WO2010130638A1 - Sulfonamide compounds, pharmaceutical compositions and uses thereof - Google Patents

Sulfonamide compounds, pharmaceutical compositions and uses thereof Download PDF

Info

Publication number
WO2010130638A1
WO2010130638A1 PCT/EP2010/056225 EP2010056225W WO2010130638A1 WO 2010130638 A1 WO2010130638 A1 WO 2010130638A1 EP 2010056225 W EP2010056225 W EP 2010056225W WO 2010130638 A1 WO2010130638 A1 WO 2010130638A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
disease
unsubstituted
compound according
compound
Prior art date
Application number
PCT/EP2010/056225
Other languages
French (fr)
Inventor
Steven Taylor
David James Hallett
Robert James Townsend
Original Assignee
Evotec Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Evotec Ag filed Critical Evotec Ag
Publication of WO2010130638A1 publication Critical patent/WO2010130638A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • 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

Definitions

  • the present invention relates to a class of sulfonamide compounds and pharmaceutical compositions comprising such compounds. Also provided are methods for preventing and/or treating conditions in mammals, that are causally related to potassium channel activity or can be alleviated by modulating potassium channel activity, such as (but not limited to) autoimmune disorders, inflammatory disorders, immune-mediated disorders, or other disorders, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, transplant rejection, and delayed type hypersensitivity using the compounds and pharmaceutical compositions provided herein.
  • autoimmune disorders inflammatory disorders
  • immune-mediated disorders or other disorders, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythemato
  • Potassium channels represent a complex class of voltage-gated ion channels from both functional and structural standpoints. Their functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. In general, four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). [0004] KCNA3 encodes the voltage-gated K V 1.3 potassium channel, which is shaker-related and is expressed in lymphocytes (T and B lymphocytes), the central nervous system, fat and other tissues.
  • T and B lymphocytes lymphocytes
  • the functional channel is composed of four identical K V 1.3 ⁇ -sub units.
  • the K V 1.3 potassium channel regulates membrane potential and thereby indirectly influences calcium signaling in human effector- memory T cells (Grissmer S. et al, Proc. Natl. Acad. Sci. U.S.A. 87(23): 9411-5; DeCoursey T.E. et al, Nature 307 (5950): 465-8; Chandy K.G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest. 111 (11): 1703-13).
  • Effector memory T cells are important mediators of multiple sclerosis, Type I diabetes mellitus, psoriasis, and rheumatoid arthritis.
  • the K v l .3 channel is expressed in T and B lymphocytes in a distinct pattern that depends on the state of lymphocyte activation and differentiation.
  • naive and central memory T cells increase expression of the Kc a 3.1 channel per cell
  • effector-memory T cells increase expression of the K V 1.3 channel.
  • human B cells naive and early memory B cells express small numbers of K V 1.3 and Kc a 3.1 channels when they are quiescent, and augment Kc a 3.1 expression after activation.
  • class-switched memory B cells express high numbers of K V 1.3 channels per cell (about 1500/cell) and this number increases after activation (Chandy K. G.
  • K v l .3 promotes the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G et al (2004) Trends Immunol 25:565-569). [0006] K v l .3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation.
  • K V 1.3 and K Ca 3.1 regulate membrane potential and calcium signaling of T cells. Calcium entry through the CRAC channel is promoted by potassium efflux through the K v l .3 and Kc a 3.1 potassium channels.
  • Blockade of K V 1.3 channels in effector-memory T cells suppresses activities like calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.
  • Effector- memory T cells were originally defined by their expression of cell surface markers, and can enter sites of inflammation in non- lymphoid tissues, while not participating in the process of lymphoid recirculation carried out by most other lymphocytes. TEMs have been shown to uniquely express high numbers of the K V 1.3 potassium channel and depend on these channels for their function.
  • K V 1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues.
  • K V 1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the K Ca 3.1 channel and are therefore protected from the effect of K V 1.3 blockade. Suppressing the function of these cells by selectively blocking the K V 1.3 channel offers the potential for highly effective therapy of autoimmune diseases with minimal effects on either beneficial immune responses or other organs (Chandy K.G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest. I l l (11): 1703-13; Beeton C. et al, Proc. Natl. Acad. Sci.
  • K v l .3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes.
  • the apoptotic protein Bax has been suggested to insert into the outer membrane of the mitochondria and occlude the pore of K V 1.3 via a lysine residue.
  • K V 1.3 blockade may be one of many mechanisms that contribute to apoptosis (Szabo I. et al, J. Biol. Chem. 280(13): 12790-8; Szabo I. et al., Proc. Natl. Acad. Sci. U.S.A. 105(39): 14861-6).
  • Autoimmune Disease is a family of disorders resulting from tissue damage caused by a malfunctioning immune system, affecting tens of millions of people worldwide. Such diseases may be restricted to a single organ, as e.g. in multiple sclerosis and Type I diabetes mellitus, or may involve multiple organs as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative and typically includes anti-inflammatory and immunosuppressive drugs. The severe side effects of many of these therapies have fueled a continuing search for more effective and selective immunosuppressive drugs.
  • Multiple sclerosis is a disease caused by autoimmune damage to the central nervous system including the brain, which affects roughly two and a half million people worldwide. Symptoms include muscle weakness and paralysis, and the disease can progress rapidly and unpredictably and may eventually lead to death. Treatment usually includes the use of anti-inflammatory and immunosuppressive drugs which have potentially severe side effects.
  • K V 1.3 has been shown to be highly expressed in autoreactive effector memory T cells from MS patients (Wulff, H et al (2003) J Clin Invest 111 :1703-1713; Rus H et al (2005) PNAS 102:11094-11099). Animal models of multiple sclerosis have been successfully treated using blockers of the K V 1.3 potassium channel. In patients with multiple sclerosis, disease- associated myelin-specific T cells from the blood are predominantly co-stimulation independent effector- memory T cells that express high numbers of K V 1.3 channels. T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the K V 1.3 channel (Wulff H. et al, J. Clin. Invest. 111(11): 1703-13; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A. 103(46): 17414-9).
  • Type 1 diabetes mellitus is a disease caused by autoimmune destruction of insulin- producing cells in the pancreas, resulting in high blood sugar and other metabolic abnormalities.
  • Type 1 diabetes mellitus affects close to four hundred thousand people in the US alone, and is usually diagnosed before age 20. Its long-term consequences may include blindness, nerve damage and kidney failure, and left untreated is rapidly fatal. Treatment involves life-long administration of insulin or pancreas transplantation, both of which may entail serious side effects (Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A. 103(46): 17414-9).
  • K v l .3 is also considered a therapeutic target for the treatment of obesity, for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus, and for preventing bone resorption in periodontal disease (Tucker K. et al, Int. J. Obes. (Lond) 32(8): 1222-32; Xu J. et al, Hum. MoI Genet. 12(5): 551-9; Xu J. et al, Proc. Natl. Acad. Sci. U.S.A. 101(9): 3112-7; Valverde P. et al, J. Dent. Res 84(6): 488-99; T suitser O. et al, J. Clin. Endocrinol. Metab. 91(2): 654-8).
  • K V 1.3 blockers are thus potential therapeutic agents as immunosuppressants or immune system modulators including for the prevention of graft rejection, and the treatment of autoimmune and inflammatory disorders.
  • K V 1.3 modulators may be used alone or in conjunction with other immunosuppressants, such as selective Kc a 3.1 Blockers or cyclosporin, in order to achieve synergism and/or to reduce toxicity, especially of cyclosporin.
  • immunosuppressants such as selective Kc a 3.1 Blockers or cyclosporin
  • 5,494,895 discloses the use of a thirty-one amino acid peptide, scorpion peptide margatoxin, as a selective inhibitor and probe of K V 1.3 channels present in human lymphocytes, and also as an immunosuppressant. However the use of this compound is limited by its potent toxicity.
  • US Patent No. 6,051,590 describe the use of the triterpene, correolide and related compounds as immunosuppressants in the treatment of conditions in mammals affected or facilitated by K V 1.3 inhibition.
  • US Patent 6,077,680 describes DNA segments and proteins of derived from sea anemone species, more particularly ShK toxin from Stichodactyla helianthus. The ShK toxin was found to block K v l.l, K V 1.3, K V 1.4 and K v 1.6, but a mutant ShK-K22DAP found to selectively block K V 1.3. Unfortunately the mutant was not sufficiently stable for clinic use.
  • ShK toxin has been shown to both prevent and treat experimental autoimmune encephalomyelitis in Lewis rats, an animal model for human multiple sclerosis (Beeton C. et al 2001, Proc. Natl. Acad, Sci. U.S.A. 98:13942-7), by selectively targeting T cells chronically activated by the myelin antigen, MBP (myelin basic protein).
  • MBP myelin antigen
  • chronically activated encephalitogenic rat T cells express a unique channel phenotype characterised by high expression of K v 1.3 channels (approximately 1500 per cell) and low numbers of K ca 3.1 channels (approximately 120 per cell). This channel phenotype is distinct from that seen in quiescent and acutely activated cells and may be a functionally relevant marker for chronically activated rat T-lymphocytes.
  • Sulfonamide compounds, and pharmaceutical compositions thereof having potency and selectivity in the prevention and treatment of conditions that have been associated with autoimmune disorders, immune-mediated disorders, inflammatory disorders, or other disorders, or conditions which benefit clinically from immunosuppressants, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, contact dermatitis, obesity, graft- versus host disease, transplant rejection, and delayed type hypersensitivity.
  • immunosuppressants including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, contact dermatitis, obesity, graft- versus host disease, transplant rejection, and delayed type hypersensitivity.
  • compounds, pharmaceutical compositions and methods provided are useful to treat, prevent or ameliorate a range of conditions in mammals such as, but not limited to, immune disorders and autoimmune diseases of various genesis or etiology, for example rheumatoid arthritis, multiple sclerosis, psoriasis, type 1 diabetes, graft-versus host disease, transplant rejection.
  • immune disorders and autoimmune diseases of various genesis or etiology, for example rheumatoid arthritis, multiple sclerosis, psoriasis, type 1 diabetes, graft-versus host disease, transplant rejection.
  • compounds, pharmaceutical compositions and methods provided are useful as antiinflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, asthma, myocardial infarction, neurodegenerative disorders, inflammatory bowel disease and autoimmune disorders, renal disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, and lipid disorders.
  • compounds are provided that have formula I: wherein each W and Z is independently CH or N; X is CO, SO, or SO 2 ; each R 1 and R 2 is independently selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ml is 1 or 2; provided that the compound is not i) N-(phenylmethyl)-N-[4-(l -piperidinylcarbonyl)phenyl]-benzenesulfonamide, or ii) N-[[4-(2,4-dioxo-5-thiazolidinyl)phenyl]methyl]-N-[3-(4- morpholinylcarbonyl)phenyl]-2-naphthalenesulfonamide; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
  • R 1 is substituted or unsubstituted 6-10 membered aryl or heteroaryl.
  • compositions comprising a fused heterocyclic compound provided herein, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • compounds provided herein useful in the pharmaceutical compositions and treatment methods disclosed herein can be pharmaceutically acceptable as prepared and used.
  • methods for preventing, treating or ameliorating a condition from among those listed herein, and particularly, such condition as may be associated with immune-mediated reactions, autoimmune conditions, or other conditions which are modulated by immunosuppression, as may be associated with, e.g., multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, and transplant rejection, which method comprises administering to a mammal in need thereof an amount of one or more of the compounds provided herein, or pharmaceutical composition thereof, effective to prevent, treat or ameliorate the condition.
  • a condition as may be associated with immune-mediated reactions, autoimmune conditions, or other conditions which are modulated by immunosuppression, as may be associated with, e.g., multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity,
  • methods for preventing, treating or ameliorating a condition that gives rise to immune responses or that relates to imbalances in the maintenance of basal activity of the immune system in a mammal.
  • the compounds provided herein have use as potassium channel modulators for the treatment of immune-mediated diseases or autoimmune conditions of various geneses or etiology, for example multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, and transplant rejection.
  • the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified.
  • methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below.
  • provided are methods of making enantiomerically pure compounds according to formula 1 by asymmetric synthesis.
  • provided are methods of making enantiomerically pure compounds according to formula 1 by chiral resolution.
  • Acute disseminated encephalomyelitis ADAM
  • Addison's disease Allopecia areata
  • Alzheimers disease Ankylosing spondylitis
  • Antiphospholipid antibody syndrome Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmune polyendocrine/polyglandular syndrome, Autoimmune thrombocytoipenia purpura, BaIo disease, Behcet disease, Bullous pemphigoid, Cardiomyopathy, Celiac sprue-dermatitis herpetiformis, Chronic fatigue immune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinating neuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinin disease, CREST syndrome
  • a still further object of this invention is to provide pharmaceutical compositions that are effective in the treatment or prevention of a variety of disease states, including the diseases associated with the central nervous system, cardiovascular conditions, chronic pulmonary obstructive disease COPD), inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, and other diseases where an immunological inflammatory component or autoimmune component is present.
  • COPD chronic pulmonary obstructive disease
  • inflammatory bowel disease rheumatoid arthritis
  • osteoarthritis osteoarthritis
  • Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
  • analogue means one analogue or more than one analogue.
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, C 1 -C 8 alkyl, C 3 -
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • 'acyl' groups are -C(O)H, -C(O)-C 1 -C 8 alkyl, -C(0)-(CH 2 ) t (C 6 -Cio aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 )t((C 3 -Ci 0 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted AcyP or 'Substituted AlkanoyP refers to a radical -C(O)R 21 , wherein R 21 is independently
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, C 1 -C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 - Ci 0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein.
  • Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • Particular exemplary 'acylamino' groups are -NR 24 C(O)-C 1 -C 8 alkyl, -NR 24 C(O)-(CH 2 )t(C 6 -C 10 aryl), -NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -NR 24 C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or C 1 -C 8 alkyl.
  • 'Substituted Acylamino' refers to a radical -NR 25 C(O)R 26 , wherein:
  • R 25 is independently
  • R 26 is independently
  • 'Acyloxy' refers to a radical -OC(O)R 27 , where R 27 is hydrogen, C 1 -C 8 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are -C(O)H, -C(O)-C 1 -C 8 alkyl, -C(O)-(CH 2 )t(C 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(0)-(CH 2 )t(C 3 -Cio cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyloxy' refers to a radical -OC(O)R 28 , wherein R 28 is independently
  • alkoxy' refers to the group -OR 29 where R 29 is C 1 -C 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl- S(O) 2 -.
  • Exemplary 'substituted alkoxy' groups are -O-(CH 2 ) t (C 6 -Ci 0 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, and OCH 2 CH 2 NMe 2 .
  • Alkoxycarbonyl' refers to a radical -C(O)-OR 30 where R 30 represents an C 1 -C 8 alkyl, C 3 -
  • alkoxycarbonyl groups are C(O)O-C 1 -C 8 alkyl, -C(O)O- (CH 2 )t(C 6 -C 10 aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 )t(C 3 -C 10 cycloalkyl), and - C(O)O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR 31 where R 31 represents:
  • 'Aryloxycarbonyl' refers to a radical -C(O)-OR where R represents an C 6 -C 10 aryl, as defined herein. Exemplary 'aryloxycarbonyl' groups is -C(O)O-(C 6 -C 1 0 aryl).
  • Aryloxycarbonyl refers to a radical -C(O)-OR where R represents
  • Heteroaryloxycarbonyl' refers to a radical -C(O)-OR 34 where R 34 represents a 5-10 membered heteroaryl, as defined herein.
  • An exemplary "aryloxycarbonyl” group is -C(O)O-(5-10 membered heteroaryl).
  • 'Substituted Heteroaryloxycarbonyl' refers to a radical -C(O)-OR 5 where R 5 represents:
  • heteroaryl substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 - C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxyl.
  • 'Alkoxycarbonylamino' refers to the group -NR 36 C(O)OR 37 , where R 36 is hydrogen, C 1 -
  • R 37 is C 1 -C 8 alkyl, C3-C 1 0 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
  • Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms.
  • Exemplary straight chained groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso- butyl, t-butyl and isoamyl.
  • Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (- O-acyl or -OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH- C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)-NR 2 ), aminocarbonyloxy (-O-C(O)-NR 2) , aminosulfonyl
  • 'substituted alkyl' refers to a C 1 -C 8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR “' SO 2 R “ , -SO 2 NR R “ , -C(O)R “ , -C(O)OR “ , -OC(O)R “ , -NR “' C(O)R “ , - C(O)NR R “ , -NR “ R “ , or -(CR “' R “” ) m OR " ; wherein each R " is independently selected from H, C 1 -C 8 alkyl, -(CH 2 )t(C 6 -C 10 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 )t(C 3 -C 10 cycloalkyl), and -(CH 2 ) t (4-10
  • 'Alkylene' refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., - CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substituted alkylene' refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O)
  • alkenyF refers to monovalent olefmically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • Substituted alkenyl' refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O
  • alkenylene' refers to divalent olefmically unsaturated hydrocarbyl groups particularly having up to about 11 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • AlkynyF refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 11 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation.
  • Substituted alkynyF refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkynyl group
  • 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R 38 ) 2 where each R 38 is independently selected from:
  • -N(R 38 ) 2 is an amino group.
  • exemplary 'substituted amino' groups are -NR 39 -C 1 -C 8 alkyl, -NR 39 -(CH 2 ) t (C 6 -Ci 0 aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 - (CH 2 ) t (C3-Cio cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 39 independently represents H or C 1 -C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.
  • Alkylamino' refers to the group -NHR 40 , wherein R 40 is C 1 -C 8 alkyl.
  • Substituted Alkylamino' refers to the group -NHR 41 , wherein R 41 is C 1 -C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, Cs-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkylarylamino refers to the group -NR 44 R 45 , wherein R 44 is aryl and R 45 is C 1 -C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -
  • Cio cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Arylamino' means a radical -NHR 46 where R 46 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl as defined herein.
  • Arylamino' refers to the group -NHR 47 , wherein R 47 is independently selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 48 R 49 , wherein each of R 48 and R 49 are independently selected from C 1 -C 8 alkyl.
  • 'Substituted Dialkylamino' refers to the group -NR 50 R 51 , wherein each of R 59 and R 51 are independently selected from C 1 -C 8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalk
  • 'Diarylamino' refers to the group -NR 52 R 53 , wherein each of R 52 and R 53 are independently selected from C 6 -C 10 aryl.
  • 'Aminosulfonyl'or 'Sulfonamide' refers to the radical -S(O 2 )NH 2 .
  • Substituted aminosulfonyl or “substituted sulfonamide” refers to a radical such as -
  • each R 54 is independently selected from:
  • 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
  • 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.
  • Particularly aryl groups include phenyl
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, cyano, hydroxy, C 1 -C 8 alkoxy, and amino.
  • Examples of representative substituted aryls include the following
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, C 1 - C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one
  • R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, substituted aryl, 5-10 membered heteroaryl.
  • Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
  • 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
  • Arylalkyloxy refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(O)NH 2 .
  • Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R 62 ) 2 wherein each R 62 is independently
  • Exemplary 'Substituted Carbamoyl' groups are -C(O) alkyl, -C(0)NR 64 -(CH 2 )t(C 6 -Cio aryl),
  • each R 64 independently represents H or C 1 -C 8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Carboxy' refers to the radical -C(O)OH.
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent
  • 'Cyano' refers to the radical -CN.
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative heteroaryls include the following: wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each W is selected from C(R 66 ) 2 , NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, C 1 -C 8 alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • heterocycloalkyl refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • thiomorpholine and its S-oxide and S,S-dioxide particularly thiomorpholine
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • heterocycloalkyl groups are shown in the following illustrative examples: wherein each W is selected from CR 6 , C(R 6 ') 2 , NR 67 , O and S; and each Y is selected from NR b , O and
  • R 67 is independently hydrogen, C 1 -C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl,
  • heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O) 2 -alkyl, and -S(O) 2 - aryl.
  • Substituting groups include carbonyl or thiocarbonyl which provide,
  • 'Nitro' refers to the radical -NO 2 .
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • NO 2 , N 2 , -N 3 , -S(O) 2 O-, -S(O) 2 OH, -S(O) 2 R 68 , -OS(O 2 )O-, -OS(O) 2 R 68 , -P(O)(O ) 2 , -P(O)(OR 68 )(O-),
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR 72 SO 2 R 73 , -SO 2 NR 73 R 72 , -C(O)R 73 , -C(O)OR 73 , -OC(O)R 73 , - NR 72 C(O)R 73 , -C(O)NR 73 R 72 , -NR 73 R 72 , -(CR 72 R 72 ) m OR 72 , wherein, each R 73 is independently selected from H, Ci-C 8 alkyl, -(CH 2 )t(C 6 -C 10 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 X(C 3 -Ci 0 cycloalkyl), and -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Each R independently represents H or C 1 -C 6 alkyl.
  • Substituted sulfanyl refers to the group -SR 74 , wherein R 74 is selected from:
  • Exemplary 'substituted sulfanyl' groups are -S-(C 1 -C 8 alkyl) and -S-(C 3 -C 10 cycloalkyl),
  • (CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • the term 'substituted sulfanyl' includes the groups
  • 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR 75 where R 75 is a C 1 -C 8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
  • 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR 76 where R 76 is a C 1 -C 8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR 77 where R 77 is a C 3 -Ci 0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
  • 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR 78 where R 78 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR 79 where R 79 is a C 6 -Cio aryl group as defined herein.
  • 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR 80 where R 80 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfmyl' refers to the group -S(O)R 81 , wherein R 81 is selected from:
  • Exemplary 'substituted sulfmyl' groups are -S(O)-(C 1 -C 8 alkyl) and -S(O)-(C 3 -Ci 0 cycloalkyl), -S(O)-(CH 2 )t(C 6 -C 10 aryl), -S(O)-(CH 2 ) t (5-10 membered heteroaryl), -S(O)-(CH 2 )t(C 3 -C 10 cycloalkyl), and -S(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -
  • substituted sulfmyl includes the groups 'alkylsulfmyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfmyl',
  • Alkylsulfmyl refers to a radical -S(O)R 82 where R 82 is a C 1 -C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
  • Substituted Alkylsulfmyl refers to a radical -S(O)R 83 where R 83 is a C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfmyl' refers to a radical -S(O)R 84 where R 84 is a C 3 -Ci 0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfmyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C 3 -Ci 0 cycloalkyl.
  • cycloalkylsulfmyl refers to the group -S(O)R 85 where R 85 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfmyl' refers to a radical -S(O)R 86 where R 86 is a C 6 -Ci 0 aryl group as defined herein.
  • Heteroarylsulfmyl refers to a radical -S(O)R 87 where R 87 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfonyl refers to the group -S(O) 2 R 88 , wherein R 88 is selected from:
  • Exemplary 'substituted sulfonyl' groups are -S(O) 2 -(CrC 8 alkyl) and -S(O) 2 -(C 3 -Ci 0 cycloalkyl), -S(O) 2 -(CH 2 )t(C 6 -C 10 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -S(O) 2 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • Alkylsulfonyl refers to a radical -S(O) 2 R 89 where R 89 is an C 1 -C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
  • 'Substituted Alkylsulfonyl' refers to a radical -S(O) 2 R 90 where R 90 is an C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfonyl' refers to a radical -S(O) 2 R 91 where R 91 is a C 3 -Ci 0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
  • cycloalkylsulfonyl refers to the group -S(O) 2 R 92 where R 92 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfonyl' refers to a radical -S(O) 2 R 93 where R 93 is an C 6 -Ci 0 aryl group as defined herein.
  • Heteroarylsulfonyl refers to a radical -S(O) 2 R 94 where R 94 is an 5-10 membered heteroaryl group as defined herein.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O) 2 OR 95 , wherein R 95 is selected from:
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(C 1 -C 8 alkyl) and -S(O) 2 -O-(C 3 -Ci 0 cycloalkyl), -S(O) 2 -O-(CH 2 ) t (C 6 -Ci 0 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 X(C 3 -Ci 0 cycloalkyl), and -S(O) 2 -O-(CH 2 ) ⁇ -IO membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 8
  • 'Aminocarbonylamino' refers to the group -NR 96 C(O)NR 96 R 96 where each R 96 is independently hydrogen C 1 -C 8 alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R 96 groups, when attached to the same N, are joined to form an alkylene group.
  • 'BicycloaryF refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • 'Bicycloheteroaryl' refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like.
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
  • 'Cycloalkylalkyl refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
  • HeterocycloalkylalkyF refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
  • 'CycloalkenyF refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefmic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • cycloalkenyl refers to those groups recited in the definition of "substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S
  • Cycloalkenyl' refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefmic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • 'Ethylene' refers to substituted or unsubstituted -(C-C)-.
  • 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality.
  • Examples of 'hydrogen bond donor' groups include -OH, -NH 2 , and -NH-R 97 and wherein R 97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
  • 'Dihydroxyphosphoryl' refers to the radical -PO(OH) 2 .
  • substituted herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
  • 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH 2 .
  • substituted herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
  • 'Nitrogen-Containing HeterocycloalkyF group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Therapeutically effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” includes that amount of a compound or composition that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • ranges are referred to herein, for example but without limitation, C 1 -C 8 alkyl
  • the citation of a range should be considered a representation of each member of said range.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 HID, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the "R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term "enantiomerically pure R- compound” refers to at least about 80% by weight R-compound and at most about 20% by weight S- compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R- compound or at most about 0.1% by weight S-compound.
  • the weights are based upon total weight of compound.
  • the term “enantiomerically pure S- compound” or “S-compound” refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R- compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound.
  • the weights are based upon total weight of compound.
  • an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S- compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • R R
  • S S
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • provided herein are compounds useful for preventing and/or treating a broad range of conditions, particularly immune-mediated disorders and autoimmune diseases, among them, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis, systemic lupus erythamatosus, obesity, bone diseases, graft rejection, and other immunologically-active disorders or conditions in mammals.
  • immune-mediated disorders and autoimmune diseases among them, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis, systemic lupus erythamatosus, obesity, bone diseases, graft rejection, and other immunologically-active disorders or conditions in mammals.
  • each W and Z is independently CH or N;
  • X is CO, SO, or SO 2 ;
  • each R 1 and R 2 is independently selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ml is 1 or 2; provided that the compound is not i) N-(phenylmethyl)-N-[4-(l -piperidinylcarbonyl)phenyl]-benzenesulfonamide, or ii) N-[[4-(2,4-dioxo-5-thiazolidinyl)phenyl]methyl]-N-[3-(4- morpholinylcarbonyl)phenyl]-2-naphthalenesulfonamide; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
  • R 1 is substituted or unsubstituted ary
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is substituted or unsubstituted heteroaryl.
  • R 1 is substituted or unsubstituted pyridyl.
  • each of W and Z is CH.
  • W is N; and Z is CH.
  • W is CH; and Z is N.
  • the compound is according to formula Ha, lib, Hc, Hd, He, or Hf: lie Nf
  • X, R , R , and ml are as described for formula I; nl is selected from 1-5 and each R 4 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfony
  • X is SO 2 .
  • R 2 is as described for formula I; nl and R 4 are as described for formula Ha-IIf; and R 3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
  • R 3 is cycloalkyl
  • R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R is cyclohexyl
  • R is heterocycloalkyl.
  • R is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
  • R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with alkyl, or hydroxy.
  • R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with aryl or heteroaryl.
  • R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with benzimidazol-2-yl.
  • IVa, IVb, IVc, IVd, IVe, or IVf
  • Y is CH or N;
  • R 2 is as described for formula I; nl and R 4 are as described for formula Ha-IIf;
  • R 3a is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
  • R 3a is COR 3b ; and R 3b is alkoxy or heterocycloalkyl.
  • R 3a is H, Me, or benzyl.
  • R a is phenyl, unsubstituted or substituted with Me, Et, i-Pr, CF 3 , OMe, OCHF 2 , OCF 3 , Cl, F, CN and NO 2 .
  • R a is pyridyl, unsubstituted or substituted with Me, Et, i-Pr, CF 3 , OMe, OCHF 2 , OCF3, Cl, F, CN and NO 2 .
  • R a is imidazolyl, or benzimidazolyl.
  • R 3a is COR 3b .
  • R 3b is OMe, OEt, or O-i-Pr.
  • R 3b is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
  • nl is 1 and R 4 is selected from H, C 1 -
  • C 4 alkyl halo C 1 -C 4 alkyl, C 1 -C 4 alkoxy, dihalo C 1 -C 4 alkoxy, trihalo C 1 -C 4 alkoxy, CN, NO 2 , and halo.
  • nl is 1 and R 4 is selected from H, Me,
  • nl is 1 and R 4 is selected from 4-Me
  • nl is 1 and R 4 is selected from 4-Cl, or
  • R is phenyl or naphthalenyl.
  • R 2 is phenyl, unsubstituted or substituted with one or more groups selected from C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, C 1 -C 4 alkoxy, dihalo C 1 -
  • R is phenyl, unsubstituted or substituted with one or more groups selected from Me, Et, i-Pr, CF 3 , OMe, OCHF 2 , OCF 3 , Cl, F, CN and
  • R 2 is heteroaryl
  • R is pyridyl, benzothiophenyl, quinolinyl, isoquinolinyl, thiophenyl, or furanyl.
  • Vb, Vc, Vd, Ve, or Vf
  • each R 2a , R 4 is independently H, halo, C 1 -C 6 alkoxy; R 3a and Y are as described for formula IVa-
  • each R 2a , and R 4 is H.
  • each R 2a , and R 4 is independently H, Cl,
  • Y is CH or N; and R 3a is phenyl, benzimidazol-2-yl, benzyl, 2-pyridyl, 2-fluorophenyl, 1 -pyrrolidinyl, CO-piperidin-1-yl, or CO-OEt.
  • R 3a is phenyl, benzimidazol-2-yl, benzyl, 2-pyridyl, 2-fluorophenyl, 1 -pyrrolidinyl, CO-piperidin-1-yl, or CO-OEt.
  • prodrugs and derivatives of the compounds according to the formulae above are derivatives of the compounds provided herein, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds provided herein, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds provided herein are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Preferred are the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds provided herein.
  • the compounds provided herein are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include pref ⁇ lled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • a minor component from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffmic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil- in- water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • the compounds provided herein can also be administered by a transdermal device.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the above-described components for orally administrable, injectable or topically administrable compositions are merely representative.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) would be dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans and non-human mammals.
  • the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for use in such methods, and for the preparation of medicaments useful for such methods.
  • a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, myocardial infarction, inflammatory bowel disease and autoimmune disorders comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
  • a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves is provided herein.
  • the present compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache).
  • acute, inflammatory pain such as pain associated with osteoarthritis and rheumatoid arthritis
  • various neuropathic pain syndromes such
  • neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myo
  • the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds provided herein When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives.
  • Adminsitration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., the Synthetic Schemes below. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00251] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds provided herein may be prepared by the reaction of a chloro derivative with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative fused heterocyclics that have been listed hereinabove.
  • the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • the enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J.
  • an enantiomerically pure compound of formula 1 may be obtained by reaction of the racemate with a suitable optically active acid or base.
  • suitable acids or bases include those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entireties.
  • Enantiomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used.
  • the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
  • the diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid.
  • the other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.
  • enantiomerically pure compound can be separated from racemic compound by chiral chromatography.
  • Various chiral columns and eluents for use in the separation of the enantiomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
  • Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to CHIRALCEL® OB, CHIRALCEL® OB- H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following instrumentation: Shimadzu, Waters or Micromass ZMD, ZQ or LCT mass spectrometers with an Agilent, Waters or Polymer Labs UV and ELS detector.
  • the HPLC conditions are tabulated below.
  • Micromass MassLynxTM Operating Software with OpenLynxTM Browser were used for data acquisition, processing and reporting.
  • B Formic Acid (acetonitrile)
  • B Formic Acid (acetonitrile)
  • Ar is R 2 , Ar 1 is R 1 , and R 1 , R 1 , and R 3 are as described herein.
  • Ar is R 2 , Ar 1 is R 1 , and R 1 , R 1 , and R 3 are as described herein.
  • Ar is R 2 , Ar 1 is R 1 , and R 1 , R 1 , and R 3 are as described herein.
  • Ar is R , Ar is R , and R , R , and R are as described herein.
  • Ar is R 2 , Ar 1 is R 1 , and R 1 , R 1 , and R 3 are as described herein.
  • Ar is R 2 , Ar 1 is R 1 , and R 1 , R 1 , and R 3 are as described herein.
  • Compounds provided herein can be evaluated using cell-based assays such as electrophysiological assays, or can be evaluated in animal models of autoimmune disease and immune- mediated responses and conditions. Examples of assays are described below.
  • the compounds provided herein can be tested for antagonist activity at voltage-gated ion channels such as voltage-gated potassium channels by measuring their ability to affect channel opening or their ability to block permeation of ions through the channel pore in response to depolarizing voltage changes across the cell membrane.
  • Functional tests of channel activity include but are not limited to ion flux resulting from channel opening measured by electrophysiological methods. These methods can be used to evaluate channel function when the relevant ion channel is heterologously expressed in a mammalian or amphibian cells. These methods can also be used to evaluate compounds provided herein in rodent primary lymphocytes and other mammalian primary cells and cell lines that endogenously express the channel of interest.
  • Compounds can further be evaluated for their ability to bind the ion channel using biochemical approaches. Compounds can also be evaluated for their ability to modify lymphocyte signaling where the channels are known to have a role (e.g., cytokine production and cellular proliferation). Finally, compounds provided herein can be tested in vivo in animal models of immune- mediated processes and disorders and autoimmune diseases known to one skilled in the art, such as, for example, models of multiple sclerosis, arthritis, type I diabetes, and hypersensitivity in rodents or other mammals.
  • FMP membrane-potential sensitive fluorescent dye
  • the buffer system used was carefully selected to optimize the cell membrane potential and favour conditions where the number of ion channels in the open state would be at a maximum.
  • the FMP dye was re-suspended in 10 ml of assay buffer according to the supplier's protocol. Cell plates were washed using a standard 384 plate washer with assay buffer, incubated with dye, and diluted in assay buffer for 5 min before compound addition. Cell plates were subsequently incubated with compounds for 60min and different concentrations, after which time the change in fluorescent signal was measured.
  • Fluorescent recordings were performed on the Tecan Safire (Tecan, Crailsheim, Germany) using excitation and emission filters of 540 and 555 nm, respectively, and incorporating a bandwidth of 5 nm (Journal of Biomolecular Screening 2006:57-64).
  • CHO-cells stably expressing the ion channels were clamped at a holding potential (HP) of -80 mV, hyperpolarized to -90 mV to determine the leak current, and depolarized for 200 ms to +40 mV. Intersweep interval was 20 sec. Pulse-cycling rate was 0.1 Hz. The area under curve (charge) during 200 ms of depolarization was analyzed. An initial period of 20 stimuli was recorded to determine a biexponential fit of endogenous current rundown. The total charge obtained is plotted against antagonist concentration on a logarithmic scale and IC50s are obtained using standard analysis protocols. After compound application, a washout period of approx. 5 min was recorded (Journal of Biomolecular Screening 2006:57-64).
  • the intracellular recording solution contained (mM): KCl 50, KF 60, NaCl 10, EGTA 20, HEPES 10; titrated to pH 7.2 with KOH.
  • CHO- cells stably expressing the ion channels were clamped at a holding potential (HP) of -100 mV, hyperpolarized to -120 mV to determine the leak current, and depolarized for 200 ms to +40 mV. Intersweep interval was 20 sec.
  • the area under curve (charge) during 200 ms of depolarization was analyzed. An initial period of approx. 15 stimuli was recorded to determine an endogenous current rundown.
  • Whole cell recordings are made either manually using a Multiclamp 200B patch-clamp amplifier and Clampex acquisition program (Molecular Devices Corporation) or by the automated 16 cell planar patch clamp instrument, QPatch (Sophion Bioscience) or Whole-cell recordings are obtained from CHO cells stably or transiently transfected with cDNA of respective ion channels.
  • solutions are either applied for periods of 1 to 3s by a gravity flow, 8-valve delivery system, or for periods of milliseconds using the quick-change Dynaflow perfusion system (Cellectricon Inc.).
  • the internal pipette solution may include 60 mM Potassium-Chloride, 60 mM Potassium Flouride, 20 mM EGTA, and 5 mM Hepes at pH 7.2; normal external solution is 140 mM NaCl, 5 mM KCl, 1 mM CaCl 2 , 2 mM MgCl 2 , 25 mM Hepes, and 10 mM glucose.
  • Concentration-response curves are obtained by recording currents in response to brief (200 msec) depolarizing voltage steps at 15 second intervals. A series of baseline current responses are obtained in the presence of regular external saline.
  • K v l .3 currents are tested for activity against other receptors to determine their selectivity for specific family members.
  • the list of receptors assayed includes, but is not restricted to K v l.l, K V 1.5, K V 1.4, K V 3.1, K V 2.1, hERG.
  • the types of assay used for selectivity determination may include Electrophysiological determination of receptor inhibition in either mammalian cells stably expressing DNA encoding the channel of interest or inherently expressing the channel, including by using manual patch clamp or planar patch clamp system. Methods and data analysis will be similar to those described above for K V 1.3.
  • Caco-2 permeability is measured according to the method described in Yee, Pharm. Res.
  • Caco-2 cells are grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium is removed from both the apical and basolateral compartments and the monolayers are preincubated with pre- warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.75 hour at 37°C in a shaker water bath at 50 cycles/min.
  • the apical buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCl 2 and 0.5 mM MgCl 2 (pH 6.5).
  • the basolateral buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCl 2 and 0.5 mM MgCl 2 (pH 7.4).
  • test compound solution (lO ⁇ M) in buffer is added to the apical compartment.
  • the inserts are moved to wells containing fresh basolateral buffer and incubated for 1 hr. Drug concentration in the buffer is measured by LC/MS analysis.
  • Flux rate (F, mass/time) is calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (Papp) is calculated from the following equation:
  • Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25 °C with 2 M HCl containing 1 mM MgCl 2 , 10 mM KCl.
  • the cells are homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,00Og for 20 minutes at 4°C.
  • the pellet is resuspended, homogenized and centrifuged once more in the same manner.
  • the resultant supernatant is discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds.
  • the membrane homogenate is aliquoted and stored at -80°C until use. An aliquot is used for protein concentration determination using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All the manipulation, stock solution and equipment are kept on ice at all time. For saturation assays, experiments are conducted in a total volume of 200 ⁇ l. Saturation is determined by incubating 20 ⁇ l of [ 3 H] -dofetilide and 160 ⁇ l of membrane homogenates (20-30 ⁇ g protein per well) for 60 min at room temperature in the absence or presence of 10 ⁇ M dofetilide at final concentrations (20 ⁇ l) for total or nonspecific binding, respectively.
  • the assay is initiated by addition of YSi poly-L-lysine Scintillation Proximity Assay (SPA) beads (50 ⁇ l, 1 mg/well) and membranes (110 ⁇ l, 20 ⁇ g/well). Incubation is continued for 60 min at room temperature. Plates are incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity is quantified by counting WALLAC MICROBETA plate counter.
  • SPA YSi poly-L-lysine Scintillation Proximity Assay
  • HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study.
  • the methodology for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998).
  • the cells are harvested from culture flasks and plated onto glass coverslips in a standard Minimum Essential Medium (MEM) medium with 10% Fetal Calf Serum (FCS).
  • MEM Minimum Essential Medium
  • FCS Fetal Calf Serum
  • HERG currents are studied using standard patch clamp techniques in the whole-cell mode. During the experiment the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl 2 , 2; MgCl 2 , 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH.
  • a standard voltage protocol is applied to the cell to evoke membrane currents.
  • the voltage protocol is as follows. The membrane is depolarized from a holding potential of -80 mV to +40 mV for 1000ms. This is followed by a descending voltage ramp (rate 0.5 mV msec-1) back to the holding potential. The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz). The amplitude of the peak current elicited around -4OmV during the ramp is measured.
  • vehicle (0.5% DMSO in the standard external solution) is applied for 10-20 min by a peristalic pump.
  • the test compound of either 0.3, 1, 3, 10 mM is applied for a 10 min period.
  • the 10 min period includes the time which supplying solution was passing through the tube from solution reservoir to the recording chamber via the pump. Exposing time of cells to the compound solution is more than 5 min after the drug concentration in the chamber well reaches the attempting concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells are exposed to high dose of dofetilide (5 mM), a specific IKr blocker, to evaluate the insensitive endogenous current.
  • dofetilide 5 mM
  • IKr blocker a specific IKr blocker
  • the compound concentration in supernatant is measured by LC/MS/MS system.
  • the half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This is converted to a half- life value using following equation:
  • Sprague-Dawley rats weighing 250-350 g. K v i.3 modulators may be administered prior to or post- induction of the inflammation model depending upon the specific model and the compound PK characteristics.
  • the route of administration may include intraperitoneal, (i.p.), subcutaneous (s.c), oral (p.o.), intranvenous (i.v.), intrathecal (i.t), or intraplantar.
  • K v l .3 modulators may be administered prior to or post-induction of the immune disease model depending upon the specific model and the compound PK characteristics.
  • the route of administration may include intraperitoneal, (i.p.), subcutaneous (s.c), oral (p.o.), intranvenous (i.v.), intrathecal (i.t.), or intraplantar.
  • the endpoints for these studies may include mediation of immune reactions, inflammatory reactions, physical parameters, cellular parameters and will be appropriate for the model being utilized.
  • EAE Experimental Allergic Encephalomyelitis
  • CNS central nervous system
  • Disease is induced in susceptible strains of mice (SJL mice) by immunization with CNS myelin antigens or alternatively, disease is passively transferred to susceptible mice using antigen stimulated CD4+ T cells (Pettinelli, J. Immunol. 127, 1981, p. 1420).
  • SJL mice susceptible strains of mice
  • CD4+ T cells antigen stimulated CD4+ T cells
  • EAE is widely recognized as an acceptable animal model for multiple sclerosis in primates (Alvord et al. (eds.) 1984.
  • Experimental allergic encephalomyelitis A useful model for multiple sclerosis. Alan R. Liss, New York).
  • TMEV Model [00373] Another experimental MS model is a viral model, whereby MS like disease is induced by
  • TMEV Theiler's murine encephalomyelitis virus
  • the TMEV picornavirus is inoculated intracerebrally in susceptible strains of mice and induces immune-mediated progressive CNS demyelination which is clinically and pathologically similar to MS.
  • Intracerebral virus injection is performed on 4-6 week old animals that are lightly anesthetized with metofane. Virus is injected using a 27 gauge needle with a Hamilton syringe that delivers a 10 ul volume which contains 2x10 5 PFU of the Daniel's strain of TMEV.
  • Intracerebral injection results in greater than 98% incidence of chronic viral infection with demyelination.
  • Chronically infected animals for remyelination experiments are generally 6-8 months post-infection.
  • Animals are sacrificed and spinal cord tissue is processed and morphological evaluation of the spinal cord of each animal is assessed histologically.
  • Mice are anesthetized with pentobarbital and perfused by intracardiac administration of fixative (phosphate buffered 4% formaldehyde with 1% glutaraldehyde, pH 7.4).
  • Spinal cords are removed and sectioned coronally into 1 mm blocks, postf ⁇ xed with osmium, and embedded in araldite.
  • One micron-thick cross-sections are cut from each block and stained with 4% paraphenyldiamine. Demyelination and remyelination are quantified using a Zeiss digital analysis system (ZIDAS) and camera lucida . For each mouse, ten spinal cord cross sections are examined which span the entire cord from the cervical to the proximal coccygeal spinal column regions. Areas of demyelination are characterized by large amounts of myelin debris, macrophages engulfing debris, cellular infiltration and naked axons.
  • ZIDAS Zeiss digital analysis system
  • Oligodendrocyte remyelination is characterized by areas of axons with abnormally thin myelin sheaths and the absence of Schwann cells. Statistical comparison of the extent of demyelination and remyelination is performed using the Student's t test. Lysolecithin Induced Demyelination:
  • mice 12 weeks old SJL/J mice are anesthetized with sodium pentobarbital and a dorsal laminectomy is performed in the upper thoracic region of the spinal cord.
  • a 34 guage needle attached to a Hamilton syringe is used to inject 1 ml of a 1% solution of lysolecithin directly into the dorsolateral aspect of the cord.
  • the wound is sutured in two layers, and mice are allowed to recover.
  • the day of lysolecithin injection was designated day 0. Seven days after lysolecithin injection, mice are treated with compound(s) (1 mg/injection each). Control mice are treated with bolus intraperitoneal injection of PBS or other appropriate control.
  • mice are sacrificed and one um thick sections are prepared.
  • the araldite block showing the largest lysolecithin- induced demyelination lesion is used for quantitative analysis.
  • the total area of the lesion is quantitated using a Zeiss interactive digital analysis system.
  • the total number of remyelinated fibers is quantitated using a Nikon microscope/computer analysis system.
  • the data is expressed as number of remyelinated axons/mm of lesion.
  • the collagen-induced arthritis model (CIA) is used as an autoimmune model for testing compounds (Myers, L.K. et al. Life Sci. (1997), 61(19): 1861-1878). Immunization of genetically susceptible rodents or primates with Type II collagen (CII) in complete Freund's adjuvant leads to the development of a severe polyarticular arthritis after about 3 weeks. Synovitis and erosions of cartilage and bone are observed as the hallmarks of CIA and mimic RA. DBA/1 mice aged between 10 and 12 weeks are administered HypnormTM (0.1 ml, intraperitoneally) and shaved at the base of the tail.
  • HypnormTM 0.1 ml, intraperitoneally
  • Bovine collagen type II (CII) is emulsified with complete Freund's adjuvant at a final concentration of 2 mg/ml, and a total of 0.1 ml is injected intradermally at three sites at the base of the tail. Twenty-one days later, a booster (0.1 ml) consisting of CII emusified with incomplete Freund's adjuvant (2 mg/ml) is injected intradermally across three sites at the tail base. A further 3 days later animals are injected with lipopolysaccharide (40 ⁇ g in 0.1 ml phosphate-buffered saline [PBS]; E. coli serotype 055:B5; Sigma- Aldrich Co.
  • PBS phosphate-buffered saline
  • mice Animals with a clinical score of 0.5 or above are used in compound assessment experiments and administered varying doses of test compound. Mice are monitored until 40 days after immunization, when they were killed and blood collected for serum and draining lymph nodes collected for assessment of stimulated cytokine secretion. Diabetes
  • IDDM blood glucose levels
  • STZ streptozotocin
  • DTH delayed type hypersensitivity

