 + +
182 >3 0.03, 87 75 + +
3.71
0.138
183 0.956 0.029, 89 86
0.64
0.046
184 0.3 44% 106 107
185 >10 0.03, 81 81
0.47
0.02 (57%@ (62%
ΙμΜ) @luM)
186 >10 0.19, 77 80
0.145
187 >10 0.071 0.085 120 107
188 0.132 0.462 107 98
48 0.082 0.302 >90 >90 + +
189 - - 0.491 56 65 + +
190 7.2 0.063 108 @ 101
3.1 60% 5 μΜ
3.73
191 100 93
192 0.84 44% 92 91
193 0.82 34% 75 76
194 0.84 46% 89 79 + +
195 107 94
(103% (90%
@ @
1 μΜ) 1 μΜ)
196 - 0.059 86 86
197 -7.0 0.108 99 97 + +
(77%
0.018
@
1 μΜ)
198 -0.049 29% 32 41 + +
162
01 2225289 vl 2-DG Glucose
ROCK2
% inhib consumption
ROCK1 ROCK2 % inhib
Example @ % inhib @ 10μΜ pAMPK pACC
IC50 IC50 @
500 nM HT1080 cells
500 nM
C6 cells Assay 1 Assay 2
199 102% 93% + +
@ 6 μ @ 6 μ
M M
0.38 36%
(56% (60%
@ @
1 μΜ) 1 μΜ)
200 0.64 60% 74 86
201 >10 0.67 78 107 + +
202 - 0.182 8% 71 74 + +
203 >3 μηι 0.07 40 51 + +
204 0.92 43% 6 92 + +
205 >10 0.026 >3 38 42 + +
206 0.64 17 23 + +
207 - - -0.14 + +
208 >10 1.3 81 72 + +
10.00
2.23
209 - - 0.22 78 72 + +
210 8.11 102% 102% + +
(86% (86%
0.143
@ @
1 μΜ) 1 μΜ)
211 - - 39 41 + +
212 >10 1.31 16 33 + +
213 10% @ 9% @ + +
5 μΜ 5 μιη
214 - - 53 77 + +
215 27% @ 27 + +
5 μΜ
216 7 + +
163
01 2225289 vl [0713] Example 250. Activation of AMPK.
[0714] HT1080 cells were treated with compounds of the invention or a known AMPK activator. Phosphothreonine antibodies were used to assess phosphorylation of threonine 172 of the a-subunit of AMPK by the upstream kinase, AMPK kinase. Phosphoserine antibodies was used to assess specific phosphorylation of skeletal muscle acetyl-CoA carboxylase (ACC) at the activity-modulating AMPK target site (Ser79). Compounds 48 and 196 (10 μΜ) induced substantial phosphorylation (activation) of AMPK and downstream phosphorylation
(inactivation) of ACC at Ser79. (Fig. 1). The level of phosphorylation was substantially greater than AICAR (500 μΜ) which served as a positive control.
[0715] Example 251. Selectivity - Compound 48 demonstrated activity against 3 targets in addition to AMPK: ROCK2, CK2, and GLUTl uptake. (Fig. 2). Otherwise, 10 μΜ Compound 48 was tested using a Novascreen panel of receptors and ion channels and found not to modulate their activity. 10 μΜ Compound 48 was also inactive against a panel of kinases including PKC, PKA, MAP, MLCK, and PKG as well as an Upstate panel of 212 kinases (ACG, CMGC, TK, TKL, STE, CAMK, and CK1 families. 30 μΜ Compound 48 was inactive against mTOR kinase.
[0716] Example 252. HT1080 fibrosarcoma cells were incubated with various concentrations of Compound 48, 2 mM AICAR (a known GLUTl inhibitor) and DMSO (vehicle control). As shown in Fig. 3, activation of AMPK by Compound 48 was specific
(phosphorylation of Thrl72) and dose dependent. The dose dependent response in ACC phosphorylation is depicted in Fig. 4.
