WO2005026137A2 - Modulators of atp-binding cassette transporters - Google Patents

Modulators of atp-binding cassette transporters Download PDF

Info

Publication number
WO2005026137A2
WO2005026137A2 PCT/US2004/029206 US2004029206W WO2005026137A2 WO 2005026137 A2 WO2005026137 A2 WO 2005026137A2 US 2004029206 W US2004029206 W US 2004029206W WO 2005026137 A2 WO2005026137 A2 WO 2005026137A2
Authority
WO
WIPO (PCT)
Prior art keywords
aliphatic
optionally substituted
phenyl
ring
substituents
Prior art date
Application number
PCT/US2004/029206
Other languages
French (fr)
Other versions
WO2005026137A3 (en
Inventor
Mark T. Miller
Sara S. Hadida Ruah
Ashavini K. Singh
Thomas Cleveland
Lewis R. Makings
Matthew Hamilton
Peter D.J. Grootenhuis
Original Assignee
Vertex Pharmaceuticals Incorporated
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 Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to AU2004272599A priority Critical patent/AU2004272599A1/en
Priority to EP04783449A priority patent/EP1664006A2/en
Priority to JP2006525534A priority patent/JP2007504255A/en
Priority to CA002537841A priority patent/CA2537841A1/en
Priority to MXPA06002567A priority patent/MXPA06002567A/en
Publication of WO2005026137A2 publication Critical patent/WO2005026137A2/en
Publication of WO2005026137A3 publication Critical patent/WO2005026137A3/en
Priority to IL174128A priority patent/IL174128A0/en
Priority to NO20061543A priority patent/NO20061543L/en
Priority to US13/174,844 priority patent/US8431605B2/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/427Thiazoles not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12Antidiarrhoeals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/08Bronchodilators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/04Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/18Drugs for disorders of the endocrine system of the parathyroid hormones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/48Drugs for disorders of the endocrine system of the pancreatic hormones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12Antidiuretics, e.g. drugs for diabetes insipidus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D263/48Nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38Nitrogen atoms
    • C07D277/44Acylated amino or imino radicals
    • C07D277/46Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles 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 in position 2
    • C07D277/82Nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5076Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving cell organelles, e.g. Golgi complex, endoplasmic reticulum

Definitions

  • the present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith.
  • the present invention also relates to methods of treating ABC transporter mediated diseases using such modulators .
  • ABC transporters are a group of membrane transporter proteins that play a major role in the transport and protection of cells against a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics .
  • ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities.
  • Some of these transporters were discovered as multidrug resistance proteins (like the MDRl-P glycoprotein, or the multidrug resistance protein, MRP1) , defending malignant cancer cells against chemotherapeutic agents.
  • MRP1 multidrug resistance proteins
  • ABC transporters play a variety of important physiological roles within the body, as well as providing a defense against harmful compounds from the environment. Moreover they represent important potential drug targets both in their own right, as well as, because in many cases therapeutic drugs are also transported out of the target cell by these molecules .
  • CFTR One of the members of the ABC transporter family, namely, CFTR, is believed be the chloride channel responsible for cAMP-mediated chloride secretion in epithelial cells, and to play a key role in the secretion of chloride and maintenance of normal electrolyte transport throughout the body.
  • CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each comprising six transmembrane segments and a nucleotide-binding domain.
  • the two repeats are separated by a large, polar, regulatory (R) -domain containing multiple potential phosphorylation sites.
  • R polar, regulatory
  • the gene associated with CFTR has been identified and sequenced (See Gregory, R. J. et al . (1990) Nature 347:382-386; Rich, D. P. et al . (1990) Nature 347:358-362), (Riordan, J. R. et al . (1989) Science 245:1066-1073) .
  • CF cystic fibrosis
  • the other elements include the epithelial Na + channel, ENaC, Na + /2C1 " /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell. [0010] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell . Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjogren's Syndrome Sjogren's Syndrome
  • COPD chronic obstructive pulmonary disease
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR Dry eye disease
  • tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as Cystic Fibrosis and Sj ⁇ grens's syndrome.
  • Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
  • Sj ⁇ grens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis . Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • the diseases associated with the first class of ER malfunction are CF (due to misfolded ⁇ F508-CFTR) , hereditary emphysema (due to ⁇ l-antitrypsin; non Piz variants) , hereditary hemochromatosis, coagulation- fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses (due to lysosomal processing enzymes) , Sandhof/Tay-Sachs (due to 3-hexosaminidase) , Crigler-Najjar type II (due to UDP-glucuron
  • the diseases associated with the latter class of ER malfunction are glycanosis CDG type 1, Hereditary emphysema (due to ⁇ l-Antitrypsin (PiZ variant) , Congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen) , ACT deficiency (due to ⁇ l-Antichymotrypsin) , Diabetes insipidus (DI) , neurophyseal DI (due to Vasopressin hormone/V2 -receptor) , neprogenic DI (due to aquaporin II) , Charcot-Marie Tooth syndrome (due to Peripheral myelin protein 22) , Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to /3APP and presenilins) , Parkinson's disease, amy
  • ETEC enterotoxogenic E-coli
  • Common viral causes of diarrhea include rotavirus and coronavirus.
  • Other infectious agents include ⁇ ryptosporidium, giardia lamblia, and salmonella, among others .
  • Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
  • the present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
  • Y' is 0, S, or NR; p is 0-2; X is a bond, 0, S, S (O) , S(0) 2 , CF 2 , CH 2/ -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O) 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H , R 2 , or R 6 ; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl ; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
  • each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R L is -OR A , -SR A , or -N(R AB ) 2 ; each R A is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each R A is optionally substituted with up to 3 substituents independently selected from R 1 , R 4 or R 7 , each R AB is independently hydrogen or C
  • R M is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ; each of 1 and X 2 is independently selected from 0, S, or NR;
  • R N is C1-C6 aliphatic or phenyl, wherein R N is optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
  • R p is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
  • R Q is C1-C6 aliphatic or aryl, wherein R Q is optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , or R 4 ;
  • R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y;
  • n is o
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
  • R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 , SR 5 , S(0)R 6 , S(0)R 5 , S0 2 R 6 , S0 2 R 5 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R ⁇ substituents;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R ⁇ substituent ;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R “7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected from
  • ABSOR-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vi tro .
  • binding domain as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al . , J. Gen. Physiol. (1998): 111(3), 477-90.
  • CFTR cystic fibrosis transmembrane regulator or a mutation thereof capable of its regulator activity, in part or full, including, but not limited to, ⁇ F508 CFTR and G551D CFTR (see, e.g., htt : //www. genet . sickkids .on. ca/cftr/, for CFTR mutations) .
  • modulating means increasing or decreasing by a measurable amount.
  • the phrase “optionally substituted” is used interchangeably with the phrase "substituted or unsubstituted.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain or branched, hydrocarbon chain that is completely saturated (alkyl) or is unsaturated (alkenyl or alkynyl) . Unless otherwise specified, an aliphatic group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms. Up to three, and preferably two, -CH 2 - in said aliphatic may be replaced with 0, S, or -NR.
  • alkylidene as used herein means a straight-chain or branched hydrocarbon chain that is completely saturated or unsaturated, and is connected to the rest of the molecule through covalent bonds.
  • exemplary alkylidene groups include methylene, ethylene, or propylene. Unless otherwise specified, an alkylidene group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms.
  • cycloaliphatic means a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring that has up to two points of attachment to the rest of the molecule.
  • preferred cycloaliphatic rings are 3-8 membered monocyclic rings, more preferably 3-6, and even more preferably, 3, 5, or 6. Also preferred, unless otherwise specified, are 8-12 membered bicyclic hydrocarbon rings, more preferably 10 membered bicyclic hydrocarbon rings.
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term “nitrogen” includes a substitutable nitrogen of a heterocyclic ring.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3 , 4-dihydro-2Jf-pyrrolyl) , NH (as in pyrrolidinyl) or as in N-substituted pyrrolidinyl.
  • unsaturated means a double bond or a triple bond. Each such bond constitutes one unit of unsaturation.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” , refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems. Unless otherwise specified, preferred aryl rings have a total of five to fourteen ring members, wherein at least one ring, if bicyclic or tricyclic, in the system is aromatic and wherein each ring in the system contains up to 6 ring members.
  • aryl may be used interchangeably with the term “aryl ring”. Phenyl is an example of aryl.
  • heterocycle means non-aromatic, monocyclic, bicyclic or tricyclic ring systems wherein one or more ring members is a heteroatom. Unless otherwise specified, each ring in the system preferably contains contains 3 to 7 ring members with preferably 1-3 heteroatoms .
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” , refers to monocyclic, bicyclic and tricyclic ring systems, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Unless otherwise specified, such ring systems preferably have a total of 5 to 15 ring members, wherein each ring in the system preferably contains 3 to 7 ring members, with preferably 1-3 heteroatoms.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • the present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
  • X is a bond, O, S, S (0) , S(0) 2 , CF 2 , CH 2 , -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O)- 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR;
  • R is H, R 2 , or R 6 ;
  • A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl;
  • C is a phenyl or 5-8 membered cycloaliphatic ring;
  • Q is selected from: each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
  • R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , 0C(0)0R 6 , 0C(0)0R 5 , OC(0)N(R 6 ) 2 , 0C(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R ⁇ substituents;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent ;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg)- straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected from halo
  • amino capping group refers to a suitable chemical group that may be attached to a nitrogen atom.
  • capping refers to when the designated amino group is attached to a suitable chemical group (e.g., protecting group). Examples of suitable amino capping groups are described in T.W. Greene et al . , Protective Groups in Organic Synthesis, 3d. Ed., John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; L. Paquette, ed.
  • Y' is S.
  • Y' is 0.
  • Y' is NR.
  • R is H.
  • R is R 2 .
  • R is R 6 .
  • p is 1.
  • p is 1 and X is attached to the carbon adjacent to Y' atom.
  • p is 1 and X is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 2.
  • X is a bond, 0, S, CH 2/ CF 2 , CHOR, C(0)NR, C(0)0-, NRC (O) , or NR.
  • X is a bond, 0, or CH 2 .
  • X is CH 2 .
  • A is an optionally substituted C3-C7 cycloaliphatic ring.
  • A is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl.
  • A is optionally substituted (C1-C10) aliphatic .
  • A is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl .
  • A is optionally substituted C6-C10 aryl ring.
  • A is optionally substituted phenyl or naphthyl .
  • A is optionally substituted C5-C12 heteroaryl ring.
  • A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl , imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl, 1,8- naphthyridinyl , pteridinyl,
  • A is optionally substituted C3-C12 heterocyclic ring.
  • A is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl , tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl .
  • A, X, and the ring attached thereto, taken together is selected from:
  • R ph is independently R 1 , R 2 , or R 3 ; and r is 0-3.
  • X 5 is CH 2 , C(O) , or CHOR;
  • X 6 is 0 or NR 2 ; and
  • R ⁇ is C1-C6 aliphatic, optionally substituted with R 1 , R 2 , or R 3 .
  • A, X, and the ring attached thereto, taken together, is selected from any of the rings i to xviii, wherein the sulfur atom in each of the thiazole ring is replaced with an oxygen atom (to provide the corresponding oxazole) .
  • each B is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each B is an optionally substituted phenyl or naphthyl. Or, each B is an unsubstituted phenyl . [0061] According to another embodiment, each B is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each B is independently an optionally substituted C5-C7 heteroaryl.
  • each B is independently selected from triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl , oxazolyl , pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl , benzthiazolyl, purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl
  • R 1 is 1,2- methylene dioxy, or 1 , 2-ethylenedioxy.
  • R 1 is R 6 , wherein R 6 is straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl , optionally substituted with R 7 .
  • R 1 is (Cl- C4 aliphatic) n -Y/ wherein n is 0 or 1, and Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 , NHR 6 , N(R 6 ) , NR 6 R 8 , COOH, COOR 6 or OR 6 ; [0066] According to another embodiment, R 1 is selected from halo, CF 3 , NH 2 , NH(C1-C4 alkyl), NHC(0)CH 3 , OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl), Cl- C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S0 2 NH(C1- C4 alkyl), or S0 2 N(C1-C
  • R 1 is selected from methyl, n-propyl, i-propyl, t-butyl, halo, CF 3 , NH 2 , NH(CH 3 ), NHC(0)CH 3 , OH, OCH 3 , OPh, O-benzyl, S- (C 2 H 5 ) , S-CH 3 , N0 2 , CN, methylenedioxy, S0 2 NH (n-propyl) , or S0 2 (n-propyl) 2 .
  • R 2 is a straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 .
  • R 2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 .
  • R 3 is optionally substituted phenyl, napthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl.
  • R 3 is an optionally substituted phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
  • R 4 is selected from OR 5 , OR 6 , SR 5 , SR 6 , NR 5 COR 5 , NR 5 COR 6 , NR 6 COR 5 , or NR 6 COR 6 .
  • R 5 is C5-C6 cycloalkyl, C6 or CIO aryl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with up to 2 R 1 .
  • R 5 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
  • R 6 is H.
  • R 6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl, optionally substituted with R 7 .
  • R 6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl.
  • R 7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or al ynyl.
  • R 7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with 1-2-methylenedioxy, 1, 2-ethylenedioxy, or (CH 2 ) n -Z.
  • R 7 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl .
  • R 8 is acetyl, arylsulfonyl or alkylsulfonyl .
  • Q in compounds of formula I is selected from:
  • the present invention provides compounds having formula I-a:
  • p is 1 .
  • p is
  • X is a bond, 0 , CH 2 ,
  • X is a bond, 0 , or CH 2 .
  • p is 1 and X is a bond.
  • X-A is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 1, and X-A is attached to the carbon adjacent to the Y'.
  • p is 1, X is CH 2 , CHOH, or C(O) , and A is an optionally substituted phenyl.
  • X is a bond, and A is an optionally substituted phenyl.
  • p is 2, each X is a bond, and each A is an optionally substituted phenyl.
  • each B is independently and optionally substituted ring selected from:
  • substituents on B include C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , - C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C (0)N(C1-C4 alkyl) 2 or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C (O) 0.(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C (0)N(C1-C4 alkyl) 2 .
  • each B is indpendently an optionally substituted ring selected from ring i, iii, iv, v, or vi. Or, wherein B is an optionally substituted ring vii .
  • B is independently ring x optionally substituted with up to two substituents selected from R 1 or phenyl optionally substituted with up to two R 1 .
  • B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, - 0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2 , or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4- alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2 .
  • each B is an optionally substituted ring selected from ring xi, xii, xiii, or xiv.
  • p is 1. Or, p is 2.
  • R is hydrogen.
  • Y' is S. Or, Y' is O.
  • X is a bond and A is optionally substituted phenyl. In certain embodiments, A is attached to the carbon atom adjacent to the nitrogen ring atom.
  • A is phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N- piperidinyl, or methylenedioxy.
  • A is phenyl, methoxyphenyl , dimethoxyphenyl , cyanophenyl , N- pyrrolidinylphenyl, methylenedioxyphenyl , halophenyl, methylphenyl , or dimethylphenyl .
  • A is phenyl, 3- methoxyphenyl , 2 -methoxyphenyl, 4-chlorophenyl, 4- cyanophenyl, 4- (N-pyrrolidinyl) phenyl, 4-tolyl, 3,4- methylenedioxyphenyl , 3 -chlorophenyl , 2,4- dimethoxyphenyl, 2-chlorophenyl, 4-bromophenyl, or 2,4- dimethylphenyl .
  • A is C3-C10 cycloaliphatic ring.
  • Exemplary ring include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
  • A is cyclohexyl or adamantyl.
  • the compounds of the present invention have one of more of the following features : a) R is hydrogen; b) Y' is S; c) A is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N-piperidinyl , or methylenedioxy; and d) B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH 2 , -C(0)0(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C(0)N(C1-C4 alkyl) 2 , or phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, -0-C1-
  • p is 1 and X is a bond.
  • p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 1, and X-A is attached to the carbon adjacent to the Y' .
  • p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
  • X is a bond, and A is an optionally substituted phenyl.
  • p is 2, each X is a bond, and each A is an optionally substituted phenyl.
  • said C1-C6 aliphatic is C1-C4 straight or branched alkylidene.
  • Exemplary alkylidenes include -CH 2 -, ⁇ CH(Me)-, -C(Me) 2 -, - CH(Et)-, -C(Et) 2 -, or -CH 2 -CH (Me) - .
  • B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl , or pyrrolidinyl.
  • B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R 1 substituents.
  • said (C1-C6 aliphatic) -B in formula I-b is selected from:
  • Ak is C1-C6 straight or branched alkylidene;
  • X 4 is CH 2 , 0 or S;
  • Ar' is phenyl optionally substituted with up to two R 1 ;
  • B is optionally substituted with up to two R 1 .
  • Ak is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , CH(Et), C(Et) 2 , CH (n-propyl) , CH(i- Pr) , CH(n-butyl), CH (but-2-yl) , or CH (t-butyl) .
  • Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) .
  • X 4 is S. Or, X 4 is 0.
  • R is hydrogen.
  • the present invention provides compounds of formula I-f:
  • R M is C1-C6 aliphatic or phenyl, wherein R M is optionally substituted with up to two substituents independently selected from R 1 , R 2 , or R 3 ;
  • R N is C1-C6 aliphatic or a 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein R N is optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
  • p is 1 and X is a bond.
  • p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 1, and X-A is attached to the carbon adjacent to the Y' .
  • p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
  • X is a bond, and A is an optionally substituted phenyl.
  • p is 2, each X is a bond, and each A is an optionally substituted phenyl.
  • X x is NH or N(C1-C4 alkyl) . Or, X x is O.
  • R M is optionally substituted phenyl .
  • R M is C1-C6 alkyl, optionally substituted with phenyl.
  • R M is C1-C4 alkyl.
  • R N is optionally substituted C3-C7 cycloaliphatic, phenyl, or benzyl.
  • R N is C1-C6 aliphatic.
  • R is hydrogen.
  • the present invention provides a compound of formula I-g:
  • p is 1 and X is a bond.
  • p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 1, and X-A is attached to the carbon adjacent to the Y' .
  • p is 1, X is CH 2 , CHOH, or C (O) , preferably CH 2 , and A is an optionally substituted phenyl.
  • X is a bond, and A is an optionally substituted phenyl.
  • p is 2, each X is a bond, and each A is an optionally substituted phenyl.
  • R p is C1-C4 alkyl, optionally substituted with up to two R 1 .
  • R p is selected from ethyl, n-propyl, i-propyl, n-butyl, but-2-yl, or t-butyl, isoamyl, optionally substituted with halo, CN, COOH, or CONH 2 .
  • R is hydrogen.
  • p is 1. Or, p is 2.
  • p is 2, and each A is optionally substituted phenyl. Or, p is 2, and each A is phenyl .
  • compounds of formula 1-g have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2 and each A is phenyl; d) R p is isoamyl, t-butyl, ethyl, isopropyl, n-propyl, l-carboxy-prop-3-yl , or 1-carboxy-2 -methyl- prop-3-yl .
  • the present invention provides compounds of formula I-h:
  • Y' is O or S
  • X 2 is O, S, or NR
  • R Q is C1-C6 aliphatic or phenyl, optionally substituted with up to two substituents independently selected from R 1 , R 2 , or R 3 .
  • p is 1 and X is a bond.
  • p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom.
  • p is 1, and X-A is attached to the carbon adjacent to the Y' .
  • p is 1, X is CH 2 , CHOH, or C(O), preferably CH 2 , and A is an optionally substituted phenyl .
  • X is a bond, and A is an optionally substituted phenyl.
  • p is 2, each X is a bond, and each A is an optionally substituted phenyl.
  • X 2 is S. Or, X 2 is O.
  • R Q is C1-C4 alkyl, optionally substituted with up to three R 1 .
  • R Q is phenyl optionally substituted with C1-C4 alkyl, or R 1 .
  • the methods of the present invention employ a compound having formula (1A) :
  • Y' is O, S, or NR
  • X is a bond, CH 2 , CHOR, C(0)0, C (O) , NR, or O
  • A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic
  • Q is selected from:
  • each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0;
  • R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
  • Y' is S.
  • Y 1 is 0.
  • Y' is NR.
  • X is a bond, CH 2 , NR, or O;
  • X is CH 2 .
  • X is CF 2 .
  • X is a bond.
  • X is O.
  • X is NR.
  • A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R 1 , R 2 , R 3 , or R4.
  • Q is B.
  • Q is -(C1-C6)- aliphatic-B.
  • Q is CH(B) .
  • Q is
  • B is phenyl.
  • X is a bond, -CHOR- , or
  • Exemplary compounds of formula ( IA) are those wherein : (i ) X is a bond, CH 2 , or O ; (i) A is optionally substituted phenyl; (iii)Q is diphenylmethyl . [00151] Exemplary compounds of formula (IA) useful in the methods of the present invention are as shown below in Table 1. [00152] According to another embodiment, the methods of the present invention employ a compound having formula (IB) :
  • Y' is 0, S, or NR
  • X is a bond, CH 2 , CHOR, C(O), C(0)0, NR, or 0
  • A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic
  • Q is selected from:
  • each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0;
  • R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
  • Y' is S.
  • Y' is 0.
  • Y' is NR.
  • X is a bond, CH 2 , NR, or 0, Or, X is a bond or CH 2 .
  • X is CF 2 .
  • X is a bond.
  • X is O.
  • X is NR.
  • A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R-*-, R 2 , R 3 , or R4.
  • Q is B.
  • Q is -(C1-C6)- aliphatic-B.
  • Q is CH(B) 2 .
  • Q is
  • B is phenyl .
  • Preferred compounds of formula IB are those wherein: (i) X is a bond, CH 2 , or 0; (ii) A is optionally substituted phenyl; (iii) Q is diphenylmethyl .
  • the methods of the present invention employ a compound having formula (IC) :
  • Y' is 0, S, or NR; each X is independently a bond, CH 2 , -CHOR-, -C(0)0-, -C(0) -, NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
  • each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O;
  • R is H, R 2 , or R 6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; and R 1 , R 2 , R 3 , R 4 , or R 5 are as defined above for formula (I) .
  • Y' is S.
  • Y' is 0.
  • y is NR.
  • X is a bond or CH 2 .
  • X is'CH 2 .
  • X is a bond.
  • X is -CHOR- Or, X is -C(O)-.
  • X is 0.
  • X is NR.
  • A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R ⁇ -, R 2 , R , or R 4 .
  • Q is B.
  • Q is -(C1-C6)- aliphatic-B.
  • Q is CH(B) 2 .
  • Q is
  • B is phenyl.
  • exemplary compounds of formula (IC) are those wherein: (i) each X is a bond, -CHOR-, or -C(O)-; (ii) each A is optionally substituted phenyl, (Cl -C6) aliphatic, or CF 3 ; (iii) Q is optionally substituted phenyl, (Cl- C6) aliphatic, or diphenylmethyl .
  • Xi is a bond, 0, S, CHOR, C (O) , C(0)0, CF 2 , CH 2 , or NR;
  • R is H or R 2 A is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic;
  • each Bi is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; wherein each Ai is optionally substituted with up to
  • R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
  • R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroary
  • X x is a bond, 0, S, CF 2 , CH 2 , or NR.
  • Xi is CH 2 , CF 2 , or O. Or Xi is CH 2 or 0. In certain embodiments, Xi is
  • Ai is an optionally substituted C3-C7 cycloaliphatic ring. In certain embodiments, Ai is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl. [00171] According to another embodiment, Ai is optionally substituted (C1-C10) aliphatic . In certin embodiments, Ai is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl . [00172] According to another embodiment, A x is optionally substituted C6-C10 aryl ring.
  • Ai is optionally substituted phenyl or naphthyl .
  • Ai is optionally substituted C5-C12 heteroaryl ring.
  • A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl, benzthiazolyl, purinyl , quinolinyl, isoquinolinyl, c
  • Ai is optionally substituted C3-C12 heterocyclic ring.
  • a x is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
  • each Bi is independently selected from optionally substituted C6-C10 aryl.
  • each Bi is independently an optionally substituted phenyl or naphthyl.
  • each B x is an unsubstituted phenyl.
  • each B is independently selected from optionally substituted C5-C12 heteroaryl ring.
  • each Bi is independently and optionally substituted C5-C7 heteroaryl ring.
  • each B x is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl , purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl, p
  • each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR.
  • each B x is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1 , 4-dioxanyl, morpholinyl, 1, -dithianyl , thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl .
  • Embodiments of R 1 , R 2 , R 3 , R , R 5 , R 6 , R 7 are independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolid
  • R 8 , and Z in compound of formula (II) are as described above for compound of formula (I) .
  • one B x is phenyl with up to two R 1 substituents
  • the other Bi is selected from pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, optionally substituted with up to two R 1 subsituents.
  • one Bi is phenyl
  • the other B % is selected from 1, 2-pyrazol-l-yl, 1- piperidinyl, 2-carboethoxy-1-piperidinyl , 4-morpholinyl , 3 -carboethoxy-1-piperidinyl, 3-methyl-1-piperidinyl , 2- ethyl -1-pyrrolidinyl , 3 -hydroxymethyl-1-piperidinyl, 4- carboethoxy-1-piperidinyl, 4 -methyl -1-piperidinyl, 1- pyrrolidinyl, 4- (pyrimidin-2-yl) -1-piperazinyl , or 4- hydroxy-piperidinyl .
  • the present invention provides a compound of formula IIA:
  • Y' is O or S
  • B is a 3-8 membered, saturated, moncyclic, ring having 0-4 heteroatoms selected from 0, S, or N
  • ring G and B are optionally substituted with up to four substituents independently selected from R 1 , R 2 , R ,
  • R 4 , or R 5 provided that when Y' is S, and: a) when B is cyclohexyl, tetrahydrofuran-2-yl , or cyclopropyl, and ring G has 1-3 halo substituents, then ring G has at least one additional substituent other than halo; and b) when B is tetrahydrofuran-2-yl, then ring G is not phenyl, trifluoromethylphenyl , methoxyphenyl, or tolyl; c) when B is cyclohexyl, then ring G is not phenyl or trifluoromethylphenyl .
  • B is tetrahydrof ranyl , piperidyl, morpholinyl, or thiomorpholinyl .
  • B is C3-C8 saturated, carbocyclic, monocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
  • ring G is phenyl optionally substituted with R 1 . Preferably, ring G is optionally substituted with up to two substituents selected from halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl) .
  • compounds of formula IIA have one or more of the following features: a) Y' is S; b) ring G is halo-substituted phenyl; c) B is phenyl optionally substituted with halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl). [00186] According to another embodiment, the present invention provides a compound of formula IIB:
  • Y' is S or 0; R is H, R 2 , or R 6 ; R B is C1-C6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each of ring G, ring H, and R B is independently and optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; provided that when Y is S, and: a) when R B is hydrogen, and ring G and ring H both have 1-3 halo substituents, then at least one of ring G and ring H has an additional substituent other than halo; b) when R B is hydrogen and ring H is unsubstituted phenyl, then ring G is not phenyl or
  • ring G is phenyl optionally substituted with up to two R 1 .
  • Exemplary RI includes C1-C4 alkyl, 0- (C1-C4 alkyl), halo, or cyano.
  • R B is Cl-6 aliphatic optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
  • R B is C1-C4 alkyl optionally substituted with up to 2 substituents selected from R 1 .
  • R B include methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, or t-butyl.
  • R B is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 0-4 heteroatoms optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
  • R B is a 3-7 membered monocyclic saturated, carbocyclic ring optionally substituted with up to 2 substituents selected from R 1 .
  • Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
  • R B is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 1-3 heteroatoms optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
  • R B is a 3-7 membered monocyclic saturated ring containing 1-3 heteroatoms optionally substituted with up to 2 substituents selected from R 1 .
  • Exemplary rings include piperidinyl, morpholinyl, or thiomorpholinyl .
  • R B is a 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O, optionally substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 .
  • the present invention provides compounds of formula IIC:
  • X 7 is O. Or, X 7 is S. Or, X 7 is NR' .
  • R c is C1-C6 alkyl, optionally substituted with up to two substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 . Or, R c is C1-C6 alkyl. Exemplary R c includes methyl, ethyl, isopropyl, n- propyl, n-butyl, sec-butyl, or t-butyl.
  • R B is phenyl optionally substituted with up to two R 1 substituents .
  • R B is phenyl.
  • R B is C1-C6 alkyl.
  • Exemplary R B includes methyl, ethyl, isopropyl, n- propyl , n-butyl, sec-butyl, or t-butyl.
  • compound of formula IIC includes one or more of the following eatures: a) ring G is benzyl optionally substituted with one RI substituent, preferably halo; b) Y' is S and R is hydrogen; c) R c is C1-C4 alkyl; d) X 7 is NH or NR' wherein R' is C1-C4 alkyl; and e) R B is C1-C4 alkyl.
  • the present invention provides a compound of formula IID:
  • R BB is phenyl optionally substituted with up to two R 1 substituents .
  • R BB is phenyl.
  • R BB is Cl- C6 alkyl.
  • Exemplary R BB includes methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or t-butyl.
  • R BB is optionally substituted C3-C8 cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl.
  • R BB is optionally substituted benzyl .
  • compounds of formula IID have one or more of the following features : a) Y' is S and R is hydrogen; b) each ring G is unsubstituted phenyl; d) X 8 is NR' , and R' is hydrogen or C1-C4 alkyl; and e) R BB is C1-C4 alkyl, benzyl, cyclopentyl, or cyclohexyl .
  • the present invention provides a compound having formula (III) :
  • Xi is a bond, O, S, CHOR, C (0) , C(0)0, CF 2 , CH 2 , or NR;
  • R is H or R 2
  • Ax is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic;
  • each B is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or 0; wherein each A x is optionally substituted with up to
  • R 1 is R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
  • R 6 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
  • R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-L substituents ;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected from halo, CN, N0 2 , CF 3
  • Xi is CH 2 , CF 2 , or 0.
  • Xi is a bond, O, S, CF 2 , CH 2 , or NR.
  • Xi is CH 2 or 0.
  • X x is CH 2 .
  • Ai is an optionally substituted C3-C7 cycloaliphatic ring.
  • a 2 is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl .
  • Ai is optionally substituted (C1-C10) aliphatic .
  • Ai is optionally substituted methyl, ethyl , propyl , butyl , pentyl , or hexyl .
  • Ai is optionally substituted C6-C10 aryl ring.
  • Ai is optionally substituted phenyl or naphthyl .
  • Ai is optionally substituted C5-C12 heteroaryl ring.
  • A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl , 1,8- naphthyridinyl, pteridinyl
  • Ai is optionally substituted C3-C12 heterocyclic ring.
  • a 2 is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl , piperidinyl, 1, 4-dioxanyl , morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
  • each B x is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each B x is independently an optionally substituted phenyl or naphthyl. Or, each Bi is an unsubstituted phenyl. [00213] According to another embodiment of formula (III) , each B x is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each Bi is independently and optionally substituted C5-C7 heteroaryl.
  • each Bi is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, carbazoly
  • each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR.
  • each Bi is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl , pyrazolinyl, pyrazolidinyl, piperidinyl, 1, -dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
  • R 1 , R 2 , R 3 , R 4 Exemplary embodiments of R 1 , R 2 , R 3 , R 4 ,
  • B is selected from: (i) ( ⁇ ) wherein: Y is O or S; and X 3 is 0 or S.
  • X 3 is O.
  • X 3 is S.
  • B is structure (i) above.
  • B is structure (ii) above.
  • R is hydrogen.
  • Y' is S.
  • Y' is 0.
  • the present invention provides compounds of formula V:
  • V wherein: Y' is 0 or S; B is selected from:
  • Ak is C1-C6 alkylidene; X 4 is CH 2 , O or S; Ar' is phenyl optionally substituted with up to two R 1 ; and B is optionally substituted with up to two R 1 .
  • Ak is selected from CH 2 , CH(CH 3 ), C(CH 3 ) 2 , CH(Et), C(Et) 2 , CH (n-propyl) , CH(i- Pr) , CH (n-butyl), CH (but-2-yl) , or CH (t-butyl) .
  • Ar ' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) .
  • X 4 is CH 2 .
  • X 4 is S. Or, X 4 is 0.
  • R is hydrogen.
  • p is 2, X is a bond, and each A is optionally substituted phenyl .
  • the compounds have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2, X is a bond, and each A is phenyl; d) B is ring (iii) above, wherein Ak is CH(CH 3 ) and Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (C1-C4 alkyl).
  • the present invention provides a compound of formula VI:
  • Y' is 0 or S;
  • R is hydrogen or R 2 ;
  • B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from O, S, or N; wherein each ring Gi, G 2 , and B is independently substituted with up to 4 substituents selected from R 1 ,
  • R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
  • R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (O) N (R 6 R 5 ) , SR 6 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic
  • B is not quinolin-2-yl or l,2-dihydro-2-oxo-quinolin- 4-yl; b) when Gi and G 2 both are phenyl, and Y' is S, then B is not l,4-benzodioxin-2-yl, cyclopropyl, cyclohexyl, thien- 2-yl, lH-thieno [2 , 3-c] pyrazol-1-phenyl-3 -methyl-5-yl, 5- methyl-thien-3-yl, 2 , 5-dichloro-thien-3-yl, 2-phenyl- quinolin-4-yl, furan-2-yl, thien-5- (4 , 5-diphenyl-2- thiazolyl-carboxamide) -2-yl, benzo [b] thiophen-2-yl , pyridin
  • Gi and G 2 are both phenyl. Or, each is independently and optionally substituted with up to two substituents selected from halo, or C1-C4 alkyl.
  • B is phenyl optionally substituted with up to two substituents selected from halo, C1-C4 alkyl, 0- (C1-C4 alkyl), COOH, C00(C1-C4 alkyl), or cyano.
  • B is 3,4- dichlorophenyl, 4-chlorophenyl, 4 -methoxyphenyl , 4- methylphenyl , 2 , 6-difluorophenyl , 2 -methylphenyl , 3 - methylphenyl , phenyl-2 -carboxylic acid, 2-chlorophenyl, 4 -cyanophenyl , or 3-methoxyphenyl .
  • B is 3-7 membered, monocyclic, saturated, carbocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
  • B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N.
  • Exemplary rings include tetrahydrofuranyl, thienyl, or pyrrolyl.
  • B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N.
  • the present invention provides a compound of formula VII : VII; wherein: Y' is 0 or S; R is hydrogen or R 2 ; R ⁇ is C1-C6 aliphatic, optionally substitute with up to 3 substituents independently selected from R 1 , R 2 , or
  • R 3 is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N; wherein each ring G x , G 2 , and B is independently substituted with up to 4 substituents selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 ,
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
  • R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 , SR 5 , S(0)R 6 , S(0)R 5 , S0 2 R 6 , S0 2 R 5 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0 2 N(R 6 ) 2 , S0 2 N(R 6
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected from hal
  • R ⁇ is C1-C6 alkyl.
  • Exemplary R** include methyl, ethyl, isopropyl, n-propyl, sec-butyl, n-butyl, or t-butyl.
  • B is optionally substituted phenyl .
  • B is 3-7 membered, monocyclic, saturated, carbocyclic ring.
  • Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
  • B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N.
  • Exemplary rings include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, or piperazinyl .
  • B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N.
  • the present invention provides a compound having formula I ' :
  • Y ' is 0 , S , or NR ;
  • R is H, R 2 , or R 6 ;
  • C is a phenyl or 5-8 membered cycloaliphatic ring;
  • Q is selected from:
  • each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 ; R L is -0R A , -SR A , or -N(R AB ) 2 ; each R A is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each R A is optionally substituted with up to 3 substituents independently selected from R 1 , R 4 or R 7 , each R ffl is independently
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or
  • R 5 ; R 4 is OR 5 , OR 6 , OC(0)R 6 , OC(0)R 5 , OC(0)OR 6 , OC(0)OR 5 , OC(0)N(R 6 ) 2 , OC(0)N(R 5 ) 2 , OC (0) N (R 6 R 5 ) , SR 6 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) - straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected
  • Y" is 0.
  • Y' is S.
  • R is hydrogen.
  • Q in formula I ' is B (structure (a) ) .
  • Preferred B include optionally substituted phenyl, or C3-C8 cycloaliphatic.
  • B in formula I' is phenyl or C3-C8 cycloalkyl optionally substituted with up to two substituents selected from R 1 , R 2 , or phenyl optionally substituted with up to two substituents selected from R 1 or R 2 .
  • Q in formula I ' is - (C1-C6 aliphatic) -B (structure (b) ) .
  • said C1-C6 aliphatic is C1-C4 straight or branched alkylidene.
  • Exemplary alkylidenes include -CH 2 -, -CH(Me)-, -C(Me) 2 -, - CH(Et)-, -C(Et) 2 -, or -CH 2 -CH (Me) - .
  • B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl, or pyrrolidinyl.
  • B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R 1 or R 2 substituents.
  • ring C is phenyl optionally substituted with up to two R 1 .
  • ring C is cyclohexenyl optionally substituted with up to two R 1 .
  • R 1 is 1, 2-methylene dioxy, or 1, 2-ethylenedioxy.
  • R 1 is R 6 , wherein R 6 is straight chain or branched (Cl- C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 7 .
  • R 1 is (C1-C4 aliphatic) n -Y, wherein n is 0 or 1, and Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 ,
  • R 1 is selected from halo, CF 3 , NH 2 , NH(C1-C4 alkyl), NHC(0)CH 3 , OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl) , C1-C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S0 2 NH(C1-C4 alkyl), or S0 2 N(C1-C4 alkyl) 2 - [00255] According to another more preferred embodiment, R 1 is selected from methyl, n-propyl, i- propyl, t-butyl, halo, CF 3 , NH 2 , NH(CH 3 ), NHC(0)CH 3 , OH, OCH 3 ,
  • R 2 is a straight chain or branched (C1-C6) lkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 . More preferably, R 2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R 1 , R 4 , or R 5 . [00257] In formula I', other embodiments of B, R L , R M , R p , R Q , Xi, X 2 , and R are as described above for formula I . [00258] Exemplary compounds of the present invention are shown below in Table 1.
  • preferred compounds of the present invention are those that measurably increase the activity of an ABC- transporter or of a fragment thereof, and preferably CFTR activity.
  • preferred compounds of the present invention are those that measurably decrease the activity of an ABC-transporter or of a fragment thereof.
  • One of skill in the art would be well aware of techniques and assays useful in measuring the increase or decrease of activity of an ABC-transporter or of a fragment thereof .
  • the present invention provides a method of modulating CFTR activity in a cell membrane of a mammal in need thereof, comprising the step of administering to said mammal a composition comprising a compound of the present invention as defined above.
  • the preferred embodiments of compound of formula (I) useful in potentiating the activity of CFTR include the preferred embodiments of the present invention described above.
  • the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of the present invention.
  • the term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity.
  • said functional ABC transporter is CFTR.
  • the preferred embodiments of compounds of formula (I) useful in increasing the number of functional ABC transporters include preferred embodiments of the compounds of the present invention as described above.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compositions having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • the present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention.
  • a "pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof.
  • Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species .
  • the compounds of the present invention may be readily prepared using methods known in the art. One such synthetic route is illustrated in Scheme 1 below:
  • reaction mixture was then either allowed to stir overnight at room temperature or subjected to microwave irradiation for 5 minutes at 200°C,
  • the crude product was then filtered, evaporated to dryness, dissolved in a minimum of dimethylsulfoxide and then purified by reverse phase preparative liquid chromatography.
  • compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxy
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate,
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C ⁇ - 4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., ammonium
  • N + (C ⁇ - 4 alkyl) 4 salts e.g., sodium and potassium
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols .
  • a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols .
  • the pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract . Suitable topical formulations are readily prepared for each of these areas or organs .
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
  • compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • the present invention provides a method of treating a ABC transporter mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above .
  • the ABC transporter mediated disease is selected from immunodeficiency disorder, inflammatory disease, allergic disease, autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease or viral disease .
  • the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type-1 hereditary angioedema, lipid processing deficiencies, such as Familial hypercholesterolemia, Type-1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,
  • the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention.
  • an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of any one of the above diseases .
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route administration effective for treating or lessening the severity of of any one of the above diseases.
  • the compounds of the present invention are useful in treating cystic fibrosis.
  • the disease so treated is selected from Tangier's disease, stargardt disease 1, age related macular dystrophy 2, retinintis pigmentosa, bare lymphocyte syndrome, PFIC-3, anemia, progressive intrahepatic cholestasis-2 , Dublin-Johnson syndrome, Pseudoxanthoma elasticum, cystic fibrosis, familial persistent hyperinsulinemic hyproglycemia of infancy, adrenolecukodystrophy, sitosterolemia, chronic obstructive pulmonary disease, asthma, disseminated bronchiectasis, chronic pancreatitis, male infertility, emphysema, or pneumonia.
  • the ABC transporter mediated disease is secretory diarrhea, or polycystic kidney disease in a mammal .
  • the present invention provides a method of treating cystic fibrosis or secretory diahrrea comprising the step of administering to said mammal a composition comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above. Most preferably, said disease is cystic fibrosis.
  • the present invention provides a method of modulating activity of an anion channel in vi tro or in vivo, comprising the step of contacting said channel with a compound of the present invention.
  • said anion channel is a chloride channel or a bicarbonate channel. More preferably, said anion channel is a chloride channel .
  • the present invention provides a method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a compound of the present invention as described above; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti- infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent.
  • a pharmaceutical composition comprising: (i) a compound of the present invention as described above; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti- infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent.
  • Preferred embodiments of compounds the present invention in the above pharmaceutical composition are those as described above .
  • the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: (i) a composition comprising a compound of the present invention; and (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof .
  • the kit is useful in measuring the activity of CFTR.
  • the activity of the ABC transporter is measured by measuring the transmembrane voltage potential.
  • Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods.
  • the optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.
  • These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
  • FRET fluorescence resonant energy transfer
  • V m fluorescent phospholipid
  • the changes in fluorescence emission can be monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
  • Preferred ABC transporters in the kit of the present invention include CFTR.
  • Hal Cl, Br, I wherein W is a group as described in the compounds of the present invention.
  • Hal Cl, Br, I wherein W is a group as described in the compounds of the present invention.
  • thiourea 4-Fluoro-l-methoxy-2-nitro-benzene A solution of methyl iodide (127.8 g, 0.9004 mol) in acetonitrile (100 mL) was slowly added to a solution of 5-fluoro-2- nitrophenol (94.2 g, 0.600 mol) and potassium carbonate (207 g, 1.50 mol) in acetonitrile (450 mL) . The mixture was heated to reflux for 15 hours. The mixture was allowed to cool, filtered, and washed twice with dichloromethane (100 mL) .
  • N' - [5- (2-Chloro-benzoyl) -thiazol-2-yl] -N, N-dimethyl- formamidine A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl -amine (23.2 g, 195 mmol) in methanol (80 mL) was heated under reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-l- (chloro-phenyl) - ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated to reflux for 4 hours.
  • the residue was diluted with dichloromethane (120 mL) and then washed with sodium hydroxide (10% aqueous solution, 50 mL ) and water (30 mL) .
  • the organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 120 mL) .
  • the combined aqueous layer was adjusted with a 10 % aqueous solution of sodium hydroxide to between pH 9 and 10 and then extracted three times with dichloromethane (150 mL) .
  • the organic layers were combined, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to yield a yellow solid. (5.2 g, 0.023 mol, 23% from 2-chloroaniline) .
  • the solvent was evaporated to dryness .
  • the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10 % aqueous solution, 100 mL ) and water (50 mL) .
  • the organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 250 mL) .
  • the combined aqueous layers were adjusted to pH 9 to 10 with a 10 % aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300mL) .
  • the organic layer was separated, dried over sodium sulfate, and evaporated to dryness.
  • the crude product was purified by silica gel column chromatography to yield the yellow-red solid product.
  • a solution of cyanamide in water (50 %, 150 mL) was added to a boiling solution of [2- (2-chloro-phenyl) - 1-methyliminomethyl-ethyl] -methyl-amine in methanol and dichloromethane .
  • the pH was brought to 4.5 by the continual addition of an aqueous solution of sulfuric acid (9 M) .
  • the mixture was refluxed for 2 hours, allowed to cool to room temperature, and adjusted to pH 9 through the addition of powdered sodium bicarbonate.
  • the mixture was extracted three times with dichloromethane (200 mL) and the combined organic layers were extracted three times with hydrochloric acid (20 % aqueous solution, 150 mL) .
  • aqueous solution was adjusted to pH 10 with sodium hydroxide (10 % aqueous solution) and extracted three times with dichloromethane (150 mL) .
  • the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black solid which was purified by column chromatography to yield the product (5.0 g, 0.23 mmol, 11 % from 2-chloroaniline) as a brown solid.
  • ESI-MS m/z calc.
  • the colorless solution was protected from light and allowed to stir for 16 hours.
  • the resulting red suspension was evaporated to dryness and dissolved in a minimum of dichloromethane.
  • This solution was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride.
  • the organic layer was separated and filtered to remove a fine red precipitate which remained suspended in the organic phase.
  • the solvent was removed and then the solid was dissolved in a minimum of 50 / 50 (v / v) ethyl acetate and 1 N aqueous solution of hydrochloric acid.
  • the layers were separated and the aqueous layer was washed with an equal volume of ethyl acetate.
  • aqueous layer was then placed in an ice bath with an equal volume of ethyl acetate .
  • Sodium hydroxide (IN) was then slowly added with vigorous swirling until the aqueous phase was basic.
  • the layers were separated and the aqueous layer was washed two additional times with ethyl acetate.
  • the combined organic layers were washed three times with an equal volume of a solution of saturated aqueous sodium bicarbonate followed by a solution of saturated aqueous sodium chloride.
  • the organic layer was then dried over sodium sulfate and evaporated to dryness to yield a pale yellow solid (1.8 g, 8.4 mmol, 34 %) ESI-MS m/z calc. 214.1, found 215.3 (M+l) + Retention time 1.90 minutes.
  • N- [5- (2-Chloro-benzoyl) -thiazol-2-yl] -2-phenyl- butyramide (102 mg, 0.265 mmol) was suspended in 1 mL of anhydrous methanol.
  • Sodium borohydride (30.3 mg, 0.801 mmol) was slowly added and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. After stirring for one hour a second aliquot of sodium borohydride (30.3 mg, 0.801 mmol) was added. The reaction mixture was allowed to stir for an additional hour and then the crude product was evaporated to dryness and then dissolved in a minimum of ethyl acetate.
  • 6-Ethoxy-benzothiazol-2-ylamine 39 mg, 0.20 mmol
  • 2 -phenyl-butyric acid 33 mg, 0.20 mmol
  • N, N-dimethylformamide 1 mL
  • triethylamine 84.1 ⁇ L, 0.600 mmol
  • 0- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours.
  • the crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25 %) .
  • ESI-MS m/z calc. 340.1, found 340.9 (M+l) + Retention time 3.55 minutes .
  • the optical membrane potential assay utilized voltage- sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4) : 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al . (1999) "Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4 (9) : 431-439).
  • VIPR Voltage/Ion Probe Reader
  • These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
  • FRET fluorescence resonant energy transfer
  • V m fluorescent phospholipid
  • the changes in fluorescence emission were monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
  • Bath Solution #1 (in mM) NaCI 160, KC1 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
  • Chloride-free bath solution Chloride salts in Bath Solution #1 are substituted with gluconate salts.
  • CC2-DMPE Prepared as a 10 mM stock solution in DMSO and stored at -20°C.
  • DiSBAC 2 (3) Prepared as a 10 mM stock in DMSO and stored at -20°C.
  • Cell Culture NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for optical measurements of membrane potential .
  • the cells are maintained at 37 °C in 51 C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs. for the potentiator assay.
  • the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hours.
  • the FRT epithelia demonstrated resistances of 4 K ⁇ / cm 2 or more.
  • the solutions were maintained at 27 °C and bubbled with air.
  • the electrode offset potential and fluid resistance were corrected using a cell-free insert.
  • the current reflects the flow of Cl " through ⁇ F508-CFTR expressed in the apical membrane.
  • the I S c was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA) . Identification of Correction Compounds Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient .
  • the cells were incubated with 10 mM of the test compound for 24 hours at 37°C and were subsequently washed 3X prior to recording.
  • the cAMP- and genistein- mediated I sc in compound-treated cells was normalized to the 27°C and 37°C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein- mediated I S c compared to the 37°C controls.
  • Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 ⁇ g/ml) , whereas apical NaCI was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl " concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 mM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • Basolateral solution in mM: NaCI (135), CaCl 2 (1.2), MgCl 2 (1.2), K 2 HP0 4 (2.4), KHP0 4 (0.6) , N-2- hydroxyethylpiperazine-N' -2- ethanesulfonic acid (HEPES) (10) , and dextrose (10) .
  • the solution was titrated to pH 7.4 with NaOH.
  • FRT Cell Culture Fisher rat epithelial cells expressing ⁇ F508- CFTR (FRT ⁇ F508"CFTR ) were used for Ussing chamber experiments for the putative ⁇ F508-CFTR modulators identified from our optical assays.
  • the cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 °C and 5% C0 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the ⁇ F508-CFTR.
  • the cells were incubated with 10 DM of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity) . Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ⁇ M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls .
  • Intracellular solution in mM: Cs-aspartate (90) , CsCl (50) , MgCl 2 (1) , HEPES (10) , and 240 ⁇ g/ml amphotericin-B (pH adjusted to 7.35 with CsOH) .
  • Extracellular solution in mM: N-methyl-D-glucamine (NMDG) -Cl (150), MgCl 2 (2), CaCl 2 (2) , HEPES (10) (pH adjusted to 7.35 with HCI) .
  • NMDG N-methyl-D-glucamine
  • CaCl 2 (2) CaCl 2 (2)
  • HEPES 10
  • the cells are maintained at 37 °C in 5% C0 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, D-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, D-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 °C for measuring the activity of correctors .
  • the ⁇ F508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI) . After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1-2 sec. To maintain ⁇ F508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F " (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min) . Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (V p ) was maintained at 80 mV.
  • V p The pipette potential
  • Extracellular solution (in mM) : NMDG (150) , aspartic acid (150), CaCl 2 (5), MgCl 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base) .
  • Intracellular solution in mM: NMDG-C1 (150) , MgCl 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCI) .
  • Cell Culture NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for excised-membrane patch-clamp recordings.
  • the cells are maintained at 37 °C in 5% C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.
  • the compounds of the present invention were found to modulate CFTR activity when tested using the above methods.
  • the activity of exemplary compounds of the present invention is recited below in Table 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Psychology (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • Food Science & Technology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biotechnology (AREA)