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds are provided according to formula (1), wherein W, X, Z, R1, R2, R3, and ml are as defined herein. Provided compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non- limiting example, pain, inflammation, cognitive disorders, anxiety, depression, and others. Provided compounds and pharmaceutical compositions thereof are also useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non- limiting example immune-mediated disorders and autoimmune diseases, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, transplant rejection, and others.

Description

SULFONAMIDE COMPOUNDS , PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
FIELD
[0001] The present invention relates to a class of sulfonamide compounds and pharmaceutical compositions comprising such compounds. Also provided are methods for preventing and/or treating conditions in mammals, that are causally related to potassium channel activity or can be alleviated by modulating potassium channel activity, such as (but not limited to) autoimmune disorders, inflammatory disorders, immune-mediated disorders, or other disorders, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, transplant rejection, and delayed type hypersensitivity using the compounds and pharmaceutical compositions provided herein.
BACKGROUND
[0002] Therapeutic strategies for the effective management of autoimmune disorders and immune-mediated disorders are sought.
[0003] Potassium channels represent a complex class of voltage-gated ion channels from both functional and structural standpoints. Their functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. In general, four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). [0004] KCNA3 encodes the voltage-gated KV1.3 potassium channel, which is shaker-related and is expressed in lymphocytes (T and B lymphocytes), the central nervous system, fat and other tissues. The functional channel is composed of four identical KV1.3 α-sub units. The KV1.3 potassium channel regulates membrane potential and thereby indirectly influences calcium signaling in human effector- memory T cells (Grissmer S. et al, Proc. Natl. Acad. Sci. U.S.A. 87(23): 9411-5; DeCoursey T.E. et al, Nature 307 (5950): 465-8; Chandy K.G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest. 111 (11): 1703-13). Effector memory T cells are important mediators of multiple sclerosis, Type I diabetes mellitus, psoriasis, and rheumatoid arthritis.
[0005] The Kvl .3 channel is expressed in T and B lymphocytes in a distinct pattern that depends on the state of lymphocyte activation and differentiation. Upon activation, naive and central memory T cells increase expression of the Kca3.1 channel per cell, while effector-memory T cells increase expression of the KV1.3 channel. Amongst human B cells, naive and early memory B cells express small numbers of KV1.3 and Kca3.1 channels when they are quiescent, and augment Kca3.1 expression after activation. In contrast, class-switched memory B cells express high numbers of KV1.3 channels per cell (about 1500/cell) and this number increases after activation (Chandy K. G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest. I l l (11): 1703-13; Wulff H. et al, J. Immunol. 173(2): 776- 86). The Kvl .3 channel promotes the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G et al (2004) Trends Immunol 25:565-569). [0006] Kvl .3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation. However, blockade of the channel does not prevent immune synapse formation (Panyi G. et al, Proc. Natl. Acad. Sci. U.S.A., 101(5):1285-90; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A., 103(46): 17414-9). [0007] KV1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells. Calcium entry through the CRAC channel is promoted by potassium efflux through the Kvl .3 and Kca3.1 potassium channels. Blockade of KV1.3 channels in effector-memory T cells suppresses activities like calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation. Effector- memory T cells (TEM) were originally defined by their expression of cell surface markers, and can enter sites of inflammation in non- lymphoid tissues, while not participating in the process of lymphoid recirculation carried out by most other lymphocytes. TEMs have been shown to uniquely express high numbers of the KV1.3 potassium channel and depend on these channels for their function. In vivo, KV1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues. In contrast, KV1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are therefore protected from the effect of KV1.3 blockade. Suppressing the function of these cells by selectively blocking the KV1.3 channel offers the potential for highly effective therapy of autoimmune diseases with minimal effects on either beneficial immune responses or other organs (Chandy K.G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest. I l l (11): 1703-13; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A., 103(46): 17414-9; Matheu M. P. et al, Immunity 29(4): 602-14). [0008] Kvl .3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes. The apoptotic protein Bax has been suggested to insert into the outer membrane of the mitochondria and occlude the pore of KV1.3 via a lysine residue. Thus, KV1.3 blockade may be one of many mechanisms that contribute to apoptosis (Szabo I. et al, J. Biol. Chem. 280(13): 12790-8; Szabo I. et al., Proc. Natl. Acad. Sci. U.S.A. 105(39): 14861-6).
[0009] Autoimmune Disease is a family of disorders resulting from tissue damage caused by a malfunctioning immune system, affecting tens of millions of people worldwide. Such diseases may be restricted to a single organ, as e.g. in multiple sclerosis and Type I diabetes mellitus, or may involve multiple organs as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is generally palliative and typically includes anti-inflammatory and immunosuppressive drugs. The severe side effects of many of these therapies have fueled a continuing search for more effective and selective immunosuppressive drugs. Among these are those which can selectively inhibit the function of effector- memory T cells, known to be involved in the etiology of many of these autoimmune diseases and thereby ameliorate many autoimmune diseases without compromising the protective immune response. [0010] Multiple sclerosis is a disease caused by autoimmune damage to the central nervous system including the brain, which affects roughly two and a half million people worldwide. Symptoms include muscle weakness and paralysis, and the disease can progress rapidly and unpredictably and may eventually lead to death. Treatment usually includes the use of anti-inflammatory and immunosuppressive drugs which have potentially severe side effects. KV1.3 has been shown to be highly expressed in autoreactive effector memory T cells from MS patients (Wulff, H et al (2003) J Clin Invest 111 :1703-1713; Rus H et al (2005) PNAS 102:11094-11099). Animal models of multiple sclerosis have been successfully treated using blockers of the KV1.3 potassium channel. In patients with multiple sclerosis, disease- associated myelin-specific T cells from the blood are predominantly co-stimulation independent effector- memory T cells that express high numbers of KV1.3 channels. T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the KV1.3 channel (Wulff H. et al, J. Clin. Invest. 111(11): 1703-13; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A. 103(46): 17414-9).
[0011] Type 1 diabetes mellitus is a disease caused by autoimmune destruction of insulin- producing cells in the pancreas, resulting in high blood sugar and other metabolic abnormalities. Type 1 diabetes mellitus affects close to four hundred thousand people in the US alone, and is usually diagnosed before age 20. Its long-term consequences may include blindness, nerve damage and kidney failure, and left untreated is rapidly fatal. Treatment involves life-long administration of insulin or pancreas transplantation, both of which may entail serious side effects (Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A. 103(46): 17414-9).
[0012] Kvl .3 is also considered a therapeutic target for the treatment of obesity, for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus, and for preventing bone resorption in periodontal disease (Tucker K. et al, Int. J. Obes. (Lond) 32(8): 1222-32; Xu J. et al, Hum. MoI Genet. 12(5): 551-9; Xu J. et al, Proc. Natl. Acad. Sci. U.S.A. 101(9): 3112-7; Valverde P. et al, J. Dent. Res 84(6): 488-99; Tschritter O. et al, J. Clin. Endocrinol. Metab. 91(2): 654-8).
[0013] Compounds which are selective KV1.3 blockers are thus potential therapeutic agents as immunosuppressants or immune system modulators including for the prevention of graft rejection, and the treatment of autoimmune and inflammatory disorders. KV1.3 modulators may be used alone or in conjunction with other immunosuppressants, such as selective Kca3.1 Blockers or cyclosporin, in order to achieve synergism and/or to reduce toxicity, especially of cyclosporin. [0014] At present there exist a number of non-selective K channels that will inhibit lymphocyte proliferation, but have adverse side effects. Other K channels exist in a wide range of tissues including the heart and brain, and generally blocking these channels is undesirable. U.S. Patent No. 5,494,895 discloses the use of a thirty-one amino acid peptide, scorpion peptide margatoxin, as a selective inhibitor and probe of KV1.3 channels present in human lymphocytes, and also as an immunosuppressant. However the use of this compound is limited by its potent toxicity.
[0015] International patent Application publication No.s WO 97/16438 and WO 09/716437, and
US Patent No. 6,051,590 describe the use of the triterpene, correolide and related compounds as immunosuppressants in the treatment of conditions in mammals affected or facilitated by KV1.3 inhibition. [0016] US Patent 6,077,680 describes DNA segments and proteins of derived from sea anemone species, more particularly ShK toxin from Stichodactyla helianthus. The ShK toxin was found to block Kvl.l, KV1.3, KV1.4 and Kv 1.6, but a mutant ShK-K22DAP found to selectively block KV1.3. Unfortunately the mutant was not sufficiently stable for clinic use. [0017] ShK toxin has been shown to both prevent and treat experimental autoimmune encephalomyelitis in Lewis rats, an animal model for human multiple sclerosis (Beeton C. et al 2001, Proc. Natl. Acad, Sci. U.S.A. 98:13942-7), by selectively targeting T cells chronically activated by the myelin antigen, MBP (myelin basic protein). The same study also indicated that chronically activated encephalitogenic rat T cells express a unique channel phenotype characterised by high expression of Kv 1.3 channels (approximately 1500 per cell) and low numbers of Kca3.1 channels (approximately 120 per cell). This channel phenotype is distinct from that seen in quiescent and acutely activated cells and may be a functionally relevant marker for chronically activated rat T-lymphocytes.
[0018] There is still a need for improved and specific therapies for immune diseases, including autoimmune diseases, and for immunosuppressive agents which lack problematic side effects and specifically target channels involved in immune cell mediated actions.
[0019] The citation of references herein shall not be construed as an admission that such is prior art to the present invention.
SUMMARY OF THE INVENTION
[0020] Sulfonamide compounds, and pharmaceutical compositions thereof, having potency and selectivity in the prevention and treatment of conditions that have been associated with autoimmune disorders, immune-mediated disorders, inflammatory disorders, or other disorders, or conditions which benefit clinically from immunosuppressants, including multiple sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, contact dermatitis, obesity, graft- versus host disease, transplant rejection, and delayed type hypersensitivity. [0021] In particular, compounds, pharmaceutical compositions and methods provided are useful to treat, prevent or ameliorate a range of conditions in mammals such as, but not limited to, immune disorders and autoimmune diseases of various genesis or etiology, for example rheumatoid arthritis, multiple sclerosis, psoriasis, type 1 diabetes, graft-versus host disease, transplant rejection. In some embodiments, compounds, pharmaceutical compositions and methods provided are useful as antiinflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, asthma, myocardial infarction, neurodegenerative disorders, inflammatory bowel disease and autoimmune disorders, renal disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, and lipid disorders. [0022] Accordingly, in one aspect, compounds are provided that have formula I:
Figure imgf000006_0001
wherein each W and Z is independently CH or N; X is CO, SO, or SO2; each R1 and R2 is independently selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ml is 1 or 2; provided that the compound is not i) N-(phenylmethyl)-N-[4-(l -piperidinylcarbonyl)phenyl]-benzenesulfonamide, or ii) N-[[4-(2,4-dioxo-5-thiazolidinyl)phenyl]methyl]-N-[3-(4- morpholinylcarbonyl)phenyl]-2-naphthalenesulfonamide; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
[0023] In one embodiment, with respect to formula I, R1 is substituted or unsubstituted 6-10 membered aryl or heteroaryl.
[0024] In another aspect, pharmaceutical compositions are provided comprising a fused heterocyclic compound provided herein, and a pharmaceutical carrier, excipient or diluent. The pharmaceutical composition can comprise one or more of the compounds described herein. [0025] It will be understood that compounds provided herein useful in the pharmaceutical compositions and treatment methods disclosed herein, can be pharmaceutically acceptable as prepared and used.
[0026] In another aspect, methods are provided for preventing, treating or ameliorating a condition from among those listed herein, and particularly, such condition as may be associated with immune-mediated reactions, autoimmune conditions, or other conditions which are modulated by immunosuppression, as may be associated with, e.g., multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, and transplant rejection, which method comprises administering to a mammal in need thereof an amount of one or more of the compounds provided herein, or pharmaceutical composition thereof, effective to prevent, treat or ameliorate the condition. [0027] In yet another aspect, methods are provided for preventing, treating or ameliorating a condition that gives rise to immune responses or that relates to imbalances in the maintenance of basal activity of the immune system in a mammal. The compounds provided herein have use as potassium channel modulators for the treatment of immune-mediated diseases or autoimmune conditions of various geneses or etiology, for example multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, psoriasis, contact dermatitis, obesity, systemic lupus erythematosus, graft-versus host disease, and transplant rejection.
[0028] In addition to the methods of treatment set forth above, the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified. [0029] In additional aspects, methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below. In certain embodiments, provided are methods of making enantiomerically pure compounds according to formula 1 by asymmetric synthesis. In certain embodiments, provided are methods of making enantiomerically pure compounds according to formula 1 by chiral resolution.
[0030] Accordingly, it is a principal object of this invention to provide a novel series of compounds which can modulate the activity of the voltage gated potassium channel Kv 1.3, and thus avert or treat any maladies that may be causally related to aberrations in such activity.
[0031] It is further an object of this invention to provide a series of compounds that can treat or alleviate maladies or symptoms of same, such as immune-mediated disorders and autoimmune diseases , that may be causally related to the activation of the Kvl .3 channel.
[0032] It is further an object of this invention to provide a series of compounds that can treat a disease or condition, wherein the disease or condition is selected from: Acute disseminated encephalomyelitis (ADEM), Addison's disease, Allopecia areata, Alzheimers disease, Ankylosing spondylitis, Antiphospholipid antibody syndrome, Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmune polyendocrine/polyglandular syndrome, Autoimmune thrombocytoipenia purpura, BaIo disease, Behcet disease, Bullous pemphigoid, Cardiomyopathy, Celiac sprue-dermatitis herpetiformis, Chronic fatigue immune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinating neuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinin disease, CREST syndrome, Crohn's disease, Cystic fibrosis, Degos disease, Dermatomyositis, Diabetes (Type I or Juvenile onset), Early onset dementia, Eczema, Endotoxin shock, Essential mixed cryoglobulinemia, Familial Mediterranean fever, Fibromyalgia, Fibromyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroidosis, Hidradenitis suppurativa, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgA nephropathy, Lambert-Eaton Myasthenic Syndrome, Leukemia, Lichen planus, Meniere disease, Mixed connective tissue disease, Multiple sclerosis, Multiphasic disseminated encephalomyelitis, Myasthenia gravis, Neuromyelitis Optica, Paraneoplastic Syndromes, Pemphigus, Pemphigus vulgaris, Pernicious anaemia, Polyarteritis nodosum, Polychondritis, Polymyalgia rhematica, Polymyositis, Primary agammaglobulinemia, Primary biliary cirrhosis, Plaque Psoriasis, Psoriatic arthritis, Raynaud phenomenon, Reiter syndrome, Restenosis following angioplasty, Rheumatic fever, Rheumatoid arthritis, Rheumatoid psoriasis, Sarcoidosis, Scleroderma, Sepsis, Sezary's disease, Sjogren's syndrome, Stiff- person syndrome, Systemic lupus erythematosis (SLE), Takayasu arteritis, Temporal arteritis (also known as "giant cell arteritis"), Transplant or Allograft rejection, Ulcerative colitis, Uveitis, Vasculitis, Vitiligo, Graft vs Host disease, pustular psoriasis, and Wegener's granulomatosis.
[0033] It is further an object of this invention to provide a series of compounds that can treat a disease or condition, wherein the disease or condition is selected from: resistance by transplantation of organs or tissue, graft- versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile- onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, Alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal bums and leukotriene B4-mediated diseases, Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonenephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy; Pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute- on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection. [0034] A still further object of this invention is to provide pharmaceutical compositions that are effective in the treatment or prevention of a variety of disease states, including the diseases associated with the central nervous system, cardiovascular conditions, chronic pulmonary obstructive disease COPD), inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, and other diseases where an immunological inflammatory component or autoimmune component is present. [0035] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
[0036] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0037] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.
[0038] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
[0039] 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R20, where R20 is hydrogen, C1-C8 alkyl, C3-
Cio cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary
'acyl' groups are -C(O)H, -C(O)-C1-C8 alkyl, -C(0)-(CH2)t(C6-Cio aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)-(CH2)t((C3-Ci0 cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4. [0040] 'Substituted AcyP or 'Substituted AlkanoyP refers to a radical -C(O)R21, wherein R21 is independently
• C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0041] 'Acylamino' refers to a radical -NR22C(O)R23, where R22 is hydrogen, C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R23 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein. Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary 'acylamino' groups are -NR24C(O)-C1-C8 alkyl, -NR24C(O)-(CH2)t(C6-C10 aryl), -NR24C(O)-(CH2)t(5-10 membered heteroaryl), -NR24C(O)-(CH2)t(C3-Ci0 cycloalkyl), and -NR24C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R24 independently represents H or C1-C8 alkyl.
[0042] 'Substituted Acylamino' refers to a radical -NR25C(O)R26, wherein:
R25 is independently
• H, C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and
R26 is independently
• H, C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R25 and R26 is other than H.
[0043] 'Acyloxy' refers to a radical -OC(O)R27, where R27 is hydrogen, C1-C8 alkyl, C3-Ci0 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary 'acyl' groups are -C(O)H, -C(O)-C1-C8 alkyl, -C(O)-(CH2)t(C6-C10 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(0)-(CH2)t(C3-Cio cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
[0044] 'Substituted Acyloxy' refers to a radical -OC(O)R28, wherein R28 is independently
• C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0045] 'Alkoxy' refers to the group -OR29 where R29 is C1-C8 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0046] 'Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl- S(O)2-. Exemplary 'substituted alkoxy' groups are -O-(CH2)t(C6-Ci0 aryl), -O-(CH2)t(5-10 membered heteroaryl), -O-(CH2)t(C3-Ci0 cycloalkyl), and -O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are OCF3, OCH2CF3, OCH2Ph, OCH2-cyclopropyl, OCH2CH2OH, and OCH2CH2NMe2.
[0047] 'Alkoxycarbonyl' refers to a radical -C(O)-OR30 where R30 represents an C1-C8 alkyl, C3-
Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary "alkoxycarbonyl" groups are C(O)O-C1-C8 alkyl, -C(O)O- (CH2)t(C6-C10 aryl), -C(O)O-(CH2)t(5-10 membered heteroaryl), -C(O)O-(CH2)t(C3-C10 cycloalkyl), and - C(O)O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4. [0048] 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR31 where R31 represents:
• C1-C8 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, or 4-10 membered heterocycloalkylalkyl, each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C6-Ci0 aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. [0049] 'Aryloxycarbonyl' refers to a radical -C(O)-OR where R represents an C6-C10 aryl, as defined herein. Exemplary 'aryloxycarbonyl' groups is -C(O)O-(C6-C 10 aryl).
[0050] 'Substituted Aryloxycarbonyl' refers to a radical -C(O)-OR where R represents
• C6-C10 aryl, substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.
[0051] 'Heteroaryloxycarbonyl' refers to a radical -C(O)-OR34 where R34 represents a 5-10 membered heteroaryl, as defined herein. An exemplary "aryloxycarbonyl" group is -C(O)O-(5-10 membered heteroaryl). [0052] 'Substituted Heteroaryloxycarbonyl' refers to a radical -C(O)-OR 5 where R 5 represents:
• 5-10 membered heteroaryl, substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.
[0053] 'Alkoxycarbonylamino' refers to the group -NR36C(O)OR37, where R36 is hydrogen, C1-
C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl as defined herein, and R37 is C1-C8 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
[0054] 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso- butyl, t-butyl and isoamyl.
[0055] 'Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (- O-acyl or -OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH- C(O)-OR27), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2), aminocarbonylamino (-NR -C(O)-NR 2), aminocarbonyloxy (-O-C(O)-NR 2), aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, heteroaryl, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. In a particular embodiment 'substituted alkyl' refers to a C1-C8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR"'SO2R", -SO2NR R", -C(O)R", -C(O)OR", -OC(O)R", -NR"'C(O)R", - C(O)NR R", -NR"R ", or -(CR"'R"")mOR"; wherein each R" is independently selected from H, C1-C8 alkyl, -(CH2)t(C6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-C10 cycloalkyl), and -(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Each of R and R independently represents H or C1-C8 alkyl.
[0056] 'Alkylene' refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., - CH2CH2CH2- and -CH(CH3)CH2-) and the like.
[0057] 'Substituted alkylene' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-.
[0058] 'AlkenyF refers to monovalent olefmically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (- CH2CH=CH2), isopropenyl (-C(CH3)=CH2), vinyl and substituted vinyl, and the like. [0059] 'Substituted alkenyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. [0060] 'Alkenylene' refers to divalent olefmically unsaturated hydrocarbyl groups particularly having up to about 11 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., - CH=CHCH2- and -C(CH3)=CH- and -CH=C(CH3)-) and the like.
[0061] 'AlkynyF refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 11 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation. Particular non-limiting examples of alkynyl groups include acetylenic, ethynyl (-C≡CH), propargyl (- CH2C=CH), and the like. [0062] 'Substituted alkynyF refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. [0063] 'Amino' refers to the radical -NH2.
[0064] 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R38)2 where each R38 is independently selected from:
• hydrogen, C1-C8 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-Ci0 cycloalkyl; or
• C1-C8 alkyl, substituted with halo or hydroxy; or
• -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-Ci0 cycloalkyl) or - (CH2)t(4-10 membered heterocycloalkyl) wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or
• both R38 groups are joined to form an alkylene group.
When both R38 groups are hydrogen, -N(R38)2 is an amino group. Exemplary 'substituted amino' groups are -NR39-C1-C8 alkyl, -NR39-(CH2)t(C6-Ci0 aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39- (CH2)t(C3-Cio cycloalkyl), and -NR39-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R39 independently represents H or C1-C8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.
[0065] 'Alkylamino' refers to the group -NHR40, wherein R40 is C1-C8 alkyl.
