Indian Patents. 262900:HETEROCYCLIC MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS

Title of Invention	HETEROCYCLIC MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
Abstract	Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

Full Text	HETEROCYCLIC MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS CROSS-REFERENCE TO RELATED APPLICATIONS [00100] The present application claims the benefit under 3 5 U.S .C. § 119 of United States Provisional Application No. 60/734,506, filed on November 8, 2005, United States Provisional Application No. 60/754,086, filed on December 27, 2005, and United States Provisional Application No. 60/802,458, filed on May 22, 2006, the entire contents of each of the above applications being incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [00101] The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance 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 [00102] ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. 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 multi-drug resistance proteins (like the MDR1-P glycoprotein, or the multi-drug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function. [00103] ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial. [00104] One member of the ABC transporter family commonly associated with disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking. [00105] The gene encoding 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 causes mutations in CFTR resulting in Cystic Fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic Fibrosis affects approximately one in every 2,500 infants 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 debilitating and fatal effects of CF, including chronic lung disease. [00106] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. 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. [00107] 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). To date, > 1000 disease causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease. [00108] The deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of AF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526- 528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to AF508-CFTR, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity. [00109] 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+/2C17K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell. [00110] 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 basoiateral 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+/2C17K+ 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. [00111] In addition to Cystic Fibrosis, 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 (COPD), dry eye disease, and Sjo"gren's Syndrome. [00112] 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 Sjogrens'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. Sjogrens'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. [0.0113] As discussed above, it is believed that the deletion of residue 508 in AF508-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)]. The diseases associated with the first class of ER malfunction are Cystic fibrosis (due to misfolded AF508-CFTR as discussed above), Hereditary emphysema (due to al-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 p- 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 hypoparathyroidism (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 al-Antitrypsin (PiZ variant), Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, n, IV procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACT deficiency (due to al-Antichymotrypsin), Diabetes insipidus (DI), Neurophyseal DI (due to Vasopvessin 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 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 (due to lysosomal cc-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect). [00114] In addition to up-regulation of CFTR activity, reducing anion secretion by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR. [00115] 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, impaired growth and death. [00116] 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: [00117] Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16 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. [00118] 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. [00119] The most common diarrhea 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 cryptosporidium, giardia lamblia, and salmonella, among others. [00120] 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. [00121] 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. [00122] There is a need for method of treating ABC transoter mediated diseases using such modulators of ABC transporter activity. [00123] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal. [00124] 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. [00125] There is a need for methods of treating CFTR-mediated diseases using such modulators of CFTR activity. [00126] There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal. SUMMARY OF THE INVENTION [00127] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity. These compounds have the general formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R3, R4, and n are described herein. [00128] These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, 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-Najjar type H, 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, amyotropnic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntingdon, 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, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS [00129] As used herein, the following definitions shall apply unless otherwise indicated. [00130] 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 vitro. 