Abstract

The present invention relates to modulators of ATP-Binding Cassette ('ABC') transporters or fragments thereof, including CF Transmembrane Regulator ('CFTR'), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Description

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including CF Transmembrane Regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators .
BACKGROUND OF THE INVENTION [0002] ABC transporters are a group of membrane transporter proteins that play a major role in the transport and protection of cells against a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics . ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDRl-P glycoprotein, or the multidrug resistance protein, MRP1) , defending malignant cancer cells against chemotherapeutic agents. Up until the present time, 48 Human ABC Transporters have been identified, and these have been arranged into 7 families based on their sequence identity and function. [0003] ABC transporters play a variety of important physiological roles within the body, as well as providing a defense against harmful compounds from the environment. Moreover they represent important potential drug targets both in their own right, as well as, because in many cases therapeutic drugs are also transported out of the target cell by these molecules . [0004] One of the members of the ABC transporter family, namely, CFTR, is believed be the chloride channel responsible for cAMP-mediated chloride secretion in epithelial cells, and to play a key role in the secretion of chloride and maintenance of normal electrolyte transport throughout the body. CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each comprising six transmembrane segments and a nucleotide-binding domain. The two repeats are separated by a large, polar, regulatory (R) -domain containing multiple potential phosphorylation sites. [0005] The gene associated with CFTR has been identified and sequenced (See Gregory, R. J. et al . (1990) Nature 347:382-386; Rich, D. P. et al . (1990) Nature 347:358-362), (Riordan, J. R. et al . (1989) Science 245:1066-1073) . A defect in this gene leads to cystic fibrosis (hereinafter "CF"), the most common fatal genetic disease in humans affecting approximately one in every 2,500 infants born in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the chronic effects of CF, including chronic lung destruction and death. [0006] In patients with Cystic fibrosis, expression of the CF associated gene in airway cells, leads to reduced cellular apical chloride conductance causing an imbalance in ion and fluid transport . It is widely believed that this leads to the abnormal mucus secretion in pancreatic ductules and in the airways that ultimately results in the pulmonary infections and epithelial cell damage typically associated with disease progression in CF. In addition to respiratory problems, CF patients typically suffer from gastrointestinal problems, and pancreatic insufficiency. Males are almost uniformly infertile and fertility is decreased in females. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population. [0007] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al . (1990) Nature 346:366- 369; Dean, M. et al . (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). At present, more than 1000 mutations in the CF gene have been identified (http: //www. genet . sickkids .on. ca/cftr/) , but population studies have indicated that the most common CF mutation, a deletion of the 3 nucleotides that encode phenylalanine at position 508 of the CFTR amino acid sequence, is associated with approximately 70% of the cases of cystic fibrosis. The mutated CFTR protein is referred to as ΔF508. [0008] It is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the endoplasmic reticulum (hereinafter "ER"), and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Hence, the cellular phenomenon of defective ER processing of other protein/s like CFTR, by the ER machinery, has been shown to be the underlying basis for a wide range of isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al . , Nature Med., 5(7), pp 745- 751 (1999); Shastry, B.S., et al . , Neurochem. International, 43_, pp 1-7 (2003) ; Rutishauser, J. , et al . , Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al . , TIPS, 21_, pp. 466- 469 (2000); Bross P., et al . , Human Mut . , 14, pp. 186-198 (1999)]. Studies have shown, however, that ΔF508-CFTR, when presented at the plasma membrane is functional as a cAMP-responsive Cl" channel (Dalemans et al . (1991), Nature Lond. 354: 526- 528; Denning et al . , supra.; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). [0009] Although CFTR transports a variety of molecules in addition to anions, it is clear that this role (the transport of anions) represents one element in an important mechanism of transporting ions and water across the epithelium. The other elements include the epithelial Na+ channel, ENaC, Na+/2C1"/K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell. [0010] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell . Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl" channels, resulting in a vectorial transport. Arrangement of Na+/2C1"/K+ co- transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride . [0011] In addition to CF, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (hereinafter "COPD"), dry eye disease, and Sjogren's Syndrome. [0012] COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis . Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD. Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD. Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as Cystic Fibrosis and Sjδgrens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjδgrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis . Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms. [0013] As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. In fact, this cellular phenomenon of defective ER processing of ABC transporters by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al . , Nature Med., 5(7), pp 745- 751 (1999); Shastry, B.S., et al . , Neurochem. International, 43_, pp 1-7 (2003); Rutishauser, J. , et al . , Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al . , TIPS, 21, pp. 466- 469 (2000); Bross P., et al . , Human Mut . , 14, pp. 186-198 (1999)] . [0014] The diseases associated with the first class of ER malfunction are CF (due to misfolded ΔF508-CFTR) , hereditary emphysema (due to αl-antitrypsin; non Piz variants) , hereditary hemochromatosis, coagulation- fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses (due to lysosomal processing enzymes) , Sandhof/Tay-Sachs (due to 3-hexosaminidase) , Crigler-Najjar type II (due to UDP-glucuronyl-sialyc- transferase) , polyendocrinopathy/ hyperinsulemia, Diabetes mellitus (due to insulin receptor) , Laron dwarfism (due to growth hormone receptor) , myleoperoxidase deficiency, primary hypoparathyroidis t (due to preproparathyroid hormone) , melanoma (due to tyrosinase) . The diseases associated with the latter class of ER malfunction are glycanosis CDG type 1, Hereditary emphysema (due to αl-Antitrypsin (PiZ variant) , Congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen) , ACT deficiency (due to αl-Antichymotrypsin) , Diabetes insipidus (DI) , neurophyseal DI (due to Vasopressin hormone/V2 -receptor) , neprogenic DI (due to aquaporin II) , Charcot-Marie Tooth syndrome (due to Peripheral myelin protein 22) , Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to /3APP and presenilins) , Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as Spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect) , Fabry disease (due to lysosomal 01- galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect) . [0015] In CF, chloride transport mediated by the CFTR is reduced resulting in the abnormal mucus secretion that characterizes the disease. By contrast in secretory diarrheas epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR. [0016] Although there are numerous causes of diarrhea, the major consequences of diarrheal diseases, resulting from excessive chloride transport are common to all, and include dehydration, acidosis, death and impaired growth. [0017] Acute and chronic diarrheas represent a major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old. [0018] Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD) . Sixteen million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel . [0019] Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life. [0020] The most common diarrheal causing bacteria is enterotoxogenic E-coli (ETEC) having the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include σryptosporidium, giardia lamblia, and salmonella, among others . [0021] Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease. [0022] Accordingly, there is a need for modulators of an ABC transporter activity, and compositions thereof, that can be used to modulate the activity of the ABC transporter in the cell membrane of a mammal . [0023] There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity. [0024] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal . [0025] There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in the cell membrane of a mammal . [0026] There is a need for methods of treating CFTR- mediated diseases using such modulators of CFTR activity. [0027] There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal . [0028] There is a need for correctors that enhance the density of CFTR in the plasma membrane by facilitating the migration of the CFTR thereto.
SUMMARY OF THE INVENTION [0029] The present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof; wherein: Y' is 0, S, or NR; p is 0-2; X is a bond, 0, S, S (O) , S(0)2, CF2, CH2/ -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O) 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H , R2 , or R6 ; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl ; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
Figure imgf000012_0001
(e) (f) (9) (h) each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5; RL is -ORA, -SRA, or -N(RAB)2; each RA is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each RA is optionally substituted with up to 3 substituents independently selected from R1, R4 or R7, each RAB is independently hydrogen or C1-C6 aliphatic optionally substituted with up to 3 substituents independently selected from R1, R4 or R7; wherein up to two methylene units in RA or Rω are optionally replaced with -CO-, -CS-, -COCO-, -CONR-, -C02- , -0C0-, -NRC02-, -0-, -NRCONR-, -OCONR- , -NRCO- , -S-, - SO, -S02-, -NR-, -S02NR-, NRS02-, or -NRS02NR; or two Rm , taken together with the nitrogen atom, is a 3-7 membered heterocyclic or heteroaryl ring containing up to 4 heteroatoms selected from 0, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1.4aliphatic)p-Y; RM is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; each of 1 and X2 is independently selected from 0, S, or NR; RN is C1-C6 aliphatic or phenyl, wherein RN is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; Rp is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; RQ is C1-C6 aliphatic or aryl, wherein RQ is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6 , S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (O) NR5R6 ,
NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6,
NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 ,
NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R^ substituent ; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R"7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, S02 -aliphatic, NH , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0)0 (-aliphatic) , or O-aliphatic; and R8 is an amino-capping group. [0030] The present invention also provides compositions comprising compounds of formula (I) and formula (I'), and methods of treating ABC transporter mediated diseases using compounds of formula (I) and formula (I ' ) .
DETAILED DESCRIPTION OF THE INVENTION [0031] As used herein, the following definitions shall apply unless otherwise indicated. [0032] The term "ABC-transporter" as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vi tro . The term "binding domain" as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al . , J. Gen. Physiol. (1998): 111(3), 477-90. [0033] The term "CFTR" as used herein means cystic fibrosis transmembrane regulator or a mutation thereof capable of its regulator activity, in part or full, including, but not limited to, ΔF508 CFTR and G551D CFTR (see, e.g., htt : //www. genet . sickkids .on. ca/cftr/, for CFTR mutations) . [0034] The term "modulating" as used herein means increasing or decreasing by a measurable amount. [0035] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted. " [0036] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain or branched, hydrocarbon chain that is completely saturated (alkyl) or is unsaturated (alkenyl or alkynyl) . Unless otherwise specified, an aliphatic group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms. Up to three, and preferably two, -CH2- in said aliphatic may be replaced with 0, S, or -NR. [0037] The term "alkylidene" as used herein means a straight-chain or branched hydrocarbon chain that is completely saturated or unsaturated, and is connected to the rest of the molecule through covalent bonds. Exemplary alkylidene groups include methylene, ethylene, or propylene. Unless otherwise specified, an alkylidene group has 1 to 12 carbon atoms, preferably, 1-6 carbon atoms, and more preferably, 1-4 carbon atoms. [0038] The term "cycloaliphatic" means a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring that has up to two points of attachment to the rest of the molecule. Unless otherwise specified, preferred cycloaliphatic rings are 3-8 membered monocyclic rings, more preferably 3-6, and even more preferably, 3, 5, or 6. Also preferred, unless otherwise specified, are 8-12 membered bicyclic hydrocarbon rings, more preferably 10 membered bicyclic hydrocarbon rings. [0039] The term "heteroatom, " unless otherwise specified, means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3 , 4-dihydro-2Jf-pyrrolyl) , NH (as in pyrrolidinyl) or as in N-substituted pyrrolidinyl. [0040] The term "unsaturated", as used herein, means a double bond or a triple bond. Each such bond constitutes one unit of unsaturation. [0041] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" , refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems. Unless otherwise specified, preferred aryl rings have a total of five to fourteen ring members, wherein at least one ring, if bicyclic or tricyclic, in the system is aromatic and wherein each ring in the system contains up to 6 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". Phenyl is an example of aryl. [0042] The term "heterocycle" , "heterocyclyl", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems wherein one or more ring members is a heteroatom. Unless otherwise specified, each ring in the system preferably contains contains 3 to 7 ring members with preferably 1-3 heteroatoms . [0043] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy" , refers to monocyclic, bicyclic and tricyclic ring systems, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Unless otherwise specified, such ring systems preferably have a total of 5 to 15 ring members, wherein each ring in the system preferably contains 3 to 7 ring members, with preferably 1-3 heteroatoms. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic" . [0044] A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. [0045] The present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formula I or formula I ' :
Figure imgf000018_0001
I I1
or a pharmaceutically acceptable salt thereof; wherein: Y' is 0, S, or NR; p is 0-2; X is a bond, O, S, S (0) , S(0)2, CF2, CH2, -CH0R-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O)- 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H, R2, or R6; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
Figure imgf000019_0001
each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, where-in each said heteroatom is independently selected from N, NH, S, or 0; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from Rx, R2 , R , R4 , or R5 ; RL is -0RA, -SRA, or -N(RAB)2; each RA is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from O, N, or S, wherein each RA is optionally substituted with up to 3 substituents independently selected from R1, R4 or R7, each Rω is independently hydrogen or C1-C6 aliphatic optionally substituted with up to 3 substituents independently selected from R1, R4 or R7; wherein up to two methylene units in RA or RAB are optionally replaced with -CO-, -CS-, -COCO-, -CONR-, -C02- , -0C0-, -NRCO2-, -0-, -NRCONR-, -0C0NR-, -NRC0-, -S-, - SO, -SO2-, -NR-, -S02NR-, NRS02-, or -NRS02NR; or two RAB, taken together with the nitrogen atom, is a 3-7 membered heterocyclic or heteroaryl ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (Cι-4aliphatic)p-Y; RM is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; each of Xx and X2 is independently selected from 0, S, or NR; RN is C1-C6 aliphatic or phenyl, wherein RN is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; Rp is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R^, R , R , or R4 ; RQ is C1-C6 aliphatic or aryl, wherein RQ is optionally substituted with up to two substituents selected from R1 , R2 , R3 , or R4 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6 , S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two R1 on adjacent ring atoms, taken together, form 1, 2-methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, 0C(0)0R6, 0C(0)0R5, OC(0)N(R6)2, 0C(0)N(R5)2, OC (0) N (R6R5) , SR6 ,
SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6),
NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (O) NR5R6 ,
NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6,
NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 ,
NR5S02NR5R6, NR5S02N(R5)2, N(OR6)Rβ, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent ; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg)- straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, S02-aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2, N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0) 0 (-aliphatic, or O-aliphatic; and R8 is an amino-capping group. [0046] The term "amino capping group" refers to a suitable chemical group that may be attached to a nitrogen atom. The term "capping" refers to when the designated amino group is attached to a suitable chemical group (e.g., protecting group). Examples of suitable amino capping groups are described in T.W. Greene et al . , Protective Groups in Organic Synthesis, 3d. Ed., John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and are exemplified in certain of the specific compounds used in this invention. [0047] According to a preferred embodiment, Y' is S. [0048] According to one embodiment, Y' is 0. [0049] According to another embodiment, Y' is NR. In one embodiment, R is H. Or, R is R2. Or, R is R6. [0050] According to another embodiment, p is 1. Or, p is 1 and X is attached to the carbon adjacent to Y' atom. Or, p is 1 and X is attached to the carbon adjacent to the ring nitrogen atom. [0051] According to another embodiment, p is 2. [0052] According to another embodiment, X is a bond, 0, S, CH2/ CF2, CHOR, C(0)NR, C(0)0-, NRC (O) , or NR. In certain embodiments, X is a bond, 0, or CH2. In other embodiments, X is CH2. [0053] According to another embodiment, A is an optionally substituted C3-C7 cycloaliphatic ring. Preferably, A is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl. [0054] According to another embodiment, A is optionally substituted (C1-C10) aliphatic . In certain embodiments, A is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl . [0055] According to another embodiment, A is optionally substituted C6-C10 aryl ring. In one embodiment, A is optionally substituted phenyl or naphthyl . [0056] According to another embodiment, A is optionally substituted C5-C12 heteroaryl ring. In certain embodiments, A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl , imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl . [0057] According to another embodiment, A is optionally substituted C3-C12 heterocyclic ring. In certain embodiments, A is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl , tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl . [0058] In some embodiments, A, X, and the ring attached thereto, taken together, is selected from:
Figure imgf000023_0001
Figure imgf000024_0001
v x Vll
Figure imgf000024_0002
xx xii lll
Figure imgf000024_0003
XXV xv vx
Figure imgf000024_0004
wherein: Rph is independently R1, R2, or R3; and r is 0-3. X5 is CH2, C(O) , or CHOR; X6 is 0 or NR2; and R^ is C1-C6 aliphatic, optionally substituted with R1, R2, or R3. [0059] In another embodiment, A, X, and the ring attached thereto, taken together, is selected from any of the rings i to xviii, wherein the sulfur atom in each of the thiazole ring is replaced with an oxygen atom (to provide the corresponding oxazole) . [0060] According to another embodiment, each B is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each B is an optionally substituted phenyl or naphthyl. Or, each B is an unsubstituted phenyl . [0061] According to another embodiment, each B is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each B is independently an optionally substituted C5-C7 heteroaryl. [0062] According to another embodiment, each B is independently selected from triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl , oxazolyl , pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl , benzthiazolyl, purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl , pteridinyl, carbazolyl, acridinyl , phenazinyl, phenothiazinyl , phenoxazinyl , indenyl , naphthyl, azulinyl, or anthracenyl . [0063] According to another embodiment, R1 is 1,2- methylene dioxy, or 1 , 2-ethylenedioxy. [0064] According to another embodiment, R1 is R6, wherein R6 is straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl , optionally substituted with R7. [0065] According to another embodiment, R1 is (Cl- C4 aliphatic) n-Y/ wherein n is 0 or 1, and Y is halo, CN, N02, CF3, OCF3, OH, SR6, S(0)R6, S02R6, NH2 , NHR6 , N(R6) , NR6R8, COOH, COOR6 or OR6; [0066] According to another embodiment, R1 is selected from halo, CF3, NH2, NH(C1-C4 alkyl), NHC(0)CH3, OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl), Cl- C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S02NH(C1- C4 alkyl), or S02N(C1-C4 alkyl)2. [0067] According to another embodiment, R1 is selected from methyl, n-propyl, i-propyl, t-butyl, halo, CF3, NH2, NH(CH3), NHC(0)CH3, OH, OCH3, OPh, O-benzyl, S- (C2H5) , S-CH3, N02, CN, methylenedioxy, S02NH (n-propyl) , or S02 (n-propyl) 2. [0068] According to one embodiment, R2 is a straight chain or branched (C1-C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R1, R4, or R5. In certain embodiments, R2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R1, R4, or R5. [0069] According to another embodiment, R3 is optionally substituted phenyl, napthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl. In certain embodiments, R3 is an optionally substituted phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl . [0070] According to one embodiment, R4 is selected from OR5, OR6, SR5 , SR6, NR5COR5, NR5COR6, NR6COR5 , or NR6COR6. [0071] According to one embodiment, R5 is C5-C6 cycloalkyl, C6 or CIO aryl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with up to 2 R1. In certain embodiments, R5 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl . [0072] According to one embodiment, R6 is H. [0073] According to another embodiment, R6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl, optionally substituted with R7. [0074] According to another embodiment, R6 is a straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or alkynyl. [0075] According to one embodiment, R7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with straight chain or branched (C1-C6) alkyl or (C2-C6 alkenyl) or al ynyl. Or, R7 is C5-C6 cycloalkyl, phenyl, naphthyl, C5-C10 heteroaryl or C3-C7 heterocyclyl, optionally substituted with 1-2-methylenedioxy, 1, 2-ethylenedioxy, or (CH2)n-Z. In certain embodiments, R7 is an optionally substituted cyclohexyl, phenyl, C5-C6 heteroaryl, or C3-C6 heterocyclyl . [0076] According to a preferred embodiment, R8 is acetyl, arylsulfonyl or alkylsulfonyl . [0077] In another embodiment, Q in compounds of formula I is selected from:
-—B ; —e— (aliphatic)-B ;
Figure imgf000027_0001
[0078] In one embodiment, the present invention provides compounds having formula I-a:
:VV IN ^ o I- a . [0079] In certain embodiments , p is 1 . Or, p is
2 . [0080] In certain embodiments , X is a bond, 0 , CH2 ,
CHOH , C (O) , or C (0) 0. Or, X is a bond, 0 , or CH2 . [0081] In certain embodiments, p is 1 and X is a bond. In one embodiment, p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom. Or, p is 1, and X-A is attached to the carbon adjacent to the Y'. [0082] In certain embodiments, p is 1, X is CH2, CHOH, or C(O) , and A is an optionally substituted phenyl. [0083] In certain embodiments, X is a bond, and A is an optionally substituted phenyl. [0084] In certain embodiments, p is 2, each X is a bond, and each A is an optionally substituted phenyl. [0085] In certain embodiments, each B is independently and optionally substituted ring selected from:
Figure imgf000028_0001
wherein X3 is O, S, or NR. [0086] Preferred substituents on B include C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, - C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C (0)N(C1-C4 alkyl) 2 or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, -C (O) 0.(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C (0)N(C1-C4 alkyl) 2. [0087] In certain embodiments, each B is indpendently an optionally substituted ring selected from ring i, iii, iv, v, or vi. Or, wherein B is an optionally substituted ring vii . [0088] In some embodiments, B is independently ring x optionally substituted with up to two substituents selected from R1 or phenyl optionally substituted with up to two R1. Preferably, B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, - 0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2, or phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4- alkyl, CN, halo, COOH, -C(0)NH2, -C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2. [0089] Or, each B is an optionally substituted ring selected from ring xi, xii, xiii, or xiv. [0090] In certain embodiments, p is 1. Or, p is 2. [0091] In some embodiments, R is hydrogen. [0092] In some embodiments, Y' is S. Or, Y' is O. [0093] In certain embodiments, X is a bond and A is optionally substituted phenyl. In certain embodiments, A is attached to the carbon atom adjacent to the nitrogen ring atom. [0094] In certain embodiments, A is phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N- piperidinyl, or methylenedioxy. [0095] In certain embodiments, A is phenyl, methoxyphenyl , dimethoxyphenyl , cyanophenyl , N- pyrrolidinylphenyl, methylenedioxyphenyl , halophenyl, methylphenyl , or dimethylphenyl . [0096] In certain embodiments, A is phenyl, 3- methoxyphenyl , 2 -methoxyphenyl, 4-chlorophenyl, 4- cyanophenyl, 4- (N-pyrrolidinyl) phenyl, 4-tolyl, 3,4- methylenedioxyphenyl , 3 -chlorophenyl , 2,4- dimethoxyphenyl, 2-chlorophenyl, 4-bromophenyl, or 2,4- dimethylphenyl . [0097] In certain other embodiments, A is C3-C10 cycloaliphatic ring. Exemplary ring include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. In certain embodiments, A is cyclohexyl or adamantyl. [0098] In certain embodiments the compounds of the present invention have one of more of the following features : a) R is hydrogen; b) Y' is S; c) A is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N-piperidinyl , or methylenedioxy; and d) B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, -C(0)0(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C(0)N(C1-C4 alkyl)2, or phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, - C(0)0(C1-C4 alkyl), -C (O)NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2. [0099] In one embodiment, the present invention provides compounds having formula I-b:
Figure imgf000030_0001
I-b. [00100] In certain embodiments, p is 1 and X is a bond. In one embodiment, p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom. Or, p is 1, and X-A is attached to the carbon adjacent to the Y' . [00101] In certain embodiments, p is 1, X is CH2, CHOH, or C(O), preferably CH2, and A is an optionally substituted phenyl . [00102] In certain embodiments, X is a bond, and A is an optionally substituted phenyl. [00103] In certain embodiments, p is 2, each X is a bond, and each A is an optionally substituted phenyl. [00104] In certain embodiments, said C1-C6 aliphatic, is C1-C4 straight or branched alkylidene. Exemplary alkylidenes include -CH2-, τCH(Me)-, -C(Me)2-, - CH(Et)-, -C(Et)2-, or -CH2-CH (Me) - . [00105] In certain embodiments, B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl , or pyrrolidinyl. Preferably, B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R1 substituents. [00106] In some embodiments, said (C1-C6 aliphatic) -B in formula I-b is selected from:
Figure imgf000031_0001
l ll ill ιv; wherein: Ak is C1-C6 straight or branched alkylidene; X4 is CH2, 0 or S; Ar' is phenyl optionally substituted with up to two R1; and B is optionally substituted with up to two R1. [00107] In some embodiments, Ak is selected from CH2, CH(CH3), C(CH3)2, CH(Et), C(Et)2, CH (n-propyl) , CH(i- Pr) , CH(n-butyl), CH (but-2-yl) , or CH (t-butyl) . [00108] In some embodiments, Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) . [00109] In some embodiments, X4 is S. Or, X4 is 0. [00110] In some embodiments, R is hydrogen. [00111] In one embodiment, the present invention provides compounds of formula I-f:
Figure imgf000032_0001
I-f; wherein: Y' is O or S; Xi is 0, S, or NR; RM is C1-C6 aliphatic or phenyl, wherein RM is optionally substituted with up to two substituents independently selected from R1, R2, or R3; RN is C1-C6 aliphatic or a 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein RN is optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5. [00112] In certain embodiments, p is 1 and X is a bond. In one embodiment, p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom. Or, p is 1, and X-A is attached to the carbon adjacent to the Y' . [00113] In certain embodiments, p is 1, X is CH2, CHOH, or C(O), preferably CH2, and A is an optionally substituted phenyl . [00114] In certain embodiments, X is a bond, and A is an optionally substituted phenyl. [00115] In certain embodiments, p is 2, each X is a bond, and each A is an optionally substituted phenyl. [00116] In some embodiments, Xx is NH or N(C1-C4 alkyl) . Or, Xx is O. [00117] In some embodiments, RM is optionally substituted phenyl . [00118] In some embodiments, RM is C1-C6 alkyl, optionally substituted with phenyl. In some embodiments, RM is C1-C4 alkyl. [00119] In some embodiments, RN is optionally substituted C3-C7 cycloaliphatic, phenyl, or benzyl. [00120] In some embodiments, RN is C1-C6 aliphatic. [00121] In some embodiments, R is hydrogen. [00122] In one embodiment, the present invention provides a compound of formula I-g:
Figure imgf000033_0001