[0066] 'Substituted Alkylamino' refers to the group -NHR41, wherein R41 is C1-C8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, Cs-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0067] 'Alkylarylamino' refers to the group -NR42R43, wherein R42 is aryl and R43 is C1-C8 alkyl.
[0068] 'Substituted Alkylarylamino' refers to the group -NR44R45, wherein R44 is aryl and R45 is C1-C8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-
Cio cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0069] 'Arylamino' means a radical -NHR46 where R46 is selected from C6-C10 aryl and 5-10 membered heteroaryl as defined herein.
[0070] 'Substituted Arylamino' refers to the group -NHR47, wherein R47 is independently selected from C6-Ci0 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0071] 'Dialkylamino' refers to the group -NR48R49, wherein each of R48 and R49 are independently selected from C1-C8 alkyl.
[0072] 'Substituted Dialkylamino' refers to the group -NR50R51, wherein each of R59 and R51 are independently selected from C1-C8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0073] 'Diarylamino' refers to the group -NR52R53, wherein each of R52 and R53 are independently selected from C6-C10 aryl.
[0074] 'Aminosulfonyl'or 'Sulfonamide' refers to the radical -S(O2)NH2.
[0075] 'Substituted aminosulfonyl" or "substituted sulfonamide" refers to a radical such as -
S(O2)N(R54)2 wherein each R54 is independently selected from:
• H, C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R54 is other than H.
[0076] Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are -
S(O2)N(R55)-C1-C8 alkyl, -S(O2)N(R55)-(CH2)t(C6-C10 aryl), -S(O2)N(R55)-(CH2)t(5-10 membered heteroaryl), -S(02)N(R55)-(CH2)t(C3-Cio cycloalkyl), and -S(O2)N(R55)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R55 independently represents H or C1-C8 alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0077] 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
[0078] 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0079] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
[0080] 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent. Particularly, 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino. [0081] Examples of representative substituted aryls include the following
Figure imgf000016_0001
In these formulae one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, C1- C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, S02alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R60 and
R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, substituted aryl, 5-10 membered heteroaryl.
[0082] 'Fused Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
[0083] 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
[0084] 'Substituted Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0085] 'Azido' refers to the radical -N3.
[0086] 'Carbamoyl or amido' refers to the radical -C(O)NH2.
[0087] 'Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R62)2 wherein each R62 is independently
• H, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H.
Exemplary 'Substituted Carbamoyl' groups are -C(O)
Figure imgf000017_0001
alkyl, -C(0)NR64-(CH2)t(C6-Cio aryl),
-C(O)N64-(CH2)t(5-10 membered heteroaryl), -C(O)NR64-(CH2)t(C3-Ci0 cycloalkyl), and -C(O)NR64-
(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R64 independently represents H or C1-C8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0088] 'Carboxy' refers to the radical -C(O)OH.
[0089] 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
[0090] 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent
[0091] 'Cyano' refers to the radical -CN. [0092] 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0093] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
[0094] 'Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. [0095] Examples of representative heteroaryls include the following:
Figure imgf000019_0001
wherein each Y is selected from carbonyl, N, NR65, O and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, and 5-10 membered heteroaryl. [0096] Examples of representative aryl having hetero atoms containing substitution include the following:
Figure imgf000019_0002
wherein each W is selected from C(R66)2, NR66, O and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, and 5-10 membered heteroaryl.
[0097] As used herein, the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1- pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine. Particular examples of heterocycloalkyl groups are shown in the following illustrative examples:
Figure imgf000020_0001
wherein each W is selected from CR6 , C(R6 ')2, NR67 , O and S; and each Y is selected from NRb , O and
S; and R67 is independently hydrogen, C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl,
C6-Ci0 aryl, 5-10 membered heteroaryl, These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O)2-alkyl, and -S(O)2- aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
[0098] 'Hydroxy' refers to the radical -OH.
[0099] 'Nitro' refers to the radical -NO2.
[00100] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents may be selected from the group consisting of: halogen, -R68, -0-, =0, -OR68, -SR68, -S-, =S, -NR68R69, =NR68, -CCl3, -CF3, -CN, -OCN, -SCN, -NO, -
NO2, =N2, -N3, -S(O)2O-, -S(O)2OH, -S(O)2R68, -OS(O2)O-, -OS(O)2R68, -P(O)(O )2, -P(O)(OR68)(O-),
-OP(O)(OR68XOR69), -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR68R69, -C(O)O-, -C(S)OR68, -
NR70C(O)NR68R69, -NR70C(S)NR68R69, -NR71C(NR70)NR68R69 and -C(NR70)NR68R69; wherein each R68, R69, R70 and R71 are independently:
• hydrogen, C1-C8 alkyl, C6-Ci0 aryl, arylalkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl; or
• C1-C8 alkyl substituted with halo or hydroxy; or
• C6-C10 aryl, 5-10 membered heteroaryl, C6-Ci0 cycloalkyl or 4-10 membered heterocycloalkyl each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
In a particular embodiment, substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
In a further particular embodiment the substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR72SO2R73, -SO2NR73R72, -C(O)R73, -C(O)OR73, -OC(O)R73, - NR72C(O)R73, -C(O)NR73R72, -NR73R72, -(CR72R72)mOR72, wherein, each R73 is independently selected from H, Ci-C8 alkyl, -(CH2)t(C6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2X(C3-Ci0 cycloalkyl), and -(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from O to 4; and
• any alkyl groups present, may themselves be substituted by halo or hydroxy; and
• any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1- C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Each R independently represents H or C1-C6alkyl.
[00101] 'Substituted sulfanyl' refers to the group -SR74, wherein R74 is selected from:
• C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00102] Exemplary 'substituted sulfanyl' groups are -S-(C1-C8 alkyl) and -S-(C3-C10 cycloalkyl),
-S-(CH2)t(C6-Cio aryl), -S-(CH2)t(5-10 membered heteroaryl), -S-(CH2)t(C3-Ci0 cycloalkyl), and -S-
(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term 'substituted sulfanyl' includes the groups
'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyl' or
'cycloalkylthio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or
'arylthio' and 'heteroarylsulfanyl' or 'heteroarylthio' as defined below.
[00103] 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR75 where R75 is a C1-C8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
[00104] 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR76 where R76 is a C1-C8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00105] 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR77 where R77 is a C3-Ci0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
[00106] 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR78 where R78 is a C3-Ci0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00107] 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR79 where R79 is a C6-Cio aryl group as defined herein. [00108] 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR80 where R80 is a 5-10 membered heteroaryl group as defined herein.
[00109] 'Substituted sulfmyl' refers to the group -S(O)R81, wherein R81 is selected from:
• C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00110] Exemplary 'substituted sulfmyl' groups are -S(O)-(C1-C8 alkyl) and -S(O)-(C3-Ci0 cycloalkyl), -S(O)-(CH2)t(C6-C10 aryl), -S(O)-(CH2)t(5-10 membered heteroaryl), -S(O)-(CH2)t(C3-C10 cycloalkyl), and -S(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfmyl includes the groups 'alkylsulfmyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfmyl',
'arylsulfmyl' and 'heteroarylsulfmyl' as defined herein.
[00111] 'Alkylsulfmyl' refers to a radical -S(O)R82 where R82 is a C1-C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
[00112] 'Substituted Alkylsulfmyl' refers to a radical -S(O)R83 where R83 is a C1-C8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00113] 'Cycloalkylsulfmyl' refers to a radical -S(O)R84 where R84 is a C3-Ci0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfmyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C3-Ci0 cycloalkyl.
[00114] 'Substituted cycloalkylsulfmyl' refers to the group -S(O)R85 where R85 is a C3-Ci0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00115] 'Arylsulfmyl' refers to a radical -S(O)R86 where R86 is a C6-Ci0 aryl group as defined herein.
[00116] 'Heteroarylsulfmyl' refers to a radical -S(O)R87 where R87 is a 5-10 membered heteroaryl group as defined herein.
[00117] 'Substituted sulfonyl' refers to the group -S(O)2R88, wherein R88 is selected from:
• C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or • C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00118] Exemplary 'substituted sulfonyl' groups are -S(O)2-(CrC8 alkyl) and -S(O)2-(C3-Ci0 cycloalkyl), -S(O)2-(CH2)t(C6-C10 aryl), -S(O)2-(CH2)t(5-10 membered heteroaryl), -S(O)2-(CH2)t(C3-Ci0 cycloalkyl), and -S(O)2-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
[00119] 'Alkylsulfonyl' refers to a radical -S(O)2R89 where R89 is an C1-C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
[00120] 'Substituted Alkylsulfonyl' refers to a radical -S(O)2R90 where R90 is an C1-C8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy. [00121] 'Cycloalkylsulfonyl' refers to a radical -S(O)2R91 where R91 is a C3-Ci0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
[00122] 'Substituted cycloalkylsulfonyl' refers to the group -S(O)2R92 where R92 is a C3-Ci0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00123] 'Arylsulfonyl' refers to a radical -S(O)2R93 where R93 is an C6-Ci0 aryl group as defined herein.
[00124] 'Heteroarylsulfonyl' refers to a radical -S(O)2R94 where R94 is an 5-10 membered heteroaryl group as defined herein.
[00125] 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO3H.
[00126] 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O)2OR95, wherein R95 is selected from:
• C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• C1-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00127] Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O)2-O-(C1-C8 alkyl) and -S(O)2-O-(C3-Ci0 cycloalkyl), -S(O)2-O-(CH2)t(C6-Ci0 aryl), -S(O)2-O-(CH2)t(5-10 membered heteroaryl), -S(O)2-O-(CH2X(C3-Ci0 cycloalkyl), and -S(O)2-O-(CH2)^-IO membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00128] 'Thiol' refers to the group -SH.
[00129] 'Aminocarbonylamino' refers to the group -NR96C(O)NR96R96 where each R96 is independently hydrogen C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R96 groups, when attached to the same N, are joined to form an alkylene group.
[00130] 'BicycloaryF refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms. [00131] 'Bicycloheteroaryl' refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred. Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
[00132] 'Compounds of the present invention', and equivalent expressions, are meant to embrace the compounds as hereinbefore described, in particular compounds according to any of the formulae herein recited and/or described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[00133] 'Cycloalkylalkyl' refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
[00134] 'HeterocycloalkylalkyF refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
[00135] 'CycloalkenyF refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefmic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
[00136] 'Substituted cycloalkenyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-.
[00137] 'Fused Cycloalkenyl' refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefmic unsaturation located to impart aromaticity to the cycloalkenyl ring.
[00138] Εthenyl" refers to substituted or unsubstituted -(C=C)-.
[00139] 'Ethylene' refers to substituted or unsubstituted -(C-C)-.
[00140] 'Ethynyl' refers to -(C=C)-.
[00141] 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality.
Examples of 'hydrogen bond donor' groups include -OH, -NH2, and -NH-R97 and wherein R97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
[00142] 'Dihydroxyphosphoryl' refers to the radical -PO(OH)2.
[00143] 'Substituted dihydroxyphosphoryl' refers to those groups recited in the definition of
"substituted" herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
[00144] 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH2.
[00145] 'Substituted aminohydroxyphosphoryl' refers to those groups recited in the definition of
"substituted" herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
[00146] 'Nitrogen-Containing HeterocycloalkyF group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone. [00147] Thioketo' refers to the group =S.
[00148] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[00149] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[00150] 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
[00151] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[00152] 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. [00153] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[00154] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.
[00155] 'Therapeutically effective amount' means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" includes that amount of a compound or composition that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[00156] 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[00157] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non- limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[00158] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.
[00159] 'Compounds of the present invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[00160] When ranges are referred to herein, for example but without limitation, C1-C8 alkyl, the citation of a range should be considered a representation of each member of said range. [00161] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the Ci to C8 alkyl, C2-C8 alkenyl, aryl, C7-Ci2 substituted aryl, and C7-Ci2 arylalkyl esters of the compounds of the invention.
[00162] As used herein, the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2HID, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[00163] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
[00164] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.
[00165] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
[00166] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
[00167] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[00168] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [00169] As used herein and unless otherwise indicated, the term "enantiomerically pure R- compound" refers to at least about 80% by weight R-compound and at most about 20% by weight S- compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R- compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
[00170] As used herein and unless otherwise indicated, the term "enantiomerically pure S- compound" or "S-compound" refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R- compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound. [00171] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S- compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
[00172] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. [00173] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
THE COMPOUNDS
[00174] In certain aspects, provided herein are compounds useful for preventing and/or treating a broad range of conditions, particularly immune-mediated disorders and autoimmune diseases, among them, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis, systemic lupus erythamatosus, obesity, bone diseases, graft rejection, and other immunologically-active disorders or conditions in mammals. [00175] In one aspect, provided herein are compounds according to formula I:
Figure imgf000030_0001
I wherein each W and Z is independently CH or N; X is CO, SO, or SO2; each R1 and R2 is independently selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ml is 1 or 2; provided that the compound is not i) N-(phenylmethyl)-N-[4-(l -piperidinylcarbonyl)phenyl]-benzenesulfonamide, or ii) N-[[4-(2,4-dioxo-5-thiazolidinyl)phenyl]methyl]-N-[3-(4- morpholinylcarbonyl)phenyl]-2-naphthalenesulfonamide; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. [00176] In one embodiment, with respect to formula I, R1 is substituted or unsubstituted aryl.
[00177] In one embodiment, with respect to formula I, R1 is substituted or unsubstituted phenyl.
[00178] In one embodiment, with respect to formula I, R1 is substituted or unsubstituted heteroaryl.
[00179] In one embodiment, with respect to formula I, R1 is substituted or unsubstituted pyridyl.
[00180] In one embodiment, with respect to formula I, each of W and Z is CH.
[00181] In one embodiment, with respect to formula I, W is N; and Z is CH.
[00182] In one embodiment, with respect to formula I, W is CH; and Z is N.
[00183] In one embodiment, with respect to formula I, the compound is according to formula Ha, lib, Hc, Hd, He, or Hf:
Figure imgf000031_0001
lie Nf
Nd wherein
X, R , R , and ml are as described for formula I; nl is selected from 1-5 and each R4 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
[00184] In one embodiment, with respect to formula I-IIf, ml is 1.
[00185] In one embodiment, with respect to formula I-IIf, ml is 2.
[00186] In one embodiment, with respect to formula I-IIf, X is SO2.
[00187] In one embodiment, with respect to formula I-IIf, X is CO.
[00188] In one embodiment, with respect to formula I, the compound is according to formula Ilia,
1Hb, IHc, HId, HIe, or 1Hf:
Figure imgf000032_0001
iiid INe wherein
R2 is as described for formula I; nl and R4 are as described for formula Ha-IIf; and R3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
[00189] In one embodiment, with respect to formula I-IIIf, R3 is cycloalkyl.
[00190] In one embodiment, with respect to formula I-IIIf, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[00191] In one embodiment, with respect to formula I-IIIf, R is cyclohexyl.
[00192] In one embodiment, with respect to formula I-IIIf, R is heterocycloalkyl. [00193] In one embodiment, with respect to formula I-IIIf, R is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
[00194] In one embodiment, with respect to formula I-IIIf, R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with alkyl, or hydroxy.
[00195] In one embodiment, with respect to formula I-IIIf, R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with aryl or heteroaryl.
[00196] In one embodiment, with respect to formula I-IIIf, R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with benzimidazol-2-yl.
[00197] In one embodiment, with respect to formula I-IIIf, the compound is according to formula
IVa, IVb, IVc, IVd, IVe, or IVf:
Figure imgf000033_0001
IVd IVe IVf wherein
Y is CH or N; R2 is as described for formula I; nl and R4 are as described for formula Ha-IIf; R3a is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3a is COR3b; and R3b is alkoxy or heterocycloalkyl.
[00198] In one embodiment, with respect to formula I-IVf, R3a is H, Me, or benzyl.
[00199] In one embodiment, with respect to formula I-IVf, R a is phenyl, unsubstituted or substituted with Me, Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
[00200] In one embodiment, with respect to formula I-IVf, R a is pyridyl, unsubstituted or substituted with Me, Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
[00201] In one embodiment, with respect to formula I-IVf, R a is imidazolyl, or benzimidazolyl.
[00202] In one embodiment, with respect to formula I-IVf, R3a is COR3b.
[00203] In one embodiment, with respect to formula I-IVf, R3b is OMe, OEt, or O-i-Pr. [00204] In one embodiment, with respect to formula I-IVf, R3b is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
[00205] In one embodiment, with respect to formula I-IVf, nl is 1 and R4 is selected from H, C1-
C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, dihalo C1-C4 alkoxy, trihalo C1-C4 alkoxy, CN, NO2, and halo.
[00206] In one embodiment, with respect to formula I-IVf, nl is 1 and R4 is selected from H, Me,
Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
[00207] In one embodiment, with respect to formula I-IVf, nl is 1 and R4 is selected from 4-Me,
4-Et, 4-i-Pr, 4-CF3, 4-OMe, 4-OCHF2, 4-OCF3, 4-Cl, 4-F, 4-CN and 4-NO2.
[00208] In one embodiment, with respect to formula I-IVf, nl is 1 and R4 is selected from 4-Cl, or
4-CF3.
[00209] In one embodiment, with respect to formula I-IVf, R is phenyl or naphthalenyl.
[00210] In one embodiment, with respect to formula I-IVf, R2 is phenyl, unsubstituted or substituted with one or more groups selected from C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, dihalo C1-
C4 alkoxy, trihalo C1-C4 alkoxy, CN, NO2, and halo.
[00211] In one embodiment, with respect to formula I-IVf, R is phenyl, unsubstituted or substituted with one or more groups selected from Me, Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and
NO2.
[00212] In one embodiment, with respect to formula I-IVf, R2 is heteroaryl.
[00213] In one embodiment, with respect to formula I-IVf, R is pyridyl, benzothiophenyl, quinolinyl, isoquinolinyl, thiophenyl, or furanyl.
[00214] In one embodiment, with respect to formula I, the compound is according to formula Va,
Vb, Vc, Vd, Ve, or Vf:
Figure imgf000034_0001
each R2a, R4 is independently H, halo, C1-C6 alkoxy; R3a and Y are as described for formula IVa-
IVf.
[00215] In one embodiment, with respect to formula I- Vf, each R2a, and R4 is H.
[00216] In one embodiment, with respect to formula I- Vf, each R2a, and R4 is independently H, Cl,
F, or OMe.
[00217] In one embodiment, with respect to formula I- Vf, Y is CH or N; and R3ais phenyl, benzimidazol-2-yl, benzyl, 2-pyridyl, 2-fluorophenyl, 1 -pyrrolidinyl, CO-piperidin-1-yl, or CO-OEt. [00218] With regard to formula I, in certain embodiments, the compound is selected from the compound listed in Table 1.
[00219] Additional embodiments within the scope provided herein are set forth in non- limiting fashion elsewhere herein and in the examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting in any manner. [00220] In certain aspects, provided herein are prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds provided herein, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds provided herein, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. [00221] Certain compounds provided herein have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds provided herein are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred are the Ci to C8 alkyl, C2-C8 alkenyl, aryl, C7-C 12 substituted aryl, and C7-C 12 arylalkyl esters of the compounds provided herein.
PHARMACEUTICAL COMPOSITIONS
[00222] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. [00223] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [00224] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
[00225] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefϊlled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. [00226] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[00227] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[00228] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffmic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil- in- water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein. [00229] The compounds provided herein can also be administered by a transdermal device.
Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety. [00230] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. [00231] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference. [00232] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
[00233] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[00234] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
Formulation 2 - Capsules
[00235] A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
Formulation 3 - Liquid
[00236] A compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[00237] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
Formulation 5 - Injection
[00238] A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
Formulation 6 - Topical [00239] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) would be dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
METHODS OF TREATMENT
[00240] The present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for use in such methods, and for the preparation of medicaments useful for such methods. [00241] In a method of treatment aspect, provided herein is a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, myocardial infarction, inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described. [00242] In yet another method of treatment aspect, provided herein is a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves. The present compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache).
[00243] In additional method of treatment aspects, provided herein are methods of treating a mammal susceptible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders; itch / pruritus such as, for example psoriasis; obesity; lipid disorders; cancer; and renal disorders method comprises administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions just described.
[00244] As a further aspect there is provided the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. We also provide the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
[00245] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
[00246] For the prevention and/or treatment of long-term conditions, such as neurodegenerative and autoimmune conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