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. [00131] The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations). [00132] The term "modulating" as used herein means increasing or decreasing, e.g. activity, by a measurable amount. Compounds that modulate ABC Transporter activity, such as CFTR activity, by increasing the activity of the ABC Transporter, e.g., a CFTR anion channel, are called agonists. Compounds that modulate ABC Transporter activity, such as CFTR activity, by decreasing the activity of the ABC Transporter, e.g., CFTR anion channel, are called antagonists. An agonist interacts with an ABC Transporter, such as CFTR anion channel, to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with an ABC Transporter, such as CFTR, and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. [00133] The phrase "treating or reducing the severity of an ABC Transporter mediated disease" refers both to treatments for diseases that are directly caused by ABC Transporter and/or CFTR activities and alleviation of symptoms of diseases not directly caused by ABC Transporter and/or CFTR anion channel activities. Examples of diseases whose symptoms may be affected by ABC Transporter and/or CFTR activity include, but are not limited to, 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-Najjar 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 D1, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranudear 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, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. [00134] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [00135] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. [00136] As used herein the term "aliphatic' encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below. [00137] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphaticsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydfoxyalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkylsulfonylamino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, cyanoalkyl, or haloalkyl. [00138] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as halo, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, acyl [e.g., aliphaticcarbonyl, cycloaliphaticcarbonyl, arylcarbonyl, heterocycloaliphaticcarbonyl or heteroarylcarbonyl], amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g., alkylsulfonyl, cycloaliphaticsulfonyl, or arylsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. [00139] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphaticsulfonyl, aliphaticaminosulfonyl, or cycloaliphaticsulfonyl], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy. [00140] As used herein, an "amido" encompasses both "aminocarbonyl" and "carbonylamino". These terms when used alone or in connection with another group refers to an amido group such as N(RXRY)-C(O)- or RYC(O)-N(RX)- when used terminally and -C(O)- . N(RX)- or -N(RX)-C(O)- when used internally, wherein Rx and RY are defined below. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylcarbonylamino), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido. [00141] As used herein, an "amino" group refers to -NR R wherein each of R and RY is independently hydrogen, alkyl, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by - NRX-. Rx has the same meaning as defined above. [00142] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic ring systems include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more Co,. 8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaJiphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanylj; cyano; halo; hydroxy; mercapto, sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted. [00143] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,/n-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (allcyJcarbony2)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyi)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfony])aryl]; (alkylsulfony])aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl;((heterocycloaliphatic)carbony])aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-w-cyanoaryl; p-halo-»?-aminoaryl; or(m-(heterocycloaliphatic)-0-(alkyl))aryl. [00144] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., aC1-4 alkyl group) that is substituted with an aryi group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is benzyl. [00145] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C1-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00146] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9,10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls. [00147] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below. [00148] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di- enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl and arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00149] As used herein, "cyclic moiety" includes cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been defined previously. [00150] As used herein, the term "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkeny] group, each of which being optionally substituted as set forth below. [00151] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03>7]nonyl. A monocycbc heterocycloalkyl group can be fused with a phenyl moiety such as tetrahydroisoquinoline. A "heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10- membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicycloheteroaliphatics are numbered according to standard chemical nomenclature. [00152] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkyny.l], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycaibonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanylj, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00153] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolmyl, orisoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, IH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzol>}thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cirmolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl, or 1,8-naphthyridyl. [00154] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H- pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. [00155] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b]jfuryl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. [00156] A heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy, aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonylj; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonylj; sulfinyl [e.g., aliphaticsulfmyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be imsubstituted. [00157] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amitio)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryi]; (cyanoaikyl)heteroatyl; (alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)araino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl]. [00158] A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group. "Aliphatic," "alkyl," and "heteroaryl" have been defined above. [00159] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have been defined above. A heteroaralkyl is