i-g wherein: Y' is 0 or S; Rp is C1-C8 aliphatic optionally substituted with up to two substituents independently selected from R1, R2, or R3. [00123] In certain embodiments, p is 1 and X is a bond. In one embodiment, p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom. Or, p is 1, and X-A is attached to the carbon adjacent to the Y' . [00124] In certain embodiments, p is 1, X is CH2, CHOH, or C (O) , preferably CH2, and A is an optionally substituted phenyl. [00125] In certain embodiments, X is a bond, and A is an optionally substituted phenyl. [00126] In certain embodiments, p is 2, each X is a bond, and each A is an optionally substituted phenyl. [00127] In some embodiments, Rp is C1-C4 alkyl, optionally substituted with up to two R1. [00128] In some embodiments, Rp is selected from ethyl, n-propyl, i-propyl, n-butyl, but-2-yl, or t-butyl, isoamyl, optionally substituted with halo, CN, COOH, or CONH2. [00129] In some embodiments, R is hydrogen. [00130] In certain embodiments, p is 1. Or, p is 2. [00131] In certain embodiments, p is 2, and each A is optionally substituted phenyl. Or, p is 2, and each A is phenyl . [00132] In certain embodiments, compounds of formula 1-g have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2 and each A is phenyl; d) Rp is isoamyl, t-butyl, ethyl, isopropyl, n-propyl, l-carboxy-prop-3-yl , or 1-carboxy-2 -methyl- prop-3-yl . [00133] In one embodiment, the present invention provides compounds of formula I-h:
Figure imgf000034_0001
I-h wherein: Y' is O or S; X2 is O, S, or NR; RQ is C1-C6 aliphatic or phenyl, optionally substituted with up to two substituents independently selected from R1, R2, or R3. [00134] In certain embodiments, p is 1 and X is a bond. In one embodiment, p is 1, and X-A is attached to the carbon adjacent to the ring nitrogen atom. Or, p is 1, and X-A is attached to the carbon adjacent to the Y' . [00135] In certain embodiments, p is 1, X is CH2, CHOH, or C(O), preferably CH2, and A is an optionally substituted phenyl . [00136] In certain embodiments, X is a bond, and A is an optionally substituted phenyl. [00137] In certain embodiments, p is 2, each X is a bond, and each A is an optionally substituted phenyl. [00138] In some embodiments, X2 is S. Or, X2 is O. [00139] In some embodiments, RQ is C1-C4 alkyl, optionally substituted with up to three R1. [00140] In some embodiments, RQ is phenyl optionally substituted with C1-C4 alkyl, or R1. [00141] According to another preferred embodiment, the methods of the present invention employ a compound having formula (1A) :
Figure imgf000035_0001
wherein: Y' is O, S, or NR; X is a bond, CH2, CHOR, C(0)0, C (O) , NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
Figure imgf000035_0002
each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; R is H, R2, or R6; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4, or R5; and R1, R2 , R3 , R4 , or R5 are as defined above for formula (I) . [00142] According to one embodiment of formula (IA) , Y' is S. [00143] According to another embodiment of formula (IA) , Y1 is 0. [00144] According to another embodiment of formula (IA) , Y' is NR. [00145] In one embodiment, X is a bond, CH2, NR, or O; [00146] According to another embodiment of formula (IA) , X is CH2. According to another embodiment of formula (IA) , X is CF2. According to yet another embodiment of formula (IA) , X is a bond. According to yet another embodiment of formula (IA) , X is O. According to yet another embodiment of formula (IA) , X is NR. [00147] According to another embodiment of formula (IA) , A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R1, R2 , R3 , or R4. [00148] According to one embodiment of formula (IA) , Q is B. Alternatively, Q is -(C1-C6)- aliphatic-B. Or, Q is CH(B) . According to another embodiment, Q is
C(B)3- Preferably, B is phenyl. [00149] In one embodiment , X is a bond, -CHOR- , or
-C (O) - , [00150] Exemplary compounds of formula ( IA) are those wherein : (i ) X is a bond, CH2 , or O ; (i) A is optionally substituted phenyl; (iii)Q is diphenylmethyl . [00151] Exemplary compounds of formula (IA) useful in the methods of the present invention are as shown below in Table 1. [00152] According to another embodiment, the methods of the present invention employ a compound having formula (IB) :
Figure imgf000037_0001
wherein: Y' is 0, S, or NR; X is a bond, CH2, CHOR, C(O), C(0)0, NR, or 0; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
Figure imgf000037_0002
each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; R is H, R2, or R6; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5 ; and R1, R2 , R3, R4, or R5 are as defined above for formula (I) . [00153] According to one embodiment of formula (IB) , Y' is S. [00154] According to another embodiment of formula (IB) , Y' is 0. [00155] According to another embodiment of formula (IB) , Y' is NR. [00156] According to one embodiment of formula (IB), X is a bond, CH2, NR, or 0, Or, X is a bond or CH2. According to another embodiment of formula (IB), X is CF2. According to yet another embodiment of formula (IB) , X is a bond. According to yet another embodiment of formula (IB), X is O. According to yet another embodiment of formula (IB) , X is NR. [00157] According to another embodiment of formula (IB) , A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R-*-, R2 , R3 , or R4. [00158] According to another embodiment of formula (IB), Q is B. Alternatively, Q is -(C1-C6)- aliphatic-B. Or, Q is CH(B)2. According to another embodiment, Q is
C (B) 3. Preferably, B is phenyl . [00159] Preferred compounds of formula IB are those wherein: (i) X is a bond, CH2, or 0; (ii) A is optionally substituted phenyl; (iii) Q is diphenylmethyl . [00160] According to another embodiment, the methods of the present invention employ a compound having formula (IC) :
Figure imgf000039_0001
wherein: Y' is 0, S, or NR; each X is independently a bond, CH2, -CHOR-, -C(0)0-, -C(0) -, NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
- B
Figure imgf000039_0002
(c) (d) each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; R is H, R2, or R6; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5 ; and R1, R2 , R3 , R4 , or R5 are as defined above for formula (I) . [00161] According to one embodiment of formula (IC) , Y' is S. [00162] According to another embodiment of formula (IC) , Y' is 0. [00163] According to another embodiment of formula (IC) , y is NR. [00164] According to another embodiment of formula (IC) , X is a bond or CH2. According to another embodiment of formula (IC) , X is'CH2. According to yet another embodiment of formula (IC) , X is a bond. Or, X is -CHOR- Or, X is -C(O)-. According to yet another embodiment of formula (IC) , X is 0. According to yet another embodiment of formula (IC) , X is NR. [00165] According to another embodiment of formula (IC) , A is phenyl or a 5-6 membered heteroaryl, preferably phenyl, wherein A is optionally substituted with up to 3 substituents selected from R^-, R2 , R , or R4. [00166] According to another embodiment of formula (IC) , Q is B. Alternatively, Q is -(C1-C6)- aliphatic-B. Or, Q is CH(B)2. According to another embodiment, Q is
C(B)3> Preferably, B is phenyl. [00167] Exemplary compounds of formula (IC) are those wherein: (i) each X is a bond, -CHOR-, or -C(O)-; (ii) each A is optionally substituted phenyl, (Cl -C6) aliphatic, or CF3; (iii) Q is optionally substituted phenyl, (Cl- C6) aliphatic, or diphenylmethyl . [00168] According to another embodiment, the present invention provides a compound having formula (ID =
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof; wherein: Xi is a bond, 0, S, CHOR, C (O) , C(0)0, CF2, CH2, or NR; R is H or R2 A is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; each Bi is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; wherein each Ai is optionally substituted with up to
4 substituents independently selected from ^, R2 , R3 , R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two i on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1 , 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6,
SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2,
S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6,
C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 ,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6),
NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (O) NR5R6 , NR5C(0)N(R5) 2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02 (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2r N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-*- substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent ; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) - straight or branched alkyl, (C -Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH )n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, S02 -aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0) O (-aliphatic, or O-aliphatic; and R8 is an amino capping group. provided that : (i) when both Bi are simultaneously phenyl and Xi is CH2, then A is not 4-fluoro-phenyl, -phenyl- piperidyl, phenyl, 2 , 4-dichloro-phenyl , 4 -methoxyphenyl , 3 ,4-dichloro-phenyl, 2 , 5-dichloro-phenyl, 4- nitro-phenyl, 4-bromo-phenyl , 4 -methyl-phenyl , 2- chloro-phenyl, 1-naphthyl, 3-trifluoromethyl-phenyl, 2, 3-dichlorophenyl, N-morpholinyl, 4-chloro-phenyl , 3-chloro-phenyl, or 3-nitro-phenyl ; (ii) when Xi is a bond or CH2, one Bi is a substituted phenyl and the other Bi is cycloaliphatic, then Ax is not (C2-C8) aliphatic; and (iii) when Xi is a bond, then Ai is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms. [00169] According to one embodiment of formula (II) , Xx is a bond, 0, S, CF2, CH2, or NR. Xi is CH2, CF2, or O. Or Xi is CH2 or 0. In certain embodiments, Xi is
CH2. [00170] According to another embodiment, Ai is an optionally substituted C3-C7 cycloaliphatic ring. In certain embodiments, Ai is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl. [00171] According to another embodiment, Ai is optionally substituted (C1-C10) aliphatic . In certin embodiments, Ai is optionally substituted methyl, ethyl, propyl , butyl , pentyl , or hexyl . [00172] According to another embodiment, Ax is optionally substituted C6-C10 aryl ring. In certain embodiments, Ai is optionally substituted phenyl or naphthyl . [00173] According to another embodiment, Ai is optionally substituted C5-C12 heteroaryl ring. In certain embodiments, A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, lH-indazolyl , benzimidazolyl, benzthiazolyl, purinyl , quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl . [00174] According to another embodiment, Ai is optionally substituted C3-C12 heterocyclic ring. In certain embodiments, Ax is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl. [00175] According to another embodiment of formula (II) , each Bi is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each Bi is independently an optionally substituted phenyl or naphthyl. Or, each Bx is an unsubstituted phenyl. [00176] According to another embodiment, each B is independently selected from optionally substituted C5-C12 heteroaryl ring. In certain embodiments, each Bi is independently and optionally substituted C5-C7 heteroaryl ring. Or, each Bx is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl , purinyl , quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl , quinoxalinyl , 1,8- naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl , indenyl , naphthyl, azulinyl, or anthracenyl . [00177] According to another embodiment, each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR. In certain embodiments, each Bx is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1 , 4-dioxanyl, morpholinyl, 1, -dithianyl , thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl . [00178] Embodiments of R1, R2 , R3 , R , R5 , R6 , R7 ,
R8 , and Z in compound of formula (II) are as described above for compound of formula (I) . [00179] In certain embodiments, one Bx is phenyl with up to two R1 substituents, and the other Bi is selected from pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, optionally substituted with up to two R1 subsituents. [00180] In certain embodiments, one Bi is phenyl, and the other B% is selected from 1, 2-pyrazol-l-yl, 1- piperidinyl, 2-carboethoxy-1-piperidinyl , 4-morpholinyl , 3 -carboethoxy-1-piperidinyl, 3-methyl-1-piperidinyl , 2- ethyl -1-pyrrolidinyl , 3 -hydroxymethyl-1-piperidinyl, 4- carboethoxy-1-piperidinyl, 4 -methyl -1-piperidinyl, 1- pyrrolidinyl, 4- (pyrimidin-2-yl) -1-piperazinyl , or 4- hydroxy-piperidinyl . [00181] According to another embodiment, the present invention provides a compound of formula IIA:
Figure imgf000046_0001
IIA wherein: Y' is O or S; B is a 3-8 membered, saturated, moncyclic, ring having 0-4 heteroatoms selected from 0, S, or N; and ring G and B are optionally substituted with up to four substituents independently selected from R1 , R2 , R ,
R4, or R5; provided that when Y' is S, and: a) when B is cyclohexyl, tetrahydrofuran-2-yl , or cyclopropyl, and ring G has 1-3 halo substituents, then ring G has at least one additional substituent other than halo; and b) when B is tetrahydrofuran-2-yl, then ring G is not phenyl, trifluoromethylphenyl , methoxyphenyl, or tolyl; c) when B is cyclohexyl, then ring G is not phenyl or trifluoromethylphenyl . [00182] According to one embodiment, B is tetrahydrof ranyl , piperidyl, morpholinyl, or thiomorpholinyl . [00183] According to another embodiment, B is C3-C8 saturated, carbocyclic, monocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl . [00184] According to another embodiment, ring G is phenyl optionally substituted with R1. Preferably, ring G is optionally substituted with up to two substituents selected from halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl) . [00185] In one embodiment, compounds of formula IIA have one or more of the following features: a) Y' is S; b) ring G is halo-substituted phenyl; c) B is phenyl optionally substituted with halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl). [00186] According to another embodiment, the present invention provides a compound of formula IIB:
Figure imgf000047_0001
IIB; wherein: Y' is S or 0; R is H, R2, or R6 ; RB is C1-C6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each of ring G, ring H, and RB is independently and optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4, or R5; provided that when Y is S, and: a) when RB is hydrogen, and ring G and ring H both have 1-3 halo substituents, then at least one of ring G and ring H has an additional substituent other than halo; b) when RB is hydrogen and ring H is unsubstituted phenyl, then ring G is not phenyl or phenyl substituted with methyl, CF3, -OMe, N02, or 1-3 halo; c) when RB is hydrogen and ring H is phenyl with methyl, 1-2 methoxy or 1-2 halo substituents, then ring G is not phenyl substituted with CF3 or 1-2 halo; d) when RB is methyl and ring H phenyl substituted with butyl, then ring G is not phenyl substituted with methyl, or 1-2 halo; and e) when RB and ring H are both unsubstituted phenyl, then ring G is not unsubstituted phenyl, or phenyl substituted with methyl, CF3, OMe, N02, or 1-2 halo. [00187] In certain embodiments, ring G is phenyl optionally substituted with up to two R1. Exemplary RI includes C1-C4 alkyl, 0- (C1-C4 alkyl), halo, or cyano. [00188] In one embodiment, RB is Cl-6 aliphatic optionally substituted with up to 4 substituents selected from R1, R2, R3 , R4, or R5. In certain embodiments, RB is C1-C4 alkyl optionally substituted with up to 2 substituents selected from R1. Exemplary RB include methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, or t-butyl. [00189] In other embodiments, RB is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 0-4 heteroatoms optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5. In certain embodiments, RB is a 3-7 membered monocyclic saturated, carbocyclic ring optionally substituted with up to 2 substituents selected from R1. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl . [00190] In other embodiments, RB is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 1-3 heteroatoms optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5. In certain embodiments, RB is a 3-7 membered monocyclic saturated ring containing 1-3 heteroatoms optionally substituted with up to 2 substituents selected from R1. Exemplary rings include piperidinyl, morpholinyl, or thiomorpholinyl . [00191] In other embodiments, RB is a 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O, optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4, or R5. [00192] According to another embodiment, the present invention provides compounds of formula IIC:
Figure imgf000049_0001
wherein: Y' is 0 or S; X7 is 0, S, or NR' ; R' is hydrogen, R2, or R6; R is hydrogen, R2 , or R6; RB is Cl-6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; Rc is C1-C6 aliphatic; wherein each of ring G, RB, and Rc is independently and optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5, as defined above. [00193] According to one embodiment, X7 is O. Or, X7 is S. Or, X7 is NR' . [00194] According to one embodiments, Rc is C1-C6 alkyl, optionally substituted with up to two substituents selected from R1, R2 , R3 , R4, or R5. Or, Rc is C1-C6 alkyl. Exemplary Rc includes methyl, ethyl, isopropyl, n- propyl, n-butyl, sec-butyl, or t-butyl. [00195] According to another embodiment, RB is phenyl optionally substituted with up to two R1 substituents . Or, RB is phenyl. [00196] According to another embodiment, RB is C1-C6 alkyl. Exemplary RB includes methyl, ethyl, isopropyl, n- propyl , n-butyl, sec-butyl, or t-butyl. [00197] In one embodiment, compound of formula IIC includes one or more of the following eatures: a) ring G is benzyl optionally substituted with one RI substituent, preferably halo; b) Y' is S and R is hydrogen; c) Rc is C1-C4 alkyl; d) X7 is NH or NR' wherein R' is C1-C4 alkyl; and e) RB is C1-C4 alkyl. [00198] According to another embodiment, the present invention provides a compound of formula IID:
Figure imgf000050_0001
IID; wherein: Y' is O or S; R is hydrogen or R2 ; X8 is 0, S , or NR ' ; R " is hydrogen, R2 , or R6 ; R is Cl-6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, S, or 0; wherein each of ring G and RBB is independently and optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5, as defined above. [00199] In certain embodiments, X8 is 0. Or, X8 is S. Or, X8 is NR' . [00200] According to another embodiment, RBB is phenyl optionally substituted with up to two R1 substituents . Or, RBB is phenyl. [00201] According to another embodiment, RBB is Cl- C6 alkyl. Exemplary RBB includes methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or t-butyl. [00202] According to another embodiment, RBB is optionally substituted C3-C8 cycloalkyl, e.g., cyclopropyl, cyclopentyl, or cyclohexyl. [00203] According to another embodiment, RBB is optionally substituted benzyl . [00204] In one embodiment, compounds of formula IID have one or more of the following features : a) Y' is S and R is hydrogen; b) each ring G is unsubstituted phenyl; d) X8 is NR' , and R' is hydrogen or C1-C4 alkyl; and e) RBB is C1-C4 alkyl, benzyl, cyclopentyl, or cyclohexyl . [00205] According to another preferred embodiment, the present invention provides a compound having formula (III) :
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof; wherein: Xi is a bond, O, S, CHOR, C (0) , C(0)0, CF2, CH2, or NR; R is H or R2 Ax is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; each B is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or 0; wherein each Ax is optionally substituted with up to
4 substituents independently selected from R^, R2 , R3 , R4, or R5; R1 is R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , COOH, COOR6 or OR6; or two R-'- on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 ,
SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2,
S02NR5R6, SO3R6, S03R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6,
C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 ,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6),
NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C (0) NR5R6 ,
NR6C(0)N(R5)2, NR5C(0)N(R6)2, NR5C (O) NR5R6 ,
NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6,
NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02NR5R6,
NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-L substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, S02 -aliphatic, NH2 , N- aliphatic, (aliphatic) , N (aliphatic) R8 , COOH, C(0)0(- aliphatic, or O-aliphatic; and R8 is an amino capping group; provided that : (i) when Xi is a bond, one Bi is phenyl and the other Bi is N-piperidyl, then A is not:
Figure imgf000054_0001
(ii) when Xi is a bond, then Ai is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms.
[00206] In certain embodiments, According to another embodiment of formula (III), Xi is CH2, CF2, or 0. In another embodiment, Xi is a bond, O, S, CF2, CH2, or NR. Or, Xi is CH2 or 0. Or, Xx is CH2. [00207] According to another embodiment of formula (III) , Ai is an optionally substituted C3-C7 cycloaliphatic ring. In certain embodiments,, A2 is an optionally substituted cyclopropyl, cyclopentyl, or cyclohexyl . [00208] According to another embodiment of formula (III), Ai is optionally substituted (C1-C10) aliphatic . In certain embodiments, Ai is optionally substituted methyl, ethyl , propyl , butyl , pentyl , or hexyl . [00209] According to another embodiment of formula (III) , Ai is optionally substituted C6-C10 aryl ring. In certain embodiments, Ai is optionally substituted phenyl or naphthyl . [00210] According to another embodiment of formula (III) , Ai is optionally substituted C5-C12 heteroaryl ring. In certain embodiments, A is selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl , triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl , cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl , 1,8- naphthyridinyl, pteridinyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl . [00211] According to another embodiment of formula (III), Ai is optionally substituted C3-C12 heterocyclic ring. In certain embodiments, A2 is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl , piperidinyl, 1, 4-dioxanyl , morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl. [00212] According to another embodiment of formula (III) , each Bx is independently selected from optionally substituted C6-C10 aryl. In certain embodiments, each Bx is independently an optionally substituted phenyl or naphthyl. Or, each Bi is an unsubstituted phenyl. [00213] According to another embodiment of formula (III) , each Bx is independently selected from optionally substituted C5-C12 heteroaryl. In certain embodiments, each Bi is independently and optionally substituted C5-C7 heteroaryl. Or, each Bi is independently selected from optionally substituted triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzo [b] thienyl , 1H-indazolyl , benzimidazolyl , benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indenyl, naphthyl, azulinyl, or anthracenyl . [00214] According to another embodiment of formula (III) , each Bi is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR. In certain embodiments, each Bi is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl , pyrazolinyl, pyrazolidinyl, piperidinyl, 1, -dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl. [00215] Exemplary embodiments of R1, R2 , R3 , R4 ,
R5, R6, R7, R8, and Z in compounds of formula (III) are as described above for compound of formula (I) . [00216] According to another embodiment, the present invention provides compounds of formula IV:
Figure imgf000056_0001
IV; wherein: B is selected from:
Figure imgf000057_0001
(i) (ϋ) wherein: Y is O or S; and X3 is 0 or S. [00217] According to one embodiment, X3 is O. Or, X3 is S. [00218] According to one embodiment, B is structure (i) above. Or, B is structure (ii) above. [00219] According to another embodiment, R is hydrogen. [00220] According to another embodiment, Y' is S. Or, Y' is 0. [00221] According to another embodiment, the present invention provides compounds of formula V:
Figure imgf000057_0002
V; wherein: Y' is 0 or S; B is selected from:
Figure imgf000057_0003
(i) (ϋ) (iϋ) ; wherein: Ak is C1-C6 alkylidene; X4 is CH2, O or S; Ar' is phenyl optionally substituted with up to two R1; and B is optionally substituted with up to two R1. [00222] In some embodiments, Ak is selected from CH2, CH(CH3), C(CH3)2, CH(Et), C(Et)2, CH (n-propyl) , CH(i- Pr) , CH (n-butyl), CH (but-2-yl) , or CH (t-butyl) . [00223] In some embodiments, Ar ' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (Cl- C4 alkyl) . [00224] In some embodiments, X4 is CH2. X4 is S. Or, X4 is 0. [00225] In some embodiments, R is hydrogen. [00226] In certain embodiments, p is 2, X is a bond, and each A is optionally substituted phenyl . [00227] In other embodiments, the compounds have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2, X is a bond, and each A is phenyl; d) B is ring (iii) above, wherein Ak is CH(CH3) and Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (C1-C4 alkyl). [00228] According to another embodiment, the present invention provides a compound of formula VI:
Figure imgf000058_0001
VI; Y' is 0 or S; R is hydrogen or R2; B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from O, S, or N; wherein each ring Gi, G2, and B is independently substituted with up to 4 substituents selected from R1,
R2, R3, R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two Ri on adjacent ring atoms, taken together, form 1, 2-methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1 , R4 , or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6,
SR5, S(0)R6, S(0)R5, S02R6, S02R5 , S02N(R6)2, S02N(R5)2,
S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6,
C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 ,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (O) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N0 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, S02 -aliphatic, NH , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8 , NHR8, N(R8) , COOH, C (O) 0 (-aliphatic, or O-aliphatic; and R8 is an amino capping group. [00229] In certain embodiments of formula VI, when R is hydrogen, then the following compounds are excluded: a) B is not quinolin-2-yl or l,2-dihydro-2-oxo-quinolin- 4-yl; b) when Gi and G2 both are phenyl, and Y' is S, then B is not l,4-benzodioxin-2-yl, cyclopropyl, cyclohexyl, thien- 2-yl, lH-thieno [2 , 3-c] pyrazol-1-phenyl-3 -methyl-5-yl, 5- methyl-thien-3-yl, 2 , 5-dichloro-thien-3-yl, 2-phenyl- quinolin-4-yl, furan-2-yl, thien-5- (4 , 5-diphenyl-2- thiazolyl-carboxamide) -2-yl, benzo [b] thiophen-2-yl , pyridin-2- ( , 5-diphenyl-2-thiazolyl-carboxamide) -6-yl, 5- nitro-thien-2-yl, 3-chloro-benzo [b] thiophen-2-yl, 4H-1- benzopyran-3-yl or 2H-l-benzopyran-3 , 4-dihydro-3-oxo-4- yl, 4H-l-benzopyran-3-yl or 2H-l-benzopyran-3 , 4-dihydro- 3-oxo-4-yl; c) when Gx and G2 both are phenyl, and Y' is O, then B is not 1, 2-dihydro-2-oxo-quinolin-4-yl or 3 , 4-dihydro-3- phenyl-phthalazin-1-yl or thien-2-yl; d) the following compounds are excluded:
Figure imgf000061_0001
d) when Y' is S, Gi and G2 are both phenyl, then B is not
Figure imgf000062_0001
[00230] In one embodiment, Gi and G2 are both phenyl. Or, each is independently and optionally substituted with up to two substituents selected from halo, or C1-C4 alkyl. [00231] In certain embodiments of formula VI, B is phenyl optionally substituted with up to two substituents selected from halo, C1-C4 alkyl, 0- (C1-C4 alkyl), COOH, C00(C1-C4 alkyl), or cyano. [00232] In other embodiments, B is 3,4- dichlorophenyl, 4-chlorophenyl, 4 -methoxyphenyl , 4- methylphenyl , 2 , 6-difluorophenyl , 2 -methylphenyl , 3 - methylphenyl , phenyl-2 -carboxylic acid, 2-chlorophenyl, 4 -cyanophenyl , or 3-methoxyphenyl . [00233] In another embodiment, B is 3-7 membered, monocyclic, saturated, carbocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl . [00234] In another emodiment, B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N. Exemplary rings include tetrahydrofuranyl, thienyl, or pyrrolyl. [00235] In another embodiment, B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N. [00236] According to another embodiment, the present invention provides a compound of formula VII :
Figure imgf000063_0001
VII; wherein: Y' is 0 or S; R is hydrogen or R2; R^ is C1-C6 aliphatic, optionally substitute with up to 3 substituents independently selected from R1, R2, or
R3; B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N; wherein each ring Gx, G2, and B is independently substituted with up to 4 substituents selected from R1, R2, R3, R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two R^ on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 ,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6),
NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (O) NR5R6 ,
NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6,
NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 ,
NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , 0CF3 , OH, S- aliphatic, S (0) -aliphatic, S02-aliphatic, NH2 , NH- aliphatic, N (aliphatic) , N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0)0 (-aliphatic, or O-aliphatic ; and R8 is an amino-capping group. [00237] In one embodiment of formula VII, when each of Gi, G2, and B is unsubstituted phenyl, and R is hydrogen, then B is not 3 , 4, 5-trimethoxyphenyl . [00238] In one embodiment, R^ is C1-C6 alkyl. Exemplary R** include methyl, ethyl, isopropyl, n-propyl, sec-butyl, n-butyl, or t-butyl. [00239] In one embodiment, B is optionally substituted phenyl . [00240] In another embodiment, B is 3-7 membered, monocyclic, saturated, carbocyclic ring. Exemplary rings include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl . [00241] In another emodiment, B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N. Exemplary rings include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, or piperazinyl . [00242] In another embodiment, B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N. [00243] According to another embodiment , the present invention provides a compound having formula I ' :
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof; wherein: Y ' is 0 , S , or NR ; R is H, R2 , or R6 ; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
Figure imgf000066_0001
(e) (f) (9) () each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5 ; RL is -0RA, -SRA, or -N(RAB)2; each RA is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each RA is optionally substituted with up to 3 substituents independently selected from R1, R4 or R7, each Rffl is independently hydrogen or C1-C6 aliphatic optionally substituted with up to 3 substituents independently selected from R1, R4 or R7; wherein up to two methylene units in RA or RAB are optionally replaced with -CO-, -CS-, -COCO-, -C0NR-, -C02- , -OCO- , -NRC02- , -0- , -NRCONR- , -OCONR- , -NRCO- , - S - , - SO , - SO2 - , -NR- , - SO2NR- , NRSO2 - , or -NRSO2NR ; or two R™, taken together with the nitrogen atom, is a 3-7 membered heterocyclic or heteroaryl ring containing up to 4 heteroatoms selected from 0, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (Cι-4aliphatic)p-Y; RM is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; each of Xi and X2 is independently selected from 0, S, or NR; RN is C1-C6 aliphatic or phenyl, wherein RN is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; Rp is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; RQ is C1-C6 aliphatic or aryl, wherein RQ is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8, N(R8)2, COOH, COOR6 or
OR6 ; or two R1 on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6 ,
SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2,
S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6,
C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 ,
C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6),
NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (Rδ) 2 , NR5C (0) NR5R6 ,
NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6,
NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 ,
NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(0R6)R5, N(OR5)R5, or N(0R5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) - straight or branched alkyl, (C2-Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N0 , CF3 , 0CF3 , OH, S- aliphatic, S (0) -aliphatic, S02-aliphatic, NH2 , NH- aliphatic, (aliphatic) 2 , (aliphatic) R8, NHR8, N(R8)2, COOH, C (O) 0 (-aliphatic, or O-aliphatic; and R8 is an amino-capping group. [00244] In one embodiment, Y" is 0. Or, Y' is S. [00245] In another embodiment, R is hydrogen. [00246] In one embodiment, Q in formula I ' is B (structure (a) ) . Preferred B include optionally substituted phenyl, or C3-C8 cycloaliphatic. In one embodiment, B in formula I' is phenyl or C3-C8 cycloalkyl optionally substituted with up to two substituents selected from R1, R2, or phenyl optionally substituted with up to two substituents selected from R1 or R2. [00247] In another embodiment, Q in formula I ' is - (C1-C6 aliphatic) -B (structure (b) ) . [00248] In certain embodiments, said C1-C6 aliphatic is C1-C4 straight or branched alkylidene. Exemplary alkylidenes include -CH2-, -CH(Me)-, -C(Me)2-, - CH(Et)-, -C(Et)2-, or -CH2-CH (Me) - . [00249] In certain embodiments, B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl, or pyrrolidinyl. Preferably, B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R1 or R2 substituents. [00250] In one embodiment, ring C is phenyl optionally substituted with up to two R1. Or ring C is cyclohexenyl optionally substituted with up to two R1. [00251] According to a preferred embodiment, R1 is 1, 2-methylene dioxy, or 1, 2-ethylenedioxy. [00252] According to another preferred embodiment , R1 is R6, wherein R6 is straight chain or branched (Cl- C6) alkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R7. [00253] According to another preferred embodiment, R1 is (C1-C4 aliphatic) n-Y, wherein n is 0 or 1, and Y is halo, CN, N02, CF3 , OCF3 , OH, SR6, S(0)R6, S02R6, NH2 ,
NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6; [00254] According to another preferred embodiment, R1 is selected from halo, CF3, NH2, NH(C1-C4 alkyl), NHC(0)CH3, OH, 0(C1-C4 alkyl), OPh, O-benzyl, S- (C1-C4 alkyl) , C1-C4 aliphatic, CN, methylenedioxy, ethylenedixoy, S02NH(C1-C4 alkyl), or S02N(C1-C4 alkyl) 2- [00255] According to another more preferred embodiment, R1 is selected from methyl, n-propyl, i- propyl, t-butyl, halo, CF3, NH2, NH(CH3), NHC(0)CH3, OH, OCH3, OPh, O-benzyl, S- (C2H5) , S-CH3, N02, CN, methylenedioxy, S02NH (n-propyl) , or S02N (n-propyl) 2. [00256] According to a preferred embodiment, R2 is a straight chain or branched (C1-C6) lkyl or (C2-C6) alkenyl or alkynyl, optionally substituted with R1, R4, or R5. More preferably, R2 is a straight chain or branched (C1-C4) alkyl or (C2-C4) alkenyl or alkynyl, optionally substituted with R1, R4, or R5. [00257] In formula I', other embodiments of B, RL, RM, R , Rp, RQ, Xi, X2, and R are as described above for formula I . [00258] Exemplary compounds of the present invention are shown below in Table 1.
Table 1
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
[00260] According to an alternative embodiment, preferred compounds of the present invention are those that measurably increase the activity of an ABC- transporter or of a fragment thereof, and preferably CFTR activity. [00261] According to another alternative embodiment, preferred compounds of the present invention are those that measurably decrease the activity of an ABC-transporter or of a fragment thereof. [00262] One of skill in the art would be well aware of techniques and assays useful in measuring the increase or decrease of activity of an ABC-transporter or of a fragment thereof . [00263] According to an alternative preferred embodiment, the present invention provides a method of modulating CFTR activity in a cell membrane of a mammal in need thereof, comprising the step of administering to said mammal a composition comprising a compound of the present invention as defined above. [00264] The preferred embodiments of compound of formula (I) useful in potentiating the activity of CFTR include the preferred embodiments of the present invention described above. [00265] According to an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of the present invention. The term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity. [00266] According to a preferred embodiment, said functional ABC transporter is CFTR. [00267] The preferred embodiments of compounds of formula (I) useful in increasing the number of functional ABC transporters include preferred embodiments of the compounds of the present invention as described above. [00268] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. [00269] The present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention. A "pharmaceutically acceptable prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species . [00270] The compounds of the present invention may be readily prepared using methods known in the art. One such synthetic route is illustrated in Scheme 1 below:
Scheme 1
Step 1
Figure imgf000216_0001
[00271] 2-Aminot iazoles. The appropriate bromoketone was dissolved in a minimum of ethanol or methanol with 1.1 equivalents of thiourea. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, and then dissolved in either dichloromethane or ethyl acetate. The reaction mixture was then extracted with IM sodium hydroxide followed by a saturated aqueous sodium chloride solution. The organic layer was then separated, dried over sodium sulfate, and evaporated to dryness to yield the desired 2- aminothiazole . Step 2 :
(a)
Figure imgf000217_0001
Cl pyridine
Figure imgf000217_0002
(b)
Figure imgf000217_0003
(c)
Figure imgf000217_0004
( )
Figure imgf000217_0005
[00272] Amides. (a) If the appropriate acid chloride was commercially available, it was added to one equivalent of the appropriate amine in minimum of pyridine. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered and evaporated to dryness. The crude product was purified by reverse phase preparative liquid chromatography. [00273] (b) Alternatively, the acid chloride was added to one equivalent of the appropriate amine in minimum of 1,4 -dioxane containing an excess of triethylamine . The reaction mixture was then either allowed to stir overnight at room temperature or subjected to microwave irradiation for 5 minutes at 200°C, The crude product was then filtered, evaporated to dryness, dissolved in a minimum of dimethylsulfoxide and then purified by reverse phase preparative liquid chromatography.
[00274] (c) If the appropriate acid chloride was not commercially available the appropriate carboxylic acid was added to a solution containing one equivalent of the appropriate amine in a minimum of pyridine. O- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (HATU, 1.4 eq.) is added, and the reaction is stirred overnight. The crude product was purified by reverse phase preparative liquid chromatography . [00275] (d) If the appropriate acid chloride was not commercially available the appropriate carboxylic acid was added to a solution containing one equivalent of the appropriate amine in a minimum of N, N-dimethylformamide with an excess of triethylamine. O- (7-Azabenzotriazol-l- yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (HATU, 1.4 eq.) is added, and the reaction is stirred overnight. The crude product was purified by reverse phase preparative liquid chromatography. [00276] One of skill in the art will recognize that the above two synthetic routes are generic and can be readily exploited for any embodiment of compound formula (I) . [00277] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers , polyethylene glycol and wool fat . [00278] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide , hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. [00279] Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(Cι-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. [00280] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol . Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00281] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides . Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00282] The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [00283] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols . [00284] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract . Suitable topical formulations are readily prepared for each of these areas or organs . [00285] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [00286] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00287] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [00288] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00289] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. [00290] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions. [00291] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. [00292] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." [00293] According to an alternative embodiment, the present invention provides a method of treating a ABC transporter mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above . [00294] According to a preferred embodiment, the ABC transporter mediated disease is selected from immunodeficiency disorder, inflammatory disease, allergic disease, autoimmune disease, destructive bone disorder, proliferative disorder, infectious disease or viral disease . [00295] In certain preferred embodiments, the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type-1 hereditary angioedema, lipid processing deficiencies, such as Familial hypercholesterolemia, Type-1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI) , neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect) , Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD) , dry eye disease, and Sjogren's Syndrome, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above . [00296] According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention. [00297] According to the invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of any one of the above diseases . [00298] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route administration effective for treating or lessening the severity of of any one of the above diseases. [00299] In one embodiment, the compounds of the present invention are useful in treating cystic fibrosis. [00300] According to a more preferred embodiment , the disease so treated is selected from Tangier's disease, stargardt disease 1, age related macular dystrophy 2, retinintis pigmentosa, bare lymphocyte syndrome, PFIC-3, anemia, progressive intrahepatic cholestasis-2 , Dublin-Johnson syndrome, Pseudoxanthoma elasticum, cystic fibrosis, familial persistent hyperinsulinemic hyproglycemia of infancy, adrenolecukodystrophy, sitosterolemia, chronic obstructive pulmonary disease, asthma, disseminated bronchiectasis, chronic pancreatitis, male infertility, emphysema, or pneumonia. [00301] According to another more preferred embodiment, the ABC transporter mediated disease is secretory diarrhea, or polycystic kidney disease in a mammal . [00302] According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis or secretory diahrrea comprising the step of administering to said mammal a composition comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above. Most preferably, said disease is cystic fibrosis. [00303] According to another embodiment, the present invention provides a method of modulating activity of an anion channel in vi tro or in vivo, comprising the step of contacting said channel with a compound of the present invention. Preferably, said anion channel is a chloride channel or a bicarbonate channel. More preferably, said anion channel is a chloride channel . [00304] According to yet another embodiment, the present invention provides a method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to the present invention. [00305] According to another embodiment, the present invention provides a pharmaceutical composition comprising: (i) a compound of the present invention as described above; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti- infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent. [00306] Preferred embodiments of compounds the present invention in the above pharmaceutical composition are those as described above . [00307] According to another embodiment, the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: (i) a composition comprising a compound of the present invention; and (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof . [00308] According to a preferred embodiment, the kit is useful in measuring the activity of CFTR. [00309] According to another preferred embodiment, the activity of the ABC transporter is measured by measuring the transmembrane voltage potential. [00310] Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods. [00311] The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4) : 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al . (1999) "Cell-based assays and instrumentation for screening ion- channel targets" Drug Discov Today 4(9): 431-439). [00312] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPR™ II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. [00313] Preferred ABC transporters in the kit of the present invention include CFTR. [00314] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLE 1
Figure imgf000229_0001
General Procedure: The appropriate bromoketone was dissolved in a minimum of ethanol or methanol with 1.1 equivalents of thiourea. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, and then dissolved in either dichloromethane or ethyl acetate. The reaction mixture was then extracted with 1 M sodium hydroxide followed by a saturated aqueous solution of sodium chloride. The organic layer was then separated, dried over sodium sulfate, and evaporated to dryness to yield the desired 2-aminothiazole .
Example 2
Figure imgf000230_0001
B3N
General Procedure: One equivalent of the appropriate carboxylic acid and one equivalent of the appropriate amine were dissolved in JV, .NT-dimethylformamide (DMF) containing triethylamine (3 equivalents) . O- (7- Azabenzotriazol-1-yl) -N,N, N' , N' -tetramethyluronium hexafluorophosphate (HATU) was added and the solution was allowed to stir. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product .
Example 3
V O cl ♦ ™ NY—Y J (x_A)p
Figure imgf000230_0002
1 ,4-dioxane and Et3N
General Procedure : The appropriate acid chloride was added to one equivalent of the appropriate amine in minimum of pyridine. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered and evaporated to dryness. The crude product was purified by reverse-phase preparative liquid chromatography. Alternatively, the acid chloride was added to one equivalent of the appropriate amine in minimum of 1, -dioxane containing an excess of triethylamine. The reaction mixture was then either allowed to stir overnight at room temperature or subjected to microwave irradiation for 5 minutes at 200 °C. The crude product was then filtered, evaporated to dryness, dissolved in a minimum of dimethylsulfoxide and then purified by reverse-phase preparative liquid chromatography.
Example 4
Figure imgf000231_0001
Hal = Cl, Br, I wherein W is a group as described in the compounds of the present invention. General Procedure: One equivalent of the halide was dissolved in a minimum of the alcohol . The reaction vessel was sealed and then subjected to microwave irradiation for 15 minutes at 125 °C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography.
Example 5
Figure imgf000231_0002
Hal=Cl, Br, I wherein W is a group as described in the compounds of the present invention. General Procedure: One equivalent of the halide was dissolved in a minimum of N, N-dimethylformamide (DMF) containing 20 equivalents of amine. The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography. 1)
Figure imgf000232_0001
thiourea
Figure imgf000232_0002
a) 4-Fluoro-l-methoxy-2-nitro-benzene A solution of methyl iodide (127.8 g, 0.9004 mol) in acetonitrile (100 mL) was slowly added to a solution of 5-fluoro-2- nitrophenol (94.2 g, 0.600 mol) and potassium carbonate (207 g, 1.50 mol) in acetonitrile (450 mL) . The mixture was heated to reflux for 15 hours. The mixture was allowed to cool, filtered, and washed twice with dichloromethane (100 mL) . The combined filtrated was evaporated to dryness to give the desired product (96 g, 0.56 mol, 93 %) , which was used directly in the next step. b) 5-Fluoro-2- ethoxy-phenylamine A solution of 4- fluoro-l-methoxy-2-nitro-benzene (85 g, 0.50 mol) in methanol (300 L) containing palladium on carbon (10 %, 8 g) was stirred for 15 hours under an atmosphere of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness to give the crude product (61.5 g, 0.436 mol, 87 %) , which was used directly in the next step. c) 2-Chloro-3- (5-fluoro-2- ethoxy-p enyl) - propionaldehyde A solution of sodium nitrite (36 g, 0.51 mole) in water (50 mL) was slowly added to a solution of 5-fluoro-2-methoxy-phenylamine (61.5 g, 0.48 mol) in hydrochloric acid (20 % aqueous solution, 115 mL) at 0 °C . After stirring for 10 minutes, a cooled (0 °C) solution of acrolein (50 mL, 0.75 mol) in acetone (100 mL) containing calcium oxide (0.56 g, 0.010 mol) was added slowly to the reaction mixture. This was then followed by a solution of cuprous chloride (5 g, 0.05 mol) in acetone (100 mL) containing hydrochloric acid (20 % aqueous solution, 10 mL) . The mixture was stirred at 0 to 30 °C for 3 hours, and then extracted three times with dichloromethane (300 mL) . The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black viscous oil. The crude product was passed through a short silica column to give the crude product, which was used directly in the next step. d) 5- (5-Fluoro-2-methoxy-benzyl) -thiazol-2-ylamine
A mixture of 2-chloro-3- (5-fluoro-2-methoxy-phenyl) - propionaldehyde (crude from above) and thiourea (29.2 g, 0.384 mol) in ethanol (400 mL) was heated to reflux for 15 hours. The solvent was removed and the residue was diluted with dichloromethane (300 mL) , sodium hydroxide (10 % aqueous solution, 150 mL) and water (200 mL) . The aqueous phase was extracted twice with dichloromethane (150 mL) . The combined organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude product was recrystallized from a mixture of ethyl acetate and hexanes to give the pure product (6.5 g, 0.027 mol, 6.2 % from 5-fluoro-2-methoxy-phenylamine) . ESI-MS /z calc. 238.1, found 239.2 (M+l)+ 1H NMR(CDC13) : δ 6.90-6.81 (m, 2 H) , 6.79-6.76 (m, 2 H) , 4.75 (br, 2 H) , 3.91 (s, 2 H) , 3.82 (s, 3 H) .
2) NaOMe N°2 H7/P -C NaN02/CuCI
Figure imgf000234_0002
N OMe N OMe CH2=CHCHO
Figure imgf000234_0001
t iourea
Figure imgf000234_0003
a) 2 -Methoxy-3 -nitro-pyridine A suspension of sodium methoxide (40.5 g, 0.750 mol) in 200 mL of methanol was slowly added to a solution of 2-chloro-3- nitro-pyridine (79.3 g, 0.500 mol) in 800 mL of methanol at 0 °C. The reaction mixture was stirred for 4 hours and then poured into 1000 g of ice. The resulting precipitate was filtered, washed with water, and dried to give 2-methoxy-3-nitro-pyridine (70. g, 0.45 mmol, 90 %) as a white solid. b) 2-Methoxy-pyridin-3-ylamine A solution of 2- methoxy-3-nitro-pyridine (70. g, 0.45 mol) in methanol (700 mL) containing palladium on carbon (7 g, 10 %) was stirred under an atmosphere of hydrogen for 15 hours. The catalyst was filtered and washed with methanol . The filtrate was evaporated to dryness to give crude 2- methoxy-pyridin-3-ylamine (48 g, 0.39 mol, 87 %) , which was used directly in the next step. c) 2 -Chloro-3 -pyridin-3 -yl-propionaldehyde A solution of sodium nitrite (20. g, 0.28 mol) in water (100 mL) was slowly added to a solution of 2-methoxy- pyridin-3-ylamine (36 g, 0.25 mol) in hydrochloric acid (20 % aqueous solution, 60 mL) at 0 °C . After stirring for 10 minutes, a cooled (0 °C) solution of acrolein (25 mL, 0.37 mol) in acetone (25 mL) containing calcium oxide (5 g, 0.09 mol) was slowly added to the reaction mixture. This was then followed by a solution of cuprous chloride (2.5 g, 0.025 mol) in acetone (25 mL) containing hydrochloric acid (20 % aqueous solution, 5 mL) . The mixture was stirred at 0 to 30 °C for 3 hours, and then extracted three times with dichloromethane (150mL) . The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black viscous oil . The crude product was passed through a short silica column to give a crude product, which was used directly in the next step. d) 5- (2-Methoxy-pyridin-3-ylmethyl) -thiazol-2- ylamine A mixture of 2-chloro-3-pyridin-3-yl- propionaldehyde (crude from above) and thiourea (14.8 g, 0.194 mol) in ethanol (200 mL) was heated to reflux overnight . The solvent was removed and the residue was diluted with dichoromethane (1.2 L) and then washed with sodium hydroxide (10 % aqueous solution, 400 mL) and water (200 mL) . The organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 400 mL) and the combined aqueous layer was brought to between pH 9 and 10 with sodium hydroxide (10 % aqueous solution) . The resulting precipitate was filtered to give the crude product, which was recrystallized, from ethyl acetate and hexanes to give the pure product (5.1 g, 0.023 mol, 5.6 % from 2-methoxy-pyridin-3-ylamine) . ESI-MS m/z calc. 221.1, found 222.2 (M+l)+.
3)
Figure imgf000236_0001
a) 2-Bromo-l- (chloro-phenyl) -ethanone Bromine (3.8 mL, 65 mmol) was added dropwise to a solution of 1- (2- chloro-phenyl) -ethanone (10. g, 65 mmol) in acetic acid (75 mL) at 0°C. The mixture was then warmed to room temperature and stirred overnight . The mixture was evaporated to dryness and used in the next step without further purification.
N' - [5- (2-Chloro-benzoyl) -thiazol-2-yl] -N, N-dimethyl- formamidine. A mixture of thiourea (4.95 g, 65.0 mmol) and dimethoxymethyl-dimethyl -amine (23.2 g, 195 mmol) in methanol (80 mL) was heated under reflux for 30 minutes. After allowing the mixture to cool, triethylamine (19.8 g, 195 mmol) and a solution of 2-bromo-l- (chloro-phenyl) - ethanone (crude from last step) in methanol (50 mL) were added. The mixture was heated to reflux for 4 hours. The solvent was removed and the residue was used directly in the next procedure . b) (2-Amino-thiazol-5-yl) - (2-chloro-phenyl) - methanone The crude N' - [5- (2-chloro-benzoyl) -thiazol-2- yl] -KT/JV-dimethyl-formamidine was dissolved in 10% aqueous hydrochloric acid (150 mL) and heated to 70 °C for 4 hours. The precipitate was filtered, washed with ether, and then suspended in a 10% aqueous sodium carbonate solution (250mL) . The suspension was stirred for 1 hour and the precipitate was filtered, washed with ether, and dried in air to give (2-amino-thiazol-5-yl) - (2-chlorophenyl) -methanone as a brown solid (8.5 g, 36 mmol, 55% from 1- (2-chloro-phenyl) -ethanone) . ESI-MS m/z calc. 238 . 0 , found 239 . 3 (M+1) + 1H NMR (DMSO) : δ : 7 . 252 (s , 1 H) , 7 . 420 - 7 . 553 (m, 4 H) , 8 . 345 (s , 2 H) .
4 )
Figure imgf000237_0001
a) 2 -Chloro-3- (2-chloro-phenyl) -propionaldehyde To a solution of 2-chloroaniline (12.7 g, 100. mmol) in hydrochloric acid (20 % aqueous solution, 40 mL) was added dropwise a solution of sodium nitrite (7.5 g, 110 mmol) in water (20 mL) at 0 to 5 °C. After stirring for 10 minutes, a cooled (0 °C) solution of acrolein (15 g, 270 mmol) in acetone (100 mL) containing calcium oxide (2.0 g, 36 mmol) was added gradually, and then followed by a solution of cuprous chloride (1 g, 10 mmol) in acetone (10 mL) containing hydrochloric acid (20 % aqueous solution, 2 mL) . The mixture was stirred at 0 to 30 °C for 3 hours and then extracted three times with dichloromethane (lOOmL) . The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate followed by a saturated aqueous solution of sodium chloride. The organic layer was separated, dried over sodium sulfate, and evaporated to dryness to give a black viscous oil. The crude product was passed through a short silica gel column to give 12 g of crude product, which was used directly in the next step. b) 5- (2 -Chloro-benzyl) -thiazol-2-ylamine A mixture of 2-chloro-3- (2-chloro-phenyl) -propionaldehyde (12 g, crude from above) and urea (6.0 g, 0.10 mol) in ethanol (120 mL) was heated to reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (120 mL) and then washed with sodium hydroxide (10% aqueous solution, 50 mL ) and water (30 mL) . The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 120 mL) . The combined aqueous layer was adjusted with a 10 % aqueous solution of sodium hydroxide to between pH 9 and 10 and then extracted three times with dichloromethane (150 mL) . The organic layers were combined, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to yield a yellow solid. (5.2 g, 0.023 mol, 23% from 2-chloroaniline) . ESI-MS m/z calc. 224.0, found 225.2 (M+l)+ XH NMR (CDC13) δ 4.07 (s, 2H) , 4.90 (bs, 2H) , 6.80 (s, 1H) , 7.37-7.15 (m, 4H) .
6) 5- (2-methoxy-benzyl) -thiazol-2-yl.amine
Figure imgf000238_0001
5- (2-methoxy-benzyl) -thiazol-2-ylamine was prepared in a manner analogous to that of 5- (2-chloro-benzyl) - thiazol-2-ylamine. ESI-MS m/z calc. 220.1, found 221.2 (M+l)+ XH NMR(CDC13) δ 7.26-7.19 (m, 1H) , 7.15 (d, J= 6.8 Hz, 1H) , 6.90-6.85 (m, 2H) , 6.79 (s, 1H) , 4.77 (bs, 2H) , 3.93 (s, 2H) , 3.84 (s, 3H) .
7) 5- (3 -Chloro-benzyl) -thiazol-2-ylamine
Figure imgf000238_0002
5- (3-Chloro-benzyl) -thiazol-2-ylamine was prepared in a manner analogous to that of 5- (2-chloro-benzyl) - thiazol-2-ylamine. ESI-MS m/z calc. 224.0, found 225.2 (M+l)+ H NMR (CDCI3) δ 7.26-7.21 (m, 3H) , 7.10 (d, J = 6.8Hz, IH) , 6.81 (s, IH) , 4.82 (bs, 2H) , 3.93 (s, 2H) .
8) 5- (4-Chloro-benzyl) -thiazol-2-ylamine
Figure imgf000239_0001
5- (4-Chloro-benzyl) -thiazol-2-ylamine was prepared in a manner analogous to that of 5- (2-chloro-benzyl) - thiazol-2-ylamine. ESI-MS m/z calc. 224.0, found 225.2 (M+l)+ XH NMR(CDC13) δ 7.26 (d, J = 8.4 Hz, 2H) , 7.14 (d, J = 8.4 Hz, 2H) , 6.79 (s, IH) , 4.85 (bs, 2H) , 3.92 (s, 2H) .
9) 5- (2 -Cyano-benzyl) -thiazol-2-ylamine
Figure imgf000239_0002
5- (2-Cyano-benzyl) -thiazol-2-ylamine was prepared in a manner analogous to that of 5- (2-chloro-benzyl) - thiazol-2-ylamine (12 g, 56 mmol, 11 % from 2- cyanoaniline) . ESI-MS m/z calc. 215.05, found 216.16 (M+l)+ ^Η NMR(CDC13) : δ 7.64 (d, IH) , 7.54 (t, IH) , 7.34 (m, 2H) , 6.87 (s, IH) , 4.89 (br, 2H) , 4.19 (s, 2H) .
10)
NaNOp/CuC
Figure imgf000239_0004
CH2=CHCHO
Figure imgf000239_0003
a) 2 -Chloro-3- (2 -methoxy-phenyl) -propionaldehyde. A solution of 2 -methoxylaniline (24.6 g, 0.200 mol) in hydrochloric acid (20 % aqueous solution, 80 mL) was slowly added to a solution of sodium nitrite (15 g, 0.22 mol) in water (40 mL) at 0 to 5 °C. After stirring for 10 minutes, a cooled (0 °C) solution of acrolein (30 g, 0.56 mol) in acetone (200 mL) containing calcium oxide (4.0 g, 72 mmol) was slowly added, followed by a solution of cuprous chloride (2.0 g, 20 mmol) in acetone (20 mL) containing hydrochloric acid (20 % aqueous solution, 4 mL) . The mixture was stirred at 0 to 30 °C for 3 hours, and then extracted with three 150 mL portions of dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated to give a black viscous oil. The crude product was passed through a short silica column to give 10 g of crude product, which was used directly in the next procedure . b) 5- (2-methoxy-benzyl) -oxazol-2-ylamine. A mixture of 2-chloro-3- (2-methoxylphenyl) -propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated to reflux overnight . The solvent was evaporated to dryness . The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10 % aqueous solution, 100 mL ) and water (50 mL) . The organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 250 mL) . The combined aqueous layers were adjusted to pH 9 to 10 with a 10 % aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300mL) . The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product. (0.72 g, 0.35 % from 2-methoxyaniline) . ESI-MS m/z calc. 204.1, found 205.1 (M+l) + XH NMR (CDC13) δ 7.26-7.20 (m, IH) , 7.14 (d, J = 7.2Hz, IH) , 6.91-6.86 (m, 2H) , 6.35 (s, IH) , 4.49 (bs, 2H) , 3.85 (s, 2H) , 3.82 (s, 3H) .
11)
Figure imgf000241_0001
5- (2-Chloro-benzyl) -oxazol-2-ylamine 5- (2-Chloro- benzyl) -oxazol-2-ylamine was prepared in a manner analogous to that of the preparation of 5- (2-methoxy- benzyl) -oxazol-2-ylamine to yield the product as a yellow solid. (3.5 g, 8.4% from 2-chloroaniline). ESI-MS m/z calc. 208.0, found 209.1 (M+1)+ 1H NMR (CDC13) δ 7.37-7.18 (m, 4H) , 6.40 (s, IH) , 4.66 (bs, 2H) , 3.97 (s, 2H) .
12)
Figure imgf000241_0002
5- (3-Chloro-benzyl) -oxazol-2-ylamine 5- (3-Chloro- benzyl) -oxazol-2-ylamine was prepared in a manner analogous to that of the preparation of 5- (2-methoxy- benzyl) -oxazol-2-ylamine to yield the product as a yellow solid (1.2 g, 2.9 % from 3-chloroaniline) . ESI-MS m/z calc. 208.0, found 209.2 ^Η NMR(CDC13) δ 7.26-7.22 (m, 3H) , 7.10 (d, J = 6.0Hz, IH) , 6.44 (s, IH) , 4.73 (bs, 2H) , 3.82 (s, 2H) .
13)
Figure imgf000241_0003
5- (4-Chloro-benzyl) -oxazol-2-ylamine 5- (4-Chloro- benzyl) -oxazol-2-ylamine was prepared in a manner analogous to that of the preparation of 5- (2-methoxy- benzyl) -oxazol-2-ylamine to yield the product as a yellow solid (1.6 g, yield 3.86 % from 4-chloroaniline) . ESI-MS m/z calc. 208.0, found 209.1 XH NMR(CDC13) δ 7.27 (d, J" = 8.4Hz, 2H) , 7.17 (d, J = 8.0 Hz, 2H) , 6.38 (s, IH) , 4.66 (bs, 2H) , 3.81 (s, 2H) .
14)
Figure imgf000242_0001
a) 2-Bromo-3-phenylpropionaldehyde A solution of bromine (15.2 g, 95.1 mmol) in 30 mL of dichloromethane was added to a solution of 3 -phenyl-propionaldehyde (13.4 g, 100 mmol) in dichloromethane (150 mL) at 0 °C over 20 minutes. The reaction mixture was allowed to stir for 2 hours and then a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (50 mL) . The combined organic layers were washed with water, a saturated aqueous solution of sodium chloride, and then evaporated to dryness to give an orange oil (14.2 g) , which was used directly in the next step. b) 5-Benzyl-oxazol-2-ylamine A mixture of 2-bromo-3- phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated to reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10 % aqueous solution, 100 mL) and water (50 mL) . The organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 250mL) . The combined aqueous layers were adjusted to between pH 9 to 10 with a 10 % aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300mL) . The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid. (1.6 g, 9.2 mmol, 9.2% from 3-phenyl- propionaldehyde) . ESI-MS m/z calc. 174.1, found 175.1 XH NMR(CDC13) δ 7.32-7.22 (m, 5H) , 6.39 (s, IH) , 4.72 (bs, 2H) , 3.84 (s, 2H) .
15)