[00247] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[00248] When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[00249] The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives.
Adminsitration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
GENERAL SYNTHETIC PROCEDURES
[00250] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., the Synthetic Schemes below. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00251] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [00252] The compounds provided herein, for example, may be prepared by the reaction of a chloro derivative with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative fused heterocyclics that have been listed hereinabove. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[00253] The enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); EX. Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S.H. Wilen Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nόgradi (1995 VCH Publishers, Inc., NY, NY).
In certain embodiments, an enantiomerically pure compound of formula 1 may be obtained by reaction of the racemate with a suitable optically active acid or base. Suitable acids or bases include those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entireties.
[00254] Enantiomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used. The identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art. The diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid. The other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.
[00255] In certain embodiments, enantiomerically pure compound can be separated from racemic compound by chiral chromatography. Various chiral columns and eluents for use in the separation of the enantiomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art. Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to CHIRALCEL® OB, CHIRALCEL® OB- H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
ANALYTICAL METHODS NMR Spectrometers Used:
Bruker AVANCE 400 MHz NMR Bruker DPX 250 MHz NMR Bruker DPX 360 MHz NMR Bruker DRX 500 MHz NMR
LCMS methods used
[00256] Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following instrumentation: Shimadzu, Waters or Micromass ZMD, ZQ or LCT mass spectrometers with an Agilent, Waters or Polymer Labs UV and ELS detector. The HPLC conditions are tabulated below. Micromass MassLynx™ Operating Software with OpenLynx™ Browser were used for data acquisition, processing and reporting.
LCMS Method A LCMS Method B
Column Waters Atlantis dC 18 Waters Atlantis dC 18
2.1 x 50mm, 5μm 100 x 2.1 mm, 3 μm
Mobile phase A = Formic Acid (aq) 0.1% A = Formic Acid (aq) 0.1%
B = Formic Acid (acetonitrile) B = Formic Acid (acetonitrile)
0.1% 0.1%
Preparative HPLC Methods Used: Prep method 1
Waters SunFire Prep C l 8 Column
OBD 5um l9 x 100mm
A, TFA (aq) 0.1% Mobile Phase
B, TFA (CH3CN) 0.1%
Prep method 2 Phenomenex Gemini C l 8
Column
AXIA 5u 100 x 21.2mm
A, 2mM amm. bicarbonate, buffered to pH 10
Mobile Phase
B, Acetonitrile:2mM amm. bicarbonate 95:5
Prep method 3
Waters SunFire Prep C l 8
Column OBD 5um l9 x 100mm
A, TFA (aq) 0.1%
Mobile Phase B, TFA (CH3CN) 0.1%
Abbreviations
Boc N-tert-Butoxycarbonyl
Cbz Benzyloxycarbonyl
CDI Carbonyl diimidazole
DCE 1 ,2-dichloroethane
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMAP N,N-dimethylaminopyridine
DMF N,N-Dimethylformamide
EDCI l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide.HCl
MeOH Methanol m.s. Molecular sieves
Rt LC/MS retention time
STAB Sodium triacetoxyborohydride
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
[00257] Various sulfonamide derivatives can be prepared using a general procedures or synthetic schemes described below.
GENERAL SYNTHETIC SCHEMES TO PREPARE VARIOUS INTERMEDIATES AND
COMPOUNDS OF THE INVENTION SYNTHETIC SCHEME 1
Figure imgf000043_0001
Ar is R2, Ar1 is R1, and R1, R1, and R3 are as described herein.
GENERAL SYNTHETIC METHODS TO PREPARE VARIOUS INTERMEDIATES AND
COMPOUNDS OF THE INVENTION
Intermediate 1
Figure imgf000043_0002
[00258] 4-Chlorobenzaldehyde (1.27g, 9mmol, 3eq.), ethyl 4-aminobenzoate (496mg, 3mmol, leq.) and acetic acid (515μl, 9mmol, 3eq.) were stirred in DCE (10ml) for 30min. STAB (1.27g, 6mmol, 2eq.) was added and the reaction stirred for 18h. The reaction was quenched with saturated aqueous NaHCθ3 (3ml) and extracted with DCM (2 x 3ml). The combined organics dried over MgSO/i, and concentrated in vacuo to yield a white solid. Heptane/EtOAc (10:1) was added, the solid filtered and washed with heptane to yield the title compound Intermediate 1 (754mg, 87%). The crude product was taken directly to the next step without purification.
Intermediate 2
4-[Benzenesulfonyl-(4-chloro-benzyl)-amino]-benzoic acid ethyl ester
Figure imgf000044_0001
[00259] Intermediate 1 (230mg, 0.79mmol, leq.) was dissolved in pyridine (10ml) and stirred for lOmins. Benzene sulfonyl chloride (305μl, 2.38mmol, 3eq.) was added and the reaction mixture stirred for 15h. The reaction mixture was evaporated in vacuo and purified by FCC (Isolute 25g cartridge; gradient elution 10% to 40% EtO Ac/heptane ) to yield the title compound Intermediate 2 as a white solid (330mg, 97%).
Intermediate 3
Figure imgf000044_0002
[00260] Intermediate 2 (330mg, 0.769mmol, leq.) was dissolved in a mixture of 2M aqueous
LiOH (10ml), methanol (2ml) and THF (10ml) and the reaction stirred for 12h. The solvents were removed in vacuo and the residue taken up into DCM (20ml). Water (60ml) and DCM (130ml) were added and the pH of the aqueous layer adjusted to pH3 with IM aqueous HCl. The organic layer was removed, dried over MgSθ4, filtered and evaporated in vacuo to yield the title compound Intermediate 3 as a white solid (316mg, 99%). The crude product was taken directly to the next step without purification.
Compound 2
Figure imgf000044_0003
[00261] CDI (lOlmg, 0.623mmol, 2.5eq.) was added to a stirred solution of Intermediate 3
(lOOmg, 0.249mmol, leq.) dissolved in DMF (2ml). After stirring for 30mins, 1-phenylpiperazine (38.19μl, 0.25mmol, leq.) was added and the reaction stirred for 2h. The solvent was removed in vacuo and the residue purified by preparative HPLC to yield the title compound 2 as a white solid (66.8mg,
49%).
Compound 10
Figure imgf000045_0001
[00262] Intermediated (lOOmg, 0.249mmol, leq.), 4-piperidinyl(l-pyrrolidinyl)methanone
(45.57mg, 0.250mol, leq.), and the procedure and purification described for example 2 were used to synthesise the title compound K) as a brown solid (35.5mg, 25%).
Compound 11
Figure imgf000045_0002
[00263] Intermediate^ (lOOmg, 0.249mmol, leq.), ethyl piperidine-4-carboxylate (38.53μl,
0.250mol, leq.), and the procedure and purification described for example 2 were used to synthesise the title compound Y\_ as a yellow gum (55.1mg, 41%).
Intermediate 4
Figure imgf000045_0003
[00264] Benzaldehyde (915μl, 9mmol, 3eq.), ethyl 4-aminobenzoate (496mg, 3mmol, leq.) and the procedure and purification described for Intermediate 1 were used to synthesise the title compound Intermediate 4 as a white solid (561mg, 73%). The crude product was taken directly to the next step without purification. Intermediate 5
Figure imgf000046_0001
[00265] Benzene sulfonyl chloride (71μl, 0.55mmol, 1.1 eq.) was added to a stirred mixture of
Intermediate 4 (128mg, 0.5mmol, leq.), TEA (77μl, 0.55mmol, l.leq.), and trimethylammonium chloride (5mg, 0.05mmol, O.leq.) in DCM (2ml). After stirring for 3h LCMS showed only 30% conversion to product hence another aliquot of TEA (140μl, lmmol, 2eq.) and benzene sulfonyl chloride (64μl, 0.5mmol, leq.) was added to the reaction mixture. After stirring for 16h the reaction was quenched with water and extracted into DCM. The combined organic layers were dried over MgSO/i, filtered and evaporated in vacuo. Purification by FCC (gradient elution, 0% to 30% EtO Ac/heptane) afforded the title compound Intermediate 5 (145mg, 73%).
Intermediate 6
Figure imgf000046_0002
[00266] Intermediate^ (145mg, 0.366mmol, leq.) was dissolved in THF (5ml). Methanol (ImI) and 2M aqueous LiOH (5ml) were added, and the reaction mixture stirred for 18h. The solvents were removed in vacuo and the residue taken up into DCM (20ml). Water (40ml) was added and the pH of the aqueous layer adjusted to pH5 with 4M aqueous HCl. The mixture was then partitioned with DCM (80ml). The organic layer was removed, dried over MgSO/i, filtered and evaporated in vacuo. DCM (30ml) was added, the mixture filtered, and the solid washed with DCM (60ml). The combined filtrate and DCM washings were evaporated in vacuo to dryness to yield the title compound Intermediate 6 as a pale yellow solid (95mg, 70%). The crude product was taken directly to the next step without purification.
Compound 3
N-Benzyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide
Figure imgf000047_0001
[00267] Intermediate^) (60mg, 0.163mmol, leq.), 1-phenylpiperazine (28μl, 0.179mol, leq.), and the procedure and purification described for example 2 were used to synthesise the title compound^ (32mg, 38%). The procedure was modified by stirring the reaction for 3h not 2h.
Compound 4
Figure imgf000047_0002
[00268] Intermediate^ (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), ethyl piperidine-
4-carboxylate (21.58μl, 0.14mmol, leq.), and the procedure and purification described for example 2 were used to synthesise the title compound 4 as a yellow gum (12mg, 17%). The procedure was modified by stirring the reaction for 28h not 2h and by forming the activated ester for 45 min not 30min.
Compound 5
Figure imgf000047_0003
[00269] Intermediate^ (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), 4-pyrid-2- yl(piperidine) (22.71mg, 0.14mmol, leq.), and the procedure and purification described for example 4 were used to synthesise the title compound 5 as a yellow gum (11.2mg, 16%).
Compound 6
N-Benzyl-N-{4-[4-(2-oxo-pyrrolidin-1-yl)-piperidine-1-carbonyl]-phenyl}-benzenesulfonamide
Figure imgf000048_0001
[00270] Intermediate_6 (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), 4-(N-2- pyrrolidinone)-piperidine (23.55mg, 0.14mmol, leq.), and the procedure and purification described for example 4 were used to synthesis e the title compound 6 as a yellow gum (11.3mg, 16%).
Compound 7 yl}-N b l b lf id
Figure imgf000048_0002
[00271] Intermediate^ (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), 2-piperidin-4-yl-
1H-benzoimidazole (28.18mg, 0.14mmol, leq.), and the procedure and purification described for example 4 were used to synthesise the title compound 7 as a yellow gum (7.9mg, 11%).
Compound 8
Figure imgf000048_0003
[00272] Intermediate^ (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), 1- methylpiperazine (14.02mg, 0.14mmol, leq.), and the procedure and purification described for example 4 were used to synthesise the title compound £ as a yellow gum (11.8mg, 19%).
Compound 9
N-Benzvl-N-{4-[4-(pvrrolidine-1-carbonyl)-piperidine-1-carbonvll-phenyl}-benzenesulfonamide
Figure imgf000049_0001
[00273] Intermediate^) (50mg, 0.136mmol, leq.), CDI (55mg, 3.4mmol, 2.5eq.), 4-piperidinyl(l- pyrrolidinyl)methanone (25.52mg, 0.14mmol, leq.), and the procedure and purification described for example 4 were used to synthesise the title compound 8 as a yellow gum (24mg, 33%). The procedure was modified by stirring the reaction for 4.5h not 2h.
Compound 12
Figure imgf000049_0002
[00274] Intermediate 3 (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), 4-pyrid-2- yl(piperidine) (19.47mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound Y2 as a yellow gum (3 lmg, 46%).
Compound 13
Figure imgf000049_0003
[00275] CDI (50mg, 3.1 lmmol, 2.5eq.) was added to a stirred solution of Intermediate 3 (50mg,
0.124mmol, leq.) in DMF (2ml). After stirring for 30mins 4-(N-2-pyrrolidinone)-piperidine (20.19mg, 0.12mmol, 0.96eq.) was added and the reaction stirred for 2h. LCMS indicated that the product had not formed hence another aliquot of 4-(N-2-pyrrolidinone)-piperidine (20.19mg, 0.12mmol, 0.96eq.) was added and the mixture stirred for 16h. Again LCMS indicated that the reaction had not proceeded hence another aliquot of 4-(N-2-pyrrolidinone)-piperidine (20.19mg, 0.12mmol, 0.96eq.) was added and the mixture heated at 60°C for 24h. The solvent was removed in vacuo and the residue purified by preparative HPLC to yield the title compound 1_3 as a colourless gum (12.4mg, 18%).
Compound 14
Figure imgf000050_0001
[00276] Intermediate _3 (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), 2-piperidin-4- yl-1H-benzoimidazole (24.15mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound 14 as a colourless gum (17.1mg, 24%).
Compound 15
Figure imgf000050_0002
[00277] Intermediate^ (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), 1- methylpiperazine (13.31 μl, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound 1_5 as a colourless gum (28.3mg, 47%).
Compound 16
[00278] Intermediate _3 (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), 2- piperazinopyrimidine (18.42μl, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound \6_ as a white solid (34.2mg, 50%). The procedure was modified as the reaction was not complete after the 2h stir. Another aliquot of 2- piperazinopyrimidine (19.71mg, 0.12mmol, 0.96eq.) was added and the reaction stirred for an additional 16h.
Compound 17
Figure imgf000051_0001
[00279] Intermediate^ (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), l-(3- dimethylaminopropyl)-piperazine (20.55mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound 1/7 as a yellow gum (3. lmg, 4%).
Compound 18
Figure imgf000051_0002
[00280] Intermediate! (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), l-(2- fluorophenyl)piperazine (21.63mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound W>_ as a white solid (15.9mg, 23%).
Compound 19
N-(4-Chloro-benzyl)-N-{4-[4-(4-fluoro-phenyl)-piperazine-1-carbonvll-phenvl}-benzenesulfonamide
Figure imgf000052_0001
[00281] Intermediate^ (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), l-(4- fluorophenyl)piperazine (21.63mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound \9_ as a yellow gum (44mg, 63%).
Compound 20 -
Figure imgf000052_0002
[00282] Intermediate! (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), l-(2- pyrazinyl)piperazine (19.71mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound 20_ as a yellow gum (36.2mg, 53%).
Compound 21 enyl}-benzenesulfonamide
Figure imgf000052_0003
[00283] Intermediate! (50mg, 0.124mmol, leq.), CDI (50mg, 3.1 lmmol, 2.5eq.), l-(3- fluorophenyl)piperazine (21.63mg, 0.12mmol, 0.96eq.), and the procedure and purification described for example 2 were used to synthesise the title compound 7Λ_ as a colourless gum (29mg, 41%).
Intermediate 7
3-(4-Chloro-benzylamino)-benzoic acid ethyl esteracid
Figure imgf000053_0001
[00284] Acetic acid (2.1ml, 36.3mmol, 3eq.) was added to a solution of 4-chlorobenzaldehyde
(4.3ml, 36.3mmol, 3eq.) and ethyl 3-aminobenzoate (2g, 12.1mmol, leq.) in DCE (25ml), and the reaction stirred for 1.5h. STAB (5.13g, 24.2mmol, 2eq.) was added and the reaction mixture stirred until LCMS indicated that the reaction was complete. The reaction was quenched with the addition of saturated aqueous NaHCθ3 until the mixture was basic. DCM (25ml) was added and the layers separated. The aqueous layer was extracted with DCM (50ml). The combined organic layers were dried over MgSO/i, and concentrated in vacuo to yield the title compound Intermediate 7 as a yellow oil that solidified on standing (6.43g, quantitative). The crude product was taken directly to the next step without purification.
Intermediate 8
Figure imgf000053_0002
[00285] Intermediate J7 (6.337g, 21.9mmol, leq.) was dissolved in pyridine (70ml) and benzene sulfonyl chloride (3.08ml, 24.1mmol, l.leq.) added. After stirring for 2Oh, EtOAc (150ml) was added to the reaction mixture, and the resulting solution washed with IM aqueous HCl (2 x 150ml). The organic layer was dried over MsSO/i, filtered, and evaporated in vacuo. Purification by FCC (10% to 20% EtO Ac/heptane) afforded the title compound Intermediate 8 (3.4 Ig, 66% over two steps).
Intermediate 9
Figure imgf000053_0003
[00286] Intermediate 8 (2g, 4.65mmol, leq.) was dissolved in THF (10ml), 2M aqueous LiOH
(4.7ml, 9.3mmol, 2eq.) was added and the reaction mixture stirred for 2h. TLC indicated that the reaction was not complete hence an additional aliquot of 2M aqueous LiOH (2ml) was added and stirring continued for another 2h. Again TLC indicated that the reaction was not complete hence a third aliquot of 2M aqueous LiOH (2ml) was added and stirring continued for another 2h. The reaction mixture was concentrated in vacuo, then dissolved in 2M aqueous HCl (25ml) and EtOAc (25ml). The layers were separated, and the aqueous phase extracted with EtOAc (25ml). The combined organic layers were dried over MgSO/i, filtered and evaporated in vacuo to yield the title compound Intermediate 9 as a white solid (1.609g, 90%). The crude product was taken directly to the next step without purification.
Compound 22
Figure imgf000054_0001
[00287] CDI (356.73mg, 2.2mmol, 10 x l.leq.) was added to a suspension of Intermediate 9
(803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml) and the mixture stirred for 30min. A 5ml aliquot of the reaction mixture was removed and added to 4-piperidinyl(l-pyrrolidinyl)methanone (40.1mg, 0.22mmol, 1.1 eq.). The reaction was stirred overnight at room temperature. The reaction was quenched by the addition of saturated ammonium chloride (5ml). The aqueous layer was separated and washed with DCM (2ml). The combined organic layers were dried over MgSO/i, filtered and evaporated in vacuo. Purification by preparative HPLC afforded the title compound 22 (71.2mg, 63%).
Compound 23
Figure imgf000054_0002
[00288] Ethyl piperidine-4-carboxylate (33.91μl, 0.22mmol, l.leq.), an aliquot (5ml) of
Intermediate 9 (803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) afforded the title compound 23 (94mg, 87%).
Compound 24
Figure imgf000055_0001
[00289] 4-Pyrid-2-yl(piperidine) (35.69mg, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9
(803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by preparative HPLC afforded the title compound 24 (27.2mg, 25%).
Compound 25
Figure imgf000055_0002
[00290] 2-Piperidin-4-yl-1H-benzoimidazole (44.28mg, 0.22mmol, l.leq.), an aliquot (5ml) of
Intermediate 9 (803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by preparative HPLC afforded the title compound 25 (30mg, 26%).
Compound 26
N-(4-Chloro-benzyl)-N-[3-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide
Figure imgf000056_0001
[00291] 1 -Phenylpiperazine (35.69mg, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9
(803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) and preparative HPLC afforded the title compound 26 (87.7mg, 80%).
Compound 27
Figure imgf000056_0002
[00292] l-(2-Pyridyl)piperazine_(35.91mg, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9
(803.74mg, 2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) afforded the title compound 27 (81.3mg, 74%).
Compound 28
Figure imgf000056_0003
[00293] 4-Phenylpiperidine (35.47mg, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9
(803.74mg, 2.0mmol, 10 x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) afforded the title compound 28 (95.1mg, 87%).
Compound 29
Figure imgf000057_0001
[00294] Piperidine (21.73μl, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9 (803.74mg,
2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) afforded the title compound 29 (77.6mg, 83%).
Compound 30
Figure imgf000057_0002
[00295] Pyrrolidine (18.07μl, 0.22mmol, l.leq.), an aliquot (5ml) of Intermediate 9 (803.74mg,
2.0mmol, 1O x leq.) in DCM (50ml), and the procedure described for example 22 were used to synthesise the crude product. Purification by FCC (50% EtO Ac/heptane) afforded the title compound 30 (83mg, 91%).
Compound 31
Figure imgf000057_0003
[00296] CDI (50mg, 0.3117mmol, 2.5eq.) was added to a solution of Intermediate 3 (50mg,
0.1247mmol, leq.) in DCM (2ml) and the mixture stirred for 30min. 1-Benzylpiperazine (24mg, 0.1372mmol, l.leq.) was added and the reaction mixture stirred for 3h. The solvent was evaporated in vacuo and the crude product purified by preparative HPLC to afford the title compound 3J_ (46.8mg,
67%). SYNTHETIC SCHEME 2
Figure imgf000058_0001
Ar is R2, Ar1 is R1, and R1, R1, and R3 are as described herein.
Intermediate 10
Figure imgf000058_0002
[00297] Benzene sulfonyl chloride (0.85ml, 6.57mmol, leq.) was added to a solution of 6- aminonicotinic acid methyl ester (Ig, 6.57mmol, leq.) suspended in pyridine (5ml) and the resulting mixture stirred for 3h. A colour change was observed from bright yellow to bright orange. The reaction mixture was partitioned between DCM and water. A precipitate was observed that was collected by filtration under suction to afford the title compound Intermediate 10 as a pale yellow solid (1.35g, 63%).
Intermediate 11
Figure imgf000058_0003
[00298] Intermediate 10 (1.35g, 4.62mmol, leq.) was suspended in acetone (20ml) in a 10ml microwave tube. Potassium carbonate (1.28g, 9.24mmol, 2eq.) was added followed by 4-chlorobenzyl bromide (1.05g, 5.08mmol, l.leq.). The reaction mixture was heated in a CEM microwave at 150W, 100°C, 200psi for 30min. The resulting mixture was partitioned between EtOAc and water. The organic layers were dried over Na2SO/), filtered and concentrated in vacuo to yield a pale yellow solid. 10% EtOAc in heptane (20ml) was added to the solid. The resulting white solid was collected by suction filtration to afford the title compound Intermediate 11 (802mg, 42%).
Intermediate 12
Figure imgf000059_0001
[00299] 2M Aqueous LiOH was added to a solution of Intermediate 11 (400mg, 0.959mmol, leq.) dissolved in THF (5ml) and methanol (ImI) and the reaction stirred for 2h. The reaction mixture was acidified to pH 2 and the precipitate collected by vacuum filtration to yield the title compound Intermediate 12 (333mg, 86%). The crude product was taken directly to the next step without purification
Compound 32
Figure imgf000059_0002
[00300] CDI (17.8mg, 0.1 lmmol, l.leq.) was added to a stirred solution of Intermediate 12
(40.3mg, 0. lmmol, leq.) was dissolved in DMF (2ml). After stirring for Ih, 1-phenylpiperazine (16.8μl, 0.1 lmmol, 1.1 eq.) was added and the reaction stirred overnight. The reaction mixture was partitioned between EtOAc (4ml) and a 1 :1 mixture of water/brine. The organic layer was washed sequentially with water (2 x 4ml) and brine (2 x 4ml), dried over MgSO/i, filtered and evaporated in vacuo to yield a yellow oil. Purification by FCC (0% to 50% EtO Ac/heptane) afforded the title compound 32 (4.4mg, 8%).
Intermediate 13
Figure imgf000060_0001
[00301] Ethyl 4-aminobenzoate (500mg, 3.026mmol, leq.) was dissolved in pyridine (5ml) and stirred for lOmin. n-Propyl sulfonyl chloride (510μl, 4.54mmol, leq.) was added and the resulting mixture stirred for 2h. The solvent was evaporated in vacuo, the residue taken up into DCM (20ml), and partitioned between DCM (50ml) and IM aqueous HCl (40ml). The organic layer was evaporated in vacuo and the residue taken up into 10% EtO Ac/heptane (10ml). The product precipitated, which was removed by vacuum filtration. The precipitate was washed with 10% EtO Ac/heptane (50ml) to afford the title compound Intermediate 13(490mg, 60%).
Intermediate 14
Figure imgf000060_0002
[00302] Intermediate 10 (200mg, 0.737mmol, leq.), potassium carbonate (204mg, 1.474mmol,
2eq.) and 4-chlorobenzyl bromide (227mg, 1.105mmol, 1.5eq.) were dissolved in acetone (4ml) and stirred at 120°C, in a microwave for 30min. The solvent was evaporated in vacuo, the residue taken up into DCM (10ml), and partitioned between DCM (10ml) and water (30ml). The organic layer was evaporated in vacuo and the residue purified by FCC (Isolute 5g cartridge; gradient elution from 0% to 100% EtO Ac/heptane) to afford the title compound Intermediate 14 as a yellow/orange solid (232mg, 79%).
Intermediate 15
Figure imgf000060_0003
[00303] Intermediate !4_(100mg, 0.2532mmol, leq.) was dissolved in a mixture of 2M aqueous
LiOH:THF:MeOH (lml:lml:0.2ml) and the reaction mixture stirred for 2h. The solvent was evaporated in vacuo, the residue taken up into DCM (10ml), and partitioned between DCM (60ml) and 2M aqueous HCl (40ml). The organic layer was evaporated in vacuo to afford the title compound Intermediate 15 (50.9mg, 55%). The crude product was taken directly to the next step without purification
Compound 34
Figure imgf000061_0001
[00304] Intermediate V2 (50mg, 0.2577mmol, leq.) was dissolved in DMF (ImI) and stirred for lOmin. CDI (62.68mg, 0.386mmol, 1.5eq.) was added and stirring continued for 30min. 1- Phenylpiperazine (59.05μl, 0.386mmol, 1.5eq.) was added and the reaction mixture stirred for 18h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 34 (14mg, 9%
Figure imgf000061_0002
Ar is R2, Ar1 is R1, and R1, R1, and R3 are as described herein.
Intermediate 16
N-(6-Cyano-pyridin-3-yl)-benzenesulfonamide
Figure imgf000062_0001
[00305] 5-Amino-2-cyanopyridine (Ig, 8.394mmol, leq.) and benzene sulfonyl chloride (1.61ml,
12.6mmol, 1.5eq.) were dissolved in pyridine (5ml) and stirred for 18h. The solvent was evaporated in vacuo, and the residue partitioned between DCM (80ml) and 2M aqueous HCl (40ml). The organic layer was evaporated in vacuo to yield a mixture of the mono and bis sulfonylated compounds. The residue was dissolved in 2M NH3 in MeOH and the resulting solution stirred at 120°C in a microwave for 30min. The solvent was removed in vacuo to yield the crude product with no bis sulfonylated contaminant. Purification by FCC (Isolute 5Og cartridge; gradient elution with )5 to 100% EtO Ac/heptane) afforded the title compound Intermediate 16 (1.12g, 52%).
Intermediate 17
Figure imgf000062_0002
[00306] 4-Chlorobenzyl bromide (1.33g, 6.479mmol, 1.5eq.), Intermediate 16 (1.12g, 4.319mmol, leq), and the procedure described for Intermediate 14 were used to synthesise the crude product. Purification by FCC (Isolute 5Og cartridge; 0% to 100% EtO Ac/heptane) afforded the title compound Intermediate 17 as a yellow gum (995mg, 60%).
Intermediate 18
Figure imgf000062_0003
[00307] A solution of Intermediate 17 (995mg, 2.592mmol, leq) in a mixture of 2M aqueous
NaOH, THF and methanol (5:5:1, 20ml) was heated with stirring at 100°C for 2h. The solvents were removed in vacuo and the residue taken up into DCM (20ml). The resulting solution was partitioned between IM aqueous HCl (50ml) and DCM (130ml). The organic layer was removed and evaporated in vacuo to afford the title compound Intermediate 18 as a pale yellow solid (961mg, 92%).
Compound 35
Figure imgf000063_0001