optionally substituted with one or more substitueuis such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylarnino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00160] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously. [00161] As used herein, an "acyl" group refers to a formyl group or RX-C(O)- (such as -alkyl-C(O)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have been defined previously. Acetyl andpivaloyl are examples of acyl groups. t [00162] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined. [00163] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously. [00164] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NRXRY or -NRX-CO-O-RZ wherein Rx and Ry have been defined above and Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. [00165] As used herein, a "carboxy" group refers to -COOH, -COORX, -OC(O)H, -OC(O)RX when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group. [00166] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1, 2, or 3 halogen. For instance, the term haloalkyl includes the group -CF3. [00167] As used herein, a "mercapto" group refers to -SH. [00168] As used herein, a "sulfo" group refers to -SO3H or -SO3RX when used terminally or -S(O)3- when used internally. [00169] As used herein, a "sulfamide" group refers to the structure -NRX-S(O)2- NRYRZ when used terminally and -NRX-S(O)2-NRY- when used internally, wherein Rx, RY, and Rz have been defined above. [00170] As used herein, a "sulfamoyl" group refers to the structure -S(O)2-NRXRY or -NRX-S(O)2-RZ when used terminally; or -S(O)2-NRX- or -NRX -S(O)2- when used internally, wherein Rx, RY, and Rz are defined above. [00171] As used herein a "sulfanyl" group refers to -S-Rx when used terminally and -S- when used internally, wherein Rx has been defined above. Examples of sulfanyls include alkylsulfanyl. [00172] As used herein a "sulfinyl" group refers to -S(O)-R when used terminally and -S(O)- when used internally, wherein Rx has been defined above. [00173] As used herein, a "sulfonyl" group refers to-S(O)2-RX when used terminally and -S(O)2- when used internally, wherein Rx has been defined above. [00174] As used herein, a "sulfoxy" group refers to -O-SO-RX or -SO-O-RX, when used terminally and -O-S(O)- or -S(O)-O- when used internally, where Rx has been defined above. [00175] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine. [00176] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)- [00177] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O- alkyl-, wherein alkyl has been defined above. [00178] As used herein, a "carbonyl" refer to -C(O)-. [00179] As used herein, an "oxo" refers to =O. [00180] As used herein, an "aminoalkyl" refers to the structure (Rx RY)N-alkyl-. [00181] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-. [00182] As used herein, a "urea" group refers to the structure -NRX-CO-NRYRZ and a "thiourea" group refers to the structure -NRX-CS~NRYRZ when used terminally and -NRX- CO-NRY- or -NRX-CS-NRY- when used internally, wherein Rx, RY, and Rz have been defined above. [00183] As used herein, a "guanidino" group refers to the structure -N=C(N (R RY))N(RXRY) wherein Rx and RY have been defined above. [00184] As used herein, the term "amidino" group refers to the structure - C=(NRX)N(RXRY) wherein Rx and RY have been defined above. [00185] In general, the term "vicinal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms. [00186] In general, the term "geminal" refers to the placement of substituents on a group that includes two or more carbon atoms,- wherein the substituents are attached to the same [00187] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RxO(O)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent to at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyI-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl- C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally. [00188] As used herein, the term "amidino" group refers to the structure -C=(NRX)N(RXRY) wherein Rx and RYhave been defined above. [00189] As used herein, "cyclic group" includes mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined. [00190] As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo(2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00191] As used herein, an "aliphatic chain" refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure -[CH2]v-, where v is 1-6. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure--[CHO]v- where Q is hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above. [00192] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R1, R2, R3, and R4, and other variables contained therein formulae I encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R1, R2, R3, and R4, and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, allcoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound. [00193] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. [00194] The phrase "up to", as used herein, refers to zero or any integer number that is equal or less than the number following the phrase. For example, "up to 3" means any one of 0,1, 2, and 3. [00195] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, 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. [00196] As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, suiface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human. [00197] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, 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 hydrogen by deuterium or tritium, or the replacement of a carbon by a C- or uC-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. COMPOUNDS [001983 Compounds of the present invention are useful modulators of ABC transporters and are useful in the treatment of ABC transport mediated diseases. A. Generic Compounds [00199] The present invention includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, or hydroxy; provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyridyl ring; Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; Each R3 and R'3 together with the carbon atom to which they are attached form an optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic; Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and Each n is 1,2,3 or 4. [00200] In another aspect, the present invention includes compounds of formula or a pharmaceutically acceptable salt thereof, wherein: one of G1 and G2 is a nitrogen, and the other is a carbon; and