a) 2-Bromo-3-phenylpropionaldehyde A solution of bromine (15.2 g, 95.1 mmol) in 30 mL of dichloromethane was added to a solution of 3 -phenyl-propionaldehyde (13.4 g, 100 mmol) in dichloromethane (150 mL) at 0 °C over 20 minutes. The reaction mixture was allowed to stir for 2 hours and then a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (50 mL) . The combined organic layers were washed with water, a saturated aqueous solution of sodium chloride, and then evaporated to dryness to give an orange oil (14.2 g) , which was used directly in the next step. b) 5-benzyl-thiazol-2-ylamine A mixture of 2-bromo- 3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated to reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10 % aqueous solution, 100 mL) and water (50 mL) . The organic layer was extracted three times with hydrochloric acid (5 % aqueous solution, 250mL) . The combined aqueous layers were brought to pH 9 to 10 with a 10 % aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300mL) . The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid. (5.2 g, 27 mmol, 27 % from 3 -phenyl - propionaldehyde). ESI-MS m/z calc. 190.1, found 191.2 XH NMR(CDC13) δ 7.32-7.21 (m, 5H) , 6.79 (s, IH) , 4.91 (bs, 2H) , 3.95 (s, 2H) .
16)
Figure imgf000244_0001
a) 2 -Chloro-3- (2-chloro-phenyl) -propionaldehyde. A solution of sodium nitrite (15 g, 0.22 mol) in water (40 mL) was slowly added to a solution of 2-chloroaniline (25.5 g, 0.200 mol) in hydrochloric acid (20 % aqueous solution, 100 mL) at 0 to 5 °C . The mixture was stirred for ten minutes and then poured into a cooled (0 °C) solution of acrolein (30. g, 0.56 mol) in acetone (200 mL) containing calcium oxide (4.0 g, 72 mmol), followed by a solution of cuprous chloride (2.0 g, 20 mmol) in acetone (20 mL) containing hydrochloric acid (20 % aqueous solution, 4 mL) . The mixture was stirred for 3 hours at room temperature, and then extracted three times with dichloromethane (150 mL) . The combined organic layers were washed with a solution of saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black viscous oil that was used directly in the next procedure. b) [2- (2 -Chloro-phenyl) -1-methyliminomethyl-ethyl] - methyl-amine. A solution of methylamine in methanol (27 %, 69 g) was slowly added to a solution of 2-chloro-3- (2- chloro-phenyl) -propionaldehyde in dichloromethane (20 mL) . The reaction mixture was allowed to stir for 12 hours and then used immediately in the next procedure . c) 5- (2-Chloro-benzyl) -l-methyl-lH-imidazol-2- ylamine. A solution of cyanamide in water (50 %, 150 mL) was added to a boiling solution of [2- (2-chloro-phenyl) - 1-methyliminomethyl-ethyl] -methyl-amine in methanol and dichloromethane . The pH was brought to 4.5 by the continual addition of an aqueous solution of sulfuric acid (9 M) . The mixture was refluxed for 2 hours, allowed to cool to room temperature, and adjusted to pH 9 through the addition of powdered sodium bicarbonate. The mixture was extracted three times with dichloromethane (200 mL) and the combined organic layers were extracted three times with hydrochloric acid (20 % aqueous solution, 150 mL) . The aqueous solution was adjusted to pH 10 with sodium hydroxide (10 % aqueous solution) and extracted three times with dichloromethane (150 mL) . The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give a black solid which was purified by column chromatography to yield the product (5.0 g, 0.23 mmol, 11 % from 2-chloroaniline) as a brown solid. ESI-MS m/z calc. 221.1, found 222.3 (M+l)+ XH NMR (CDC13) : δ 7.30-7.37 (m, 1 H) , 7.15-7.18 (m, 2 H) , 7.03-7.06 (m, 1 H) , 6.43 (s, 1 H) , 3.94 (s, 2H) , 3.80 (br, 2H) , 3.15 (s, 3 H) .
17 )
Figure imgf000246_0001
a) 2-Bromo-3-oxo-hexanoic acid ethyl ester 3-Oxo- hexanoic acid ethyl ester (4.0 mL, 25 mmol) and magnesium perchlorate (1.7 g, 7.6 mmol) were placed in 500 mL of ethyl acetate and allowed to stir for 5 minutes. JV- Bromosuccinimide (4.7 g, 26 mmol) was added and the reaction mixture was allowed to stir for 15 minutes, at which time thin-layer chromatography (10 % ethyl acetate in hexanes, silica gel, 254 nm irradiation) indicated the reaction was complete. The reaction mixture was diluted with 500 mL of ethyl ether and washed three times with an equal volume of saturated aqueous sodium chloride . The organic layer was then dried over sodium sulfate and evaporated to dryness. This material was used in the next step without further purification. b) Amino-4-propyl-thiazole-5-carboxylic acid ethyl ester 2 -Bromo-3 -oxo-hexanoic acid ethyl ester (5.9 g, 25 mmol) , was dissolved in 60 mL of ethanol containing triethylamine (4.2 mL, 30 mmol) and thiourea (1.9 g, 25 mmol) . The colorless solution was protected from light and allowed to stir for 16 hours. The resulting red suspension was evaporated to dryness and dissolved in a minimum of dichloromethane. This solution was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was separated and filtered to remove a fine red precipitate which remained suspended in the organic phase. The solvent was removed and then the solid was dissolved in a minimum of 50 / 50 (v / v) ethyl acetate and 1 N aqueous solution of hydrochloric acid. The layers were separated and the aqueous layer was washed with an equal volume of ethyl acetate. After discarding the organic layers, the aqueous layer was then placed in an ice bath with an equal volume of ethyl acetate . Sodium hydroxide (IN) was then slowly added with vigorous swirling until the aqueous phase was basic. The layers were separated and the aqueous layer was washed two additional times with ethyl acetate. The combined organic layers were washed three times with an equal volume of a solution of saturated aqueous sodium bicarbonate followed by a solution of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield a pale yellow solid (1.8 g, 8.4 mmol, 34 %) ESI-MS m/z calc. 214.1, found 215.3 (M+l)+ Retention time 1.90 minutes.
18) 4- (2-Methoxy-phenyl) -thiazol-2-ylamine.
Figure imgf000247_0001
2 -Bromo-1- (2 -methoxy-phenyl) -ethanone (0.6388 g, 2.789 mmol) and thiourea (0.2289 g, 3.007 mmol) were dissolved in a 20 L of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with IM sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (0.529 g, 2.56 mmol, 92.0 %) . ESI-MS m/z calc. 206.3, found 207.1 (M+l)+ Retention time 1.86 minutes . XH NMR (400 MHz, CD3CN) δ 3.91 (s, 3H) , 5.54 (s, 2H) , 6.97-7.02 ( , IH) , 7.03-7.06 (m, IH) , 7.23 (s, IH) , 7.24-7.29 (m, IH) , 8.06 (dd, J" = 7.8, 1.8 Hz, IH) .
19) 4-(3-Methoxy-phenyI)-thiazol-2-ylamine.
Figure imgf000248_0001
2 -Bromo-1- (3 -methoxy-phenyl) -ethanone (0.7291 g, 3.183 mmol) and thiourea (0.2665 g, 3.501 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with IM sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the product (0.619 g, 3.00 mmol, 94.3 %) . ESI-MS m/z calc. 206.3, found 207.0 (M+l) + Retention time 1.86 minutes. XH NMR (400 MHz, CD3CN) δ 3.84 (s, 3H) , 5.67 (s, 2H) , 6.85- 6.91 (m, 2H) , 7.31 (t, J = 7.9 Hz, IH) , 7.36-7.43 (m, 2H) .
20) 4-Phenyl-thiazol-2-ylamine
Figure imgf000249_0001
2 -Bromo-1-phenyl-ethanone (19.9 g, 0.100 mol) and thiourea (7.9 g, 0.10 mol) were mixed in a 150 mL of methanol. The reaction mixture was warmed to dissolve the reagents and then allowed to stir overnight at room temperature. The methanol was evaporated to dryness and the crude product was dissolved in a minimum of ethyl acetate. The crude product was then extracted twice with IM sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (16.8 g, 0.0953 mol, 95.3 %) of product. ESI-MS m/z calc. 176.0, found 177.2 (M+l)+ Retention time 1.41 minutes. ^Η NMR (400 MHz, CD3CN) δ 5.73 (s, 2H) , 6.87 (s, IH) , 7.28-7.34 (m, IH) , 7.36-7.43 (m, 2H) , 7.79-7.85 (m, 2H) .
21)
Figure imgf000249_0002
a) 2-Pyridin-3-yl-butyric acid ethyl ester Pyridin- 3-yl-acetic acid ethyl ester (22.5g, 0.136 mol) in tetrahydrof uran (50 mL)was slowly added to a suspension of sodium hydride (60% in mineral oil, 6 g, 0.4 mol) in tetrahydrofuran (50 mL) t 0 °C. A solution of ethyl iodide (23.4g, 0.150 mol) in tetrahydrofuran (50 L) was added to and the reaction mixture was allowed to stir overnight at room temperature. The mixture was poured into ice and the aqueous layer was extracted three times with ethyl acetate. The organic layer washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude residue was purified by preparative reverse phase liquid • chromatography (13.5g, 0.0699 mol, 51.3 %) . ESI-MS m/z calc. 193.1, found 194.2 (M+1)+ 1H MR (CDC13) δ: 9.42-9.39 (m, 2 H) , 8.58-8.55 (m, 1 H) , 8.17-8.13 (m, 1 H) , 5.09- 4.97 (m, 2 H) , 4.35 (t, 1 H, J" = 7.6 Hz), 3.04-2.95 (m, 1 H) , 2.74-2.65 (m, 1 H) , 2.10 (t, 3 H, J=7.2 Hz), 1.79 (t, 3 H, J = 7.6 Hz) . b) 2-Pyridin-3-yl-butyric acid A mixture of 2- Pyridin-3-yl-butyric acid ethyl ester (8 g, 0.04 mol) and a 20 % aqueous solution of hydrochloric acid (50 mL) was heated to reflux for 3 hours . The solvent evaporated to dryness to yield the desired product (5 g, 0.02 mol, 50 %) , ESI-MS m/z calc. 165.1, found 166.5 (M+1)+ 1H NMR (DMSO-ds) : δ 8.86 (s, 1 H) , 8.80 (d, 1 H, J" = 5.6 Hz) , 8.47 (d, 1 H, J = 8.0 Hz), 7.97 (dd, 1 H, J = 5.6, 8.0 Hz), 3.83 (t, 1 H, J = 8.0 Hz), 2.07-2.04 (m, 1 H) , 1.82- 1.80 ( , 1 H) , 0.80 (t, 3 H, J" = 7.6 Hz) .
22) -NT-{5- [ (2 -Chloro-phenyl) -hydroxy- ethyl] -thiazol-2- yl} -2 -phenyl-butyramide
Figure imgf000251_0001
N- [5- (2-Chloro-benzoyl) -thiazol-2-yl] -2-phenyl- butyramide (102 mg, 0.265 mmol) was suspended in 1 mL of anhydrous methanol. Sodium borohydride (30.3 mg, 0.801 mmol) was slowly added and the resulting pale yellow solution was allowed to stir for 1 hour at room temperature. After stirring for one hour a second aliquot of sodium borohydride (30.3 mg, 0.801 mmol) was added. The reaction mixture was allowed to stir for an additional hour and then the crude product was evaporated to dryness and then dissolved in a minimum of ethyl acetate. The organic layer was washed three times with an equal volume of IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was further purified by reverse-phase preparative liquid chromatography to yield the pure product (46 mg, 0.12 mmol, 45 %) ESI-MS m/z calc. 386.1, found 387.3 (M+l)+ Retention time 3.83 minutes.
23) N- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2,2-diphenyl- acetamide
Figure imgf000251_0002
5- (2-Chloro-benzyl) -thiazol-2-ylamine (45 g, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). 0- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (10.3 mg, 0.0246 mmol, 12 %) . ESI-MS m/z calc. 418.1, found 419.2 (M+l)+ Retention time 3.85 minutes. XH NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H) , 5.30 (s, IH) , 7.23-7.47 (m, 15H) .
24) N~ (7-Oxo-4,5, 6,7 -tetrahydro-benzothiazol-2-yl) -2- phenyl-butyramide
Figure imgf000252_0001
Et3N
2-Amino-5, 6-dihydro-4H-benzothiazol-7-one (34 mg, 0.20 mmol) and 2 -phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (1 L) containing triethylamine (84.1 μL, 0.600 mmol). O- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (31 mg, 0.099 mmol, 49 %) . ESI-MS m/z calc. 314.1, found 315.3 (M+l)+ Retention time 2.90 minutes . 25) (2 -Diphenylacetylamino-thiazol-4-yl) -acetic acid methyl ester
Figure imgf000253_0001
(2-Amino-thiazol-4-yl) -acetic acid methyl ester (45 mg, 0.20 mmol) and diphenyl-acetic acid (37 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O- (7- Azabenzotriazol-1-yl ) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (29.4 mg, 0.0802 mmol, 40. %) . ESI-MS m/z calc. 380.1, found 381.3 (M+l)+ Retention time 3.28 minutes .
26) 2-Diphenylacetylamino-thiazole-4-carboxylic acid ethyl ester
Figure imgf000253_0002
2-Amino-thiazole-4-carboxylic acid methyl ester (32 mg, 0.20 mmol) and diphenyl-acetic acid (42 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O- (7- Azabenzotriazol-1-yl) -N,N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (19 mg, 0.052 mmol, 26 %) . ESI-MS m/z calc. 366.1, found 367.1 (M+l)+ Retention time 3.34 minutes .
27) N- [5- (2-Methoxy-pyridin-3-ylmethyl) -thiazol-2-yl] -2- phenyl-butyramide
Figure imgf000254_0001
Et3N 5- (2-Methoxy-pyridin-3-ylmethyl) -thiazol-2-ylamine (44 mg, 0.20 mmol) and 2 -phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). 0- (7-
Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (15 mg, 0.041 mmol, 21 %) . ESI-MS m/z calc. 367.1, found 368.1 (M+l)+ Retention time 3.24 minutes .
28) 2-Bromo-iV- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl-acetamide
Figure imgf000254_0002
Et3N
5- (2-Chloro-benzyl) -thiazol-2-ylamine (450 mg, 2.0 mmol) and bromo-phenyl -acetic acid (430 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (280 μL, 2.0 mmol). O- (7-Azabenzotriazol- 1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (836 mg, 2.2 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography using a gradient of 10-30 % ethyl acetate in hexanes to yield a pale yellow solid (633 mg, 1.50 mmol, 75.0 %) . ESI-MS m/z calc. 420.0, found 421.2 (M+l)+ Retention time 3.63 minutes.
29) 2-Bromo-W- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl-acet.amide
Figure imgf000255_0001
Et3N 5- (2-Chloro-benzyl) -thiazol-2-ylamine (0.484 g, 2.1( mmol) and 2 -bromo-butyric acid (0.360 g, 2.16 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (302 μL, 2.16 mmol). 0- (7-Azabenzotriazol- 1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (1.15 g, 3.02 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography. ESI-MS m/z calc. 372.0, found 373.2 (M+l)+ Retention time 3.41 minutes.
30) N- [5- (4 -Chloro-benzyl) -oxazol-2-yl] -2-cyclopentyl-2- phenyl- cetamide
Figure imgf000255_0002
5- (4-Chloro-benzyl) -oxazol-2-ylamine (42 mg, 0.20 mmol) and cyclohexyl-phenyl-acetic acid (44 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). 0- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (9.6 mg, 0'.023 mmol, 12 %) . ESI-MS m/z calc. 408.9, found 409.4 (M+l)+ Retention time 3.76 minutes .
31) N- [5- (2-Chloro-benzyl) -1-methyl-lH-imidazol-2 -yl] -2- phenyl-butyr-amide
Figure imgf000256_0001
Et3N
5- (2-Chloro-benzyl) -1-methyl-lH-imidazol-2 -ylamine (44 mg, 0.20 mmol) and 2 -phenyl -butyric acid (33 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). 0- (7- Azabenzotriazol-1-yl) -N, N,N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (13 mg, 0.035 mmol, 18 %) . ESI-MS m/z calc. 367.2, found 368.1 (M+l)+ Retention time 2.42 minutes .
32) N- (6-Ethoxy-benzothiazol-2-yl) -2 -phenyl-butyramide
Figure imgf000257_0001
Et3N
6-Ethoxy-benzothiazol-2-ylamine (39 mg, 0.20 mmol) and 2 -phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N, N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). 0- (7- Azabenzotriazol-1-yl) -N, N, N' , N' -tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25 %) . ESI-MS m/z calc. 340.1, found 340.9 (M+l)+ Retention time 3.55 minutes .
33 ) 4 -Methyl-iV- (4 -phenyl-thiazol-2 -yl) -benzamide pyridine
Figure imgf000257_0002
Figure imgf000257_0003
4-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4 -methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (20.6 mg, 0.0635 mmol, 31.8 %) . ESI-MS m/z calc. 294.1, found 295.2 (M+l)+ Retention time 3.55 minutes.
34) 4-Methyl-iV- (4-phenyl-thiazol-2-yl) -benza pyridine
Figure imgf000258_0001
Figure imgf000258_0002
mide 5-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (10.4 mg, 0.0353 mmol, 17.7 %) . ESI-MS m/z calc. 294.1, found 295.4 (M+l)+ Retention time 3.40 minutes .
35) N- [4- (2 -Methoxy-phenyl) -thiazol-2-yl] -4-methyl- benzamide
pyridine
Figure imgf000258_0003
Figure imgf000258_0004
4- (2-Methoxy-phenyl) -thiazol-2-ylamine (41.3 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (7.32 mg, 0.0226 mmol, 11.3 %) . ESI-MS m/z calc. 324.1, found 325.2 (M+l)+ Retention time 3.75 minutes .
36 ) N- [4 - (2 -Methoxy-phenyl) - thiazol-2 -yl] -benzamide pyridine
Figure imgf000258_0005
Figure imgf000258_0006
4- (2-Methoxy-phenyl) -thiazol-2-ylamine (41.3 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (11.4 mg, 0.0367 mmol, 18.4 %) . ESI-MS m/z calc. 310.1, found 311.2 (M+l)+ Retention time 3.55 minutes .
37) N- (4, 5-Diphenyl-thiazol-2-yl) -benzamide
Figure imgf000259_0001
4, 5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1 ,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol) . The reaction mixture was subjected to microwave irradiation for 5 minutes at 200 °C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (7.21 mg, 0.0202 mmol, 10.1 %) . ESI-MS m/z calc. 356.1, found 357.2 (M+l)+ Retention time 3.95 minutes.
38) N- (4,5-Diphenyl-thiazol-2-yl) -4 -methyl-benzamide
Figure imgf000260_0001
4, 5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol) . The reaction mixture was subjected to microwave irradiation for 5 minutes at 200 °C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (18.6 mg, 0.0502 mmol, 25.1 %) . ESI-MS m/z calc. 370.1, found 371.2 (M+l)+ Retention time 4.13 minutes .
39) N- (4,5-Diphenyl-thiazol-2-yl) -4-methoxy-benzamide
Figure imgf000260_0002
4, 5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methoxy-benzoyl chloride (34.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature . The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (12.5 mg, 0.0323 mmol, 16.2 %) . ESI-MS m/z calc. 386.1, found 387.2 (M+l)+ Retention time 3.95 minutes.
40 ) 4 -Methyl-iV- (4 -p- tolyl -thiazol-2 -yl) -benzamide
Figure imgf000261_0001
4-p-Tolyl~thiazol-2-ylamine (38.1 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature . The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (13.5 mg, 0.0438, 21.9 %) . ESI-MS m/z calc. 308.1, found 309.0 (M+l)+ Retention time 3.72 minutes.
41) 4-Methyl-27- (5-methyl-thiazol-2-yl) -benzamide
Figure imgf000261_0002
5-Methyl-thiazol-2-ylamine (22.8 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol) . The reaction mixture was stirred overnight at room temperature . The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (9.29 mg, 0.0400, 20.0 %) . ESI -MS m/z calc . 232 . 1 , found 233 . 2 (M+l ) + Retention time 2 . 65 minutes .
42 ) N- [5- (2 -Chloro-benzyl) -thiazol-2 -yl] -2 -methoxy-2 - phenyl - acetamide
Figure imgf000262_0001
2 -Bromo-N- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 5 mL of methanol. The reaction vessel was sealed and then subjected to microwave irradiation for 15 minutes at 125 °C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (16 mg, 0.043, 43 %) . ESI-MS m/z calc. 372.1, found 373.2 (M+l)+ Retention time 3.43 minutes. XH NMR (400 MHz, CD3CN) δ 3.42 (s, 3H) , 4.23 (s, 2H) , 4.94 (s, IH) , 7.21-7.53 (m, 10H)
43) iV- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-methylamino-2- phenyl-acet-amide
Figure imgf000262_0002
2-Bromo-iV- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N, N-dimethylformamide containing 1.0 mL of methylamine (2.0 M in tetrahydrofuran, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (29 mg, 0.078, 78 %) . ESI-MS m/z calc. 371.1, found 372.2 (M+l)+ Retention time 2.33 minutes. ^Η NMR (400 MHz, MeOD) δ 2.66 (s, 3H) , 4.23 (s, 2H) , 5.09 (s, IH) , 7.13-7.56 (m, 10H) .
44) JV- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-morpholin-4-
Figure imgf000263_0001
2-Bromo-JV- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 L of N,N-dimethylformamide containing morpholine (174 mg, 2.00 mmol) . The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.072, 72 %) . ESI-MS m/z calc. 427.1, found 428.0 (M+l)+ Retention time 2.40 minutes.
45) N- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-dimethylamino- 2 -phenyl-acetamide
Figure imgf000263_0002
2-Bromo-iV- [5- (2-chloro-benzyl) -thiazol-2-yl] -2- phenyl -acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N, N-dimethylformamide containing di ethylamine (90.2 mg, 2.00 mmol) . The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (13 mg, 0.034, 34 %) . ESI-MS m/z calc. 385.1, found 386.0 (M+l)+ Retention time 2.40 minutes.
46) N- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-dimethylamino- 2-phenyl-acet mide
Figure imgf000264_0001
2-Bromo-i\r- [5- (2-chloro-benzyl) -thiazol-2-yl] - butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of W/iV-dimethylformamide containing aniline (186 mg, 2.00 mmol) . The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (24 mg, 0.062, 62 %) . ESI-MS m/z calc. 385.1, found 386.1 (M+l)+ Retention time 3.48 minutes.
47) N- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-ethylamino- butyramide
Figure imgf000264_0002
2-Bromo-JNT- [5- (2-chloro-benzyl) -thiazol-2-yl] - butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of
Figure imgf000264_0003
containing ethylamine (2 M in tetrahydrofuran, 1.00 L, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (19 mg, 0.056, 56 %) . ESI-MS m/z calc. 337.1, found 338.0 (M+l)+ Retention time 2.08 minutes.
48) -V- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-piperidin-l- yl-butyramide
Figure imgf000265_0001
2-Bromo-iV- [5- (2-chloro-benzyl) -thiazol-2-yl] - butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N, N-dimethylformamide containing piperidine (170 mg, 2.0 mmol) . The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C . The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.082, 82 %) . ESI-MS m/z calc. 377.1, found 378.2 (M+l)+ Retention time 2.21 minutes.
49) N- [5- (2-Chloro-benzyl) -thiazol-2-yl] -2-diethylamino- butyramide
Figure imgf000265_0002
2-Bromo-JT- [5- (2-chloro-benzyl) -thiazol-2-yl] - butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 L of N/ N-dimethylformamide containing diethylamine (146 mg, 2.00 mmol) . The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80 °C, The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (14 mg, 0.038, 38 %) . ESI-MS m/z calc. 365.1, found 366.2 (M+l)+ Retention time 2.18 minutes. Analytical data for exemplary compounds of the present invention is recited below in Table 2 below. Table 2
Figure imgf000266_0001
Figure imgf000266_0002
Figure imgf000267_0001
Figure imgf000267_0002
Figure imgf000268_0002
Figure imgf000268_0001
EXAMPLE 6 Assays for Detecting and Measuring ΔF508-CFTR Correction and Potentiator Properties of Compounds
A) Membrane potential optical methods for assaying ΔF508-CFTR modulation properties of compounds The optical membrane potential assay utilized voltage- sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4) : 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al . (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9) : 431-439).
These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPR™ II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
Identification of Correction Compounds To identify small molecules that correct the trafficking defect associated with ΔF508-CFTR; a single- addition HTS assay format was developed. The cells were incubated in serum-free medium for 16 hrs at 37 °C in the presence or absence (negative control) of test compound. As a positive control, cells plated in 384-well plates were incubated for 16 hrs at 27 °C to "temperature- correct" ΔF508-CFTR. The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate ΔF508-CFTR, 10 mM forskolin and the CFTR potentiator, genistein (20 mM) , were added along with Cl"-free medium to each well. The addition of Cl"-free medium promoted Cl" efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.
Identification of Potentiator Compounds To identify potentiators of ΔF508-CFTR, a double- addition HTS assay format was developed. During the first addition, a Cl"-free medium with or without test compound was added to each well. After 22 sec, a second addition of Cl~-free medium containing 2 - 10 DM forskolin was added to activate ΔF508-CFTR. The extracellular Cl" concentration following both additions was 28 mM, which promoted Cl" efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.
Solutions
Bath Solution #1: (in mM) NaCI 160, KC1 4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH. Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts. CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20°C. DiSBAC2(3) : Prepared as a 10 mM stock in DMSO and stored at -20°C.
Cell Culture NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for optical measurements of membrane potential . The cells are maintained at 37 °C in 51 C02 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs. for the potentiator assay. For the correction assays, the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hours.
B) Electrophysiologiσal Assays for assaying ΔF508-CFTR modulation properties of compounds
1. Ussing Chamber Assay Ussing chamber experiments were performed on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in the optical assays. FRT^F5OS-CFTR ep helial cells grown on Costar Snapwell cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA) , and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA) . Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 KΩ/ cm2 or more. The solutions were maintained at 27 °C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the flow of Cl" through ΔF508-CFTR expressed in the apical membrane. The ISc was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA) . Identification of Correction Compounds Typical protocol utilized a basolateral to apical membrane Cl" concentration gradient . To set up this gradient , normal ringer was used on the basolateral membrane, whereas apical NaCI was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl" concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 mM) and the PDE inhibitor, IBMX (100 mM) , were applied followed by the addition of the CFTR potentiator, genistein (50 mM) . As observed in other cell types, incubation at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 mM of the test compound for 24 hours at 37°C and were subsequently washed 3X prior to recording. The cAMP- and genistein- mediated Isc in compound-treated cells was normalized to the 27°C and 37°C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein- mediated ISc compared to the 37°C controls.
Identification of Potentiator Compounds Typical protocol utilized a basolateral to apical membrane Cl" concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 μg/ml) , whereas apical NaCI was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl" concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 mM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ΔF508-CFTR potentiators was compared to that of the known potentiator, genistein.
Solutions
Basolateral solution (in mM) : NaCI (135), CaCl2 (1.2), MgCl2 (1.2), K2HP04 (2.4), KHP04 (0.6) , N-2- hydroxyethylpiperazine-N' -2- ethanesulfonic acid (HEPES) (10) , and dextrose (10) . The solution was titrated to pH 7.4 with NaOH.
Apical solution (in mM) : Same as basolateral solution with NaCI replaced with Na Gluconate (135) .
Cell Culture Fisher rat epithelial (FRT) cells expressing ΔF508- CFTR (FRTΔF508"CFTR) were used for Ussing chamber experiments for the putative ΔF508-CFTR modulators identified from our optical assays. The cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 °C and 5% C02 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 μg/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the ΔF508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 °C or 37 °C with and without the compounds for 24 hours. 2. Whole-cell recordings The macroscopic ΔF508-CFTR current (IΔFSOS) in temperature and test compound-corrected NIH3T3 cells stably expressing ΔF508-CFTR were monitored using the perforated-patch, whole-cell recording. Briefly, voltage-clamp recordings of IΔFSOS were performed at room temperature using an Axopatch 200B patch-clamp amplifier
(Axon Instruments Inc., Foster City, CA) . All recordings were acquired at a sampling frequency of 10 kHz and low- pass filtered at 1 kHz. Pipettes had a resistance of 5- 6 MΩ when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for Cl" (Ecι) at room temperature was -28 mV. All recordings had a seal resistance > 20 GΩ and a series resistance < 15 MΩ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.) . The bath contained < 250 ml of saline and was continuously perifused at a rate of 2 ml/min using a gravity-driven perfusion system.
Identification of Correction Compounds To determine the activity of correction compounds for increasing the density of functional ΔF508-CFTR in the plasma membrane, we used the above-described perforated- patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate ΔF508-CFTR, 10 mM forskolin and 20 mM genistein were added to the cells. Under our recording conditions, the current density following 24 -hr incubation at 27°C was higher than that observed following 24-hr incubation at 37 °C. These results are consistent with the known effects of low-temperature incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 DM of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity) . Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ΔM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls .
Identification of Potentiator Compounds The ability of ΔF508-CFTR potentiators to increase the macroscopic ΔF508-CFTR Cl" current (IΔFSOS) n NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose- dependent increase in IDFSOS with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated Ecι (-28 mV) .
Solutions
Intracellular solution (in mM) : Cs-aspartate (90) , CsCl (50) , MgCl2 (1) , HEPES (10) , and 240 μg/ml amphotericin-B (pH adjusted to 7.35 with CsOH) . Extracellular solution (in mM) : N-methyl-D-glucamine (NMDG) -Cl (150), MgCl2 (2), CaCl2 (2) , HEPES (10) (pH adjusted to 7.35 with HCI) . Cell Culture NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for whole-cell recordings. The cells are maintained at 37 °C in 5% C0 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, D-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For whole-cell recordings, 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 °C for measuring the activity of correctors .
3. Single-channel recordings The single-channel activities of temperature-corrected ΔF508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. Briefly, voltage- clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz. Patch pipettes were fabricated from Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MΩ when filled with the extracellular solution. The ΔF508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI) . After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1-2 sec. To maintain ΔF508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F" (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min) . Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (Vp) was maintained at 80 mV.
Channel activity was analyzed from membrane patches containing < 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment . To determine the single-channel current amplitude, the data recorded from 120 sec of ΔF508-CFTR activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (PQ) were determined from 120 sec of channel activity. The P0 was determined using the Bio-Patch software or from the relationship P0 = 1/i (N) , where I = mean current, i = single-channel current amplitude, and N = number of active channels in patch.
Solutions
Extracellular solution (in mM) : NMDG (150) , aspartic acid (150), CaCl2 (5), MgCl2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base) .
Intracellular solution (in mM) : NMDG-C1 (150) , MgCl2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCI) .
Cell Culture NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 °C in 5% C02 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, /3-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.
The compounds of the present invention were found to modulate CFTR activity when tested using the above methods. The activity of exemplary compounds of the present invention is recited below in Table 3. EC50: "+++" means <10 uM; "++" means between lOuM to 25 uM; "+" means between 25 uM to 60uM.
% Efficacy: "+" means < 25%; "++" means between 25% to 100%; "+++" means > 100%.
Table 3
Figure imgf000278_0001
Figure imgf000278_0002
Figure imgf000279_0001
Figure imgf000279_0002
Figure imgf000280_0001
Figure imgf000280_0002
Figure imgf000281_0002
Figure imgf000281_0001