[00308] Intermediate 18 (50mg, 0.1244mmol, leq.), 2-piperidin-4-yl-1H-benzoimidazole
(37.55mg, 0.1866mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound 3^ as its bis TFA salt (25mg, 35%).
Compound 36
Figure imgf000063_0002
[00309] Intermediate 18 (50mg, 0.1244mmol, leq.), 1 -benzylpiperazine (32.88mg, 0.1866mmol,
1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound^ as its bis TFA salt (32mg, 56%).
Compound 37
l-{5-[Benzenesulfonyl-(4-chloro-benzyl)-amino]-pyridine-2-carbonyl}-piperidine-4-carboxylic acid ethyl ester
Figure imgf000064_0001
[00310] Intermediate 18 (50mg, 0.1244mmol, leq.), ethyl piperidine-4-carboxylate (28.77μl,
0.1866mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound 37 as its mono TFA salt (25mg, 37%).
Compound 38
Figure imgf000064_0002
[00311] Intermediate 18 (50mg, 0.1244mmol, leq.), piperidine (18.43μl, 0.1866mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound 3J3 as its mono TFA salt (14mg, 24%).
Compound 39
Figure imgf000064_0003
[00312] Intermediate 18 (50mg, 0.1244mmol, leq.), 4-pyrid-2-yl(piperidine) (30.27mg,
0.1866mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound 39 as its mono TFA salt (31mg, 46%).
Compound 40
Figure imgf000065_0001
[00313] Intermediate d (50mg, 0.1244mmol, leq.), 1 -phenylpiperazine (28.55μl, 0.1866mmol,
1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC then FCC (Isolute 2g cartridge, gradient elution 0% to 100% EtO Ac/heptane) afforded the title compound 40 as its free base (15mg, 22%).
Compound 41
Figure imgf000065_0002
[00314] Intermediate d (50mg, 0.1244mmol, leq.), 1 -methylpiperazine (20.69μl, 0.1866mmol,
1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC then FCC (Isolute 2g cartridge, gradient elution 0% to 100% EtO Ac/heptane) afforded the title compound 4J_ as its free base (12.2mg, 20%).
Compound 42
N-(4-Chloro-benzvl)-N-{6-[4-(pvrrolidine-1-carbonyl)-piperidine-1-carbonyll-pvridin-3-vl}- benzenesulfonamide
Figure imgf000066_0001
[00315] Intermediate 18 (50mg, 0.1244mmol, leq.), 4-piperidinyl(l-pyrrolidinyl)methanone
(34.01mg, 0.1866mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) as solvent rather than DMF and by using 1.5 eq. of CDI not 2.5 eq. Purification by preparative HPLC afforded the title compound 42 as its mono TFA salt (30mg, 43%).
Compound 54
Figure imgf000066_0002
[00316] Intermediate 18 (50mg, 0.1244mmol, leq.), and CDI (30mg, 0.1866mmol, 1.5eq.) were dissolved in DCM (2ml) and stirred for Ih. 4-Hydroxypiperidine (15mg, 0.149mmol, 1.2eq.) was added and the reaction mixture stirred for 3h at room temperature. The reaction mixture was partitioned between water (2ml) and DCM (3 x 6ml). The combined organic layers were dried over MgSO/i, filtered and evaporated in vacuo. Purification by preparative HPLC afforded the title compound 54 (6.7mg, 11%).
Compound 55
Figure imgf000066_0003
[00317] Intermediate 18 (50mg, 0.1244mmol, leq.), 4-(3-fluorophenyl)-piperidine (27mg,
0.149mmol, 1.2eq.), and the procedure and purification described for example 54 were used to synthesise the title compound 55_ (16.5mg, 24%). The following compounds were synthesized using the scheme shown in Synthetic Route 2
Intermediate 19
Figure imgf000067_0001
[00318] Ethyl 4-aminobenzoate (3g, 18.18mmol, leq.) and benzene sulfonyl chloride (2.79ml,
21.8mmol, 1.2eq.) were dissolved in pyridine (20ml) and stirred for 18h. The reaction mixture was evaporated in vacuo and the residue dissolved in 2M NH3 in methanol (30ml). The resulting solution was heated at 90°C in a microwave for 30min. The solvent was removed in vacuo and the residue taken up into 10% EtOAc in heptane. The product precipitated as a white solid, which was collected by filtration. The product was washed with 10% EtOAc in heptane (50ml) and dried to afford the title compound Intermediate 19 as a white solid (5.74g, quantitative).
Intermediate 20
Figure imgf000067_0002
[00319] Intermediate 19 (lOOmg, 0.3279mmol, leq.), potassium carbonate (90mg, 0.6557mmol,
2eq.) and 4-fluorobenzyl bromide (61.57μl, 0.4918mmol, 1.5eq.) were dissolved in DMF (2ml) and stirred at 120°C, in a microwave for 30min. The solvent was evaporated in vacuo and the residue purified by preparative HPLC to afford the title compound Intermediate 20 as a yellow/orange solid (60mg, 44%).
Intermediate 21
4-[Benzenesulfonyl-(4-fluoro-benzyl)-amino]-benzoic acid
Figure imgf000068_0001
[00320] A solution of Intermediate 20 (60mg, 0.1453mmol, leq) in a mixture of 2M aqueous
LiOH, THF and methanol (lml:lml:0.2ml) was stirred at room temperature for 18h. The solvents were removed in vacuo and the residue partitioned between 2M aqueous HCl (10ml) and DCM (30ml). The organic layer was removed and evaporated in vacuo to afford the title compound Intermediate 21 as a pale yellow solid (50mg, 89%). The crude product was taken directly to the next step without purification.
Compound 43
Figure imgf000068_0002
[00321] Intermediate 21 (50mg, 0.1297mmol, leq.), 1 -phenylpiperazine (30μl, 0.1945mmol,
1.5eq.), CDI (31mg, 0.1945mmol, 1.5eq.), and the procedure described for example 2 were used to synthesise the crude product. The procedure was modified by using DCM (2ml) not DMF and by stirring for 18h not 2h. Purification by FCC (Isolute 2g cartridge, eluting with 0% the 100% EtO Ac/heptane) afforded the title compound 43 (21.3mg, 31%).
Intermediate 22
Figure imgf000068_0003
[00322] Intermediate 19 (305mg, lmmol, leq.), potassium carbonate (208mg, 1.5mmol, 1.5eq.) and 4-chlorobenzyl bromide (206mg, lmmol, leq.) were dissolved in acetone (5ml) and heated at 80°C in a sealed tube for 3h. The reaction mixture was partitioned between water (10ml) and DCM (2 x 10ml) The combined organic layers were dried over MgSO/i, filtered, and evaporated in vacuo to afford the title compound Intermediate 22 as a white solid (421mg, 98%).
Intermediate 23
Figure imgf000069_0001
[00323] Intermediate 22 (129mg, 0.3mmol, leq.), was dissolved in THF (0.5ml), 2M aqueous
LiOH (0.5ml) added followed by methanol (0.25ml). The reaction mixture was stirred at room temperature for 3h. The reaction was acidified to pH3 with IM aqueous HCl and the product extracted into DCM. The combined organic layers were dried over Na2SO/), filtered and evaporated in vacuo to afford the title compound Intermediate 23 as a white solid (120mg, quantitative). The crude product was taken directly to the next step without purification.
Compound 44
Figure imgf000069_0002
[00324] DMF (1 drop, catalytic) then oxalyl chloride (lOOμl, l.lόmmol, 3.9eq.) were added to solution of Intermediate 23 (120mg, 0.3mmol, leq.) in DCM (5ml). After stirring for 2h the reaction was concentrated in vacuo and the residue suspended in DCM (5ml). Piperidine (lOOμl, l.Olmmol, 3.36eq.) was added and stirring continued for Ih. The reaction was quenched with IM aqueous HCl and extracted with DCM. The combined organic layers were dried over Na2SO/), filtered and concentrated in vacuo. Purification by FCC (30% EtO Ac/heptane) afforded the title compound 44 (53mg, 38%).
SYNTHETIC SCHEME 4
Figure imgf000070_0001
Ar is R , Ar is R , and R , R , and R are as described herein.
Intermediate 24 id
Figure imgf000070_0002
[00325] Intermediate 19 (1.5g, 4.912mmol, leq), and the procedure described for Intermediate 7Λ_ were used to synthesise the title compound Intermediate 24 (l.lg, 95%).
Intermediate 25
Figure imgf000070_0003
[00326] Intermediate 24 (l.lg, 4mmol, leq.) was dissolved in DCM (15ml) and stirred for lOmin.
CDI (713mg, 4.4mmol, l.leq.) was added and stirring continued for 30min. 1-Phenylpiperazine (608μl, 4.8mmol, 1.2eq.) was added and the reaction mixture stirred for 3h. The solvent was removed in vacuo and the residue purified by FCC (0% to 100% EtO Ac/heptane) to afford the title compound Intermediate 25 (320mg, 19%). Compound 45
Figure imgf000071_0001
[00327] Sodium hydride (60% in mineral oil, 9.5mg, 0.39588mmol, 2eq.) was added to a stirred solution of Intermediate 25 (50mg, 0.188mmol, leq.) in DMF (2ml) and stirred for 45min. 2- Bromomethyl-pyridine (30.65mg, 0.1781mmol, 1.5eq.) was added and the reaction mixture stirred at room temperature under an atmosphere of N2 for 2h. LCMS indicated that no product had formed. In order to drive the reaction to completion the following sequence was followed:
• An additional aliquot of 2-bromomethyl-pyridine was added and the reaction mixture stirred at room temperature under an atmosphere of N2 for 6h.
• An additional aliquot of sodium hydride was added and the reaction mixture stirred at 100°C under an atmosphere of N2 for 45min.
• A solution of 2-bromomethyl-pyridine (30.65mg, 0.1781mmol, 1.5eq.) in dry DMF (ImI) was added and the reaction mixture stirred at 100°C under an atmosphere of N2 for 3h.
• The reaction mixture was stirred at 100°C under an atmosphere of N2 overnight.
The reaction mixture was evaporated in vacuo and the residue partitioned between water (20ml) and EtOAc (40ml). The organic layer was dried over MgSO/i, filtered evaporated in vacuo to yield the crude product. Purification by preparative HPLC afforded the title compound 45 (lOmg, 16%).
Compound 46
Figure imgf000071_0002
[00328] Sodium hydride (60% in mineral oil, 9.5mg, 0.39588mmol, 2eq.) was added to a stirred solution of Intermediate 25 (50mg, 0.188mmol, leq.) in DMF (2ml) and stirred for 45min. 3- Chloromethyl-pyridine (22.71mg, 0.1781mmol, 1.5eq.) was added and the reaction mixture stirred at room temperature under an atmosphere of N2 for 2h. LCMS indicated that no product had formed. Hence, another aliquot of sodium hydride was added and the reaction stirred at 100°C in a sealed tube. 3- Chloromethyl-pyridine in DMF was then added and the reaction mixture stirred at 100°C in a sealed tube for 18h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (20ml) and EtOAc (40ml). The organic layer was dried over MgSθ4, filtered evaporated in vacuo to yield the crude product. Purification by preparative HPLC afforded the title compound 46 (lOmg, 16%).
Compound 47
Figure imgf000072_0001
[00329] Sodium hydride (60% in mineral oil, 9.5mg, 0.39588mmol, 2eq.) was added to a stirred solution of Intermediate 25 (50mg, 0.188mmol, leq.) in DMF (2ml) and stirred for 45min. 3,4- Dichlorobenzyl bromide (42.74mg, 0.1781mmol, 1.5eq.) was added and the reaction mixture stirred at room temperature under an atmosphere of N2 for 2h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (20ml) and EtOAc (40ml). The organic layer was dried over MgSO/i, filtered evaporated in vacuo to yield the crude product. Purification by preparative HPLC afforded the title compound 47 (5mg, 7%).
Compound 48
Figure imgf000072_0002
[00330] Sodium hydride (60% in mineral oil, 6.65mg, 0.1663mmol, 2eq.) was dissolved in dry
DMF (0.5ml) and stirred at room temperature under an atmosphere of N2 for 15min. A solution of Intermediate 25 (35mg, 0.08314mmol, leq.) in DMF (ImI) was added and the reaction mixture stirred at room temperature under an atmosphere of N2 for 45min. 3-Fluorobenzyl-bromide (15.3μl, 0.1247mmol, 1.5eq.) was added and the reaction stirred at room temperature under an atmosphere of N2 for 2h. The solvent was removed in vacuo and the residue partitioned between water (20ml) and EtOAc (40ml). The organic layer was evaporated in vacuo. Purification of the residue by FCC (gradient elution, 0% to 100% EtO Ac/heptane) yielded the product in only 85% purity. Hence, the product was taken up into 10% DCM/EtOAc, from which the product precipitated. The solid was removed by filtration and washed with 10% DCM/EtOAc (10ml). Another FCC (gradient elution, 0% to 100% EtO Ac/heptane) afforded the title compound 48 (9mg, 21%).
The following compounds were synthesized using the scheme shown in Synthetic Route 1
Intermediate 26
Figure imgf000073_0001
[00331] Pyrimidine-5-carboxaldehyde (lOOmg, 0.6053mmol, leq.) was dissolved in DCE (2ml) and stirred for lOmin. Ethyl 4-aminobenzoate (130mg, 1.21mmol, 2eq.) and acetic acid (70μl, 1.21mmol, 2eq.) were added and the reaction mixture stirred for Ih. STAB (192mg, 0.9079mmol, 1.5eq.) was added and the reaction stirred for 2h. The reaction was partitioned between saturated aqueous NaHCθ3 and DCM. The organic layer was dried over a hydrophobic frit, concentrated in vacuo and the residue taken up into heptane/EtOAc (9:1). The resulting bright yellow precipitate was filtered and washed with heptane/EtOAc (9:1) (20ml) to yield the title compound Intermediate 26 (164mg, quantitative). The crude product was taken directly to the next step without purification.
Intermediate 27
4-(Benzenesulfonyl-pyrimidin-5-ylmethyl-amino)-benzoic acid ethyl ester
Figure imgf000073_0002
[00332] Intermediate 26 (80mg, 0.3109mmol, leq.) was dissolved in pyridine (2ml) and stirred for lOmins. Benzene sulfonyl chloride (60μl, 0.4664mmol, 1.5eq.) was added and the reaction mixture stirred for 3h. The reaction mixture was partitioned between water (30ml) and EtOAc (60ml). The organic layer was washed with brine (3 x 20ml), dried over MgSθ4, filtered and evaporated in vacuo. Purification by preparative HPLC afforded the title compound Intermediate 27 as a white solid (45mg, 36%).
Intermediate 28
4-(Benzenesulfonyl-pyrimidin-5-ylmethyl-amino)-benzoic acid -intermediate
Figure imgf000074_0001
[00333] Intermediate 27 (45mg, 0.1132mmol, leq.) was dissolved in a mixture of 2M aqueous
LiOH (2ml), methanol (0.2ml) and THF (2ml) and the reaction stirred for 2h. The solvents were removed in vacuo and the residue partitioned between EtOAc (60ml) and IM aqueous HCl (30ml). The organic layer was removed, dried over MgSθ4, filtered and evaporated in vacuo to yield the title compound Intermediate 28 as a yellow gum (40mg, 96%). The crude product was taken directly to the next step without purification.
Compound 49
Figure imgf000074_0002
[00334] CDI (21mg, 0.1299mmol, 1.2eq.) was added to a stirred solution of Intermediate 28
(40mg, 0.1083mmol, leq.) dissolved in DMF (2ml). After stirring for Ih, 1-phenylpiperazine (20μl, 0.1299mmol, 1.2eq.) was added and the reaction stirred for 2h. The reaction mixture was partitioned between EtOAc (30ml) and brine (3 x 20ml). The organic layer was dried over MgSO/i, filtered and evaporated in vacuo. Purification by preparative HPLC afforded the title compound 49 as a yellow gum (16mg, 29%).
SYNTHETIC SCHEME 5
Figure imgf000075_0001
Ar is R2, Ar1 is R1, and R1, R1, and R3 are as described herein.
Intermediate 29
Figure imgf000075_0002
[00335] BOC2O (904mg, 4.14mmol, 1.2eq.) was added to a solution of Intermediate 1 (Ig,
3.45mmol, leq.) and DMAP (42mg, 0.345, O.leq.) in THF (20ml) and the reaction stirred for 2h. Analysis indicated that the reaction was only 46% complete. Hence, another aliquot of BOC2O (904mg, 4.14mmol, 1.2eq.) was added and stirring continued for 16h. The solvent was removed in vacuo and the residue partitioned between 10% aqueous citric acid and DCM. The combined organics were dried over Na2SO4, filtered and evaporated in vacuo. Purification by FCC (0%, 10% then 20% EtO Ac/heptane) afforded the title compound Intermediate 29 as a colourless oil (1.97g, quantitative). NMR indicated that the product was still contained BoC2O. The product was taken directly to the next step without further purification.
Intermediate 30
4-[tert-Butoxycarbonyl-(4-chloro-benzyl)-amino]-benzoic acid
Figure imgf000076_0001
[00336] Intermediate 29 (1.97g, 3.45mmol, leq.) was suspended in a mixture of 2M aqueous
LiOH (10ml), methanol (5ml) and THF (10ml) and the reaction stirred for 2h. The solvents were removed in vacuo, the residue acidified to pH4 with IM aqueous HCl (30ml) and the product extracted into DCM. The organic layer was removed, dried over Na2SO/), filtered and evaporated in vacuo to yield the title compound Intermediate 28 as a white solid (1.16g, 93%). The crude product was taken directly to the next step without purification.
Intermediate 31
Figure imgf000076_0002
[00337] CDI (247mg, 1.523mmol, l.leq.) was added to a stirred solution of Intermediate 30 (0.5g,
1.385mmol, leq.) dissolved in DCM (10ml). After stirring for 15mins, 1-phenylpiperazine (233μl,
1.523mmol, 1.1 eq.) was added and the reaction stirred for 16h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM. The combined organics were removed, dried over
Na2SOzI, filtered and evaporated in vacuo. A white solid was obtained that was washed with 10%
EtO Ac/heptane and filtered to yield the title compound Intermediate 31 as a white solid (650mg, 94%).
The crude product was taken directly to the next step without further purification.
Intermediate 32
Figure imgf000076_0003
[00338] Intermediate 31 (650mg, 1.3mmol, leq.) was dissolved in a mixture of TFA (5ml) and
DCM (5ml) and stirred for Ih. The solvent was removed in vacuo, the residue basified with saturated aqueous NaHCθ3, and the product extracted into DCM. The combined organics were dried over MgSO/i, filtered, and concentrated in vacuo. A white solid was obtained that was washed with 10% EtO Ac/heptane and suction filtered to yield the title compound Intermediate 32 as a white solid (513mg, 97%). The crude product was taken directly to the next step without further purification.
Compound 50
Figure imgf000077_0001
[00339] Pyridine-3-sulfonyl chloride hydrochloride (26.37mg, 0.12mmol, leq.) was added to a solution of Intermediate 32 (50mg, 0.12mmol, leq.) in pyridine (ImI) and the reaction stirred for 16h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 50 (40mg, 59%).
Compound 51
Figure imgf000077_0002
[00340] 4-Fluorobenzenesulfonyl chloride (23.97mg, 0.12mmol, leq.) was added to a solution of
Intermediate 32 (50mg, 0.12mmol, leq.) in pyridine (ImI) and the reaction stirred for 16h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 5J_ (37.6mg, 54%). Compound 52
Figure imgf000078_0001
[00341] 3-Fluorobenzenesulfonyl chloride (23.97mg, 0.12mmol, leq.) was added to a solution of
Intermediate 32 (50mg, 0.12mmol, leq.) in pyridine (ImI) and the reaction stirred for 16h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 52 (33.2mg, 48%).
Compound 53
Figure imgf000078_0002
[00342] 2-Fluorobenzenesulfonyl chloride (23.97mg, 0.12mmol, leq.) was added to a solution of
Intermediate 32 (50mg, 0.12mmol, leq.) in pyridine (ImI) and the reaction stirred for 16h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 53 (29.7mg, 43%).
SYNTHETIC SCHEME 6 Reductive
Figure imgf000079_0001
Ar is R2, Ar1 is R1, and R1, R1, and R3 are as described herein.
Intermediate 33
Figure imgf000079_0002
[00343] 4-Chlorobenzaldehyde (0.59g, 4.2mmol, leq.), methyl 6-aminopyridine-2-carboxylate
(0.7g, 4.6mmol, l.leq.) and acetic acid (0.24ml, 4.2mmol, leq.) were stirred in DCE (7ml) for lOmin. STAB (0.89g, 4.2mmol, leq.) was added and the reaction stirred overnight. The solvent was concentrated in vacuo and the residue purified by FCC (10% EtO Ac/heptane) to yield the title compound Intermediate 33 (360mg, 31%).
Intermediate 34
Figure imgf000079_0003
[00344] 4-Fluorobenzenesulfonyl chloride (0.28g, 1.4mmol, l.leq.) was added to a solution of
Intermediate 33 (0.36g, 1.3mmol, leq.) in pyridine (3.3ml) and the reaction stirred for 4h. LCMS indicated that the reaction was not complete hence another aliquot of 4-fluorobenzenesulfonyl chloride (0.253g, 1.3mmol, leq.) was added and the reaction heated at 80°C overnight. The solvent was removed in vacuo, diluted with DCM and purified by FCC (Isolute 1Og cartridge, 10%, 20%, 50% then 100% EtO Ac/heptane) to afford the title compound Intermediate 34 as a white solid (0.45g, 80%).
Compound 56
Figure imgf000080_0001
[00345] Anhydrous MgCl2 (20mg, 0.2mmol, 2eg.) was added to Intermediate 34 (45mg, O.lmmol, leq.) in THF (2ml). After stirring for 5min piperidine (20μl, 0.2mmol, 2eq.) was added. LCMS after stirring for Ih indicated that no product had been formed hence another aliquot of anhydrous MgCl2 (40mg, 0.4mmol, 4eq.) was added and the reaction heated at 120°C in a microwave for 30min. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound 56 (18.3mg, 36%).
Compound 57
Figure imgf000080_0002
[00346] l-(3-Fluorophenyl)piperazine (54mg, 0.3mmol, 6eq.) was added to a mixture of anhydrous MgCl2 (30mg, 0.3mmol, 6eq.) and Intermediate 34 (22.5mg, 0.05mmol, leq.) in THF (2ml) and the mixture heated at 120°C in a 200W microwave for 30min. The solvent was removed in vacuo.
The residue was purified by FCC (10% to 50% EtO Ac/heptane) and then preparative HPLC to afford the title compound 57 (5.7mg, 19%).
Intermediate 35
Figure imgf000081_0001
[00347] STAB (1.05g, 4.9mmol, 1.3eq.) was added to a solution of 4-chlorobenzaldehyde (0.53g,
3.8mmol, leq.), 5-amino-nicotinic acid methyl ester (0.632g, 4.2mmol, l.leq.) and acetic acid (0.22ml, 3.8mmol, leq.) in DCE (12ml) and the reaction stirred overnight. The reaction was diluted with DCM and washed with saturated NaHCθ3. The organic layer was dried over Na2SO/), filtered and evaporated in vacuo. Purification by FCC (20%, 33.33%, then 50% EtO Ac/heptane) afforded the title compound Intermediate 35 (235mg, 20%).
Intermediate 36
Figure imgf000081_0002
[00348] 4-Fluorobenzenesulfonyl chloride (0.36g, 1.9mmol, 2.2 eq.) was added to a solution of
Intermediate 35 (0.235g, 0.85mmol, leq.) in pyridine (2.3ml) and the reaction heated at reflux overnight. The solvent was removed in vacuo, the residue diluted with DCM and purified by FCC (Isolute 1 Og cartridge, 10%, 20%, then 50% EtO Ac/heptane) to afford the title compound Intermediate 34 as a white solid (0.29g, 79%).
Compound 58 N-(4-Chloro-benzyl)-4-fluoro-N-[5-(piperidine-1-carbonyl)-pyridin-3-yl]-benzenesulfonamide
Figure imgf000082_0001
[00349] A mixture of anhydrous MgCl2 (30mg, 0.3mmol, 6eq.) and Intermediate 36 (22 mg,
0.05mmol, leq.) in THF (1.1ml) were stirred for 5min, then piperidine (30μl, 0.3mmol, 6eq.) was added. The reaction mixture was heated at 120°C in a 200W microwave for 30min. The solvent was removed in vacuo. The residue was purified by FCC (10% to 50% EtO Ac/heptane) and then preparative HPLC to afford the title compound 58 (5mg, 22%).
[00350] The syntheses of representative compounds of this invention can be carried out in accordance with the methods set forth above and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art.
ASSAYS
[00351] Compounds provided herein can be evaluated using cell-based assays such as electrophysiological assays, or can be evaluated in animal models ofautoimmune disease and immune- mediated responses and conditions. Examples of assays are described below.
[00352] The compounds provided herein can be tested for antagonist activity at voltage-gated ion channels such as voltage-gated potassium channels by measuring their ability to affect channel opening or their ability to block permeation of ions through the channel pore in response to depolarizing voltage changes across the cell membrane. Functional tests of channel activity include but are not limited to ion flux resulting from channel opening measured by electrophysiological methods. These methods can be used to evaluate channel function when the relevant ion channel is heterologously expressed in a mammalian or amphibian cells. These methods can also be used to evaluate compounds provided herein in rodent primary lymphocytes and other mammalian primary cells and cell lines that endogenously express the channel of interest.
[00353] Compounds can further be evaluated for their ability to bind the ion channel using biochemical approaches. Compounds can also be evaluated for their ability to modify lymphocyte signaling where the channels are known to have a role (e.g., cytokine production and cellular proliferation). Finally, compounds provided herein can be tested in vivo in animal models of immune- mediated processes and disorders and autoimmune diseases known to one skilled in the art, such as, for example, models of multiple sclerosis, arthritis, type I diabetes, and hypersensitivity in rodents or other mammals.
[00354] The following biological examples are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof.
Cell Culture
[00355] Chinese hamster ovary (CHO) cell lines stably expressing myc-epitope tagged Kvl .3 and flag-epitope tagged KvI.5 were generated by transfection of the respective cDNA into the cells, subsequent selection exploiting the blastcidin marker and re-cloning to obtain a clonal cell line. Expression of KV1.3 and KV1.5 was followed by immunofluorescence analysis using the anti myc- (KvI.3) or anti- flag (Kv1.5)-antibody and subsequently by electrophysiological investigations (see below). Cells expressing the ion channels were maintained and cultivated twice weekly in MEM-alpha medium (Sigma) supplemented with 10% fetal calf serum (FCS), 1% glutamine (Sigma) and 1% Pen/Strep (Invitrogen). For the fluorometric assay cells were plated into Corning Costar 384 tissue culture plates 24 h prior to screening using a Multidrop (Labsystems). Cells were plated at 10,000 cells per well in a total volume of 75 μL and incubated overnight at 37°C and 5% CO2. For electrophysiological investigations using the manual patch clamping rig cells were plated the day before the analysis in 2cm-dishes at a density of 2.5E4 cells/ml. For tests on the planar patch clamping systems cells were harvested using trypsin/EDTA (Sigma), washed twice in PBS, and used at a density of approx 5E6/ml.
Fluorometric assay
[00356] Changes in membrane potential were detected through the use of a membrane-potential sensitive fluorescent dye (FMP; Molecular Devices). The buffer system used was carefully selected to optimize the cell membrane potential and favour conditions where the number of ion channels in the open state would be at a maximum. The FMP dye was re-suspended in 10 ml of assay buffer according to the supplier's protocol. Cell plates were washed using a standard 384 plate washer with assay buffer, incubated with dye, and diluted in assay buffer for 5 min before compound addition. Cell plates were subsequently incubated with compounds for 60min and different concentrations, after which time the change in fluorescent signal was measured. Fluorescent recordings were performed on the Tecan Safire (Tecan, Crailsheim, Germany) using excitation and emission filters of 540 and 555 nm, respectively, and incorporating a bandwidth of 5 nm (Journal of Biomolecular Screening 2006:57-64).
Electrophysiology - manual patch clamping