[0717] Example 253. Human skeletal muscle cells were incubated with various concentrations of Compound 48, 1 mM or 2 mM AICAR (GLUTl inhibitor) and DMSO (vehicle control). Activation of AMPK by Compound 48 was specific (phosphorylation of Thrl72) and dose dependent (Fig. 5).
[0718] Example 254. Human adipocytes were incubated with various concentrations of Compound 48, and DMSO (vehicle control). As shown in Fig. 6, activation of AMPK by Compound 48 was specific (phosphorylation of Thrl72) and dose dependent. AMPK activation was not observed in hepatocytes.
164
NY01 2225289 vl [0719] Example 255. AMPK activation by Compound 48 is rapid and reversible. Fig. 7 shows the time course of AMPL activation in HT-1080 cells. AMPK phosphorylation at Thrl72 was observed within 15 min. after treatment with Compound 48. In contrast, activation of AMPK by AICAR was not evident until 1 hour after treatment. AMPK activation by Compound 48 is also reversible. One set of HT-1080 cells (controls) was incubated with DMSO, 10 μΜ Compound 48, or 2 mM AICAR and examined for AMPK phosphorylation and ACC
phosphorylation after 3, 4, or six hours (controls). A second set of HT-1080 cells was incubated with DMSO, 10 μΜ Compound 48, or 2 mM AICAR for 2 hours, washed, and sampled after an additional 1, 2, or 4 hours. One hour following removal of Compound 48, AMPK
phosphorylation at Thrl72 and ACC phosphorylation at Ser79 were greatly diminished. (Fig. 8).
[0720] Example 256. [AMP]/[ATP] ratio. Cells expressing high levels of GLUT1 were treated with Compound 48. In tumor cells treated with Compound 48, a significant increase in the [AMP]/[ATP] ratio was observed, along with increased levels of AMP. No increase was observed in muscle cells. (Fig. 9).
[0721] Example 257. AMPK activation was observed in a fibrosarcoma tumor line deprived of glucose. HT1080 cells were incubated with glucose or transferred to glucose-free media. Cells under both conditions were then treated with Compound 48, AICAR, or DMSO (control). (Fig. 10). AMPK and ACC activation by Compound 48 was rapid, with significant phosphorylation observed within 15 minutes of treatment. Glucose deprivation alone resulted in observable ACC phosphorylation only after 2-6 hr. following the shift to glucose-free media, and increased AMPK phosphorylation was not observed. A separate experiment was performed using glucose-pyruvate free media. Under those conditions, rapid activation of AMPK was observed.
[0722] Example 258. CAM kinase kinase inhibition reduces AMPK phosphorylation below basal levels. Compound 48 overcomes the inhibition and raises phosphorylation amounts. Downstream ACC phosphorylation is consistent with increased AMPK activity. (Fig. 11)
[0723] Example 259. Diet-induced obese (DIO) C57/BL/6J mice were fed a high fat diet with and without Compound 48 (90 mg/kg) or low-fat chow. In mice supplemented with Compound 48, there was an immediate increase in fatty acid oxidation, which was maintained throughout the dosing period (8 days). (Fig. 12).
165
NY01 2225289 vl [0724] Example 260. Ob knockout mice (ob/ob) were fed a high fat diet with or without Compound 48. Administration of Compound 48 resulted in improvements in serum insulin, blood glucose, serum cholesterol, visceral fat, liver weight, and serum ALT. (Fig. 13).
[0725] Example 261. AMPK activation (phosphorylation) is correlated with GLUT1 inhibition in muscle and adipose tissue. However, in hepatocytes, GLUT1 inhibition, for example using Compound 48, is not accompanied by increased AMPK phosphorylation.
Moreover, glucose uptake is not inhibited by cytochalasin or phloretin/phlorizin. The likely explanation is that hepatocytes utilize GLUT2 instead. Nevertheless, liver steatosis (fatty liver), which is observed in Apo E_/~ mice maintained on a high fat diet is not observed in those mice when the high fat diet is supplemented with Compound 48. This is attributed to ROCK2 inhibition, which blocks differentiation of hepatic stellate cells.