Claims

Claims
1. A method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of formul I or formula I ' :
Figure imgf000282_0001
I I " or a pharmaceutically acceptable salt thereof; wherein: Y' is 0, S, or NR; p is 0-2; X is a bond, O, S, S (0) , S(0)2, CF2, CH2, -CHOR-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O)- 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H, R2, or Rδ; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl ; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
-e—B ; ——(C1-C6aliphatic)-B ; B ;
(a) (b)
Figure imgf000282_0002
Figure imgf000282_0003
(e) (f) (g) (h) each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each A, B, and C is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5 ; RL is -ORA, -SRA, or -N(RAB)2; each RA is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from 0, N, or S, wherein each RA is optionally substituted with up to 3 substituents independently selected from R1, R4 or R7, each RAB is independently hydrogen or C1-C6 aliphatic optionally substituted with up to 3 substituents independently selected from R1, R4 or R7; wherein up to two methylene units in RA or R^ are optionally replaced with -CO-, -CS-, -COCO-, -C0NR-, -C02- , -0C0-, -NRC02-, -0-, -NRC0NR-, -0C0NR-, -NRC0-, -S-, - SO, -S02-, -NR-, -S02NR-, NRS02- , or -NRS02NR; or two RAB, taken together with the nitrogen atom, is a 3-7 membered heterocyclic or heteroaryl ring containing up to 4 heteroatoms selected from 0, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (Cι-4aliphatic) P-Y; RM is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; each of Xi and X2 is independently selected from 0, S, or NR; RN is C1-C6 aliphatic or phenyl, wherein RN is optionally substituted with up to two substituents selected from R1 , R2 , R3 , or R4 ; Rp is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; RQ is C1-C6 aliphatic or aryl, wherein RQ is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two Ri on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R^, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) Rβ , C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (Cχ-Cg) - straight or branched alkyl, (C2~Cg) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, SO2 -aliphatic, NH , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8, NHR8, N(R8)2, COOH, C (O) 0 (-aliphatic) , or O-aliphatic; and R8 is an amino-capping group.
2. The method according to claim 1, wherein Y' is S or O.
3. The method according to claim 2, wherein p is 1 and X is attached to the carbon adjacent to Y' atom.
4. The method according to claim 2, wherein p is 1 and X is attached to the carbon adjacent to the ring nitrogen atom.
5. The method according to claim 2, wherein, p is 2.
6. The method according to claim 1, wherein X is a bond, 0, S, CH2, CF2, CHOR, C(0)NR, C(0)0, NRC(O), or NR.
7. The method according to claim 6, wherein X is a bond, CH2, CHOH, C(0), or C(0)0.
8. The method according to claim 1, wherein A is optionally substituted (C1-C10) aliphatic .
9. The method according to claim 8, wherein A is optionally substituted methyl, ethyl, propyl, butyl, pentyl , or hexyl .
10. The method according to claim 1, wherein A is optionally substituted C6-C10 aryl ring. I
11. The method according to claim 10, wherein A is optionally substituted phenyl or naphthyl.
12. The method according to claim 1, wherein A, X, and the ring attached thereto, taken together, is selected from: ,
Figure imgf000286_0001
Figure imgf000286_0002
v vi vii
Figure imgf000287_0001
xi xii xiii
Figure imgf000287_0002
xiv xv xvi
Figure imgf000287_0003
xvii or xvixi wherein: Rph is independently R1, R2, or R3; and r is 0-3. X5 is CH2, C(O), or CHOR; X6 is 0 or NR2; and RAk is C1-C6 aliphatic, optionally substituted with R1, R2, or R3.
13. The method according to claim 12, wherein each B is independently an optionally substituted phenyl or naphthyl .
14. The method according to claim 1, wherein said compound has formula I-a:
Figure imgf000288_0001
I -a .
15. The method according to claim 14, wherein said B is selected from:
Figure imgf000288_0002
11 iii iv v VI
Figure imgf000288_0003
wherein X3 is O, S, or NR.
16. The method according to claim 15, wherein B is substituted with up to two R1 substituents.
17. The method according to claim 16, wherein said substituent is selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, -C(0)0(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C(0)N(C1-C4 alkyl) 2, or phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, - C(0)0(C1-C4 alkyl), -C (O) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2.
18. The method according to claim 15, wherein said B is selected from rings i, iii, iv, v, vi, or vii.
19. The method according to claim 15, wherein said B is ring x.
20. The method according to claim 15, wherein said B is selected from ring xi, xii, xiii, or xiv.
21. The method according to claim 15, wherein X is a bond and A is optionally substituted phenyl and A is attached to the carbon atom adjacent to the nitrogen ring atom.
22. The method according to claim 21, wherein A is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, cyano, halo, N- pyrrolidinyl , N-piperidinyl, or methylenedioxy.
23. The method according claim 22, wherein A is phenyl , 3 -methoxyphenyl , 2-methoxyphenyl , 4-cyanophenyl , 4-chlorophenyl, 4- (N-pyrrolidinyl) phenyl, 4-tolyl, 3,4- methylenedioxyphenyl , 3-chlorophenyl , 2,4- dimethoxyphenyl , 2-chlorophenyl, 4-bromophenyl, 2,5- dimethy1phenyl , or 2 , 4-dimethylphenyl .
24. The method according to claim 15, wherein A is selected from cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
25. The method according to claim 15, wherein the compounds have one or more of the following features : a) R is hydrogen; b) Y' is S; c) A is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, cyano, halo, N-pyrrolidinyl, N-piperidinyl , or methylenedioxy; and d) B is phenyl optionally substituted with up to two substituents selected from C1-C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, -C(0)0(C1-C4 alkyl), -C(0)NH(C1- C4 alkyl), -C(0)N(C1-C4 alkyl) 2, or phenyl optionally substituted with up to two substituents selected from Cl- C4 alkyl, -0-C1-C4 alkyl, CN, halo, COOH, -C(0)NH2, - C(0)0(C1-C4 alkyl), -C (0) NH (C1-C4 alkyl), -C(0)N(C1-C4 alkyl) 2.
26. The method according to claim 1, wherein said compounds have formula I-b: R s YYVN r-(C1-C6aliphatic)-B
I-b.
27. The method according to claim 26, wherein p is
1, X is a bond, and A is an optionally substituted phenyl ring.
28. The method according to claim 26 wherein p is
2, each X is a bond, and each A is an optionally substituted phenyl .
29. The method according to claim 26 wherein
X is CH2, CHOH, or C(0),and A is an optionally substituted phenyl .
30. The method according to claim 26 wherein said C1-C6 aliphatic is C1-C4 straight or branched alkylidene.
31. The method according to claim 30, wherein said alkylidene is selected from -CH2-, -CH(Me)-, -C(Me)2-, - CH(Et)-, -C(Et)2~, or -CH2-CH (Me) - .
32. The method according to claim 26, wherein B is selected from C3-C8 cycloalkyl, phenyl, piperidyl, or pyrrolidinyl, optionally substituted with up to two R1 substituents .
33. The method according to claim 26, wherein said (C1-C6 aliphatic) -B, together, is selected from:
YAk
Figure imgf000291_0001
i ii iii iv; wherein: Ak is C1-C6 straight or branched alkylidene; X4 is CH2, O or S; Ar ' is phenyl optionally substituted with up to two R1 ; and B is optionally substituted with up to two R1.
34. The method according to claim 33, wherein Ak is selected from CH2, CH(CH3), C(CH3)2, CH(Et), C(Et)2, CH(n- propyl) , CH(i-Pr), CH (n-butyl), CH (but-2-yl) , or CH(t- butyl) .
35. The method according to claim 33, wherein Ar ' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (C1-C4 alkyl) .
36. The method according to claim 33, wherein X4 is S or O.
37. The method according to claim 26 or 33, wherein R is hydrogen.
38. The method according to claim 1, wherein said compound has formula I-f:
Figure imgf000292_0001
I-f; wherein: Y' is 0 or S; Xi is 0, S, or NR; RM is C1-C6 aliphatic or phenyl, wherein RM is optionally substituted with up to two substituents independently selected from R1, R2, or R3; RN is C1-C6 aliphatic or a 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; wherein RN is optionally substituted with up to 4 substituents independently selected from R^, R2 , R3 , R4 , or R5.
39. The method according to claim 38, wherein p is
1.
40. The method according to claim 38, wherein X is CH2, CHOH, or C(0) .
41. The method according to claim 38, wherein X is a bond, and A is an optionally substituted phenyl.
42. The method according to claim 38, wherein p is 2, each X is a bond, and each A is an optionally substituted phenyl.
43. The method according to claim 38, wherein Xi is NH or N(C1-C4 alkyl) .
44. The method according to claim 38, wherein Xi is O.
45. The method according to claim 38, wherein RM is optionally substituted phenyl .
46. The method according to claim 38, wherein RM is C1-C4 alkyl.
47. The method according to claim 38, wherein RN is optionally substituted C3-C7 cycloaliphatic, phenyl, or benzyl .
48. The method according to claim 38, wherein RN is C1-C6 aliphatic.
49. The method according to claim 38, R is hydrogen .
50. The method according to claim 38, wherein Y1 is S.
51. The method according to claim 1, wherein said compound has formula I-g:
Figure imgf000293_0001
i-g wherein: Y1 is O or S; Rp is C1-C8 aliphatic optionally substituted with up to two substituents independently selected from R1, R2, or R3.
52. The method according to claim 51, wherein p is 1 and X is a bond.
53. The method according to claim 51, wherein p is
1, X is CH2, CHOH, or C (0) .
54. The method according to claim 51, wherein X is a bond, and A is an optionally substituted phenyl.
55. The method according to claim 51, wherein p is
2, each X is a bond, and each A is an optionally substituted phenyl .
56. The method according to claim 51, wherein Rp is C1-C4 alkyl, optionally substituted with up to two R1.
57. The method according to claim 56, wherein Rp is selected from ethyl, n-propyl, i-propyl, n-butyl, but-2- yl , isoamyl, or t-butyl, optionally substituted with halo, CN, COOH, or C0NH2.
58. The method according to claim 51, wherein R is hydrogen .
59. The method according to claim 51, wherein said compounds have one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2 and each A is phenyl; d) Rp is isoamyl, t-butyl, ethyl, isopropyl, n- propyl, l-carboxy-prop-3-yl, or 1-carboxy-2 -methyl-prop- 3-yl.
60. The method according to claim 1, wherein said compound has formula I-h:
Figure imgf000295_0001
I-h wherein: Y' is O or S; X2 is O, S, or NR; RQ is C1-C6 aliphatic or phenyl, optionally substituted with up to two substituents independently selected from R1, R2, or R3.
61. The method according to claim 60, wherein p is 1 and X is a bond.
62. The method according to claim 60, wherein X is CH2, CHOH, or C (0) .
63. The method according to claim 60, wherein X is a bond, and A is an optionally substituted phenyl.
64. The method according to claim 60, wherein p is 2, each X is a bond, and each A is an optionally substituted phenyl.
65. The method according to claim 60, wherein X2 is S.
66. The method according to claim 60, wherein X2 is O.
67. The method according to claim 60, wherein RQ is C1-C4 alkyl, optionally substituted with up to three R1.
68. The method according to claim 60, wherein RQ is C1-C4 alkyl, optionally substituted with up to one R1.
69 . The method according to claim 60, wherein RQ is phenyl optionally substituted with C1-C4 alkyl, or R1.
70. The method according to claim 60, wherein R is hydrogen.
71. The method according to claim 1, wherein said compound has formula (IA) :
Figure imgf000296_0001
wherein: X is a bond, CH2, CHOR, C (O) , NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
— B
Figure imgf000296_0002
<°) (d) . each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; R is H, R2, or R6 ; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5 ; and R1, R2, R3, R4, or R5 are as defined in claim 1.
72. The method according to claim 71, wherein X is CH2.
73. The method according to claim 71, X is a bond.
74. The method according to claim 71, wherein A is phenyl or a 5-6 membered heteroaryl, wherein A is optionally substituted with up to 3 substituents selected from R1, R2, R3 , or R .
75. The method according to claim 71, wherein A is optionally substituted phenyl.
76. The method according to claim 71, wherein Q is B.
77. The method according to claim 71, wherein Q is -(C1-C6)- aliphatic-B.
78. The method according to claim 71, wherein Q is CH(B)2.
79. The method according to claim 71, wherein Q is C(B)3.
80. The method according to claim 71, wherein B is phenyl .
81. The method according to claim 71, wherein: (i) X is a bond, CHOH, C (O) , CH2, or 0; (ii) A is optionally substituted phenyl; and (iii) Q is diphenylmethyl .
82. The method according to claim 1, wherein said compound has formula (IB) :
Figure imgf000298_0001
wherein: X is a bond, CH2, CHOR, C (0) , NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from: B ;
Figure imgf000298_0002
(c) (d) each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; R is H, R2, or R6; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5.
83. The method according to claim 82, X is a bond or CH2.
84. The method according to claim 82, wherein X is a bond.
85. The method according to claim 82, wherein A is phenyl or a 5-6 membered heteroaryl, wherein A is optionally substituted with up to 3 substituents selected from R1, R2, R3 , or R4.
86. The method according to claim 82, wherein Q is B.
87. The method according to claim 82, wherein Q is -(C1-C6)- aliphatic-B.
88. The method according to claim 82, wherein Q is CH(B)2.
89. The method according to claim 82, wherein Q is C(B)3.
90. The method according to claim 82, wherein B is phenyl .
91. The method according to claim 82, wherein: (i) X is a bond, CHOH, C(0), CH2, or O; (ii) A is optionally substituted phenyl; and (iii) Q is diphenylmethyl .
92. The method according to claim 1, wherein said compound has formula (IC) :
Figure imgf000300_0001
wherein: each X is independently a bond, CH2, CHOR, C(O), NR, or O; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; Q is selected from:
— B ;
Figure imgf000300_0002
(°) (d) . each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; R is H, R2, or R6; wherein each A and B is independently and optionally substituted with up to 4 substituents independently selected from R1, R2 , R3 , R4 , or R5.
93. The method according to claim 92, X is a bond or CH2.
94. The method according to claim 92, wherein X is CH2.
95. The method according to claim 92, wherein X is a bond.
96. The method according to claim 92, wherein A is phenyl or a 5-6 membered heteroaryl, wherein A is optionally substituted with up to 3 substituents selected from R1, R2, R3, or R4.
97. The method according to claim 92, wherein Q is B.
98. The method according to claim 92, wherein Q is - (C1-C6)- aliphatic-B.
99. The method according to claim 92, wherein Q is CH(B)2.
100. The method according to claim 92, wherein Q is C(B)3.
101. The method according to claim 92, wherein B is phenyl .
102. The method according to claim 92, wherein: (i) each X is a bond or CH2; (ii) each A is optionally substituted phenyl, (Cl- C6) aliphatic, or CF3; and (iii) Q is optionally substituted phenyl, (Cl- C6) aliphatic, or diphenylmethyl .
103. The method according to claim 102, wherein X is CH2.
104. A compound having formula (II) :
Figure imgf000302_0001
or a pharmaceutically acceptable salt thereof; wherein: Xi is a bond, 0, S, CF2, CHOR, C(O), C(0)0, CH2, or NR; R is H or R2 Ai is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl; each Bx is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or 0; wherein each Ai is optionally substituted with up to
4 substituents independently selected from R^, R2 , R , R4, or R5; R1 is R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6 , S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , COOH, COOR6 or OR6; or two Ri on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, 0C(0)0R6, OC(0)OR5, 0C(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)0R6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) R6 , C(0)N(OR5)R6, C(O)N(0R6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 Ri substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2-C5) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, O2 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic , Sθ2~aliphatic, NH2 , N- aliphatic, N (aliphatic) 2 , N (aliphatic) R8 , COOH, C(0)0(- aliphatic, or O-aliphatic; and R8 is an amino protecting group; provided that : (i) when both Bx are simultaneously phenyl and Xx is CH2, then A is not 4 -fluoro-phenyl, 4-phenyl- piperidyl, phenyl, 2 , 4-dichloro-phenyl , 4-methoxyphenyl, 3 , 4-dichloro-phenyl, 2 , 5-dichloro-phenyl , 4- nitro-phenyl, 4-bromo-phenyl , 4-methyl-phenyl, 2- chloro-phenyl, 1-naphthyl, 3 -trifluoromethyl-phenyl , 2 , 3-dichlorophenyl, N-morpholinyl , 4-chloro-phenyl , 3 -chloro-phenyl, or 3 -nitro-phenyl ; (ii) when Xx is a bond or CH2, one Bi is a substituted phenyl and the other Bx is cycloaliphatic, then Ai is not (C2-C8) aliphatic; and (iii) when Xx is a bond, then Ax is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms .
105. The compound according to claim 104, wherein Xi is CH2, CHOR, C(O), C(0)0, CF2, or O.
106. The compound according to claim 104, wherein Xi is CH2, CHOR, C(O), C(0)0.
107. The compound according to claim 104, wherein Xi is CH2.
108. The compound according to claim 104, wherein Ai is selected from phenyl, triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, thiadiazolyl, triazolyl, oxadiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, indolizinyl, indolyl, isoindolyl, benzofuranyl , benzo [b] thienyl, IH-indazolyl, benzimidazolyl, benzthiazolyl , purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl , indenyl , naphthyl, azulinyl, or anthracenyl .
109. The compound according to claim 104, wherein each Bx is independently selected from optionally substituted C6-C10 aryl.
110. The compound according to claim 104, wherein each Bi is independently an optionally substituted phenyl or naphthyl .
111. The compound according to claim 104, wherein each Bx is an unsubstituted phenyl .
112. The compound according to claim 104, wherein each Bx is independently selected from optionally substituted C5-C12 heteroaryl.
113. The compound according to claim 112, wherein each B is independently and optionally substituted C5-C7 heteroaryl .
114. The compound according to claim 113, wherein each B is independently selected from optionally substituted pyrazolyl or imidazolyl .
115. The compound according to claim 104, wherein Bx is selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl, tetrahydrothienyl , dioxolanyl, pyrrolinyl, pyranyl, pyrazolinyl, pyrazolidinyl , piperidinyl, 1, 4-dioxanyl , morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
116. A compound having formula (III]
Figure imgf000306_0001
or a pharmaceutically acceptable salt thereof; wherein: Xx is a bond, 0, S, CF2, CHOR, C(0), C(0)0, CH2, or NR; R is H or R2 Ai is (C2-C10) aliphatic, aryl, heteroaryl, heterocyclic, or cycloaliphatic; each Bi is independently selected from 3-7 membered monocyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms selected from N, NH, S, or O; wherein each Ai is optionally substituted with up to
4 substituents independently selected from R1, R2 , R3 , R4, or R5; R1 is R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6 , S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , COOH, COOR6 or OR6; or two R1 on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)0R6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (O) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(0R6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-L substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cς) - straight or branched alkyl, (C2-C5) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N0 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, Sθ2~aliphatic, NH2 , N-
(aliphatic) , N (aliphatic) 2 , N (aliphatic) R8, NHR8, N(R8)2,
COOH, C (0)0 (-aliphatic, or O-aliphatic; and R8 is an amino protecting group; provided that : (i) when Xx is a bond, one Bx is phenyl and the other Bi is N-piperidyl, then A is not:
Figure imgf000308_0001
ii) when X is a bond, then Ai is not an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen ring atoms
117. The compound according to claim 116, wherein Xx is a bond, CH2, CHOR, C(0), C(0)0, CF2, or 0.
118. The compound according to claim 116, wherein Xx is bond, CH2, CHOR, C (O) , C(0)0.
119. The compound according to claim 116, wherein Ax is optionally substituted (C1-C10) aliphatic .
120. The compound according to claim 119, wherein x is optionally substituted methyl, ethyl, propyl, butyl, pentyl , or hexyl .
121. The compound according to claim 116, wherein Ax is optionally substituted C6-C10 aryl ring.
122. The compound according to claim 121, wherein Ax is optionally substituted phenyl or naphthyl.
123. The compound according to claim 116, wherein A is optionally substituted C5-C12 heteroaryl ring.
124. The compound according to claim 123, wherein A is pyridinyl.
125. The compound according to claim 116, wherein each Bi is independently selected from optionally substituted C6-C10 aryl.
126. The compound according to claim 125, wherein each Bx is independently an optionally substituted phenyl or naphthyl .
127. The compound according to claim 126, wherein each Bx is an unsubstituted phenyl .
128. The compound according to claim 116, wherein each Bx is independently an optionally substituted 3-12 membered heterocyclic ring having up to 4 heteroatoms selected from 0, S, or NR.
129. The compound according to claim 128, wherein each Bx is independently selected from optionally substituted aziridine, oxirane, thiirane, pyrrolidyl, tetrahydrofuranyl , tetrahydrothienyl, dioxolanyl, pyrrolinyl, pyranyl , pyrazolinyl, pyrazolidinyl, piperidinyl, 1 , 4-dioxanyl , morpholinyl, 1 , 4-dithianyl, thiomorpholinyl, piperazinyl, 3H-indolyl, or indolinyl.
130. A compound of formula IIA:
Figure imgf000310_0001
IIA; or a pharmaceutically acceptable salt thereof; wherein: Y' is 0 or S; B is a 3-8 membered, saturated, moncyclic, ring having 0-4 heteroatoms selected from O, S, or N; and ring G and B are optionally substituted with up to four substituents independently selected from R1, R2 , R3 , R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two R1 on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (Cχ-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1 , 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2) n~2; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, SO2 -aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0)0 (-aliphatic, or O-aliphatic; and R8 is an amino capping group; provided that when Y' is S, and: a) when B is cyclohexyl, tetrahydrofuran-2-yl , or cyclopropyl, and ring G has 1-3 halo substituents, then ring G has at least one additional substituent other than halo; and b) when B is tetrahydrofuran-2-yl, then ring G is not phenyl, trifluoromethylphenyl , methoxyphenyl, or tolyl ; c) when B is cyclohexyl, then ring G is not phenyl or trifluoromethylphenyl .
131. The compound according to claim 130, wherein B is tetrahydrofuranyl , piperidyl, morpholinyl, or thiomorpholinyl .
132. The compound according to claim 130, wherein B is C3-C8 saturated, carbocyclic, monocyclic ring.
133. The compound according to claim 130, wherein B is selected from cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
134. The compound according to claim 130, wherein ring G is phenyl optionally substituted with up to two R1.
135. The compound according to claim 134, wherein ring G is optionally substituted with up to two substituents selected from halo, cyano, C1-C4 alkyl, or 0- (C1-C4 alkyl) .
136. The compound according to claim 135, wherein said compound has one or more of the following features: a) Y' is S; b) ring G is halo-substituted phenyl; c) B is phenyl optionally substituted with halo, cyano, C1-C4 alkyl, or O- (C1-C4 alkyl).
137. A compound formula IIB:
Figure imgf000313_0001
IIB; or a pharmaceutically acceptable salt thereof; wherein: Y' is S or 0; R is H, R2, or R6; RB is C1-C6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each , said heteroatom is independently selected from N, NH, S, or 0; wherein each of ring G, ring H, and RB is independently and optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8, N(R8)2, COOH, COOR6 or
OR6 ; or two Ri on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, S03R5, C(0)R5, C(0)0R5, C(0)R6, C(0)0R6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02 (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg)- straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2) n _Z' Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, SO2 -aliphatic, NH2 , NH- aliphatic, (aliphatic) 2 , N (aliphatic) R8, NHR8, N(R8)2,
COOH, C (0) 0 (-aliphatic, or O-aliphatic; and R8 is an amino capping group; provided that when Y is S, and: a) when RB is hydrogen, and ring G and ring H both have 1-3 halo substituents, then at least one of ring G and ring H has an additional substituent other than halo; b) when RB is hydrogen and ring H is unsubstituted phenyl, then ring G is not phenyl or phenyl substituted with methyl, CF3, -OMe, N02, or 1-3 halo; c) when RB is hydrogen and ring H is phenyl with methyl, 1-2 methoxy or 1-2 halo substituents, then ring G is not phenyl substituted with CF3 or 1-2 halo; d) when RB is methyl and ring H phenyl substituted with butyl, then ring G is not phenyl substituted with methyl, or 1-2 halo; and e) when RB and ring H are both unsubstituted phenyl, then ring G is not unsubstituted phenyl, or phenyl substituted with methyl, CF3, OMe, N02, or 1-2 halo.
138. The compound according to claim 137, wherein ring G is phenyl optionally substituted with up to two R1.
139. The compound according to claim 138, wherein R1 is selected from C1-C4 alkyl, 0- (C1-C4 alkyl), halo, or cyano .
140. The compound according to claim 137, wherein RB is Cl-6 aliphatic optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5.
141. The compound according to claim 140, wherein RB is C1-C4 alkyl optionally substituted with up to 2 substituents selected from RY
142. The compound according to claim 141, wherein RB is selected from methyl, ethyl, n-propyl, isopropyl, sec- butyl, n-butyl, or t-butyl.
143. The compound according to claim 137, wherein RB is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 0-4 heteroatoms optionally substituted with up to 4 substituents selected from R^,
R2, R3, R4, or R5.
144. The compound according to claim 143, wherein RB is a 3-7 membered monocyclic saturated, carbocyclic ring optionally substituted with up to 2 substituents selected from R1.
145. The compound according to claim 144, wherein RB is selected from cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
146. The compound according to claim 143, wherein RB is a 3-7 membered monocyclic saturated, unsaturated or aromatic ring containing 1-3 heteroatoms optionally substituted with up to 4 substituents selected from Ri,
R2, R3, R4, or R5.
147. The compound according to claim 143, RB is a 3- 7 membered monocyclic saturated ring containing 1-3 heteroatoms optionally substituted with up to 2 substituents selected from R1.
148. The compound according to claim 147, wherein RB is selected from piperidinyl, morpholinyl, or thiomorpholinyl .
149. The compound according to claim 137, wherein RB is a 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O, optionally substituted with up to 4 substituents selected from R1,
R2, R3, R4, or R5.
150 A compound of formula I IC :
Figure imgf000317_0001
IIC ; wherein: Y' is 0 or S; X7 is O, S, or NR'; R' is hydrogen, R2, or Rs; R is hydrogen, R2 , or R6 ; RB is Cl-6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or 0; Rc is C1-C6 aliphatic; wherein each of ring G, RB, and Rc is independently and optionally substituted with up to 4 substituents selected from R1, R2 , R3 , R4 , or R5 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8, N(R8)2, COOH, COOR6 or
OR6 ; or two R^ on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from Ri , R , or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R^-, R2 , R4 or
R5; R4 is OR5, OR6, 0C(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (O) NR5R6 , NR5C(0)N(R5)2/ NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1 , 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n- ; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, Sθ2-aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 / N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0) O (-aliphatic, or O-aliphatic; and R8 is an amino capping group.
151. The compound according to claim 150, wherein X7 is O.
152. The compound according to claim 150, wherein X7 is S.
153. The compound according to claim 150, wherein X7 is NR' .
154. The compound according to claim 150, wherein Rc is C1-C6 alkyl, optionally substituted with up to two substituents selected from R1 , R2 , R3 , R4 , or R5.
155. The compound according to claim 154, wherein Rc is C1-C6 alkyl.
156. The compound according to claim 155, wherein Rc is selected from methyl, ethyl, isopropyl, n-propyl, n- butyl , sec-butyl, or t-butyl.
157. The compound according to claim 150, wherein RB is phenyl optionally substituted with up to two R^ substituents .
158. The compound according to claim 157, wherein RB is phenyl .
159. The compound according to claim 150, wherein RB is selected from methyl, ethyl, isopropyl, n-propyl, n- butyl, sec-butyl, or t-butyl.
160. The compound according to claim 150, wherein said compound has one or more of the following features: a) ring G is optionally substituted with one R1 substituent ; b) Y1 is S and R is hydrogen; c) Rc is C1-C4 alkyl; d) X7 is NH or NR' wherein R' is C1-C4 alkyl; and e) RB is C1-C4 alkyl.
161. A compound of formula IID:
Figure imgf000320_0001
IID; wherein : Y ' is O or S ; R is hydrogen or R2; X8 is 0, S, or NR1; R1 is hydrogen, R2, or R5; RBB is Cl-6 aliphatic or a 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, S, or 0; wherein each of ring G and RBB is independently and optionally substituted with up to 4 substituents selected from R1, R2, R3, R4, or R5 ; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or
OR6 ; or two R1 on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1 , R2 , R4 or
R5; R4 is OR5, OR6, 0C(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, SO3R5, C(0)R5, C(0)0R5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6) , C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6) , NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C -Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2-methylenedioxy, 1,2- ethylenedioxy, or (CH2)n ~Z'' Z is selected from halo, CN, N02 , CF3 , 0CF3 , OH, S- aliphatic, S (0) -aliphatic, Sθ2-aliphatic, NH2 , NH- (aliphatic) , N (aliphatic) 2 , N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (O) 0 (-aliphatic, or O-aliphatic; and R8 is an amino capping group.