[00357] Patch-clamp experiments were performed in the voltage-clamp mode and whole-cell currents were recorded in (extracellular solution) NaCl 13OmM, KCl 5.4mM, MgCl2 ImM, CaCl2 1.8mM, HEPES 10 mM, and glucose 5 mM, pH 7.4, with NaOH. Intracellular solution was KCl 13OmM, HEPES 1OmM, glucose 5 mM, EGTA 1 mM, ATP-Mg 2 mM, and MgCl2 1 mM, pH 7.2, with KOH. For investigating effects and reversibility of a test compound on the potassium channels CHO-cells stably expressing the ion channels were clamped at a holding potential (HP) of -80 mV, hyperpolarized to -90 mV to determine the leak current, and depolarized for 200 ms to +40 mV. Intersweep interval was 20 sec. Pulse-cycling rate was 0.1 Hz. The area under curve (charge) during 200 ms of depolarization was analyzed. An initial period of 20 stimuli was recorded to determine a biexponential fit of endogenous current rundown. The total charge obtained is plotted against antagonist concentration on a logarithmic scale and IC50s are obtained using standard analysis protocols. After compound application, a washout period of approx. 5 min was recorded (Journal of Biomolecular Screening 2006:57-64).
Electrophysiology -patch clamping using the PatchLiner and the Port-a-Patch
[00358] Recordings were made at room temperature using the Patchliner or Port-a-Patch planar patch-clamp systems (Nanion, Mϋnchen, Germany) in whole-cell mode according to Nanion's standard procedures. Prior to recordings cells were detached from culture flasks with 0.05% trypsin/EDTA and re- suspended at a density of approx. 5E6/ml cells per ml. The bath (external) solution contained (mM): NaCl 140, KCl 4, MgCl2 1, CaCl2 2, Hepes 10, glucose 5; titrated to pH 7.4 with NaOH. The intracellular recording solution contained (mM): KCl 50, KF 60, NaCl 10, EGTA 20, HEPES 10; titrated to pH 7.2 with KOH. For investigating effects and reversibility of a test compound on the potassium channels CHO- cells stably expressing the ion channels were clamped at a holding potential (HP) of -100 mV, hyperpolarized to -120 mV to determine the leak current, and depolarized for 200 ms to +40 mV. Intersweep interval was 20 sec. The area under curve (charge) during 200 ms of depolarization was analyzed. An initial period of approx. 15 stimuli was recorded to determine an endogenous current rundown. In case of the Port-a-Patch the rundown was biexponentially fitted. In case of the PatchLiner the block of the compounds were referred to the charge obtained just prior to compound application. The total charge obtained is plotted against antagonist concentration on a logarithmic scale and IC50s are obtained using standard analysis protocols. After compound had been added a washout was recorded to analyse the reversibility of the block.
Electrophysiological Experiments Whole cell patch clamp:
[00359] Whole cell recordings are made either manually using a Multiclamp 200B patch-clamp amplifier and Clampex acquisition program (Molecular Devices Corporation) or by the automated 16 cell planar patch clamp instrument, QPatch (Sophion Bioscience) or Whole-cell recordings are obtained from CHO cells stably or transiently transfected with cDNA of respective ion channels. For the manual patch- clamp recordings, solutions are either applied for periods of 1 to 3s by a gravity flow, 8-valve delivery system, or for periods of milliseconds using the quick-change Dynaflow perfusion system (Cellectricon Inc.). The internal pipette solution may include 60 mM Potassium-Chloride, 60 mM Potassium Flouride, 20 mM EGTA, and 5 mM Hepes at pH 7.2; normal external solution is 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 2 mM MgCl2, 25 mM Hepes, and 10 mM glucose. Concentration-response curves are obtained by recording currents in response to brief (200 msec) depolarizing voltage steps at 15 second intervals. A series of baseline current responses are obtained in the presence of regular external saline. To obtain inhibition curves, compounds are applied to the cells at increasing concentrations for a defined time period while obtaining current responses. The periods of compound application at each concentration and the number of voltage steps applied to the cell at each concentration are constant for the entire test concentration series. Currents are measured in cells that are voltage clamped at -90 millivolts. Averaged steady- state current level at the end of the 3 minute compound application is measured and normalized to the maximum current response in control saline. These points are then plotted on a logarithmic scale and fitted by a Hill function. The IC5O is calculated from the resulting Hill fit.
Selectivity screens:
[00360] Compounds that inhibit Kvl .3 currents are tested for activity against other receptors to determine their selectivity for specific family members. The list of receptors assayed includes, but is not restricted to Kvl.l, KV1.5, KV1.4, KV3.1, KV2.1, hERG. The types of assay used for selectivity determination may include Electrophysiological determination of receptor inhibition in either mammalian cells stably expressing DNA encoding the channel of interest or inherently expressing the channel, including by using manual patch clamp or planar patch clamp system. Methods and data analysis will be similar to those described above for KV1.3.
Drug Metabolism and Pharmacokinetics Caco-2 permeability:
[00361] Caco-2 permeability is measured according to the method described in Yee, Pharm. Res.
14:763-6, 1997. Caco-2 cells are grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium is removed from both the apical and basolateral compartments and the monolayers are preincubated with pre- warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.75 hour at 37°C in a shaker water bath at 50 cycles/min. The apical buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgCl2 (pH 6.5). The basolateral buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCl2 and 0.5 mM MgCl2 (pH 7.4). At the end of the preincubation, the media is removed and test compound solution (lOμM) in buffer is added to the apical compartment. The inserts are moved to wells containing fresh basolateral buffer and incubated for 1 hr. Drug concentration in the buffer is measured by LC/MS analysis.
[00362] Flux rate (F, mass/time) is calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (Papp) is calculated from the following equation:
Papp (cm/sec) = (F * VD) / (SA * MD) where SA is surface area for transport (0.3 cm2), VD is the donor volume (0.3 ml), MD is the total amount of drug on the donor side at t = 0. All data represent the mean of 2 inserts. Monolayer integrity is determined by Lucifer Yellow transport.
Human dofetilide binding:
[00363] Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25 °C with 2 M HCl containing 1 mM MgCl2, 10 mM KCl. The cells are homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,00Og for 20 minutes at 4°C. The pellet is resuspended, homogenized and centrifuged once more in the same manner. The resultant supernatant is discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds. The membrane homogenate is aliquoted and stored at -80°C until use. An aliquot is used for protein concentration determination using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All the manipulation, stock solution and equipment are kept on ice at all time. For saturation assays, experiments are conducted in a total volume of 200 μl. Saturation is determined by incubating 20 μl of [3H] -dofetilide and 160 μl of membrane homogenates (20-30 μg protein per well) for 60 min at room temperature in the absence or presence of 10 μM dofetilide at final concentrations (20 μl) for total or nonspecific binding, respectively. All incubations are terminated by rapid vacuum filtration over polyetherimide (PEI) soaked glass fiber filter papers using Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.5 at 25 °C). Receptor-bound radioactivity is quantified by liquid scintillation counting using Packard LS counter.
[00364] For the competition assay, compounds are diluted in 96 well polypropylene plates as 4- point dilutions in semi-log format. All dilutions are performed in DMSO first and then transferred into 50 mM Tris buffer (pH 7.5 at 25 °C) containing 1 mM MgCl2, 10 mM KCl so that the final DMSO concentration became equal to 1%. Compounds are dispensed in triplicate in assay plates (4 μl). Total binding and nonspecific binding wells are set up in 6 wells as vehicle and 10 μM dofetilide at final concentration, respectively. The radioligand was prepared at 5.6x final concentration and this solution is added to each well (36 μl). The assay is initiated by addition of YSi poly-L-lysine Scintillation Proximity Assay (SPA) beads (50 μl, 1 mg/well) and membranes (110 μl, 20 μg/well). Incubation is continued for 60 min at room temperature. Plates are incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity is quantified by counting WALLAC MICROBETA plate counter.
HERG assay:
[00365] HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998). Before the day of experimentation, the cells are harvested from culture flasks and plated onto glass coverslips in a standard Minimum Essential Medium (MEM) medium with 10% Fetal Calf Serum (FCS). The plated cells are stored in an incubator at
37 °C maintained in an atmosphere of 95%02/5%C02. Cells are studied between 15-28 hrs after harvest. [00366] HERG currents are studied using standard patch clamp techniques in the whole-cell mode. During the experiment the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings are made using a patch clamp amplifier and patch pipettes which have a resistance of 1-3 MOhm when filled with the standard internal solution of the following composition (mM); KCl, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15 MOhm and seal resistances >lGOhm are accepted for further experimentation. Series resistance compensation is applied up to a maximum of 80%. No leak subtraction is done. However, acceptable access resistance depended on the size of the recorded currents and the level of series resistance compensation that can safely be used. Following the achievement of whole cell configuration and sufficient time for cell dialysis with pipette solution (>5 min), a standard voltage protocol is applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane is depolarized from a holding potential of -80 mV to +40 mV for 1000ms. This is followed by a descending voltage ramp (rate 0.5 mV msec-1) back to the holding potential. The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz). The amplitude of the peak current elicited around -4OmV during the ramp is measured. Once stable evoked current responses are obtained in the external solution, vehicle (0.5% DMSO in the standard external solution) is applied for 10-20 min by a peristalic pump. Provided there are minimal changes in the amplitude of the evoked current response in the vehicle control condition, the test compound of either 0.3, 1, 3, 10 mM is applied for a 10 min period. The 10 min period includes the time which supplying solution was passing through the tube from solution reservoir to the recording chamber via the pump. Exposing time of cells to the compound solution is more than 5 min after the drug concentration in the chamber well reaches the attempting concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells are exposed to high dose of dofetilide (5 mM), a specific IKr blocker, to evaluate the insensitive endogenous current.
[00367] All experiments are performed at room temperature (23 ± 1°C). Evoked membrane currents were recorded on-line on a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the patch clamp amplifier and a specific data analyzing software. Peak current amplitude, which occurred at around -40 mV, is measured off line on the computer.
[00368] The arithmetic mean of the ten values of amplitude is calculated under vehicle control conditions and in the presence of drug. Percent decrease of IN in each experiment is obtained by the normalized current value using the following formula: IN = (1- ID/IC )xlOO, where ID is the mean current value in the presence of drug and IC is the mean current value under control conditions. Separate experiments are performed for each drug concentration or time-matched control, and arithmetic mean in each experiment is defined as the result of the study. Half-life in human liver microsomes (HLM): [00369] Test compounds (1 μM) are incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM
(HLlOl) in 100 mM potassium phosphate buffer (pH 7.4) at 37°C on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. NADPH is only added to the reaction mixture of the P450 group. An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH was added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at -10 and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system. The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This is converted to a half- life value using following equation:
Half-life = In 2 / k. In Vivo Assays:
[00370] Various in vivo inflammatory, and visceral pain assays can be conducted in male
Sprague-Dawley rats weighing 250-350 g. Kvi.3 modulators may be administered prior to or post- induction of the inflammation model depending upon the specific model and the compound PK characteristics. The route of administration may include intraperitoneal, (i.p.), subcutaneous (s.c), oral (p.o.), intranvenous (i.v.), intrathecal (i.t), or intraplantar.
[00371] Various models of autoimmune disease or immune-mediated disorders or diseases are available and may be suitable for testing compounds. The Kvl .3 modulators may be administered prior to or post-induction of the immune disease model depending upon the specific model and the compound PK characteristics. The route of administration may include intraperitoneal, (i.p.), subcutaneous (s.c), oral (p.o.), intranvenous (i.v.), intrathecal (i.t.), or intraplantar. The endpoints for these studies may include mediation of immune reactions, inflammatory reactions, physical parameters, cellular parameters and will be appropriate for the model being utilized. Multiple Sclerosis EAE Model:
[00372] Several animal models are utilized for testing compounds for effectiveness in treating
MS. One immune-mediated model is the Experimental Allergic Encephalomyelitis (EAE) model where injection of certain myelin components into genetically susceptible animals leads to T cell-mediated CNS demyelination. EAE is a T cell mediated autoimmune disease of the central nervous system (CNS). Disease is induced in susceptible strains of mice (SJL mice) by immunization with CNS myelin antigens or alternatively, disease is passively transferred to susceptible mice using antigen stimulated CD4+ T cells (Pettinelli, J. Immunol. 127, 1981, p. 1420). EAE is widely recognized as an acceptable animal model for multiple sclerosis in primates (Alvord et al. (eds.) 1984. Experimental allergic encephalomyelitis— A useful model for multiple sclerosis. Alan R. Liss, New York). TMEV Model: [00373] Another experimental MS model is a viral model, whereby MS like disease is induced by
Theiler's murine encephalomyelitis virus (TMEV) (Dal Canto, M.C., and Lipton, H.L., Am. J. Path., 88:497-500 (1977)). The TMEV picornavirus is inoculated intracerebrally in susceptible strains of mice and induces immune-mediated progressive CNS demyelination which is clinically and pathologically similar to MS. Intracerebral virus injection is performed on 4-6 week old animals that are lightly anesthetized with metofane. Virus is injected using a 27 gauge needle with a Hamilton syringe that delivers a 10 ul volume which contains 2x105 PFU of the Daniel's strain of TMEV. Intracerebral injection results in greater than 98% incidence of chronic viral infection with demyelination. Chronically infected animals for remyelination experiments are generally 6-8 months post-infection. Animals are sacrificed and spinal cord tissue is processed and morphological evaluation of the spinal cord of each animal is assessed histologically. Mice are anesthetized with pentobarbital and perfused by intracardiac administration of fixative (phosphate buffered 4% formaldehyde with 1% glutaraldehyde, pH 7.4). Spinal cords are removed and sectioned coronally into 1 mm blocks, postfϊxed with osmium, and embedded in araldite. One micron-thick cross-sections are cut from each block and stained with 4% paraphenyldiamine. Demyelination and remyelination are quantified using a Zeiss digital analysis system (ZIDAS) and camera lucida . For each mouse, ten spinal cord cross sections are examined which span the entire cord from the cervical to the proximal coccygeal spinal column regions. Areas of demyelination are characterized by large amounts of myelin debris, macrophages engulfing debris, cellular infiltration and naked axons. Oligodendrocyte remyelination is characterized by areas of axons with abnormally thin myelin sheaths and the absence of Schwann cells. Statistical comparison of the extent of demyelination and remyelination is performed using the Student's t test. Lysolecithin Induced Demyelination:
[00374] 12 weeks old SJL/J mice are anesthetized with sodium pentobarbital and a dorsal laminectomy is performed in the upper thoracic region of the spinal cord. A 34 guage needle attached to a Hamilton syringe is used to inject 1 ml of a 1% solution of lysolecithin directly into the dorsolateral aspect of the cord. The wound is sutured in two layers, and mice are allowed to recover. The day of lysolecithin injection was designated day 0. Seven days after lysolecithin injection, mice are treated with compound(s) (1 mg/injection each). Control mice are treated with bolus intraperitoneal injection of PBS or other appropriate control. Three weeks and five weeks after the lysolecithin injection, mice are sacrificed and one um thick sections are prepared. The araldite block showing the largest lysolecithin- induced demyelination lesion is used for quantitative analysis. The total area of the lesion is quantitated using a Zeiss interactive digital analysis system. The total number of remyelinated fibers is quantitated using a Nikon microscope/computer analysis system. The data is expressed as number of remyelinated axons/mm of lesion. Arthritis
[00375] The collagen-induced arthritis model (CIA) is used as an autoimmune model for testing compounds (Myers, L.K. et al. Life Sci. (1997), 61(19): 1861-1878). Immunization of genetically susceptible rodents or primates with Type II collagen (CII) in complete Freund's adjuvant leads to the development of a severe polyarticular arthritis after about 3 weeks. Synovitis and erosions of cartilage and bone are observed as the hallmarks of CIA and mimic RA. DBA/1 mice aged between 10 and 12 weeks are administered Hypnorm™ (0.1 ml, intraperitoneally) and shaved at the base of the tail. Bovine collagen type II (CII) is emulsified with complete Freund's adjuvant at a final concentration of 2 mg/ml, and a total of 0.1 ml is injected intradermally at three sites at the base of the tail. Twenty-one days later, a booster (0.1 ml) consisting of CII emusified with incomplete Freund's adjuvant (2 mg/ml) is injected intradermally across three sites at the tail base. A further 3 days later animals are injected with lipopolysaccharide (40 μg in 0.1 ml phosphate-buffered saline [PBS]; E. coli serotype 055:B5; Sigma- Aldrich Co. Ltd, Poole, UK) intraperitoneally to synchronize disease (Caccese R, et al (1992) Mediators Inflamm 1 :273-279) The development and progression of arthritis is monitored every 2-3 days and assigned a clinical score based on visual signs of arthritis (0.25 = swelling in a single digit; 0.5 = swelling in more than one digit; 1 = swelling and erythema of the paw; 2 = swelling of the paw and ankle; 3 = complete inflammation of the paw; the maximum score for each mouse was therefore 12) and the thickness of hind paws is measured using POCO 2T calipers (Krosplin Langenmesstechnik, Schlϋchtern, Germany) . Animals with a clinical score of 0.5 or above are used in compound assessment experiments and administered varying doses of test compound. Mice are monitored until 40 days after immunization, when they were killed and blood collected for serum and draining lymph nodes collected for assessment of stimulated cytokine secretion. Diabetes
[00376] The main clinical feature of IDDM is elevated blood glucose levels (hyperglycemia) which is caused by auto-immune destruction of insulin-producing β-cells in the islets of Langerhans of the pancreas. A useful animal model in testing compounds for treating IDDM is the NOD mouse. The NOD mouse represents a model in which auto-immunity against beta-cells is the primary event in the development of IDDM. Diabetogenesis is mediated through a multi- factorial interaction between a unique MHC class II gene and multiple, unlinked, genetic loci, as in the human disease. [00377] Another animal model for studying the effects of compounds in IDDM is the streptozotocin (STZ) model (Hartner, A. et al. (2005), BMC Nephrol. 6(1 ):6). This model has been used extensively as an animal model to study the mechanisms involved in the destruction of pancreatic beta cells in IDDM. Diabetes is induced in rodents by the beta-cell toxin streptozotocin (STZ). STZ is taken up by the pancreatic beta cell through the glucose transporter GLUT-2. This substance decomposes intracellularly, and causes damage to DNA either by alkylation or by the generation of NO. The appearance of DNA strand breaks leads to the activation of the abundant nuclear enzyme poly(ADP- ribose) polymerase (PARP), which synthesizes large amounts of the (ADP-ribose) polymer, using NAD+ as a substrate. As a consequence of PARP activation, the cellular concentration of NAD+ may then decrease to very low levels, which is thought to abrogate the ability of the cell to generate sufficient energy and, finally, to lead to cell death. Delayed Type Hypersensitivity [00378] A pediatric animal model using the delayed type hypersensitivity (DTH) skin test is utilized to further evaluate compounds. Sprague Dawley rats (1 week old) are sensitized against keyhole limpet hemocyanin (KLH). Animals are then challenged 2 weeks later by an intradermal injection of KLH (0.3 mg) in sterile saline. Rats with positive DTH skin reactions at 24 and 48 hours after challenge (baseline) are divided randomly into control and compound treatment groups. Before each procedure (day 0) and on postoperative days 3 and 6, animals are again challenged intradermally with KLH (0.3 mg). DTH skin reaction is evaluated 24 and 48 hours later.
[00379] Cobb et al have also described a model utilizing a hairless guinea pig for the determination of delayed-type hypersensitivity to tuberculin (Cobb A et al (2001) Int Immunopharmacology l(2):349-353). This DTH model uses hairless (IAF/HA-HO) guinea pigs, sensitized with complete Freund's adjuvant and repeatedly skin tested with tuberculin, purified protein derivative, (PPD). At 10 weeks after sensitization, intradermal PPD elicited minimal erythema at 6 h, which increased over the next 18 h to a maximum at 24 h, and declined by 48 h. The response could be quantified by bioassay using graded doses of PPD. Reactions at 24 h were characterized by predominantly mononuclear cell deep and superficial dermal infiltrate. Graft Rejection
[00380] Compounds are tested for prevention or alteration of human T-cell mediated skin graft rejection in a reconstituted mouse model of skin transplantation. Human T-cell mediated destruction of allogeneic diurnal microvessels is evaluated in a severe combined immunodefϊcient mouse in accordance with Murray et al (Murray, A. G. et al (1994) PNAS USA 91 :9146-9153).
[00381] The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. In the examples, all temperatures are in degrees Celsius (unless otherwise indicated). Compounds that can be prepared in accordance with the methods provided herein along with their biological activity data are presented in following Table. The syntheses of these representative compounds are or can be carried out in accordance with the methods set forth above.
Exemplary Compounds of the Invention
[00382] The following compounds have been or can be prepared according to the synthetic methods described herein. Manual or automated patch-clamp assays were performed as described above and the activity of each compound is expressed as follows:
+ IC50 >100O nM
++ IC50 501-100O nM
+++ IC50 101-50O nM
++++ IC50 < 10O nM
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
NMR Data
Example 9
[00384] 1H NMR (400 MHz, MeOD) δ ppm 1.65 (3 H, br. s.) 1.75 - 1.93 (3 H, m) 1.93 - 2.02 (2
H, m) 2.77 - 2.96 (2 H, m) 3.06 - 3.18 (1 H, m) 3.39 (2 H, t, J=6.85 Hz) 3.57 (3 H, t, J=6.60 Hz) 4.61 (1 H, br. s.) 4.83 (2 H, s) 7.11 - 7.30 (9 H, m) 7.54 - 7.60 (2 H, m) 7.65 - 7.72 (3 H, m)
Example 18
[00385] 1H NMR (400 MHz, CDCl3) δ ppm 2.96 - 3.20 (4 H, m) 3.54 (2 H, br. s.) 3.93 (2 H, br. s.) 4.71 (2 H, s) 6.90 - 7.11 (6 H, m) 7.15 - 7.24 (4 H, m) 7.31 - 7.36 (2 H, m) 7.49 - 7.56 (2 H, m) 7.61 - 7.71 (3 H, m)
Example 29
[00386] 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (2 H, br. s.) 1.57 (4 H, d, J=3.42 Hz) 3.01 (2 H, br. s.) 3.55 (2 H, br. s.) 4.63 (2 H, s) 6.89 (1 H, s) 6.93 (1 H, dt, J=6.85, 2.20 Hz) 7.05 - 7.13 (4 H, m) 7.16 - 7.24 (2 H, m) 7.38 - 7.45 (2 H, m) 7.50 - 7.60 (3 H, m)
Example 39
[00387] 1H NMR (250 MHz, CDCl3) δ ppm 1.81 - 2.23 (4 H, m) 2.97 (1 H, br. s.) 3.25 (1 H, br. s.) 3.53 - 3.69 (1 H, m) 4.05 (1 H, br. s.) 4.74 (2 H, d, J=3.81 Hz) 4.89 (1 H, br. s.) 7.13 - 7.26 (4 H, m) 7.45 (1 H, dd, J=8.38, 2.44 Hz) 7.50 - 7.81 (8 H, m) 8.25 - 8.39 (2 H, m) 8.85 (1 H, s) Example 54
[00388] 1H NMR (500 MHz, CDCl3) δ ppm 1.49 (1 H, d, J=3.51 Hz) 1.54 - 1.68 (2 H, m) 1.89 (2
H, br. s.) 3.23 - 3.30 (1 H, m) 3.39 - 3.46 (1 H, m) 3.76 (1 H, br. s.) 4.00 (1 H, d, J=3.66 Hz) 4.15 (1 H, br. s.) 4.73 (2 H, s) 7.14 - 7.18 (2 H, m) 7.21 - 7.25 (2 H, m) 7.41 (1 H, dd, J=8.32, 2.52 Hz) 7.52 - 7.57 (3 H, m) 7.64 - 7.70 (3 H, m) 8.20 (1 H, d, J=2.29 Hz)
Example 55
[00389] 1H NMR (500 MHz, CDCl3) δ ppm 3.18 - 3.23 (2 H, m) 3.27 - 3.32 (2 H, m) 3.76 - 3.80
(2 H, m) 3.90 - 3.95 (2 H, m) 4.74 (2 H, s) 6.56 - 6.62 (2 H, m) 6.69 (1 H, dd, J=8.09, 1.83 Hz) 7.15 - 7.26 (5 H, m) 7.43 (1 H, dd, J=8.39, 2.44 Hz) 7.53 - 7.58 (2 H, m) 7.64 - 7.71 (4 H, m) 8.24 (1 H, d, J=2.14 Hz)
[00390] From the foregoing description, various modifications and changes in the compositions and methods provided herein will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.
[00391] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. [00392] At least some of the chemical names of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
[00393] Chemical structures shown herein were prepared using ISIS® /DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Claims