[0726] Example 262. Kidney function was assessed by measuring urinary protein excretion. Administration of Compound 48 greatly reduced urinary protein/albumin levels, indicating reduced impairment of kidney function (Fig. 14).
166
NY01 2225289 vl

Claims

WE CLAIM:
1. A compound having the form la I:
Figure imgf000168_0001
wherein:
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-0-(CH2Vcycloalkyl, -(CH2) ,-0-C(=0)-NR13R14, -NH-C(=0)-(CH2) ,-NR13R14,
-NH-C(=0)-X-R15, -(CH2) S(=0)2NR13R14, -0-(CH2) S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, -(C C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, - (Ci-C6 alkyl)-NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents
167
NYOl 2225289 vl independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(d-C6 alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4;
168
NYOl 2225289 vl R3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfiuoro lower alkyl, -(CH2)«-NR33R34, -Y-R32, -0-(CH2)«-C02R32,
-0-(CH2)«-C(=0)NR33R34, -0-(CH2)e-heteroaiyl, -0-(CH2)e-cycloalkyl,
-0-C(=0)-(CH2)«-NR33R34, -0-(CH2)c-NR33R34, -NH-C(=0)-(CH2)«-NR33R34,
-NH-C(=0)-Y-R35, -NH-C(=0)-(CH2)«-NR33R34;
R32 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR36R37, -(Ci-C6 alkyl)-C(=0)NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfiuoro alkyl; R33 and R34 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-C(=0)NR36R37, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfiuoro alkyl;
or R33 and R34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfiuoro alkyl;
Y is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R35 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR36R37, -C02R38, -0-(CH2yC02R38, and -C(=0)NR36R37,
R36 and R37 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfiuoro alkyl;
169
NYOl 2225289 vl or R and R may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
R4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR43R44, -Z-R42, -0-(CH2)fl-C02R42,
-0-(CH2)«-C(=0)NR43R44, -0-(CH2)iJ-heteroaryl, -0-(CH2)iJ-cycloalkyl,
-0-C(=0)-(CH2)iJ-NR43R44, -0-(CH2)c-NR43R44, -NH-C(=0)-(CH2)i2-NR43R44,
-NH-C(=0)-Z-R45, -NH-C(=0)-(CH2)fl-NR43R44;
R42 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR46R47, -(Ci-C6 alkyl)-C(=0)NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-C(=0)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R43 and R44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
Z is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
170
NYOl 2225289 vl R is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR46R47, -C02R48, -0-(CH2yC02R48, and -C(=0)NR46R47;
R46 and R47 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R46 and R47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
each a is independently selected from 0 to 6;
each b is independently selected from 0 to 6;
each c is independently selected from 2 to 6;
R5 is selected from the group consisting of H and Ci-C6 alkyl;
R6 is selected from the group of formula (I A) and (IB):
Figure imgf000172_0001
wherein
Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
171
NYOl 2225289 vl Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
m is 0 to 2;
wherein Formula IA is not
Figure imgf000173_0001
2. The compound of claim 1, wherein R6 is formula IA,
and formula IA is selected from the group consisting of:
Figure imgf000173_0002
wherein the dotted line represents an optional double bond; Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
3. The compound of claim 1, wherein R6 is formula IB,
and formula IB is selected from the group consisting of:
Figure imgf000173_0003
172
NY01 2225289 vl
Figure imgf000174_0001
wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
4. The compound of claim 1, having the formula II:
Figure imgf000174_0002
wherein R1, R2, R3, R4, R5, R7, Ring B, Q, n and m are as stated for formula I.
5. The compound of claim 4, having the formula III:
Figure imgf000174_0003
wherein R1, R2, R3, R4, and n are as stated for formula I.
6. The compound of claim 1, having I the formula V:
173
NY01 2225289 vl
Figure imgf000175_0001
wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro alkyl; and R1, R2, R3, R4, and n and are as stated for formula I.