162. The compound according to claim 161, wherein X8 is O.
163. The compound according to claim 161, wherein X8 is S.
164. The compound according to claim 161, wherein Xa is NR' .
165. The compound according to claim 161, wherein
RBB is phenyl optionally substituted with up to two R1 substituents .
166. The compound according to claim 161, wherein RBB is phenyl .
167. The compound according to claim 161, wherein RBB is selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or t-butyl.
168. The compound according to claim 161, wherein RBB is an optionally substituted C3-C8 cycloalkyl.
169. The compound according to claim 168, wherein RBB is selected from cyclopropyl, cyclopentyl, or cyclohexyl .
170. The compound according to claim 161, wherein RBB is optionally substituted benzyl.
171. The compound according to claim 161, wherein said compound has one or more of the following features: a) Y' is S and R is hydrogen; b) each ring G is unsubsituted phenyl; d) X8 is NR', and R' is hydrogen or C1-C4 alkyl; and e) RBB is C1-C4 alkyl, benzyl, cyclopentyl, or cyclohexyl .
172. A compound of formula IV:
Figure imgf000324_0001
IV; or a pharmaceutically acceptable salt thereof; wherein: Y' is O, S, or NR; p is 0-2; X is a bond, 0, S, S (0) , S(0)2, CF2, CH2, -CHOR-, - C(O)-, -0-C(0)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C (O) - 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H, R2, or R6; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl; B is selected from:
Figure imgf000324_0002
(i) (ϋ) wherein: X3 is O or S; wherein A and B each is independently and optionally substituted with up to 4 substituents selected from Rl, R2, R3, R4 or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6 , S(0)R6, S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two Ri on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R^, R , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)0R6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (0) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (O) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02 (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 Rl substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2~Cg) straight or branched alkenyl or alkynyl, 1 , 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2) n-2'- Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, SO2 -aliphatic, H2 , NH- aliphatic, (aliphatic) 2, (aliphatic) R8 , NHR8, N(R8)2, COOH, C (0) 0 (-aliphatic, or O-aliphatic; and R8 is an amino-capping group.
173. The compound according to claim 172, wherein X3 is O.
174. The compound according to claim 172, wherein R is hydrogen.
175. The compound according to claim 172, wherein Y' is S.
176. The compound according to claim 172, wherein Y' is 0.
177. A compound of formula V:
Figure imgf000326_0001
V; or a pharmaceutically acceptable salt thereof; wherein: Y' is O or S; p is 0-2; X is a bond, 0, S, S (0) , S(0)2, CF2, CH2, -CHOR-, - C(O)-, -O-C(O)-, -C(0)-0, -C(0)-NR, -NR-C(O)-, -NR-C(O)- 0-, -0-C(0)-NR-, -NR-C(O) -NR-, or NR; R is H, R2, or R6 ; A is aliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl ; B is selected from:
Figure imgf000327_0001
(i) (ϋ) (ϋi) ; wherein: Ak is C1-C6 alkylidene; X4 is CH2, O or S; Ar ' is phenyl optionally substituted with up to two
R1; B is optionally substituted with up to two R1; wherein A is independently and optionally substituted with up to 4 substituents selected from R^-,
R2, R3, R4 or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1 ; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S0 R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two Ri on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R , R2 , R4 or R5; R4 is OR5, OR6, OC(0)R6, 0C(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (0) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)0R5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (O) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C_-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n -Z'' Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, Sθ2~aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2, N (aliphatic) R8, NHR8, N(R8)2, COOH, C (0)0 (-aliphatic, or O-aliphatic; and R8 is an amino capping group.
178. The compound according to claim 177, wherein Ak is selected from CH2, CH(CH3), C(CH3)2, CH(Et), C(Et)2, CH(n-propyl) , CH(i-Pr), CH (n-butyl), CH (but-2-yl) , or
CH (t-butyl) .
179. The compound according to claim 177, wherein Ar ' is phenyl optionally substituted with halo, C1-C4 alkyl, or 0- (C1-C4 alkyl).
180. The compound according to claim 177, wherein X4 is CH2.
181. The compound according to claim 177, wherein X4 is O or S.
182. The compound according to claim 177, wherein R is hydrogen.
183. The compound according to claim 177, wherein p is 2, X is a bond, and each A is optionally substituted phenyl .
184. The compound according to claim 177, wherein said compound has one or more of the following features: a) Y' is S; b) R is hydrogen; c) p is 2, X is a bond, and each A is phenyl; d) B is ring (iii) above, wherein Ak is CH(CH3) and Ar' is phenyl optionally substituted with halo, C1-C4 alkyl, or O- (C1-C4 alkyl).
185. A compound of formula VI:
Figure imgf000330_0001
VI; or a pharmaceutically acceptable salt thereof; Y' is 0 or S; R is hydrogen or R2; B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N; wherein each ring Gi, G2, and B is independently substituted with up to 4 substituents selected from R1 , R2, R3, R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , 0CF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two Ri on adjacent ring atoms, taken together, form 1 , 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R^, R2 , R4 or
R5; R4 is OR5, OR6, 0C(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6, SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (Cχ-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, SO2 -aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 , N (aliphatic) R8, NHR8, N(R8)2,
COOH, C (0) O (-aliphatic, or O-aliphatic; and R8 is an amino capping group; provided that when R is hydrogen: a) B is not quinolin-2-yl or 1 , 2-dihydro-2-oxo- quinolin-4-yl ; b) when G and G2 both are phenyl, and Y' is S, then B is not 1, 4-benzodioxin-2-yl , cyclopropyl,, cyclohexyl, thien-2-yl, lH-thieno [2 , 3-c] pyrazol-1-phenyl -3 -methyl -5- yl , 5-methyl-thien-3-yl , 2 , 5-dichloro-thien-3-yl , 2- phenyl-quinolin-4-yl , furan-2-yl, thien-5- (4 , 5-diphenyl- 2-thiazolyl-carboxamide) -2-yl, benzo [b] thiophen-2-yl , pyridin-2- (4 , 5-diphenyl-2-thiazolyl-carboxamide) -6-yl , 5- nitro-thien-2-yl, 3-chloro-benzo [b] thiophen-2-yl , 4H-1- benzopyran-3-yl or 2H-l-benzopyran-3 , 4-dihydro-3-oxo-4- yl , 4H-l-benzopyran-3-yl or 2H-l-benzopyran-3 , 4-dihydro- 3 -oxo-4 -yl ; c) when Gi and G2 both are phenyl, and Y' is O, then B is not 1, 2-dihydro-2-oxo-quinolin-4-yl or 3,4-dihydro- 3 -phenyl -phthalazin-1-yl or thien-2-yl; d) the following compounds are excluded:
Figure imgf000332_0001
Figure imgf000333_0002
e) when Y' is S, Gi and G2 are both phenyl, then B is
Figure imgf000333_0001
no
186. The compound according to claim 185, wherein Gx and G2 are both phenyl .
187. The compound according to claim 185, wherein each of Gi and G2 is independently and optionally substituted with up to two substituents selected from halo, or C1-C4 alkyl.
188. The compound according to claim 185, wherein B is phenyl optionally substituted with up to two substituents selected from halo, C1-C4 alkyl, 0- (C1-C4 alkyl), COOH, C00(C1-C4 alkyl), or cyano.
189. The compound according to claim 185, wherein B is phenyl, phenyl-2-carboxylic acid methyl ester, 3,4- dichlorophenyl, 4-chlorophenyl , 4-methoxyphenyl , 4- methylphenyl , 2 , 6-difluorophenyl , 2 -methylphenyl, 3- methylphenyl , phenyl-2 -carboxylic acid, 2-chlorophenyl, 4-cyanophenyl, 2 -methoxyphenyl, 3-chlorophenyl , or 3- ethoxyphenyl .
190. The compound according to claim 185, wherein B is 3-7 membered, monocyclic, saturated, carbocyclic ring.
191. The compound according to claim 190, wherein B is selected from cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
192. The compound according to claim 185, wherein B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from O, S, or N.
193. The compound according to claim 192, wherein B is selected from tetrahydrofuranyl .
194. A compound of formula VII :
Figure imgf000334_0001
or a pharmaceutically acceptable salt thereof; wherein: Y' is O or S; R is hydrogen or R2; RA is C1-C6 aliphatic, optionally substituted with up to 3 substituents independently selected from R1, R2, or R3; B is phenyl, 3-7 membered, monocyclic, saturated, carbocyclic ring, or 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N, or 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from O, S, or N; wherein each ring Gx, G2, and B is independently substituted with up to 4 substituents selected from R^, R2, R3, R4, or R5; R1 is oxo, R6 or ( (C1-C4) aliphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6 , S(0)R6, S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two R1 on adjacent ring atoms, taken together, form 1, 2 -methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, OC(0)N(R5)2, OC (O) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, SO3R6, SO3R5, C(0)R5, C(0)OR5, C(0)R6, C(0)OR6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(OR5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (O) N (R6) 2 , NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (O) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2, NR6S02NR5R6, NR6S02N (R5) 2 , NR5S02N (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(0R5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R-1- substituents ; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C^-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CT^n-2'" Z is selected from halo, CN, N0 , CF3 , OCF3 , OH, S- aliphatic, S (0) -aliphatic, S02 -aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 , N(aliphatic) R8 , NHR8, N(R8)2, COOH, C (O)O (-aliphatic, or O-aliphatic; and R8 is an amino-capping group; provided that when each of Gx, G2, and B is unsubstituted phenyl, and R is hydrogen, then B is not 3,4,5- trimethoxyphenyl .
195. The compound according to claim 194, wherein R^ is selected from methyl, ethyl, isopropyl, n-propyl, sec-butyl, n-butyl, or t-butyl.
196. The compound according to claim 194, wherein B is optionally substituted phenyl.
197. The compound according to claim 194, wherein B is 3-7 membered, monocyclic, saturated, carbocyclic ring.
198. The compound according to claim 197, wherein B is selected from cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl .
199. The compound according to claim 194, wherein B is a 3-10 membered saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having up to 4 heteroatoms selected from 0, S, or N.
200. The compound according to claim 199, wherein B is selected from tetrahydrofuranyl , tetrahydrothiophenyl, pyrrolidinyl, or piperazinyl.
201. The compound according to claim 194, wherein B is a 5-10 membered monocyclic or bicyclic heteroaryl ring having up to 4 heteroatoms selected from 0, S, or N.
202. A compound of formula I':
Figure imgf000338_0001
I'; or a pharmaceutically acceptable salt thereof; wherein: Y' is O, S, or NR; R is H, R2, or R6; C is a phenyl or 5-8 membered cycloaliphatic ring; Q is selected from:
Figure imgf000338_0002
(e) (f) (9) (h) each B is independently selected from 3-7 membered monocyclic or 8-14 membered bicyclic or tricyclic, saturated, unsaturated or aromatic ring containing 0-4 heteroatoms in each ring, wherein each said heteroatom is independently selected from N, NH, S, or O; wherein each B and C is independently and optionally substituted with up to 4 substituents independently selected from R1 , R2 , R3 , R4 , or R5 ;
Figure imgf000338_0003
each RA is independently hydrogen, C1-C6 aliphatic, or a 3-7 membered carbocyclic or heterocyclic ring, saturated or unsaturated ring, having up to 3 heteroatoms selected from O, N, or S, wherein each RA is optionally substituted with up to 3 substituents independently selected from R1, R4 or R7, each RAB is independently hydrogen or C1-C6 aliphatic optionally substituted with up to 3 substituents independently selected from R1, R4 or R7; wherein up to two methylene units in RA or RAB are optionally replaced with -CO-, -CS-, -COCO-, -CONR-, -C02- , -OCO-, -NRCO2-, -0-, -NRCONR-, -OCONR-, -NRCO-, -S-, - SO, -S02-, -NR-, -S02NR-, NRS02-, or -NRS02NR; or two R*3, taken together with the nitrogen atom, is a 3-7 membered heterocyclic or heteroaryl ring containing up to 4 heteroatoms selected from 0, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (Cι-aliphatic) P-Y; RM is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; each of X and X2 is independently selected from O, S, or NR; RN is C1-C6 aliphatic or phenyl, wherein RN is optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; Rp is C1-C6 aliphatic, optionally substituted with up to two substituents selected from R1, R2 , R3 , or R4 ; RQ is C1-C6 aliphatic or aryl, wherein RQ is optionally substituted with up to two substituents selected from R1, R , R3 , or R4 ; R1 is oxo, R6 or ( (C1-C4) liphatic) n-Y; n is 0 or 1; Y is halo, CN, N02 , CF3 , OCF3 , OH, SR6, S(0)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8 , N(R8)2, COOH, COOR6 or OR6 ; or two R1 on adjacent ring atoms, taken together, form 1, 2-methylenedioxy or 1, 2-ethylenedioxy; R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5 ; R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2 , R4 or
R5; R4 is OR5, OR6, OC(0)R6, OC(0)R5, OC(0)OR6, OC(0)OR5, OC(0)N(R6)2, 0C(0)N(R5)2, OC (0) N (R6R5) , SR6 , SR5, S(0)R6, S(0)R5, S02R6, S02R5, S02N(R6)2, S02N(R5)2, S02NR5R6, S03R6, SO3R5, C(0)R5, C(0)0R5, C(0)R6, C(0)0R6, C(0)N(R6)2, C(0)N(R5)2, C(0)N(R5R6), C (O) N (OR6) R6 , C(0)N(0R5)R6, C(0)N(OR6)R5, C (0) N (OR5) R5 , C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(0)R5, NR6C(0)R6, NR6C(0)R5, NR5C(0)R6, NR6C(0)OR6, NR5C(0)OR6, NR6C(0)OR5, NR5C(0)OR5, NR6C (0) N (R6) 2 ,
NR6C(0)NR5R6, NR6C(0)N(R5)2, NR5C (0) N (R6) 2 , NR5C (0) NR5R6 , NR5C(0)N(R5)2, NR6S02R6, NR6S02R5, NR5S02R5, NR5S02R6, NR6S02N(R6)2Λ NR6S02NR5R6, NR6S02 (R5) 2 , NR5S02 (R6) 2 , NR5S02NR5R6, NR5S02N(R5)2, N(OR6)R6, N(OR6)R5, N(0R5)R5, or N(OR5)R6; R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R^ substituents; R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent; R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (Cχ-Cg) - straight or branched alkyl, (C2~C ) straight or branched alkenyl or alkynyl, 1, 2 -methylenedioxy, 1,2- ethylenedioxy, or (CH2)n-Z; Z is selected from halo, CN, N02 , CF3 , OCF3 , OH, S- aliphatic, S (O) -aliphatic, S02 -aliphatic, NH2 , NH- aliphatic, N (aliphatic) 2 / N (aliphatic) R8 , NHR8, N(R8)2, COOH, C (O) O (-aliphatic, or O-aliphatic; and R8 is an amino-capping group.
203. The compound according to claim 202, wherein Y' is 0.
204. The compound according to claim 202, wherein Y' is S.
205. The compound according to claim 202, wherein R is hydrogen.
206. The compound according to claim 202, wherein Q in formula I ' is B (structure (a) .
207. The compound according to claim 202, wherein Q in formula I' is - (C1-C6 aliphatic) -B (structure (b) ) .
208. The compound according to claim 207, wherein said C1-C6 aliphatic is C1-C4 straight or branched alkylidene .
209. The compound according to claim 208, wherein said alkylidene is selected from -CH2-, -CH(Me)-, -C(Me)2- , -CH(Et)-, -C(Et)2-, or -CH2-CH (Me) - .
210. The compound according to claim 202, wherein B is selected from optionally substituted phenyl, or C3-C8 cycloaliphatic .
211. The compound according to claim 210, wherein B is phenyl or C3-C8 cycloalkyl optionally substituted with up to two substituents selected from R1, R2, or phenyl optionally substituted with up to two substituents selected from R1 or R2.
212. The compound according to claim 202, wherein B is selected from optionally substituted C3-C8 cycloalkyl, phenyl, piperidyl, or pyrrolidinyl.
213. The compound according to claim 212, wherein B is phenyl, cyclopentyl, cyclohexyl, or piperidyl, optionally substituted with up to two R1 or R2 substituents .
214. The compound according to claim 202, wherein ring C is phenyl optionally substituted with up to two R1.
215. The compound according to claim 202, wherein ring C is cyclohexenyl optionally substituted with up to two R1.
216. The method according to claim 1, wherein said ABC-transporter or a fragment thereof is in vivo .
217. The method according to claim 1, wherein said ABC-transporter or a fragment thereof is in vi tro .
218. The method according to claim 1, wherein said ABC-transporter is CFTR.
219. A method of treating an ABC transporter mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to any one of claims 1-104, or a compound according to any one of claims 105-215.
220. The method according to claim 219, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation- cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI) , neurophyseal DI , Neprogenic DI , Charcot-Marie Tooth syndrome, Perlizaeus- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect) , Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease.
221. The method according to claim 220, wherein said disease is cystic fibrosis.
222. A method of modulating activity of an anion channel in vi tro ox in vivo, comprising the step of contacting said channel with a compound according to any one of claims 1-104, or a compound according to any one of claims 105-215.
223. The method according to claim 222, wherein said anion channel is a chloride channel or a bicarbonate channel .
224. The method according to claim 223, wherein said anion channel is a chloride channel.
225. A method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to any one of claims 1-104, or a compound according to any one of claims 105-220.
226. The method according to claim 225, wherein said disease is cystic fibrosis.
227. A pharmaceutical composition comprising a compound according to any one of claims 104-215, and a pharmaceutically acceptable carrier.
228. A pharmaceutical composition comprising: (i) a compound according to any one of claims
105-215; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator, or a nutritional agent.
229. A kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: (i) a composition comprising a compound according to any one of claims 105-215; and (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof .
230. The kit according to claim 229, wherein said ABC transporter is CFTR.
PCT/US2004/029206 2003-09-06 2004-09-07 Modulators of atp-binding cassette transporters WO2005026137A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU2004272599A AU2004272599A1 (en) 2003-09-06 2004-09-07 Modulators of ATP-binding cassette transporters
EP04783449A EP1664006A2 (en) 2003-09-06 2004-09-07 Modulators of atp-binding cassette transporters
JP2006525534A JP2007504255A (en) 2003-09-06 2004-09-07 Regulators of ATP-binding cassette transporters
CA002537841A CA2537841A1 (en) 2003-09-06 2004-09-07 Modulators of atp-binding cassette transporters
MXPA06002567A MXPA06002567A (en) 2003-09-06 2004-09-07 Modulators of atp-binding cassette transporters.
IL174128A IL174128A0 (en) 2003-09-06 2006-03-06 Heterocyclic compounds and pharmaceutical compositions containing the same
NO20061543A NO20061543L (en) 2003-09-06 2006-04-05 Modulators of ATPBinding Cassette Transportm
US13/174,844 US8431605B2 (en) 2003-09-06 2011-07-01 Modulators of ATP-binding cassette transporters

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50044403P 2003-09-06 2003-09-06
US60/500,444 2003-09-06

Publications (2)

Publication Number Publication Date
WO2005026137A2 true WO2005026137A2 (en) 2005-03-24
WO2005026137A3 WO2005026137A3 (en) 2005-07-21

Family

ID=34312193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/029206 WO2005026137A2 (en) 2003-09-06 2004-09-07 Modulators of atp-binding cassette transporters

Country Status (13)

Country Link
US (6) US7973169B2 (en)
EP (1) EP1664006A2 (en)
JP (1) JP2007504255A (en)
KR (1) KR20060088537A (en)
CN (1) CN1898221A (en)
AU (1) AU2004272599A1 (en)
CA (1) CA2537841A1 (en)
IL (1) IL174128A0 (en)
MX (1) MXPA06002567A (en)
NO (1) NO20061543L (en)
RU (1) RU2006111093A (en)
WO (1) WO2005026137A2 (en)
ZA (1) ZA200602755B (en)

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095367A1 (en) * 2004-04-01 2005-10-13 Pfizer Products Inc. Thiazole-amine compounds for the treatment of neurodegenerative disorders
EP1700856A1 (en) * 2003-12-26 2006-09-13 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivative
WO2008050600A1 (en) * 2006-10-25 2008-05-02 Neugen Pharma Inc. Therapeutic or preventive agent for intractable disease based on oxidative stress-mediated cell death as molecular background
WO2008090382A1 (en) * 2007-01-25 2008-07-31 The University Of Sheffield Thiazole and oxazole derivatives for use in the treatment of prion diseases, cancer and conditions of the central nervous system as well as in the regulation of stem cells
EP1976839A2 (en) * 2006-01-26 2008-10-08 Foldrx Pharmaceuticals, Inc. Compounds and methods for modulating protein trafficking
JP2008542279A (en) * 2005-05-24 2008-11-27 バーテックス ファーマシューティカルズ インコーポレイテッド ATP-binding cassette transporter modulator
EP2042494A1 (en) * 2006-06-27 2009-04-01 Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. 2,4,5-trisubstituted thiazole compounds,preparation methods, pharmaceutical compositions and medical uses thereof
JP2009522277A (en) * 2005-12-28 2009-06-11 バーテックス ファーマシューティカルズ インコーポレイテッド 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (phenyl) cyclopropane-carboxamide derivatives and related as modulators of ATP binding cassette transporters for the treatment of cystic fibrosis Compound
WO2009150137A2 (en) 2008-06-10 2009-12-17 Novartis Ag Organic compounds
WO2010115556A1 (en) * 2009-03-31 2010-10-14 Universiteit Leiden Compounds and uses
EP2300004A2 (en) * 2008-05-15 2011-03-30 Duke University Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
WO2011050325A1 (en) 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
EP2332933A1 (en) 2007-05-07 2011-06-15 Novartis AG Epithelial sodium channel (ENaC) inhibitors
WO2011076732A1 (en) * 2009-12-21 2011-06-30 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating gastrointestinal disorders
WO2011076734A1 (en) * 2009-12-21 2011-06-30 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases
WO2012014699A1 (en) * 2010-07-28 2012-02-02 湧永製薬株式会社 Therapeutic agent for neurological diseases
WO2012026565A1 (en) 2010-08-27 2012-03-01 帝人ファーマ株式会社 Method for producing phenyl-substituted heterocyclic derivative by means of coupling method using a palladium compound
WO2012035158A1 (en) 2010-09-17 2012-03-22 Novartis Ag Pyrazine derivatives as enac blockers
EP2444120A1 (en) 2007-12-10 2012-04-25 Novartis AG Spirocyclic amiloride analogues as ENac blockers
US8227462B2 (en) 2008-09-10 2012-07-24 Novartis Ag Pyrrolidine-1,2-dicarboxamide derivatives
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
US8357707B2 (en) 2009-07-02 2013-01-22 Novartis Ag 2-carboxamide cycloamino ureas
EP2547676A2 (en) * 2010-03-17 2013-01-23 Taivex Therapeutics Inc. Modulators of hec1 activity and methods therefor
RU2476429C2 (en) * 2007-07-31 2013-02-27 Сионоги Энд Ко., Лтд. Pharmaceutical composition containing optically active compound possessing activity of thrombopoietin receptor agonist, and intermediate compound therefor
WO2013033037A2 (en) * 2011-08-26 2013-03-07 The Regents Of The University Of California Novel antiprion compounds
US8404684B2 (en) 2003-05-02 2013-03-26 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
WO2013140319A1 (en) 2012-03-19 2013-09-26 Novartis Ag Crystalline form of a succinate salt
EP2754658A1 (en) 2009-02-27 2014-07-16 Teijin Pharma Limited Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst
WO2014114825A1 (en) 2013-01-22 2014-07-31 Consejo Superior De Investigaciones Científicas (Csic) Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
US8940771B2 (en) 2007-12-20 2015-01-27 Novartis Ag Organic compounds
US8999983B2 (en) 2011-11-29 2015-04-07 Taivex Therapeutics Corporation Modulators of Hec1 activity and methods therefor
US9156775B2 (en) 2010-11-12 2015-10-13 Duke University Substituted 1,3-thiazoles as heat shock transcription factor 1 activators
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
WO2017178174A1 (en) * 2016-04-11 2017-10-19 Genfit Methods of treatment of cholestasis and fibrosis
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9976183B2 (en) 2011-11-21 2018-05-22 Taivex Therapeutics Corporation Biomarkers for cancers responsive to modulators of HEC1 activity
US10058546B2 (en) 2012-07-16 2018-08-28 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10117855B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10231954B2 (en) 2014-02-04 2019-03-19 Lytix Biopharma As Neurodegenerative therapies
US10239867B2 (en) 2006-04-07 2019-03-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
WO2019241376A1 (en) * 2018-06-14 2019-12-19 The Trustees Of Columbia University In The City Of New York Treatment of cognitive disorders using nitazoxanide (ntz), nitazoxanide (ntz) analogs, and metabolites thereof
US10626111B2 (en) 2004-01-30 2020-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
CN112312913A (en) * 2018-03-23 2021-02-02 优曼尼蒂治疗公司 Compounds and uses thereof
US10987348B2 (en) 2006-04-07 2021-04-27 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11071736B2 (en) 2011-11-21 2021-07-27 Taivex Therapeutics Corporation Modulators of HEC1 activity and methods therefor
GB2615307A (en) * 2022-01-28 2023-08-09 Adorx Therapeutics Ltd Antagonist compounds
EP4342467A1 (en) * 2022-09-20 2024-03-27 Masarykova Univerzita Ku inhibitors for use in tumor therapy
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
UA80295C2 (en) 2002-09-06 2007-09-10 Biogen Inc Pyrazolopyridines and using the same
CA2537841A1 (en) 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
ES2328824T3 (en) * 2003-11-14 2009-11-18 Vertex Pharmaceuticals Incorporated USEFUL TIAZOLS AND OXAZOLES AS MODULATORS OF CONNECTORS OF CASETE TYPE FROM UNION TO ATP.
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
BR122018075478B8 (en) 2004-06-24 2023-10-31 Vertex Pharma atp link cassette carrier modulators
JP2008521864A (en) * 2004-12-03 2008-06-26 トランステック・ファーマ、インコーポレイテッド Heteroaromatic glucokinase activator
WO2007021982A2 (en) 2005-08-11 2007-02-22 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US7671221B2 (en) * 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
HUE049976T2 (en) 2005-12-28 2020-11-30 Vertex Pharma Pharmaceutical compositions of the amorphous form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
EA200801716A1 (en) * 2006-01-18 2009-04-28 Амген Инк. THIAZOLE COMPOUNDS AND THEIR APPLICATION
WO2007087427A2 (en) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8211925B2 (en) * 2006-04-28 2012-07-03 Transtech Pharma, Inc. Benzamide glucokinase activators
US8563573B2 (en) * 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
AU2008276521B2 (en) 2007-07-17 2011-11-03 Amgen Inc. Heterocyclic modulators of PKB
CA2693473A1 (en) * 2007-07-17 2009-01-22 Amgen Inc. Thiadiazole modulators of pkb
HUE028426T2 (en) 2007-08-24 2016-12-28 Vertex Pharma Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
DK2217572T3 (en) 2007-11-16 2014-02-03 Vertex Pharma Isoquinolines as modulators of ATP binding cassette transporters
US20100036130A1 (en) * 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
BRPI0820681A2 (en) * 2007-12-07 2019-09-24 Vertex Pharma 3- (6- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylperidin-2-yl) benzoic acid formulations
NZ588006A (en) * 2008-03-31 2012-08-31 Vertex Pharma Pyridine derivatives as CFTR modulators, in particular N-(6-(benzylamino)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide
CA2736545A1 (en) 2008-09-29 2010-04-01 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
BRPI0919930A2 (en) * 2008-10-23 2016-02-16 Vertex Pharma cystic fibrosis transmembrane conductance regulator modulators
UA104876C2 (en) * 2008-11-06 2014-03-25 Вертекс Фармасьютікалз Інкорпорейтед Modulators of atp-binding cassette transporters
EP2408750B1 (en) 2009-03-20 2015-08-26 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
CN102803237B (en) * 2009-06-12 2014-09-24 埃科特莱茵药品有限公司 Oxazole and thiazole derivatives as alx receptor agonists
BR112012026257A2 (en) 2010-04-07 2017-03-14 Vertex Pharma solid forms of 3- (6- (1- (2-, 2-difluorbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
KR101367568B1 (en) * 2011-05-31 2014-02-27 임우석 Modulation of abnormal protein in neurodegenerative disease by controlling ATP-binding cassette transporter
US20140155419A1 (en) * 2011-07-29 2014-06-05 Erkan Baloglu Compounds and methods
DE102011083271A1 (en) * 2011-09-23 2013-03-28 Beiersdorf Ag Aromatic amidothiazoles, their cosmetic or dermatological use and cosmetic or dermatological preparations containing such aromatic amidothiazoles
DE102011083283A1 (en) * 2011-09-23 2013-03-28 Beiersdorf Ag Heteroalkylamidothiazoles, their cosmetic or dermatological use and cosmetic or dermatological preparations containing such Heteroalkylamidothiazolen
SI2776427T1 (en) 2011-11-08 2017-05-31 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
JP2015511583A (en) 2012-02-27 2015-04-20 バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated Pharmaceutical composition and its administration
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
ES2702288T3 (en) 2014-10-07 2019-02-28 Vertex Pharma Co-crystals of transmembrane conductance regulator modulators of cystic fibrosis
EP3932914A1 (en) 2015-03-13 2022-01-05 Valo Health, Inc. Alpha-cinnamide compounds and compositions as hdac8 inhibitors
US10947207B2 (en) 2016-08-05 2021-03-16 The Regents Of The University Of California GP130 modulators
EP3534899B1 (en) 2016-11-03 2022-06-01 Corvus Pharmaceuticals, Inc. Compounds and methods for modulating interleukin-2-inducible t-cell kinase
JP2022554389A (en) * 2019-11-05 2022-12-28 デルミラ インコーポレイテッド MrgprX2 antagonists for treating inflammatory disorders
CN114874155B (en) * 2022-05-10 2024-02-06 华南理工大学 Benzyl thiazole amine compound, preparation method and anti-tumor application thereof
CN116621794A (en) * 2023-05-22 2023-08-22 上海大学 5-benzyl-2-amino-1, 3-thiazole derivative and synthetic method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022846A1 (en) * 1993-03-30 1994-10-13 Pfizer Inc. Compounds enhancing antitumor activity of other cytotoxic agents
US5622953A (en) * 1993-03-29 1997-04-22 Basf Aktiengesellschaft 1-amino-3-phenoxy propane derivatives as modulator agents and their applications
WO2001046199A1 (en) * 1999-12-22 2001-06-28 Eli Lilly And Company Methods and compounds for inhibiting mrp1