WHAT IS CLAIMED IS:
1. A compound having a formula 1 :
Figure imgf000101_0001
I wherein each W and Z is independently CH or N; X is CO, SO, or SO2; each R1 and R2 is independently selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; ml is 1 or 2; provided that the compound is not i) N-(phenylmethyl)-N-[4-(l -piperidinylcarbonyl)phenyl]-benzenesulfonamide, or ii) N-[[4-(2,4-dioxo-5-thiazolidinyl)phenyl]methyl]-N-[3-(4- morpholinylcarbonyl)phenyl]-2-naphthalenesulfonamide, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
2. A compound according to claim 1, wherein R1 is substituted or unsubstituted aryl.
3. A compound according to claim 1, wherein R1 is substituted or unsubstituted phenyl.
4. A compound according to claim 1, wherein R1 is substituted or unsubstituted heteroaryl.
5. A compound according to claim 1, wherein R1 is substituted or unsubstituted pyridyl.
6. A compound according to claim 1, wherein each of W and Z is CH.
7. A compound according to claim 1, wherein W is N; and Z is CH.
8. A compound according to claim 1, wherein W is CH; and Z is N.
9. A compound according to claim 1, wherein the compound is according to formula Ha, lib, Hc, Hd, He, or Hf:
Figure imgf000102_0001
Nd lie Nf wherein
X, R2, R3, and ml are as in claim 1 ; nl is selected from 1-5 and each R4 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, sulfo, substituted sulfo, substituted sulfinyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
10. A compound according to any one of claims 1 -9, wherein ml is 1.
11. A compound according to any one of claims 1-9, wherein ml is 2.
12. A compound according to any one of claims 1-11, wherein X is SO2.
13. A compound according to any one of claims 1-11, wherein X is CO.
14. A compound according to claim 1 , wherein the compound is according to formula Ilia, 1Hb, IUc,
HId, me, or IHf:
Figure imgf000103_0001
iiid INe wherein
R2 is as in claim 1; nl and R4 are as in claim 6; and R3 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
15. A compound according to any one of claims 1-14, wherein R3 is cycloalkyl.
16. A compound according to any one of claims 1-14, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
17. A compound according to any one of claims 1-14, wherein R is cyclohexyl.
18. A compound according to any one of claims 1-14, wherein R3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
19. A compound according to any one of claims 1-14, wherein R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with alkyl, or hydroxy.
20. A compound according to any one of claims 1-14, wherein R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with aryl or heteroaryl.
21. A compound according to any one of claims 1-14, wherein R is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted with benzimidazol-2-yl.
22. A compound according to claim 1, wherein the compound is according to formula IVa, IVb, IVc, IVd, IVe, or IVf:
Figure imgf000104_0001
wherein
Y is CH or N; R2 is as in claim 1 ; nl and R4 are as in claim 6; R > 33aa . is H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3a is C0R3b; and R3b is alkoxy or heterocycloalkyl.
23. A compound according to claim 22, wherein R a is H, Me, or benzyl.
24. A compound according to claim 22, wherein R3a is phenyl, unsubstituted or substituted with Me,
Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
25. A compound according to claim 22, wherein R3a is pyridyl, unsubstituted or substituted with Me,
Et, i-Pr, CF3, OMe, OCHF2, 0CF3, Cl, F, CN and NO2.
26. A compound according to claim 22, wherein R a is imidazolyl, or benzimidazolyl.
27. A compound according to claim 22, wherein R3a is C0R3b.
28. A compound according to claim 27, wherein R3b is OMe, OEt, or O-i-Pr.
29. A compound according to claim 27, wherein R3b is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
30. A compound according to any one of claims 9-29, wherein nl is 1 and R4 is selected from H, C1-
C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, dihalo C1-C4 alkoxy, trihalo C1-C4 alkoxy, CN, NO2, and halo.
31. A compound according to any one of claims 9-29, wherein nl is 1 and R4 is selected from H, Me,
Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
32. A compound according to any one of claims 9-29, wherein nl is 1 and R4 is selected from 4-Me,
4-Et, 4-i-Pr, 4-CF3, 4-OMe, 4-OCHF2, 4-OCF3, 4-Cl, 4-F, 4-CN and 4-NO2.
33. A compound according to any one of claims 9-29, wherein nl is 1 and R4 is selected from 4-Cl, or
4-CF3.
34. A compound according to any one of claims 1-33, wherein R is phenyl or naphthalenyl.
35. A compound according to any one of claims 1-33, wherein R2 is phenyl, unsubstituted or substituted with one or more groups selected from C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, dihalo C1-C4 alkoxy, trihalo C1-C4 alkoxy, CN, NO2, and halo.
36. A compound according to any one of claims 1-33, wherein R is phenyl, unsubstituted or substituted with one or more groups selected from Me, Et, i-Pr, CF3, OMe, OCHF2, OCF3, Cl, F, CN and NO2.
37. A compound according to any one of claims 1-33, wherein R2 is heteroaryl.
38. A compound according to any one of claims 1-33, wherein R is pyridyl, benzothiophenyl, quinolinyl, isoquinolinyl, thiophenyl, or furanyl.
39. A compound according to claim 1, wherein the compound is according to formula Va, Vb, Vc, Vd, Ve, or Vf:
Figure imgf000105_0001
wherein each R2a, R4 is independently H, halo, C1-C6 alkoxy; R3a and Y are as in claim 22.
40. A compound according to claim 39, wherein each R2a, and R4 is H.
41. A compound according to claim 39, wherein each R2a, and R4 is independently H, Cl, F, or OMe.
42. A compound according to any one of claims 39-41, wherein Y is CH or N; and R3ais phenyl, benzimidazol-2-yl, benzyl, 2-pyridyl, 2-fluorophenyl, 1 -pyrrolidinyl, CO-piperidin-1-yl, or CO- OEt.
43. A compound according to claim 1, wherein the compound is selected from compounds listed in Table 1; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1. The pharmaceutical composition of claim 44, wherein the carrier is suitable for parenteral administration. The pharmaceutical composition of claim 44, wherein the carrier is suitable for oral administration. The pharmaceutical composition of claim 44 wherein the carrier is suitable for topical administration. A method for the prevention or treatment of a disease or condition in a mammal that is related to aberrant activity of KV1.3, comprising administering to the mammal an effective disease- or condition-treating amount of a compound of any one of claims 1 -43 or a composition of any of claims 44-47. The method of claim 48, wherein the disease or condition is selected from: inflammation, arthritis, rheumatoid arthritism, multiple sclerosis; and osteoarthritis, myocardial infarction, autoimmune diseases and disorders, itch / pruritus, psoriasis; pain, acute pain, inflammatory pain, diseases and disorders which are mediated by or result in neuroinflammation, neurological and neurodegenerative diseases and disorders; inflammatory bowel disease; respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; and diseases and disorders which are mediated by or result in inflammation. The method of claim 48, wherein the disease or condition is Parkinson's disease. The method of claim 48, wherein the disease or condition is Alzheimer's disease. The method of claim 48, wherein the disease or condition is pain. The method of claim 52, wherein the pain is associated with osteoarthritis, rheumatoid arthritis, The method of claim 53, wherein the disease or condition is neuropathic pain. The method of claim 48, wherein the disease or condition is an autoimmune disease. The method of claim 48, wherein the disease or condition is an inflammatory disease or condition. The method of claim 48, wherein the disease or condition is a neurological or neurodegenerative disease or condition. A compound according to any of claims 1-43 for use in the treatment of a disease or condition, wherein the disease or condition is selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, , Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation, encephalitis;; neurological and neurodegenerative diseases and disorders; inflammatory bowel disease; respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, autoimmune diseases and disorders, itch / pruritus, psoriasis; and obesity. A compound according to any of claims 1-43 for use in the treatment of a disease or condition, wherein the disease or condition is selected from: Acute disseminated encephalomyelitis (ADEM), Addison's disease, Allopecia areata, Alzheimers disease, Ankylosing spondylitis, Antiphospholipid antibody syndrome, Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmune polyendocrine/polyglandular syndrome, Autoimmune thrombocytoipenia purpura, BaIo disease, Behcet disease, Bullous pemphigoid, Cardiomyopathy, Celiac sprue- dermatitis herpetiformis, Chronic fatigue immune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinating neuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinin disease, CREST syndrome, Crohn's disease, Cystic fibrosis, Degos disease, Dermatomyositis, Diabetes (Type I or Juvenile onset), Early onset dementia, Eczema, Endotoxin shock, Essential mixed cryoglobulinemia, Familial Mediterranean fever, Fibromyalgia, Fibromyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroidosis, Hidradenitis suppurativa, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgA nephropathy, Lambert-Eaton Myasthenic Syndrome, Leukemia, Lichen planus, Meniere disease, Mixed connective tissue disease, Multiple sclerosis, Multiphasic disseminated encephalomyelitis, Myasthenia gravis, Neuromyelitis Optica, Paraneoplastic Syndromes, Pemphigus, Pemphigus vulgaris, Pernicious anaemia, Polyarteritis nodosum, Polychondritis, Polymyalgia rhematica, Polymyositis, Primary agammaglobulinemia, Primary biliary cirrhosis, Plaque Psoriasis, Psoriatic arthritis, Raynaud phenomenon, Reiter syndrome, Restenosis following angioplasty, Rheumatic fever, Rheumatoid arthritis, Rheumatoid psoriasis, Sarcoidosis, Scleroderma, Sepsis, Sezary's disease, Sjogren's syndrome, Stiff-person syndrome, Systemic lupus erythematosis (SLE), Takayasu arteritis, Temporal arteritis (also known as "giant cell arteritis"), Transplant or Allograft rejection, Ulcerative colitis, Uveitis, Vasculitis, Vitiligo, Graft vs Host disease, pustular psoriasis, and Wegener's granulomatosis. Use of a compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition which requires KV1.3 inhibition. A compound according to any of claims 1-43 for use in the treatment of a disease or condition, wherein the disease or condition is selected from: resistance by transplantation of organs or tissue, graft- versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile- onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, Alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis,
Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper- responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal bums and leukotriene B4-mediated diseases, Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonenephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy; Pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on- chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.
PCT/EP2010/056225 2009-05-14 2010-05-07 Sulfonamide compounds, pharmaceutical compositions and uses thereof WO2010130638A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17849709P 2009-05-14 2009-05-14
US61/178,497 2009-05-14