A compounds having the formula X:
Figure imgf000175_0002
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-O-iCH^-cycloalkyl, -(CH2) ,-0-C(=0)-NR13R14, -NH-C(=0)-(CH2) ,-NR13R14,
-NH-C(=0)-X-R15, -(CH2) S(=0)2NR13R14, -0-(CH2) S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-C(=0)NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-C6 alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(d-C6 alkyl), -(C C6 alkyl)-C(=0)NR16R17,
174
NYOl 2225289 vl aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-C8 alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
-(Ci-C6 alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
175
NYOl 2225289 vl x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4;
R3 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR33R34, -Y-R32, -0-(CH2)«-C02R32,
-0-(CH2)«-C(=0)NR33R34, -0-(CH2)e-heteroaiyl, -0-(CH2)e-cycloalkyl,
-0-C(=0)-(CH2)fl-NR33R34, -0-(CH2)c-NR33R34, -NH-C(=0)-(CH2)fl-NR33R34,
-NH-C(=0)-Y-R35, -NH-C(=0)-(CH2)«-NR33R34;
R32 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR36R37, -(Ci-C6 alkyl)-C(=0)NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R33 and R34 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(d-C6 alkyl), -(C C6 alkyl)-NR36R37, -(Ci-C6 alkyl)-C(=0)NR36R37, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R33 and R34 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
Y is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R35 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-C6 alkyl)-NR36R37, -C02R38, -0-(CH2yC02R38, and -C(=0)NR36R37,
176
NYOl 2225289 vl R and R independently selected from the group consisting of H, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R36 and R37 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R38 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR36R37,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
R4 is selected from the group consisting of H, lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, perfluoro lower alkyl, -(CH2)«-NR43R44, -Z-R42, -0-(CH2)fl-C02R42,
-0-(CH2)fl-C(=0)NR43R44, -0-(CH2)iJ-heteroaryl, -0-(CH2)iJ-cycloalkyl,
-0-C(=0)-(CH2)iJ-NR43R44, -0-(CH2)c-NR43R44, -NH-C(=0)-(CH2)i2-NR43R44,
-NH-C(=0)-Z-R45, -NH-C(=0)-(CH2)«-NR43R44;
R42 is selected from the group consisting of Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-Ce alkyl)-NR46R47, -(Ci-C6 alkyl)-C(=0)NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(C C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-C(=0)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo,
177
NYOl 2225289 vl Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R43 and R44 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
alternatively, R3 and R4 may be taken together to form a 5- or 6-membered ring;
Z is selected from a covalent bond, O, NH, and Ci-C6 alkyl;
R45 is selected from the group consisting of H, aryl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl),
-(Ci-Ce alkyl)-NR46R47, -C02R48, -0-(CH2yC02R48, and -C(=0)NR46R47;
R46 and R47 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
or R46 and R47 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR46R47,
-(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0-(Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl;
each a is independently selected from 0 to 6;
each b is independently selected from 0 to 6;
each c is independently selected from 2 to 6;
R5 is selected from the group consisting of H and Ci-C6 alkyl;
R6 is selected from the group of formula (I A) and (IB):
178
NYOl 2225289 vl
Figure imgf000180_0001
wherein
Ring A is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R7 is selected from the group consisting of halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
m is 0 to 2.
8. The compound of claim 7 having the formula XI:
Figure imgf000180_0002
wherein R1, R2, R3, R4, and n are as stated for formula X.
9. The compound of claqim 7, having the formula XII:
179
NY01 2225289 vl
Figure imgf000181_0001
wherein R1, R2, and n are as stated above for formula X.