Family Cites Families (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4129742A1 (en) 1991-09-06 1993-03-11 Bayer Ag HETEROCYCLICALLY SUBSTITUTED CHINOLYLMETHOXY-PHENYLACETAMIDE
GB9823871D0 (en) * 1998-10-30 1998-12-23 Pharmacia & Upjohn Spa 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents
TW593241B (en) * 1999-04-20 2004-06-21 Hoffmann La Roche Carbamic acid derivatives
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
DE60332475D1 (en) 2002-10-30 2010-06-17 Vertex Pharma COMPOSITIONS USED FOR THE INHIBITION OF ROCK AND OTHER KINASES
US20050113423A1 (en) 2003-03-12 2005-05-26 Vangoor Frederick F. Modulators of ATP-binding cassette transporters
DE602004022819D1 (en) 2003-06-06 2009-10-08 Vertex Pharma TRANSPORTER OF ATP-BINDING CASSETTE
CA2537841A1 (en) 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
RU2006115602A (en) 2003-10-08 2007-11-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) ATF-BINDING CASSETTE CARRIER MODULATORS
ES2328824T3 (en) 2003-11-14 2009-11-18 Vertex Pharmaceuticals Incorporated USEFUL TIAZOLS AND OXAZOLES AS MODULATORS OF CONNECTORS OF CASETE TYPE FROM UNION TO ATP.
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
EP3219709B1 (en) 2004-01-30 2020-03-18 Vertex Pharmaceuticals Incorporated Intermediate compound of modulators of atp-binding cassette transporters
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
BR122018075478B8 (en) 2004-06-24 2023-10-31 Vertex Pharma atp link cassette carrier modulators
WO2006099256A2 (en) 2005-03-11 2006-09-21 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
CN101223146A (en) 2005-05-24 2008-07-16 沃泰克斯药物股份有限公司 Modulators of ATP-binding cassette transporters
WO2007021982A2 (en) 2005-08-11 2007-02-22 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CA2624683A1 (en) 2005-10-06 2007-04-19 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US20120232059A1 (en) 2005-11-08 2012-09-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette Transporters
EP3208272B1 (en) 2005-11-08 2020-01-08 Vertex Pharmaceuticals Incorporated Heterocyclic modulators of atp-binding cassette transporters
EP1979367A2 (en) 2005-12-24 2008-10-15 Vertex Pharmaceuticals Incorporated Quinolin-4-one derivatives as modulators of abc transporters
CA2635214A1 (en) 2005-12-27 2007-07-05 Vertex Pharmaceuticals Incorporated Compounds useful in cftr assays and methods therewith
CA2856037C (en) 2005-12-28 2017-03-07 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
HUE049976T2 (en) 2005-12-28 2020-11-30 Vertex Pharma Pharmaceutical compositions of the amorphous form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US7671221B2 (en) 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
EP3882245A1 (en) 2006-04-07 2021-09-22 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
US7645789B2 (en) 2006-04-07 2010-01-12 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators
WO2007134279A2 (en) 2006-05-12 2007-11-22 Vertex Pharmaceuticals Incorporated Compositions of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US7754739B2 (en) 2007-05-09 2010-07-13 Vertex Pharmaceuticals Incorporated Modulators of CFTR
EP2170901B1 (en) 2007-05-25 2015-07-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2009023509A2 (en) 2007-08-09 2009-02-19 Vertex Pharmaceuticals Incorporated Therapeutic combinations useful in treating cftr related diseases
HUE028426T2 (en) 2007-08-24 2016-12-28 Vertex Pharma Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
RU2010114732A (en) 2007-09-14 2011-10-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) SOLID FORMS OF N- [2,4-BIS (1,1-DIMETHYLETHYL) -5-HYDROXYPHENYL] -1,4-DIHYDRO-4-OXOCHINOLIN-3-CARBOXAMIDE
ES2445442T3 (en) 2007-09-14 2014-03-03 Vertex Pharmaceuticals Inc. Modulators of cystic fibrosis transmembrane conductance regulator
DK2217572T3 (en) 2007-11-16 2014-02-03 Vertex Pharma Isoquinolines as modulators of ATP binding cassette transporters
ES2604178T3 (en) 2007-12-07 2017-03-03 Vertex Pharmaceuticals Incorporated Process for producing cycloalkylcarboxyamido-pyridinebenzoic acids
BRPI0820681A2 (en) 2007-12-07 2019-09-24 Vertex Pharma 3- (6- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylperidin-2-yl) benzoic acid formulations
US20100036130A1 (en) 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
EA201070698A1 (en) 2007-12-07 2011-02-28 Вертекс Фармасьютикалз Инкорпорейтед SOLID FORMS OF 3- (6- (1- (2,2-DIFTLOROXENO [D] [1,3] -DIOXOL-5-IL) CYCLOPROPANKARAROXAMIDO) -3-METHYLPYRIDIN-2-IL) Benzoic Acid
CN101925603B (en) 2007-12-13 2013-12-04 沃泰克斯药物股份有限公司 Modulators of cystic fibrosis transmembrane conductance regulator
NZ736561A (en) 2008-02-28 2018-02-23 Vertex Pharma Heteroaryl derivatives as cftr modulators
US8216666B2 (en) 2008-02-29 2012-07-10 The Procter & Gamble Company Substrates having improved crockfastness
NZ588006A (en) 2008-03-31 2012-08-31 Vertex Pharma Pyridine derivatives as CFTR modulators, in particular N-(6-(benzylamino)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide
WO2010019239A2 (en) 2008-08-13 2010-02-18 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US20100256184A1 (en) 2008-08-13 2010-10-07 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
CA2736545A1 (en) 2008-09-29 2010-04-01 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
AU2009308232B2 (en) 2008-10-23 2016-02-04 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20110257223A1 (en) 2008-10-23 2011-10-20 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance Regulator
PL2358680T3 (en) 2008-10-23 2013-08-30 Vertex Pharma Solid forms of n-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide
BRPI0919930A2 (en) 2008-10-23 2016-02-16 Vertex Pharma cystic fibrosis transmembrane conductance regulator modulators
WO2010078103A1 (en) 2008-12-30 2010-07-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP2408750B1 (en) 2009-03-20 2015-08-26 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
DK2408749T3 (en) 2009-03-20 2018-08-13 Vertex Pharma CYSTIC FIBROSE TRANSMEMBRAN CONDUCTOR CONTROLLER MODULATORS
EP2477991B1 (en) 2009-09-17 2015-04-15 Vertex Pharmaceuticals Incorporated Process for preparing azabicyclic compounds
MX2012004792A (en) 2009-10-22 2013-02-01 Vertex Pharma Compositions for treatment of cystic fibrosis and other chronic diseases.
US8389727B2 (en) 2009-10-23 2013-03-05 Vertex Pharmaceuticals Incorporated Solid forms of N-(4-(7-Azabicyclo[2.2.1]Heptan-7-yl)-2-Trifluoromethyl)Phenyl)-4-Oxo-5-(Trifluoromethyl)-1,4-Dihydroquinoline-3-Carboxamide
NZ600172A (en) 2009-10-23 2014-07-25 Vertex Pharma Process for preparing modulators of cystic fibrosis transmembrane conductance regulator
AU2011227021A1 (en) 2010-03-19 2012-10-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
ES2845449T3 (en) 2010-03-25 2021-07-26 Vertex Pharma Solid amorphous dispersion of (R) -1 (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro-2 (1-hydroxy-2-methylpropan-2-yl) -1h-indol-5yl) -cyclopropanecarboxamide
BR112012026257A2 (en) 2010-04-07 2017-03-14 Vertex Pharma solid forms of 3- (6- (1- (2-, 2-difluorbenzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid
JP2013523833A (en) 2010-04-07 2013-06-17 バーテックス ファーマシューティカルズ インコーポレイテッド 3- (6- (1- (2,2-difluorobenzo [D] [1,3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid pharmaceutical composition and Its administration
NZ603042A (en) 2010-04-22 2015-02-27 Vertex Pharma Pharmaceutical compositions comprising cftr modulators and administrations thereof
WO2011133751A2 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
WO2011133953A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
CA2796646A1 (en) 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
CA2798412A1 (en) 2010-05-20 2011-11-24 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
AR081920A1 (en) 2010-05-20 2012-10-31 Vertex Pharma PRODUCTION PROCESSES OF TRANSMEMBRANE CHEMICAL FIBROSIS DRIVER REGULATOR MODULATORS
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
JP2013536231A (en) 2010-08-23 2013-09-19 バーテックス ファーマシューティカルズ インコーポレイテッド (R) -1- (2,2-difluorobenzo [D] [1,3] dioxol-5-yl) -N- (1- (2,3-dihydroxypropyl) -6-fluoro-2- (1 -Hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide and its administration
BR112013004130A2 (en) 2010-08-27 2016-07-05 Vertex Pharma pharmaceutical composition and administrations thereof
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
SI2776427T1 (en) 2011-11-08 2017-05-31 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
SG10201606135TA (en) 2012-01-25 2016-09-29 Vertex Pharma Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
JP2015511583A (en) 2012-02-27 2015-04-20 バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated Pharmaceutical composition and its administration
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
WO2013185112A1 (en) 2012-06-08 2013-12-12 Vertex Pharmaceuticals Incorporated Pharmaceuticl compositions for the treatment of cftr -mediated disorders
CA2878057A1 (en) 2012-07-16 2014-01-23 Rossitza Gueorguieva Alargova Pharmaceutical compositions of (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide and administration thereof
HRP20181740T4 (en) 2012-11-02 2024-01-05 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cftr mediated diseases
US20140221424A1 (en) 2013-01-30 2014-08-07 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for use in the treatment of cystic fibrosis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5622953A (en) * 1993-03-29 1997-04-22 Basf Aktiengesellschaft 1-amino-3-phenoxy propane derivatives as modulator agents and their applications
WO1994022846A1 (en) * 1993-03-30 1994-10-13 Pfizer Inc. Compounds enhancing antitumor activity of other cytotoxic agents
WO2001046199A1 (en) * 1999-12-22 2001-06-28 Eli Lilly And Company Methods and compounds for inhibiting mrp1

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315345 Database accession no. 2004:2168428 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315346 Database accession no. 2004:2165307 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315347 Database accession no. 2004:129998 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315348 retrieved from 2004:129995 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315349 Database accession no. 2003:2436529 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315350 Database accession no. 2003:2409317 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315351 retrieved from 203:2408779 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315352 Database accession no. 2003:2405436 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315353 retrieved from 2003:2404671 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315354 Database accession no. 2003:2392971 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315355 Database accession no. 2003:2390037 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315356 Database accession no. 2003:2261323 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315357 Database accession no. 2003:2188914 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315358 Database accession no. 2003:2188913 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315359 Database accession no. 2003:2129249 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315360 Database accession no. 2001:2447116 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315361 Database accession no. 2003:3205177 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315362 Database accession no. 2003:3203968 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315363 Database accession no. 2003:2432307 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315364 Database accession no. 2003:2422797 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315365 Database accession no. 2003:2422757 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315366 Database accession no. 2003:2402881 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315367 Database accession no. 2003:2399932 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315368 Database accession no. 2003:2369458 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002315369 Database accession no. 2003:2227674 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316943 Database accession no. 2003:2219078 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316944 Database accession no. 2003:2104943 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316945 Database accession no. 2001:1582533 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316946 Database accession no. 2001:1582532 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316947 Database accession no. 2001:958580 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316948 Database accession no. 2001540788 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316949 Database accession no. 2001496267 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316950 Database accession no. 2001:126000 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316951 Database accession no. 2001:124564 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316952 Database accession no. 2001:25507 *
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002316953 Database accession no. 2000:928510 *
See also references of EP1664006A2 *

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8404684B2 (en) 2003-05-02 2013-03-26 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
AU2004309279B2 (en) * 2003-12-26 2010-07-15 Kyowa Kirin Co., Ltd. Thiazole derivative
EP1700856A4 (en) * 2003-12-26 2009-06-24 Kyowa Hakko Kirin Co Ltd Thiazole derivative
EP1700856A1 (en) * 2003-12-26 2006-09-13 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivative
NO338017B1 (en) * 2003-12-26 2016-07-18 Kyowa Hakko Kirin Co Ltd Thiazole derivatives, pharmaceutical compositions containing them, and their use
US10626111B2 (en) 2004-01-30 2020-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7384968B2 (en) 2004-04-01 2008-06-10 Pfizer Inc. Thiazole-amine compounds for the treatment of neurodegenerative disorders
WO2005095367A1 (en) * 2004-04-01 2005-10-13 Pfizer Products Inc. Thiazole-amine compounds for the treatment of neurodegenerative disorders
JP2008542279A (en) * 2005-05-24 2008-11-27 バーテックス ファーマシューティカルズ インコーポレイテッド ATP-binding cassette transporter modulator
JP2013010800A (en) * 2005-05-24 2013-01-17 Vertex Pharmaceuticals Inc Modulator of atp-binding cassette transporter
US11084804B2 (en) 2005-11-08 2021-08-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
JP2009522277A (en) * 2005-12-28 2009-06-11 バーテックス ファーマシューティカルズ インコーポレイテッド 1- (Benzo [d] [1,3] dioxol-5-yl) -N- (phenyl) cyclopropane-carboxamide derivatives and related as modulators of ATP binding cassette transporters for the treatment of cystic fibrosis Compound
JP2013056908A (en) * 2005-12-28 2013-03-28 Vertex Pharmaceuticals Inc 1-(BENZO [d] [1,3] DIOXOL-5-YL) -N- (PHENYL) CYCLOPROPANE- CARBOXAMIDE DERIVATIVE AND RELATED COMPOUND AS MODULATOR OF ATP-BINDING CASSETTE TRANSPORTER FOR TREATMENT OF CYSTIC FIBROSIS
EP1976839A2 (en) * 2006-01-26 2008-10-08 Foldrx Pharmaceuticals, Inc. Compounds and methods for modulating protein trafficking
EP1976839A4 (en) * 2006-01-26 2011-06-15 Foldrx Pharmaceuticals Inc Compounds and methods for modulating protein trafficking
US10239867B2 (en) 2006-04-07 2019-03-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11639347B2 (en) 2006-04-07 2023-05-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10987348B2 (en) 2006-04-07 2021-04-27 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10975061B2 (en) 2006-04-07 2021-04-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
EP2042494A4 (en) * 2006-06-27 2011-06-29 Inst Pharm & Toxicology Amms 2,4,5-trisubstituted thiazole compounds,preparation methods, pharmaceutical compositions and medical uses thereof
US8053581B2 (en) * 2006-06-27 2011-11-08 Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.C. China Trisubstituted thiazole compounds, preparations methods, pharmaceutical compositions and medicals uses thereof
JP2009541367A (en) * 2006-06-27 2009-11-26 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシス ピーエルエイ 2,4,5-Trisubstituted thiazole compounds, pharmaceutical compositions containing them, and their preparation and medical use
EP2042494A1 (en) * 2006-06-27 2009-04-01 Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. 2,4,5-trisubstituted thiazole compounds,preparation methods, pharmaceutical compositions and medical uses thereof
WO2008050600A1 (en) * 2006-10-25 2008-05-02 Neugen Pharma Inc. Therapeutic or preventive agent for intractable disease based on oxidative stress-mediated cell death as molecular background
WO2008090382A1 (en) * 2007-01-25 2008-07-31 The University Of Sheffield Thiazole and oxazole derivatives for use in the treatment of prion diseases, cancer and conditions of the central nervous system as well as in the regulation of stem cells
EP2332933A1 (en) 2007-05-07 2011-06-15 Novartis AG Epithelial sodium channel (ENaC) inhibitors
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
RU2476429C2 (en) * 2007-07-31 2013-02-27 Сионоги Энд Ко., Лтд. Pharmaceutical composition containing optically active compound possessing activity of thrombopoietin receptor agonist, and intermediate compound therefor
US10597384B2 (en) 2007-12-07 2020-03-24 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US12065432B2 (en) 2007-12-07 2024-08-20 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
EP2444120A1 (en) 2007-12-10 2012-04-25 Novartis AG Spirocyclic amiloride analogues as ENac blockers
EP2520574A1 (en) 2007-12-10 2012-11-07 Novartis AG Amiloride analogues substituted on the cyclic guanidine moiety as ENaC blockers for treating respiratory diseases
US8940771B2 (en) 2007-12-20 2015-01-27 Novartis Ag Organic compounds
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9718784B2 (en) 2008-05-15 2017-08-01 Duke University Substituted pyrazoles as heat shock transcription factor activators
EP2300004A4 (en) * 2008-05-15 2012-05-30 Univ Duke Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
EP2300004A2 (en) * 2008-05-15 2011-03-30 Duke University Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
US9315449B2 (en) 2008-05-15 2016-04-19 Duke University Substituted pyrazoles as heat shock transcription factor activators
WO2009150137A2 (en) 2008-06-10 2009-12-17 Novartis Ag Organic compounds
US8476268B2 (en) 2008-09-10 2013-07-02 Novartis Ag Pyrrolidine-1,2-dicarboxamide derivatives
US8710085B2 (en) 2008-09-10 2014-04-29 Novartis Ag Pyrrolidine-1,2-dicarboxamide derivatives
US8227462B2 (en) 2008-09-10 2012-07-24 Novartis Ag Pyrrolidine-1,2-dicarboxamide derivatives
EP2754658A1 (en) 2009-02-27 2014-07-16 Teijin Pharma Limited Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst
WO2010115556A1 (en) * 2009-03-31 2010-10-14 Universiteit Leiden Compounds and uses
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
US8357707B2 (en) 2009-07-02 2013-01-22 Novartis Ag 2-carboxamide cycloamino ureas
WO2011050325A1 (en) 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
EP2813227A1 (en) 2009-10-22 2014-12-17 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
WO2011076732A1 (en) * 2009-12-21 2011-06-30 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating gastrointestinal disorders
WO2011076734A1 (en) * 2009-12-21 2011-06-30 Euroscreen S.A. Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases
EP2547676A2 (en) * 2010-03-17 2013-01-23 Taivex Therapeutics Inc. Modulators of hec1 activity and methods therefor
US9409902B2 (en) 2010-03-17 2016-08-09 Taivex Therapeutics Corporation Modulators of HEC1 activity and methods therefor
AU2011227398C1 (en) * 2010-03-17 2014-11-27 Taivex Therapeutics Corporation Modulators of Hec1 activity and methods therefor
KR101609856B1 (en) * 2010-03-17 2016-04-07 타이벡스 세라피틱스 코포레이션 Modulators of hec1 activity and methods therefor
CN103038231A (en) * 2010-03-17 2013-04-10 台维克斯医疗公司 Modulators of HEC1 activity and methods therefor
CN103038231B (en) * 2010-03-17 2016-04-20 泰纬生命科技股份有限公司 HEC1 active regulator and method thereof
AU2014210678B2 (en) * 2010-03-17 2015-08-20 Taivex Therapeutics Corporation Modulators of hec1 activity and methods therefor
EP2547676A4 (en) * 2010-03-17 2013-08-14 Taivex Therapeutics Inc Modulators of hec1 activity and methods therefor
AU2011227398B2 (en) * 2010-03-17 2014-06-12 Taivex Therapeutics Corporation Modulators of Hec1 activity and methods therefor
US8946268B2 (en) 2010-03-17 2015-02-03 Taivex Therapeutics, Inc. Modulators of HEC1 activity and methods therefor
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10906891B2 (en) 2010-03-25 2021-02-02 Vertex Pharmaceuticals Incoporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US11578062B2 (en) 2010-03-25 2023-02-14 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US11052075B2 (en) 2010-04-07 2021-07-06 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
JP5782032B2 (en) * 2010-07-28 2015-09-24 株式会社ニュージェン・ファーマ Drugs for neurological diseases
WO2012014699A1 (en) * 2010-07-28 2012-02-02 湧永製薬株式会社 Therapeutic agent for neurological diseases
US8975411B2 (en) 2010-07-28 2015-03-10 Neugen Pharma Inc. Therapeutic agent for neurological diseases
WO2012026565A1 (en) 2010-08-27 2012-03-01 帝人ファーマ株式会社 Method for producing phenyl-substituted heterocyclic derivative by means of coupling method using a palladium compound
WO2012035158A1 (en) 2010-09-17 2012-03-22 Novartis Ag Pyrazine derivatives as enac blockers
US9447058B2 (en) 2010-11-12 2016-09-20 Duke University Substituted 1,3-thiazoles as heat shock transcription factor 1 activators
US9717709B2 (en) 2010-11-12 2017-08-01 Duke University Substituted pyrazoles as heat shock transcription factor activators
US9156775B2 (en) 2010-11-12 2015-10-13 Duke University Substituted 1,3-thiazoles as heat shock transcription factor 1 activators
WO2013033037A2 (en) * 2011-08-26 2013-03-07 The Regents Of The University Of California Novel antiprion compounds
WO2013033037A3 (en) * 2011-08-26 2013-06-06 The Regents Of The University Of California Novel antiprion compounds
US9976183B2 (en) 2011-11-21 2018-05-22 Taivex Therapeutics Corporation Biomarkers for cancers responsive to modulators of HEC1 activity
US11071736B2 (en) 2011-11-21 2021-07-27 Taivex Therapeutics Corporation Modulators of HEC1 activity and methods therefor
US8999983B2 (en) 2011-11-29 2015-04-07 Taivex Therapeutics Corporation Modulators of Hec1 activity and methods therefor
WO2013140319A1 (en) 2012-03-19 2013-09-26 Novartis Ag Crystalline form of a succinate salt
US10058546B2 (en) 2012-07-16 2018-08-28 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
US9592224B2 (en) 2013-01-22 2017-03-14 Donsejo Superior De Investigaciones Científicas (Csic) Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
EP3348550A1 (en) 2013-01-22 2018-07-18 Consejo Superior de Investigaciones Cientificas (CSIC) Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
WO2014114825A1 (en) 2013-01-22 2014-07-31 Consejo Superior De Investigaciones Científicas (Csic) Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10231954B2 (en) 2014-02-04 2019-03-19 Lytix Biopharma As Neurodegenerative therapies
US10980746B2 (en) 2014-04-15 2021-04-20 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US11951212B2 (en) 2014-04-15 2024-04-09 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
US10117855B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10130612B2 (en) 2016-04-11 2018-11-20 Genfit Methods of treatment for cholestatic and fibrotic diseases
US10130613B2 (en) 2016-04-11 2018-11-20 Genfit Methods of treatment for cholestatic and fibrotic diseases
WO2017178174A1 (en) * 2016-04-11 2017-10-19 Genfit Methods of treatment of cholestasis and fibrosis
US10117856B2 (en) 2016-04-11 2018-11-06 Genfit Methods of treatment for cholestatic and fibrotic diseases
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
CN112312913A (en) * 2018-03-23 2021-02-02 优曼尼蒂治疗公司 Compounds and uses thereof
CN112312913B (en) * 2018-03-23 2024-03-08 詹森药业有限公司 Compounds and uses thereof
WO2019241376A1 (en) * 2018-06-14 2019-12-19 The Trustees Of Columbia University In The City Of New York Treatment of cognitive disorders using nitazoxanide (ntz), nitazoxanide (ntz) analogs, and metabolites thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof
GB2615307A (en) * 2022-01-28 2023-08-09 Adorx Therapeutics Ltd Antagonist compounds
EP4342467A1 (en) * 2022-09-20 2024-03-27 Masarykova Univerzita Ku inhibitors for use in tumor therapy
WO2024061390A1 (en) * 2022-09-20 2024-03-28 Masarykova Univerzita Ku inhibitors for use in tumor therapy

Also Published As

Publication number Publication date
EP1664006A2 (en) 2006-06-07
CN1898221A (en) 2007-01-17
NO20061543L (en) 2006-06-06
IL174128A0 (en) 2006-08-01
US20130252333A1 (en) 2013-09-26
RU2006111093A (en) 2007-10-27
US20160228414A1 (en) 2016-08-11
US8431605B2 (en) 2013-04-30
KR20060088537A (en) 2006-08-04
US7973169B2 (en) 2011-07-05
US20150025076A1 (en) 2015-01-22
JP2007504255A (en) 2007-03-01
US8741939B2 (en) 2014-06-03
MXPA06002567A (en) 2006-09-04
US20050176789A1 (en) 2005-08-11
US9249131B2 (en) 2016-02-02
US20140072995A1 (en) 2014-03-13
US20120004216A1 (en) 2012-01-05
US8853415B2 (en) 2014-10-07
WO2005026137A3 (en) 2005-07-21
ZA200602755B (en) 2007-06-27
AU2004272599A1 (en) 2005-03-24
CA2537841A1 (en) 2005-03-24

Similar Documents

Publication Publication Date Title
US9249131B2 (en) Modulators of ATP-binding cassette transporters
EP1716122B1 (en) Modulators of atp-binding cassette transporters
EP1682127B1 (en) Thiazoles and oxazoles useful as modulators of atp-binding cassette transporters
US9550761B2 (en) Modulators of ATP-binding cassette transporters
US20130012536A1 (en) Modulators of atp-binding cassette transporters

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480031503.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BW BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE EG ES FI GB GD GE GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MK MN MW MX MZ NA NI NO NZ PG PH PL PT RO RU SC SD SE SG SK SY TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SZ TZ UG ZM ZW AM AZ BY KG MD RU TJ TM AT BE BG CH CY DE DK EE ES FI FR GB GR HU IE IT MC NL PL PT RO SE SI SK TR BF CF CG CI CM GA GN GQ GW ML MR SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2537841

Country of ref document: CA

Ref document number: 2006525534

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 174128

Country of ref document: IL

Ref document number: 1020067004627

Country of ref document: KR

Ref document number: PA/a/2006/002567

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2004272599

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 546080

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2004783449

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 850/KOLNP/2006

Country of ref document: IN

Ref document number: 2006111093

Country of ref document: RU

WWE Wipo information: entry into national phase

Ref document number: 2006/02755

Country of ref document: ZA

Ref document number: 200602755

Country of ref document: ZA

ENP Entry into the national phase

Ref document number: 2004272599

Country of ref document: AU

Date of ref document: 20040907

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004272599

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2004783449

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020067004627

Country of ref document: KR