R1, R2, R3, R'3, R4, and n are defined above. Specific Embodiments A. Substituent Ri [00201] Each R1 is independently an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, or hydroxy. [00202] In some embodiments, one R1 is an optionally substituted C1-6 aliphatic. In several examples, one R1 is an optionally substituted C1_6 alkyl, an optionally substituted C2-6 alkenyl, or an optionally substituted C2-6 alkynyl. In several examples, one R1 is C1.6 alkyl, C2-6 alkenyl, or C2-6 alkynyl. [00203] In several embodiments, one R1 is an aryl or heteroaryl with 1,2, or 3 substituents. In several examples, one R1 is a monocyclic aryl or heteroaryl. In several embodiments, R1 is an aryl or heteroaryl with 1, 2, or 3 substituents. In several examples, R1 is a monocyclic aryl or heteroaryl. [00204] In several embodiments, at least one R1 is an optionally substituted aryl or an optionally substituted heteroaryl and R1 is bonded to the core structure at the 6 position on the pyR1dine R1ng. [00205] In several embodiments, at least one R1 is an optionally substituted aryl or an optionally substituted heteroaryl and R1 is bonded to the core structure at the 5 position on the pyR1dine R1ng. [00206] In several embodiments, one R1 is phenyl with up to 3 substituents. In several embodiments, Rj is phenyl with up to 3 substituents. [00207] In several embodiments, one R1 is a heteroaryl R1ng with up to 3 substituents. In certain embodiments, one R1 is a monocyclic heteroaryl R1ng with up to 3 substituents. In other embodiments, one R1 is a bicyclic heteroaryl R1ng with up to 3 substituents. In several embodiments, R1 is a heteroaryl R1ng with up to 3 substituents. In certain embodiments, R1 is a monocyclic heteroaryl R1ng with up to 3 substituents. In other embodiments, B.x is a bicyclic heteroaryl R1ng with up to 3 substituents. [00208] In several embodiments, one R1 is carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl]. Or, one R1 is amido [e.g., aminocarbonyl]. Or, one R1 is amino. Or, is halo. Or, is cyano. Or, hydroxyl. [00209] In some embodiments, R1 is hydrogen, methyl, ethyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F, Cl, methoxy, ethoxy, i-propoxy, t- butoxy, CF3, OCF3, CN, hydroxyl, or amino. In several examples, R1 is hydrogen, methyl, methoxy, F, CF3 or OCF3. In several examples, R1 can be hydrogen. Or, R1 can be methyl. Or, R1 can be CF3. Or, R1 can be methoxy. [00210] In several embodiments, R1 is substituted with no more than three substituents selected from halo, oxo, or optionally substituted aliphatic, cycloaliphatic, heterocycloaliphatic, amino [e.g., (aliphatic)aminoj, amido [e.g., aminocarbonyl, ((aliphatic)amino)carbonyl, and ((aliphatic)2amino)carbonyl], carboxy [e.g., alkoxycarbonyl and hydroxycarbonyl], sulfamoyl [e.g., aminosulfonyl, ((aliphatic)2amino)sulfonyl, ((cycloaliphatic)aliphatic)aminosulfonyl, and ((cycloaliphatic)amino)sulfonyl], cyano, alkoxy, aryl, heteroaryl [e.g., monocyclic heteroaryl and bicycloheteroaryl], sulfonyl [e.g., aliphaticsulfonyl or (heterocycloaliphatic)sulfonyl], sulfinyl [e.g., aliphaticsulfinyl], aroyl, heteroaroyl, or heterocycloaliphaticcarbonyl. [00211] In several embodiments, R1 is substituted with halo. Examples of R1 substituents include F, Cl, and Br. In several examples, R1 is substituted with F. [00212] In several embodiments, R1 is substituted with an optionally substituted aliphatic. Examples of R1 substituents include optionally substituted alkoxyaliphatic, heterocycloaliphatic, aminoalkyl, hydroxyalkyl, (heterocycloalkyl)aliphatic, alkylsulfonylaliphatic, alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic, alkylaminoaliphatic, or alkylcarbonylaliphatic. [00213] In several embodiments, R1 is substituted with an optionally substituted amino. Examples of R1 substituents include aliphaticcarbonylamino, aliphaticamino, arylamino, or aliphaticsulfonylamino. [00214] In several embodiments, R1 is substituted with a sulfonyl. Examples of R1 substituents include heterocycloaliphaticsulfonyl, aliphatic sulfonyl, alphaticaminosulfony!, aminosulfonyl, aliphaticcarbonylaminosulfonyl, alkoxyalkylheterocycloalkylsulfonyl, alkylheterocycloalkylsulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, (heterocycloalkyl)alkylaminosulfonyl, and heterocycloalkylsulfonyl. [00215] In several embodiments, R1 is substituted with carboxy. Examples of R1 substituents include alkoxycarbonyl and hydroxycarbonyl. [00216] In several embodiments R1 is substituted with amido. Examples of R1 substituents include alkylaminocarbonyl, aminocarbonyl, ((aliphatic)2amino)carbonyl, and [((aliphatic)aminoaliphatic)amino]carbonyl. [00217] In several embodiments, R1 is substituted with carbonyl. Examples of R1 substituents include arylcarbonyl, cycloaliphaticcarbonyl, heterocycloaliphaticcarbonyl, and heteroarylcarbonyi. [00218] In some embodiments, R1 is hydrogen. In some embodiments, R1 is - ZAR5, wherein each ZA is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -CO2-, -OCO-, -NRACO2-, -O-, - NRACONRA-, -OCONRA-, -NRANRA-7 -NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, - NRASO2-, or -NRASO2NRA-. Each R5 is independently RA, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3. Each RA is independently a C1-8 aliphatic group, a cycloaliphatic, a heterocycloaliphatic, an aryl, or a heteroaryl, each of which is optionally substituted with 1, 2, or 3 of Ru. Each RD is -ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, - SO2NRE-, -NRESO2-, or -NRESO2NRE-. Each R9is independently RE, halo, -OH, -NH2, -NO2, - CN, -CF3, or -OCF3. Each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00219] In some embodiments, each RD is independently -ZDR9; wherein each ZD can independently be a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -O-, - NHC(O)-, -C(O)NRE-, -SO,-, -NHSO3-, -NHC(O)-, -NRESO2-, -SO2NH-, -SO2NRE-, -NH-, or - C(O)O-. In some embodiments, one carbon unit of ZD is replaced by -O-. Or, by -NHC(O)-. Or, by -C(O)NRE-. Or, by -SO2-. Or, by NHSO2-. Or, by -NHC(O)-. Or, by -SO-. Or, by - NRESO2-. Or, by -SO2NH-. Or, by -SO2NRE-. Or, by -NH-. Or, by -C(O)O-. [00220] In some embodiments, R9 is hydrogen. In some embodiments, R9 is independently an optionally substituted aliphatic. In some embodiments, R9 is an optionally substituted cycloaliphatic. Or, is an optionally substituted heterocycloaliphatic. Or, is an optionally substituted aryl. Or, is an optionally substituted