A compounds having the formula XV
Figure imgf000181_0002
wherein
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-0-(CH2) cycloalkyl, -(CH2) O-C(=0)-NR13R14, -NH-C(=0)-(CH2) NR13R14,
-NH-C(=0)-X-R15, -(CH2) ,-S(=0)2NR13R14, -0-(CH2) ,-S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, -(C C6 alkyl)-0-(C C6 alkyl)-0-(C C6 alkyl),
-(Ci-C6 alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring
180
NYOl 2225289 vl containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6, alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, oxo, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-O-(aryl),
-(Ci-Ce alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17,
-(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(C C6 alkyl)-NR16R17, -(C C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
181
NYOl 2225289 vl y is selected from 0 to 6;
z is selected from 2 to 6;
each R9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
e is selected from 0 to 3;
Ring A is a 5- or 6-membered ring which may comprise 0-3 ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy;
R" is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; and
is selected from 0 to 2.
11. The compound of claim 10, wherein the Ring A of compound XV is a 5- or 6-membered aromatic ring which comprises 1-3 ring heteroatoms selected from N, O and S.
12. The compound of claim 10, wherein Ring A of compound XV has the structure selected from the group consisting of:
Figure imgf000183_0001
wherein Rla is selected from the group consisting of H, lower alkyl, and perfluoro lower alkyl; and R2a is selected from the group consisting of H and lower alkyl.
13. The compounds of claim 10 having the formula XVI:
182
NY01 2225289 vl
Figure imgf000184_0001
wherein
R1 is selected from the group consisting of aryl, -(CH2) NR13R14, -X-R12,
-(CH2) C(=0)NR13R14, -0-(CH2) C02R12, -0-(CH2) C(=0)NR13R14,
-0-(CH2) cycloalkyl, -(CH2) O-C(=0)-NR13R14, -NH-C(=0)-(CH2) NR13R14,
-NH-C(=0)-X-R15, -(CH2) ,-S(=0)2NR13R14, -0-(CH2) ,-S(=0)2NR13R14,
-NH-S(=0)2-X-R15, -NH-(CH2) NR13R14; -0-(CH2) heteroaryl,
-0-C(=0)-(CH2) NR13R14, and -0-(CH2)z-NR13R14;
R12 is selected from the group consisting of Ci-Cio alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, -(C C6 alkyl)-0-(C C6 alkyl)-0-(C C6 alkyl),
-(Ci-C6 alkyl)-NR16R17, aryl, -(Ci-C6 alkyl)-O-(aryl), aralkyl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R13 and R14 are independently selected from the group consisting of H, Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(=0)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, -S02-alkyl, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R13 and R14 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, C3-C7 cycloalkyl, -S02-alkyl, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
X is selected from a covalent bond, O, and Ci-C6 alkyl;
R15 is selected from the group consisting of H, Ci-Cg alkyl, aryl, heteroaryl, C3-C7 cycloalkyl,
-(Ci-Ce alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-O-(aryl),
183
NYOl 2225289 vl -(Ci-Ce alkyl)-C(=0)NR16R17, -0-(CH2)x-C02R18, -0-(CH2)x-C(=0)NR16R17, -(Ci-C6 alkyl)-C02R18; and a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
R16 and R17 independently selected from the group consisting of H, Ci-C8 alkyl, C2-C8 alkenyl, C2-Cg alkynyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoro alkyl;
or R16 and R17 may be taken together form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkyl, C2-C6 alkenyl, Ci-C6 alkoxy, oxo, hydroxy, cyano and C1-C3 perfluoro alkyl;
R18 is selected from the group consisting of aryl, aralkyl, heteroaryl, Ci-C6 alkyl, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl), -(Ci-C6 alkyl)-NR16R17, -(Ci-C6 alkyl)-0-(Ci-C6 alkyl)-0- (Ci-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, Ci-C6 alkoxy, hydroxy, cyano and C1-C3 perfluoroalkyl;
x is selected from 1 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R9 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
e is selected from 0 to 3;
Ring B is a 5- or 6-membered ring which may comprise 0-2 additional ring heteroatoms selected from N, O and S, and may be unsubstituted or may be substituted with 1 to 3 substituents selected from halo, CN, oxo, hydroxy, amino, lower alkyl, perfluoro lower alkyl, and lower alkoxy; and
Q is selected from CH or N.