Publications (1)

Publication Number Publication Date
WO2010130638A1 true WO2010130638A1 (en) 2010-11-18

Family

ID=42358100

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/056225 WO2010130638A1 (en) 2009-05-14 2010-05-07 Sulfonamide compounds, pharmaceutical compositions and uses thereof

Country Status (1)

Country Link
WO (1) WO2010130638A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012151452A1 (en) * 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use in therapy
WO2012151451A1 (en) * 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US20130172326A1 (en) * 2010-11-23 2013-07-04 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
US8758802B2 (en) 2009-12-14 2014-06-24 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US20150011551A1 (en) * 2012-02-22 2015-01-08 Sanford- Burnham Medical Reseach Institute Sulfonamide compounds and uses as tnap inhibitors
US9108921B2 (en) 2013-03-15 2015-08-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
WO2016146575A1 (en) 2015-03-13 2016-09-22 4Sc Discovery Gmbh Kv1.3 inhibitors and their medical application
WO2016146583A1 (en) 2015-03-13 2016-09-22 4Sc Discovery Gmbh Kv1.3 inhibitors and their medical application
US9657004B2 (en) 2009-04-06 2017-05-23 Agios Pharmaceuticals, Inc Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US9662327B2 (en) 2011-06-17 2017-05-30 Agios Pharmaceuticals, Inc Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer
US9675589B2 (en) 2013-03-14 2017-06-13 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9982309B2 (en) 2009-10-21 2018-05-29 Agios Pharmaceuticals, Inc. Method for treating cell proliferation related disorders
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
CN109651297A (en) * 2019-01-22 2019-04-19 杭州壹瑞医药科技有限公司 A kind of N- benzyl-N- aryl sulfonic acid amides analog derivative and preparation and application
CN109705033A (en) * 2019-01-22 2019-05-03 杭州壹瑞医药科技有限公司 N- heteroaryl sulfonamide analog derivative and preparation and application
CN109942537A (en) * 2018-03-03 2019-06-28 中国人民解放军第二军医大学 A kind of ALDH2 agonist, preparation method and its usage
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10610125B2 (en) 2009-03-13 2020-04-07 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
WO2020120479A1 (en) * 2018-12-11 2020-06-18 Sanofi Peptide binder
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10736863B2 (en) 2015-11-13 2020-08-11 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
RU2787757C2 (en) * 2011-05-03 2023-01-12 Аджиос Фармасьютикалз, Инк. Methods for use of pyruvate kinase activators
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024655A1 (en) * 2000-09-20 2002-03-28 Merck & Co., Inc. Isoquinolinone potassium channel inhibitors
US20040110793A1 (en) * 2002-04-19 2004-06-10 John Lloyd Heterocyclo inhibitors of potassium channel function
WO2007026962A1 (en) * 2005-08-31 2007-03-08 Daiichi Sankyo Company, Limited Phenylene derivative
WO2010023448A1 (en) * 2008-08-29 2010-03-04 Xention Limited Novel potassium channel blockers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024655A1 (en) * 2000-09-20 2002-03-28 Merck & Co., Inc. Isoquinolinone potassium channel inhibitors
US20040110793A1 (en) * 2002-04-19 2004-06-10 John Lloyd Heterocyclo inhibitors of potassium channel function
WO2007026962A1 (en) * 2005-08-31 2007-03-08 Daiichi Sankyo Company, Limited Phenylene derivative
WO2010023448A1 (en) * 2008-08-29 2010-03-04 Xention Limited Novel potassium channel blockers

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
BEETON C. ET AL., PROC. NATL. ACAD, SCI. U.S.A., vol. 98, 2001, pages 13942 - 7
BEETON C. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 103, no. 46, pages 17414 - 9
CACCESE R ET AL., MEDIATORS INFLAMM, vol. 1, 1992, pages 273 - 279
CHANDY K.G. ET AL., TRENDS PHARMACOL. SCI., vol. 25, no. 5, pages 280 - 9
COBB A ET AL., INT IMMUNOPHARMACOLOGY, vol. 1, no. 2, 2001, pages 349 - 353
DAL CANTO, M.C.; LIPTON, H.L., AM. J. PATH., vol. 88, 1977, pages 497 - 500
DALE; MOSHER, J. AM. CHEM. SOC., vol. 95, 1973, pages 512
DECOURSEY T.E. ET AL., NATURE, vol. 307, no. 5950, pages 465 - 8
GRISSMER S. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 87, no. 23, pages 9411 - 5
HARTNER, A. ET AL., BMC NEPHROL., vol. 6, no. 1, 2005, pages 6
JOURNAL OF BIOMOLECULAR SCREENING, 2006, pages 57 - 64
MATHEU M. P. ET AL., IMMUNITY, vol. 29, no. 4, pages 602 - 14
MURRAY, A.G. ET AL., PNAS USA, vol. 91, 1994, pages 9146 - 9153
MYERS, L.K. ET AL., LIFE SCI., vol. 61, no. 19, 1997, pages 1861 - 1878
PANYI G. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 101, no. 5, pages 1285 - 90
PANYI, G ET AL., TRENDS IMMUNOL, vol. 25, 2004, pages 565 - 569
PETTINELLI, J. IMMUNOL., vol. 127, 1981, pages 1420
RUS H ET AL., PNAS, vol. 102, 2005, pages 11094 - 11099
S.H. WILEN; A. COLLET; J. JACQUES, TETRAHEDRON, 1977, pages 2725
SZABO 1. ET AL., J. BIOL. CHEM., vol. 280, no. 13, pages 12790 - 8
SZABO I. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 105, no. 39, pages 14861 - 6
TEN HOEVE; H. WYNBERG, JOURNAL OF ORGANIC CHEMISTRY, vol. 50, 1985, pages 4508 - 4514
TSCHRITTER O. ET AL., J. CLIN. ENDOCRINOL. METAB., vol. 91, no. 2, pages 654 - 8
TUCKER K. ET AL., INT. J. OBES. (LOND), vol. 32, no. 8, pages 1222 - 32
VALVERDE P. ET AL., J. DENT. RES, vol. 84, no. 6, pages 488 - 99
WULFF H. ET AL., J. CLIN. INVEST., vol. 111, no. 11, pages 1703 - 13
WULFF H. ET AL., J. IMMUNOL., vol. 173, no. 2, pages 776 - 86
WULFF, H ET AL., J CLIN INVEST, vol. 111, 2003, pages 1703 - 1713
WULFFH. ET AL., J. CLIN. INVEST., vol. 111, no. 11, pages 1703 - 13
XU J. ET AL., HUM. MOL GENET., vol. 12, no. 5, pages 551 - 9
XU J. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 101, no. 9, pages 3112 - 7
YEE, PHARM. RES., vol. 14, 1997, pages 763 - 6
ZHOU ET AL., BIOPHYS. J., vol. 74, 1998, pages 230 - 41

Cited By (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10610125B2 (en) 2009-03-13 2020-04-07 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
US9657004B2 (en) 2009-04-06 2017-05-23 Agios Pharmaceuticals, Inc Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US9938259B2 (en) 2009-04-06 2018-04-10 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US10988448B2 (en) 2009-06-29 2021-04-27 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US11866411B2 (en) 2009-06-29 2024-01-09 Agios Pharmaceutical, Inc. Therapeutic compounds and compositions
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
USRE49582E1 (en) 2009-06-29 2023-07-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10711314B2 (en) 2009-10-21 2020-07-14 Agios Pharmaceuticals, Inc. Methods for diagnosing IDH-mutant cell proliferation disorders
US9982309B2 (en) 2009-10-21 2018-05-29 Agios Pharmaceuticals, Inc. Method for treating cell proliferation related disorders
US9283237B2 (en) 2009-12-14 2016-03-15 University Of Massachusetts Methods of inhibiting presbyopia
US8758802B2 (en) 2009-12-14 2014-06-24 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US8846930B2 (en) * 2010-11-23 2014-09-30 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
US9156834B2 (en) 2010-11-23 2015-10-13 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
US20130172326A1 (en) * 2010-11-23 2013-07-04 Pierre Fabre Medicament Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US10087169B2 (en) 2010-12-21 2018-10-02 Agios Pharmaceuticals, Inc. Bicyclic PKM2 activators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US9199968B2 (en) 2010-12-29 2015-12-01 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
IL276414B2 (en) * 2011-05-03 2023-06-01 Agios Pharmaceuticals Inc Pyruvate kinase activators for use in therapy
RU2675656C2 (en) * 2011-05-03 2018-12-21 Аджиос Фармасьютикалз, Инк. Pyruvate kinase activators for use in therapy
WO2012151451A1 (en) * 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
CN114432312A (en) * 2011-05-03 2022-05-06 安吉奥斯医药品有限公司 Pyruvate kinase activators for therapy
US10632114B2 (en) 2011-05-03 2020-04-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9682080B2 (en) 2011-05-03 2017-06-20 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use in therapy
RU2787757C2 (en) * 2011-05-03 2023-01-12 Аджиос Фармасьютикалз, Инк. Methods for use of pyruvate kinase activators
WO2012151452A1 (en) * 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use in therapy
EP3406251A1 (en) * 2011-05-03 2018-11-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9193701B2 (en) 2011-05-03 2015-11-24 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use in therapy
US9404081B2 (en) 2011-05-03 2016-08-02 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US11793806B2 (en) 2011-05-03 2023-10-24 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9662327B2 (en) 2011-06-17 2017-05-30 Agios Pharmaceuticals, Inc Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US11667673B2 (en) 2012-01-19 2023-06-06 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10717764B2 (en) 2012-01-19 2020-07-21 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10640534B2 (en) 2012-01-19 2020-05-05 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9458147B2 (en) * 2012-02-22 2016-10-04 Sanford-Burnham Medical Research Institute Sulfonamide compounds and uses as TNAP inhibitors
CN104334527A (en) * 2012-02-22 2015-02-04 桑福德-伯纳姆医学研究院 Sulfonamide compounds and uses as tnap inhibitors
US20150011551A1 (en) * 2012-02-22 2015-01-08 Sanford- Burnham Medical Reseach Institute Sulfonamide compounds and uses as tnap inhibitors
US10370333B2 (en) 2012-02-22 2019-08-06 Sanford-Burnham Prebys Medical Discovery Institute Sulfonamide compounds and uses as TNAP inhibitors
US9884826B2 (en) 2012-02-22 2018-02-06 Sanford-Burnham Medical Research Institute Sulfonamide compounds and uses as TNAP inhibitors
US10413529B2 (en) 2013-03-14 2019-09-17 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US9789091B2 (en) 2013-03-14 2017-10-17 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US9675589B2 (en) 2013-03-14 2017-06-13 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9108921B2 (en) 2013-03-15 2015-08-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
JP2016512203A (en) * 2013-03-15 2016-04-25 アジオス ファーマシューティカルズ， インコーポレイテッド Therapeutic compounds and compositions
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10172864B2 (en) 2013-07-11 2019-01-08 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11021515B2 (en) 2013-07-25 2021-06-01 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10799490B2 (en) 2014-03-14 2020-10-13 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US10449184B2 (en) 2014-03-14 2019-10-22 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US11504361B2 (en) 2014-03-14 2022-11-22 Servier Pharmaceuticals Llc Pharmaceutical compositions of therapeutically active compounds
WO2016146575A1 (en) 2015-03-13 2016-09-22 4Sc Discovery Gmbh Kv1.3 inhibitors and their medical application
WO2016146583A1 (en) 2015-03-13 2016-09-22 4Sc Discovery Gmbh Kv1.3 inhibitors and their medical application
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10736863B2 (en) 2015-11-13 2020-08-11 University Of Massachusetts Methods of inhibiting cataracts and presbyopia
CN109942537A (en) * 2018-03-03 2019-06-28 中国人民解放军第二军医大学 A kind of ALDH2 agonist, preparation method and its usage
CN109942537B (en) * 2018-03-03 2023-11-17 中国人民解放军第二军医大学 ALDH2 agonist, preparation method and application thereof
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
RU2808687C2 (en) * 2018-12-11 2023-12-01 Санофи Binder for peptides
US11098102B2 (en) 2018-12-11 2021-08-24 Sanofi Insulin conjugates
WO2020120479A1 (en) * 2018-12-11 2020-06-18 Sanofi Peptide binder
CN109651297B (en) * 2019-01-22 2022-05-27 杭州壹瑞医药科技有限公司 N-benzyl-N-aryl sulfonamide derivative and preparation and application thereof
WO2020151687A1 (en) * 2019-01-22 2020-07-30 杭州壹瑞医药科技有限公司 N-benzyl-n-arylsulfonamide derivative and preparation and use thereof
CN109705033A (en) * 2019-01-22 2019-05-03 杭州壹瑞医药科技有限公司 N- heteroaryl sulfonamide analog derivative and preparation and application
CN109651297A (en) * 2019-01-22 2019-04-19 杭州壹瑞医药科技有限公司 A kind of N- benzyl-N- aryl sulfonic acid amides analog derivative and preparation and application
WO2020151686A1 (en) * 2019-01-22 2020-07-30 杭州壹瑞医药科技有限公司 N-heteroaryl sulfonamide derivative, preparation and use thereof in treatment of autoimmune diseases
US11993576B2 (en) 2019-01-22 2024-05-28 Hangzhou Yirui Pharmaceutical Technology Co., Ltd N-benzyl-N-arylsulfonamide derivative and preparation and use thereof

Similar Documents

Publication Publication Date Title
WO2010130638A1 (en) Sulfonamide compounds, pharmaceutical compositions and uses thereof
EP2709985B1 (en) Amine derivatives as potassium channel blockers
DE602004010848T2 (en) DERIVATIVES OF 1-PIPERAZINE AND 1-HOMOPIPERAZINE CARBOXYLATES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS INHIBITORS OF THE FAAH ENZYME
JP6843114B2 (en) Muscarine agonist
WO2009011904A1 (en) Compounds useful as faah modulators and uses thereof
WO2014134774A1 (en) Compounds inhibiting leucine-rich repeat kinase enzyme activity
JP2019502688A (en) Diamino-alkylamino-linked arylsulfonamide compounds having selective activity in voltage-gated sodium channels
US8921550B2 (en) Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives
CA2991937A1 (en) Substituted amide derivatives having multimodal activity against pain
WO2013170072A2 (en) Compounds for the treatment of neurological disorders
KR20240049561A (en) Benzazepine aromatic ring derivatives and their applications in medicine
AU2018223982A1 (en) 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitors
KR20210049858A (en) [1,2,4]triazolo[1,5-A]pyridine compounds and uses thereof as JAK inhibitors
WO2011142825A2 (en) Novel sulfur containing compounds
WO2012047703A2 (en) Cyclopropyl-spiro-piperidines useful as sodium channel blockers
TWI770841B (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
EP2909170A1 (en) Substituted carbamate compounds and their use as transient receptor potential (trp) channel antagonists
EP3072884B1 (en) 3-azabicyclo[3.1.0]hexane derivative and use thereof for medical purposes
JP7168456B2 (en) Indoline derivatives and methods of using and producing them
WO2010059610A1 (en) 6, 7 -dihydro- 5h- pyrrolo [3, 4-d] pyrimidin-4-yl] -quinolin-3 -ylamine compounds useful as faah modulators and uses thereof
JP2023521836A (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitors, and pharmaceutical compositions containing the same
JP6639651B2 (en) Therapeutic compounds for pain and their synthesis
KR102613509B1 (en) Macrocyclic pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for the prevention or treatment of neurodegenerative disease containing the same as an active ingredient
EP2524912A1 (en) Amine derivatives
WO2021233427A1 (en) Fused ring compounds, preparation method therefor, pharmaceutical compositions and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10720384

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10720384

Country of ref document: EP

Kind code of ref document: A1