heteroaryl. Or, halo. [00221] In some embodiments, one R1 is aryl or heteroaryl, each optionally substituted with 1,2, or 3 of RD, wherein RD is defined above. [00222] In several embodiments, one R1 is carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl]. Or, one R1 is amido [e.g., aminocarbonyl]. Or, one R1 is amino. Or, is halo. [00223] In some embodiments, one R1 that is attached to 5- or 6- position of the pyR1dyl R1ng is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of RD, wherein RD is defined above. In some embodiments, the one R1 attached to the 5- or 6- postion of the pyR1dyl R1ng is phenyl optionally substituted with 1, 2, or 3 of RD, wherein RD is defined above. In some embodiments, the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is heteroaryl optionally substituted with 1, 2, or 3 of RD. In several embodiments, the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur. In other embodiments, the 5 or 6 membered heteroaryl is substituted with 1 RD. [00224] In some embodiments, one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is a phenyl substituted with 1 RD. In some embodiments, one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is a phenyl substituted with 2 RD. In some embodiments, one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is a phenyl substituted with 3 RD. [00225] In several embodiments, R1 is: W1 is -C(O)-, -SO2-, or -CH-2-; D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy, and amino; and RD is defined above. [00226] In several embodiments, W2 is -C(O)-. Or, W1 is -SO2-. Or, W1 is -CH2-. [00227] In several embodiments, D is OH. Or, D is an optionally substituted C1-6 aliphatic or an optionally substituted C3-C8 cycloaliphatic. Or, D is an optionally substituted alkoxv. Or, D is an optionally substituted amino. wherein each" of A and B is independently H, an optionally substituted C1-6 aliphatic, an optionally substituted C3-C8 cycloaliphatic, or A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. [00229] In several embodiments, A is H and B is an optionally substituted C1-6 aliphatic. In several embodiments, B is substituted with 1, 2, or 3 substituents. Or, both, A and B, are H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkyamino, or an optionally substituted group selected from cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl. [00230] In several embodiments, A is H and B is an optionally substituted C1-6 aliphatic. Or, both, A and B, are H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, and an optionally substituted heterocycloaliphatic. [00231] In several embodiments, B is C1-6 alkyl, optionally substituted with oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, or an optionally substituted group selected from cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl. In several embodiments, B is substituted with oxo, C1-6 alkyl, hydroxy, hydroxy-(C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1. 6)alkyl, C3_8 cycloaliphatic, 3-8 membered heterocycloaliphatic, phenyl, and 5-10 membered heteroaryl. In one example, B is C1-6 alkyl substituted with optionally substituted phenyl. [00232] In several embodiments, A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. In several examples, the heterocycloaliphatic R1ng is optionally substituted with 1,2, or 3 substituents. Exemplary such R1ngs include optionally substituted pyrrolidinyl, pipeR1dinyl, morpholinyl, and piperazinyl. Exemplary substituents on such R1ngs include halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl (e.g., alkylcarbonyl), amino, amido, and carboxy. In some embodiments, the substituent is halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy. [00233] In several embodiments, RD is hydrogen, halo, or an optionally substituted group selected from aliphatic, cycloaliphatic, amino, hydroxy, alkoxy, carboxy, amido, carbonyl, cyano, aryl, or heteroaryl. In several examples, RD is hydrogen, halo, an optionally substituted C1-6 aliphatic, or an optionally substituted alkoxy. In several examples, RD is hydrogen, F, Cl, an optionally substituted C1-6 alkyl, or an optionally substituted -O(C1-6 alkyl). Examples of RD include hydrogen, F, Cl, methyl, ethyl, i-propyl, r-butyl, -OMe, -OEt, i- propoxy, t-butoxy, CF3, or -OCF3. In some examples, RDis hydrogen, F, methyl, methoxy, CF3, W1 is -C(O)-, -SO2-, or -CH2-; Each of A and B is independently H, an optionally substituted C1-6 aliphatic, an optionally substituted C3-C8 cycloaliphatic; or A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. [00235] In some embodiments, one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1, 2, or 3 of RD; wherein RD is -ZDR9; wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -OCOKRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, - SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, -NO2, - CN, -CF3, or -OCF3; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00236] In several examples, one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloaliphatic. [00237] In some embodiments, one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloalkyl or an optionally substituted C3-C8 - cycloalkenyl. [00238] In several embodiments, one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is C3-C8 cycloalkyl or C3-Cs cycloalkenyl. Examples of cycloalkyl and cycloalkenyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,- cycloheptyl, B. Substituent R2 [00241] Each R2 can be hydrogen. Each R2 can be an optionally substituted group selected from C1-6 aliphatic, C3-6 cycloaliphatic, phenyl, and heteroaryi. [00242] In several embodiments, R2 is aC1-6 aliphatic optionally substituted with 1, 2, or 3 halo, C1-2 aliphatic, or alkoxy. In several examples, R2 can be substituted methyl, ethyl, propyl, or butyl. In several examples, R1 can be methyl, ethyl, propyl, or butyl. [00243] In several embodiments, R2 is hydrogen. C. Substituents R3 and R1 [00244] Each R3 and R'3 together with the carbon atom to which they are attached form a C3-7 cycloaliphatic or a heterocycloaliphatic, each of which is optionally substituted with 1,2, or 3 substituents. [00245] In several embodiments, R3 and R'3 together with the carbon atom to which they are attached form a C3.7 cycloaliphatic or a C3.7 heterocycloaliphatic, each of which is optionally substituted with 1,2, or 3 of -ZBR7, wherein each ZB is independently a bond, or an optionally substituted branched or straight C1-4 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONR8-, -CONRBNRB-, -CO2-, - OCO-, -NRBCO2~, -O~, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO~, -S-, -SO-, -SO2-, - NRB-, -SO2NRB-, -NRBSO2-, or -NRBSO2NRB-; each R7is independently RB, halo, -OH, -NH2, - NO2, -CN, -CF3, or -OCF3; and each RB is independently hydrogen, an optionally substituted C1. 