184
NYOl 2225289 vl The compound of claim 10 havin the formula XVII
Figure imgf000186_0001
wherein R1, R9 and e are as stated above for formula XV.
15. A method of treating neoplastic diseases comprising administering to a patient an effective amount of a compound according to claims 1 to 14.
16. A method of treating metabolic diseases comprising administering to a patient an effective amount of a compound according to claims 1 to 14.
17. A method of treating neoplastic diseases comprising administering to a patient an effective amount of a compound of the formula IV:
Figure imgf000186_0002
wherein R1, R2, R3, R4, n and m are as stated above for formula I.
18. A method of treating metabolic diseases comprising administering to a patient an effective amount of a compound of the formula IV:
185
NY01 2225289 vl
Figure imgf000187_0001
NY012225289 vl
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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014512347A (en) * 2011-03-28 2014-05-22 エフ．ホフマン−ラ ロシュ アーゲー Thiazolopyrimidine compounds
WO2014080291A2 (en) * 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
JP2015533125A (en) * 2012-10-05 2015-11-19 カドモン コーポレイション，リミティド ライアビリティ カンパニー RHO kinase inhibitor
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
WO2016068099A1 (en) * 2014-10-28 2016-05-06 塩野義製薬株式会社 Heterocyclic derivative having ampk activating effect
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9833453B2 (en) 2013-02-20 2017-12-05 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
JP2018518518A (en) * 2015-06-26 2018-07-12 カドモン コーポレイション，リミティド ライアビリティ カンパニー Glucose uptake inhibitor
US10112935B2 (en) 2015-02-27 2018-10-30 Lycera Corporation Indazolyl thiadiazolamines and related compounds for inhibition of Rho-associated protein kinase and the treatment of disease
WO2018201006A1 (en) * 2017-04-28 2018-11-01 Kadmon Corporation, Llc Treatment of inflammatory conditions and autoimmune diseases with glucose uptake inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10266536B2 (en) 2013-03-14 2019-04-23 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US10329282B2 (en) 2017-06-30 2019-06-25 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10556898B2 (en) 2016-08-26 2020-02-11 Lycera Corporation Indazolyl-1,2,4-thiadiazolamines and related compounds for inhibition of Rho-associated protein kinase and the treatment of disease
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10729691B2 (en) 2015-06-26 2020-08-04 Kadmon Corporation, Llc Treatment of infectious diseases with glucose uptake inhibitors
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
WO2021129589A1 (en) * 2019-12-27 2021-07-01 广东东阳光药业有限公司 New crystal form of kd-025 and preparation method therefor
CN114105976A (en) * 2020-08-28 2022-03-01 杭州邦顺制药有限公司 Selective ROCK2 kinase inhibitors
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
US20220363648A1 (en) * 2018-06-25 2022-11-17 Kadmon Corporation , Llc Glucose Uptake Inhibitors
EP3932404A4 (en) * 2019-03-01 2022-11-30 Beijing Tide Pharmaceutical Co., Ltd. Method for treating fatty liver disease and/or steatohepatitis
US11542256B2 (en) 2017-09-03 2023-01-03 Angion Biomedica Corp. Vinylheterocycles as Rho-associated coiled-coil kinase (ROCK) inhibitors
US11773083B2 (en) 2020-07-22 2023-10-03 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030083327A1 (en) * 2000-09-15 2003-05-01 Robert Davies Pyrazole compounds useful as protein kinase inhibitors
US20040097503A1 (en) * 2000-12-12 2004-05-20 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US20080207614A1 (en) * 2004-12-31 2008-08-28 Sk Chemicals Co., Ltd. Quinazoline derivatives for the treatment and prevention of diabetes and obesity