8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryi. [00246] In several embodiments, R3 and R'3 together with the carbon atom to which they are attached form a 3, 4, 5, or 6 membered cycloaliphatic that is optionally substituted with 1, 2, or 3 substituents. In several examples, R3, R'3, and the carbon atom to which they are attached form an optionally substituted cyclopropyl group. In several alternative examples, R3, R'3, and the carbon atom to which they are attached form an optionally substituted cyclobutyl group. In several other examples, R3, Rr3, and the carbon atom to which they are attached form an optionally substituted cyclopentyl group. In other examples, R3, R'3) and the carbon atom to which they are attached form an optionally substituted cyclohexyl group. In more examples, R3 and R'3 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl. [00247] In several embodiments, R3 and R'3 together with the carbon atom to which they are attached form a 5, 6, or 7 membered optionally substituted heterocycloaliphatic. In other examples, R3, R'3 and the carbon atom to which they are attached form an optionally substituted tetrahydropyranyl group. [00248] In some embodiments, R3 and R'3 together with the carbon atom to which they are attached form an unsubstituted C3.7 cycloaliphatic or an unsubstituted heterocycloaliphatic. In several examples, R3 and R'3 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl. D. Substituent R4 [00249] Each R4 is independently an optionally substituted aryl or an optionally substituted heteroaryl. [00250] In several embodiments, R4 is an aryl having 6 to 10 members (e.g., 7 to 10 members) optionally substituted with 1, 2, or 3 substituents. Examples of R4 include optionally substituted benzene, naphthalene, or indene. Or, examples of R4 can be optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indenyl. [00251] In several embodiments, R4 is an optionally substituted heteroaryi. Examples of R4 include monocyclic and bicyclic heteroaryl, such a benzofused R1ng system in which the phenyl is fused with one or two 4-8 membered heterocycloaliphatic groups. [00252] In some embodiments, R4 is an aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of -ZCR8. In some embodiments, R4 is an aryl optionally substituted with 1, 2, or 3 of -ZcRg. In some embodiments, R4 is phenyl optionally substituted with 1, 2, or 3 of -ZcRg. Or, R4 is a heteroaryl optionally substituted with 1, 2, or 3 of -ZCR8. Each Zc is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, - CONRC-, -CONRCNRC-, -CO2-, -OCO-, -NRCCO2-, -O-, -NRcCONRc-,-OCONRc-, -NRCNRC- , -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -SO2NRC-, -KRCSO2-, or -NRCSO2NRC-. Each R8is independently Rc, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OGF3. Each Rc is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00253] In some embodiments, two occurrences of —ZCR8, taken together with carbons to which they are attached, form a 4-8 membered saturated, partially saturated, or aromatic R1ng with up to 3 R1ng atoms independently selected from the group consisting of O, NH, NRC, and S; wherein Rc is defined herein. [00254] In several embodiments, R4 is one selected from E. Exemplary Compound Families [00255] In several embodiments, R1 is an optionally substituted cyclic group that is attached to the core structure at the 5 or 6 position of the pyR1dine R1ng. [00256] In several examples, R1 is an optionally substituted aryl that is attached to the 5 position of the pyR1dine R1ng. In other examples, R1 is an optionally substituted aryl that is attached to the 6 position of the pyR1dine R1ng. [00257] In more examples, R1 is an optionally substituted heteroaryl that is attached to the 5 position of the pyR1dine R1ng. In still other examples, R1 is an optionally substituted heteroaryl that is attached to the 6 position of the pyR1dine R1ng. [00258] In other embodiments, R1 is an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic that is attached to the pyR1dine R1ng at the 5 or 6 position. [00259] Accordingly, another aspect of the present invention provides compounds of formula (II): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R'3, and R4 are defined in formula I. [00260] In some embodiments, each R1 is aryl or heteroaryl optionally substituted with 1, 2, or 3 of RD, wherein RD is -ZDRc,, wherein each ZD is independently a bond or an optionally substituted branched or straightC1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, ~CONRENRE-, -CO2-, - OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, - NRB-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, - NO2, -CN, -CF3) or -OCF3; each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic. an optionally substituted aryl. or an optionally substituted heteroaryl. [00261] In some embodiment, each R1 is cycloaliphatic or heterocycloaliphatic optionally substituted with 1, 2, or 3 of RD; wherein RD is defined above. [00262] Another aspect of the present invention provides compounds of formula or a pharmaceutically acceptable salt thereof, wherein R1 R2) R3, R'3, and R4 are defined in formula I. [00263] In some embodiments, each R1 is aryl or heteroaryl optionally substituted with 1,2, or 3 of RD, wherein RD is -ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight Ci.6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, - OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, - NRE-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, - NO2, -CN, -CF3, or -OCF3; each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycioaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00264] In some embodiments, each R1 is cycloaliphatic or heterocycioaliphatic optionally substituted with 1, 2, or 3 of RD; wherein RD is defined above. [00265] In another aspect, the present invention includes compounds of formula or a pharmaceutically acceptable salt thereof, wherein R2, R3, R'3, and R4 are defined in formula I. [00266] RD is -ZDR9; wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, - SO2NRE-, -NRESO2-, or -NRESO2NRE-. [00267] R9 is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3. [00268] Each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycioaliphatic, an optionally substituted aryl,.or an optionally substituted heteroaryl. [00269] In several embodiments, ZD is independently a bond or is an optionally substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -SO2-, -CONRE-, - NRESO2-, or -SO2NRE-. For example, ZD is an optionally substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -SO2-. In other examples, Rg is an optionally substituted heteroaryl or an optionally substituted heterocycloaliphatic. In additional examples, R9 is an optionally substituted heterocycloaliphatic having 1-2 nitrogen atoms, and R9 attaches directly to -SO2- via a R1ng nitrogen. [00270] In another aspect, the present invention includes compounds of formula V-A or formula V-B: or a pharmaceutically acceptable salt thereof, wherein: T is an optionally substituted C1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by --CO-, -CS-, -COCO-, -SO2-, -B(OH)-, or -B(O(C1-6 alkyl))s Each of R1' and R1" is independently a bond or an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy; RD1 is attached to carbon 3" or 4"; each RD1 and RD2 is -ZDRg, wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE~, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, - SO2NRE-, -NRESO2-, or -NRESO2NRE-; R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; or RD1 and RD2 , taken together with atoms to which they are attached, form a 3-8 membered saturated, partially unsaturated, or aromatic R1ng with up to 3 R1ng members independently selected from the group consisting of O, NH, NRE, and S; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00271] In some embodiments, T is an optionally substituted -CH2-. In some other embodiments, T is an optionally substituted -CH2CH2-. [00272] In some embodiments, T is optionally substituted by -ZBR10; wherein each Z is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced by -CO-, - CS-, -CONRF-, -CONRFNRF-, -CO2-, -OCO-, -NRFCO2-, -O-, -NRFCONRF-, -OCONRF-, - INRFNRF-, -NRFCO-, -S-, -SO-, -SO2-, -NRF-, -SO2NRF-, -NRFSO2-, or -NRFSO2NRF-; R1o is independently RF halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; each RF is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. In one example, ZE is -O-. [00273] In some embodiments, R10 can be an optionally substituted C1-6 alkyl, an optionally substituted C2.6 alkenyl, an optionally substituted C3-7 cycloaliphatic, or an optionally substituted C6-10 aryl- In one embodiment, R1o is methyl, ethyl, z-propyl, or /-butyl. [00274] In some embodiments, up to two carbon units of T are optionally substituted by -CO-, -CS-, -B(OH)-, or -B(O(C1-6 alkyl)-. [00275] In some embodiments, T is selected from the group consisting of -CH2-, - CH2-. Or,Tis-CF2-. Or, T is-C(CH3)2-. [00276] In some embodiments, each of R1' and R1" is hydrogen. In some embodiments, each of R1' and R1" is independently -ZAR5j wherein each ZA is independently a bond or an optionally substituted branched or straight Cj.6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, - CONRANRA-, -CO2-, -OCO-, -NRACO2-, -O-, -NRACONRA-, -OCONRA-, -NRANRA-, - NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, -NRASO2-, or -NRASO2NRA-. Each R5 is independently RA, halo, -OH, -NH2, -NO2, -CN, -CF3> or -OCF3. Each RA is independently an optionally substituted group selected from C1-8 aliphatic group, a cycloaliphatic, a heterocycloaliphatic, an ary], and a heteroaryl. [00277] In some embodiments, R1' is selected from the group consisting of H, C1-6 aliphatic, halo, CF3, CHF2, -O(C1-6 aliphatic), C3-C5 cycloalkyl, or C4-C6 heterocycloalkyl containing one oxygen atom. In some embodiments, R11 is selected from the group consisting of H, methyl, ethyl, z'-propyl, t-butyl, F. Cl, CF3, CHF2, ~OCH3, -OCH2CH3, -O-(i-propyl), or -O- (f-butyl). More preferably, R11 is H. Or, R1' is methyl. Or, ethyl. Or, CF3. [00278] In some embodiments, R1" is selected from the group consisting of H, C1- 6 aliphatic, halo, CF3, CHF2, and -O(C1-6 aliphatic). In some embodiments, R1" is selected from the group consisting of H, methyl, ethyl, i-propyl, f-butyl, F. Cl, CF3, CHF2, -OCH3, - OCH2CH3, -O-(i-propyl), or -O-(t-butyl). More preferably, R1" is H. Or, R1" is methyl. Or, ethyl. Or, CF3. [00279] In some embodiments, RD1 is attached to carbon 3" or 4", and is -ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight Q-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, - OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, -NRESO2-, or - NRESO2NRE-. In yet some embodiments, ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -CO-, -SO-, -SO2-, -COO-, -OCO-, -CONRE-, -NRECO-, NRECO2-, -O-, -NRESO2- , or -SO2NRE-. In some embodiments, one carbon unit of ZD is optionally replaced by -CO-. Or, by-SO-. Or,by-SO2-. Or,by-COO-. Or,by-OCO-. Or, by -CONRE-. Or, by-NRECO-. Or,by-NRECO2-. Or,by-O-. Or, by-NRESO2-. Or, by-SO2NRE-. [00280] In several embodiments, R9 is hydrogen, halo, -OH, -NH2, -CN, -CF3, - OCF3) or an optionally substituted group selected from the group consisting of C1-6 aliphatic, C3. 8 cycloaliphatic, 3-8 membered heterocycloaliphatic, Cw aryU and 5-10 membered heteroaryl. In several examples, R9 is hydrogen, F, Cl, -OH, -CN, -CF3, or -OCF3. In some embodiments, R is C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, - COORE, and -CONRERE. In several examples, Rg is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i- propyl, t-butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(O)NH2, -CH2O(C1-6 alkyl), - CH2CH2O(C1-6 alkyl), and -C(O)(C1-6 alkyl). [00281] In one embodiment, R is hydrogen. In some embodiments, R9 is selected from the group consisting of C1-6 straight or branched alkyl or C2-6 straight or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, - COORE, and -CONRERE. [00282] In other embodiments, R9 is C3-8 cycloaliphatic optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, - NRERE, -ORE, -COORE, and -CONRERE. Examples of cycloaliphatic include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. [00283] In yet other embodiments, R9 is a 3-8 membered heterocyclic with 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NRE, and S; wherein said heterocyclic is optionally substituted by 1 ox 2 substituents independently selected from the group RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE. Example of 3-8 