US20100048567A1 (en) * 2008-04-16 2010-02-25 Portola Pharmaceuticals Inc. Inhibitors of syk and JAK protein kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030083327A1 (en) * 2000-09-15 2003-05-01 Robert Davies Pyrazole compounds useful as protein kinase inhibitors
US20040097503A1 (en) * 2000-12-12 2004-05-20 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US20080207614A1 (en) * 2004-12-31 2008-08-28 Sk Chemicals Co., Ltd. Quinazoline derivatives for the treatment and prevention of diabetes and obesity
US20100048567A1 (en) * 2008-04-16 2010-02-25 Portola Pharmaceuticals Inc. Inhibitors of syk and JAK protein kinases

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014512347A (en) * 2011-03-28 2014-05-22 エフ．ホフマン−ラ ロシュ アーゲー Thiazolopyrimidine compounds
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9605003B2 (en) 2011-07-19 2017-03-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
EP2903618B1 (en) 2012-10-05 2022-06-01 Kadmon Corporation, LLC Rho kinase inhibitors
CN113773308A (en) * 2012-10-05 2021-12-10 卡德门企业有限公司 RHO kinase inhibitors
JP2015533125A (en) * 2012-10-05 2015-11-19 カドモン コーポレイション，リミティド ライアビリティ カンパニー RHO kinase inhibitor
CN105120869A (en) * 2012-10-05 2015-12-02 卡德门企业有限公司 Rho kinase inhibitors
US10183931B2 (en) 2012-10-05 2019-01-22 Kadmon Corporation, Llc Rho kinase inhibitors
CN113620933A (en) * 2012-10-05 2021-11-09 卡德门企业有限公司 RHO kinase inhibitors
EP4116293A3 (en) * 2012-10-05 2023-03-29 Kadmon Corporation, LLC Rho kinase inhibitors
JP2019034949A (en) * 2012-10-05 2019-03-07 カドモン コーポレイション，リミティド ライアビリティ カンパニー RHO kinase inhibitor
CN113637007A (en) * 2012-10-05 2021-11-12 卡德门企业有限公司 RHO kinase inhibitors
US10696660B2 (en) 2012-10-05 2020-06-30 Kadmon Corporation, Llc Rho kinase inhibitors
EP2903618A4 (en) * 2012-10-05 2017-05-10 Kadmon Corporation, LLC Rho kinase inhibitors
US9815820B2 (en) 2012-10-05 2017-11-14 Kadmon Corporation, Llc Rho kinase inhibitors
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
WO2014080291A2 (en) * 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
WO2014080291A3 (en) * 2012-11-21 2014-09-12 Rvx Therapeutics Inc. Biaryl derivatives as bromodomain inhibitors
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9861637B2 (en) 2012-12-21 2018-01-09 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US9598367B2 (en) 2012-12-21 2017-03-21 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US10966987B2 (en) 2013-02-15 2021-04-06 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9877970B2 (en) 2013-02-15 2018-01-30 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10398703B2 (en) 2013-02-15 2019-09-03 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9833453B2 (en) 2013-02-20 2017-12-05 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10758539B2 (en) 2013-02-20 2020-09-01 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9861634B2 (en) 2013-02-20 2018-01-09 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US10285991B2 (en) 2013-02-20 2019-05-14 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US11369611B2 (en) 2013-02-20 2022-06-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10266536B2 (en) 2013-03-14 2019-04-23 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
US10717739B2 (en) 2013-03-14 2020-07-21 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11446306B2 (en) 2013-06-21 2022-09-20 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10772892B2 (en) 2013-06-21 2020-09-15 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10010556B2 (en) 2013-06-21 2018-07-03 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10618906B2 (en) 2013-11-01 2020-04-14 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11713323B2 (en) 2013-11-01 2023-08-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10160765B2 (en) 2013-11-01 2018-12-25 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10975090B2 (en) 2013-11-01 2021-04-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2016068099A1 (en) * 2014-10-28 2016-05-06 塩野義製薬株式会社 Heterocyclic derivative having ampk activating effect
US10123994B2 (en) 2014-10-28 2018-11-13 Shionogi & Co., Ltd. Heterocyclic derivative having AMPK-activating activity
CN107108521A (en) * 2014-10-28 2017-08-29 盐野义制药株式会社 Hete rocyclic derivatives with AMPK activations
JPWO2016068099A1 (en) * 2014-10-28 2017-08-10 塩野義製薬株式会社 Heterocyclic derivatives having AMPK activating action
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10112935B2 (en) 2015-02-27 2018-10-30 Lycera Corporation Indazolyl thiadiazolamines and related compounds for inhibition of Rho-associated protein kinase and the treatment of disease
CN108349910A (en) * 2015-06-26 2018-07-31 卡德门企业有限公司 glucose uptake inhibitor
US10273248B2 (en) 2015-06-26 2019-04-30 Kadmon Corportion, LLC Glucose uptake inhibitors
US10729691B2 (en) 2015-06-26 2020-08-04 Kadmon Corporation, Llc Treatment of infectious diseases with glucose uptake inhibitors
EP3313825A4 (en) * 2015-06-26 2019-03-13 Kadmon Corporation, LLC Glucose uptake inhibitors
JP2018518518A (en) * 2015-06-26 2018-07-12 カドモン コーポレイション，リミティド ライアビリティ カンパニー Glucose uptake inhibitor
US11028079B2 (en) 2015-11-25 2021-06-08 Convergene, Llc Small molecule BET bromodomain inhibitors and uses thereof
AU2016361441B2 (en) * 2015-11-25 2021-08-12 Convergene Llc Bicyclic BET bromodomain inhibitors and uses thereof
EP4050005A1 (en) * 2015-11-25 2022-08-31 Convergene Llc Bicyclic bet bromodomain inhibitors and uses thereof
US10508106B2 (en) 2015-11-25 2019-12-17 Convergene Llc Bicyclic BET bromodomain inhibitors and uses thereof
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
US10556898B2 (en) 2016-08-26 2020-02-11 Lycera Corporation Indazolyl-1,2,4-thiadiazolamines and related compounds for inhibition of Rho-associated protein kinase and the treatment of disease
US11104685B2 (en) 2016-09-08 2021-08-31 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11021487B2 (en) 2016-09-08 2021-06-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10626121B2 (en) 2016-09-08 2020-04-21 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11071735B2 (en) 2017-04-28 2021-07-27 Kadmon Corporation, Llc Treatment of inflammatory conditions and autoimmune diseases with glucose uptake inhibitors
WO2018201006A1 (en) * 2017-04-28 2018-11-01 Kadmon Corporation, Llc Treatment of inflammatory conditions and autoimmune diseases with glucose uptake inhibitors
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US10329282B2 (en) 2017-06-30 2019-06-25 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
US11542256B2 (en) 2017-09-03 2023-01-03 Angion Biomedica Corp. Vinylheterocycles as Rho-associated coiled-coil kinase (ROCK) inhibitors
US20220363648A1 (en) * 2018-06-25 2022-11-17 Kadmon Corporation , Llc Glucose Uptake Inhibitors
EP3932404A4 (en) * 2019-03-01 2022-11-30 Beijing Tide Pharmaceutical Co., Ltd. Method for treating fatty liver disease and/or steatohepatitis
CN114746412A (en) * 2019-12-27 2022-07-12 广东东阳光药业有限公司 Novel crystal form of KD-025 and preparation method thereof
WO2021129589A1 (en) * 2019-12-27 2021-07-01 广东东阳光药业有限公司 New crystal form of kd-025 and preparation method therefor
US11773083B2 (en) 2020-07-22 2023-10-03 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts
US11932627B2 (en) 2020-07-22 2024-03-19 Teva Pharmaceuticals International Gmbh Solid state forms of Belumosudil and Belumosudil salts
CN114105976A (en) * 2020-08-28 2022-03-01 杭州邦顺制药有限公司 Selective ROCK2 kinase inhibitors
CN114105976B (en) * 2020-08-28 2024-04-26 杭州邦顺制药有限公司 Selective ROCK2 kinase inhibitors

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