membered heterocyclic include but are not limited to [00285] In some embodiments, RD1 and RD2, taken together with carbons to which they are attached, form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic R1ng with 0-2 R1ng atoms independently selected from the group consisting of O, NH, NRE, and S. Examples of Rm and RD2, taken together with phenyl containing carbon atoms 3" and 4", include but are not limited to [00286] In some embodiments, RD2 is selected from the group consisting of H, RE, halo, -OH, -(CH2)rNRERE, -(CH2)r-ORE, -SO2-RE, -NRE-SO2-RE, -SO2NRERE, -C(O)RE, - C(O)ORE, -OC(O)ORE, -NREC(O)ORE, and -C(O)NRERE; wherein r is 0,1, or 2. In other embodiments, RD2 is selected from the group consisting of H, C1-6 aliphatic, halo, -CN, -NH2, - NH(C1-6 aliphatic), -N(C1-6 aliphatic)2, -CH2-N(C1-6 aliphatic)2, -CH2-NH(C1-6 aliphatic), - CH2NH2, -OH, -O(C1-6 aliphatic), -CH2OH, -CH2-O(C,-6 aliphatic), -SO2(C1-6 aliphatic), -N(C1-6 aliphatic)-SO2(C1-6 aliphatic), -NH-SO2(C1-6 aliphatic), -SO2NH2, -SO2NH(C1-6 aliphatic), - SO2N(C1-6 aliphatic)2, -C(O)(C1-6 aliphatic), ~C(O)O(C1-6 aliphatic), -C(O)OH, ~OC(O)O(C1-6 aliphatic), -NHC(O)(C1-6 aliphatic), -NHC(O)O(C1-6 aliphatic), -N(C1-6 a]iphatic)C(O)O(C1-6 aliphatic), -C(O)NH2, and -C(O)N(C1-6 aliphatic)2. In several examples, RD2 is selected from the group consisting of H, C1-6 aliphatic, halo, -CN, -NH2, -CH2NH2, -OH, -O(C1-6 aliphatic), - CH2OH, -SO2(C1-6 aliphatic), -NH-SO2(C1-6 aliphatic), -C(O)O(C1-6 aliphatic), -C(O)OH, - NHC(O)(C1-6 aliphatic), -C(O)NH2, -C(O)NH(C1-6 aliphatic), and -C(O)N(C1-6 aliphatic)2. For examples, RD2 is selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, t- butyl, F, Cl, CN, -NH2, -CH2NH2, -OH, -OCH3, -O-ethyl, -O-(i-propyl), -0-(n-propyl), - CH2OH, -SO2CH3, -NH-SO2CH3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OH, -NHC(O)CH3, - C(O)NH2, and -C(O)N(CH3)2. In one embodiment, RD2 is hydrogen. In another embodiment, RD2 is methyl. Or, RM is ethyl. Or, RD2 is F. Or, RD2 is Cl. Or, -OCH3. [00287] In one embodiment, the present invention provides compounds of [00289] In one embodiment, R1 is selected from the group consisting of H,C1-6 aliphatic, halo, CF3, CHF2, -O(C1-6 aliphatic), C3-C5 cycloalkyl, or C4-C6 heteiocycloalkyl containing one oxygen atom. Exemplary embodiments include H, methyl, ethyl, i-propyl, t- butyl, F. Cl, CF3, CHF2, -OCH3, -OCH2CH3, -O-(i-propyl), -O-(r-butyl), cyclopropyl, or oxetanyl. More preferably, R3'is H. Or, R1'is methyl. Or, ethyl. Or, CF3. Or, oxetanyl. [00290] In one embodiment, Rm is Z°R9, wherein ZD is selected from CONH, NHCO, SO2NH, SO2N(C1-6 alkyl), NHSO2, CH2NHSO2, CH2N(CH3)SO2, CH2NHCO, COO, SO2, or CO. In one embodiment, Rm is Z0R9, wherein ZD is selected from CONH, SO2NH, SO2N(C1-6 alkyl), CH2NHSO2, CH2N(CH3)SO2, CH2NHCO, COO, SO2, or CO. [08291] lit one embodiment, ZD is COO and R9 is K. In one embodiment, ZP is COO and R9 is an optionally substituted straight or branched C1-6 aliphatic. In one embodiment, ZD is COO and R9 is an optionally substituted straight or branched C1-6 alkyl. In one embodiment, ZD is COO and R9 is C1-6 alkyl. In one embodiment, ZD is COO and R9 is methyl. [00292] In one embodiment, ZD is CONH and R9 is H. In one embodiment, ZD is CONH and R9 is an optionally substituted straight or branched C1-6 aliphatic. In one embodiment, ZD is CONH and R9 is straight or branched C1-6 alkyl. In one embodiment, ZD is CONH and R9 is methyl. In one embodiment, ZD is CONH and R9 is an optionally substituted straight or branched C1-6 alkyl. In one embodiment, In one embodiment, ZD is CONH and R9 is 2-(dimethylamino)-ethyl. [00293] In some embodiments, ZD is CH2NHCO and R9 is an optionally substituted straight or branched C1-6 aliphatic or an optionally substituted alkoxy. In some embodiments, ZD is CH2NHCO and R9 is straight or branched C1-6 alkyl optionally substituted with halo, oxo, hydroxyl, or an optionally substituted group selected from aliphatic, cyclic, aryl, heteroaryl, alkoxy, amino, carboxyl, or carbonyl. In one embodiment, ZD is CH2NHCO and R9 is methyl. In one embodiment, ZD is CH2NHCO and R9 is CF3. In one embodiment, ZD is CH2NHCO and R9 is t-butoxy. [00294] In one embodiment, ZD is SO2NH and R9 is H. In some embodiments, ZD is SO2NH and R9 is an optionally substituted straight or branchedC1-6 aliphatic. In some embodiments, ZD is SO2NH and R9 is is straight or branched C1-6 alkyl optionally substituted with halo, oxo, hydroxyl, or an optionally substituted group selected fromC1-6 aliphatic, 3-8 membered cyclic, C6-10 aryl, 5-8 membered heteroaryl, alkoxy, amino, amido, carboxyl, or carbonyl. In one embodiment, 7? is SO2NH and R9 is methyl. In one embodiment, Zp is SO2NH and R9 is ethyl. In one embodiment, ZD is SO2NH and R9 is i-propyl. In one embodiment, ZD is SO2NH and R9 is f-butyl. In one embodiment, ZD is SO2NH and R9 is 3,3- dimethylbutyl. In one embodiment, ZD is SO2NH and R9 is CH2CH2OH. In one embodiment, ZD is SO2NH and R9 is CH(CH3)CH2OH. In one embodiment, ZD is SO2NH and R9 is CH2CH(CH3)OH. In one embodiment, ZD is SO2NH and R9 is CH(CH2OH)2. In one embodiment, ZD is SO2NH and R9 is CH2CH(OH)CH2OH. In one embodiment, ZD is SO2NH and R9 is CH2CH(OH)CH2CH3. In one embodiment, ZD is SO2NH and R9 is C(CH3)2CH2OH. In one embodiment, ZD is SO2NH and R9 is CH(CH2CH3)CH2OH. In one embodiment, ZD is SO2NH and R9 is CH2CH2OCH2CH2OH. In one embodiment, ZD is SO2NH and R9 is C(CH3)(CH2OH)2. In one embodiment, ZD is SO2NH and R9 is CH2CH(OH)CH2C(O)OH. In one embodiment, ZD is SO2NH and R9 is CH2CH2N(CH3)2. In one embodiment, ZD is SO2NH and R9 is CH2CH2NHC(O)CH3. In one embodiment, ZD is SO2NH and R9 is CH(CH(CH3)2)CH2OH. In one embodiment, ZD is SO2NH and R9 is CH(CH2CH2CH3)CH2OH. In one embodiment, ZD is SO2NH and R9 is 1-tetrahydrofuryl-methyl. In one embodiment, Z is SO2NH and R9 is furylmethyl. In one embodiment, ZD is SO2NH and R9 is (5-methylfuryl)- methyl. In one embodiment, ZD is SO2NH and R9 is 2-pyrrolidinylethyl. In one embodiment, ZD is SO2NH and R9 is 2-(l-methylpyrrolidinyl)-ethyl. In one embodiment, ZD is SO2NH and R9 is 2-(4-morpholinyl)-ethyl. In one embodiment, ZD is SO2KH and R9 is 3-(4-morpholinyl)- propyl. In one embodiment, ZD is SO2NH and R9 is C(CH2CH3)(CH2OH)2. In one embodiment, ZD is SO2NH and R9 is 2-(lH-imidazol-4-yl)ethyl. In one embodiment, ZD is SO2NH and R9 is 3-(lH-imidazol-l-yl)-propyl. In one embodiment, ZD is SO2NH and R9 is 2- (2-pyR1dinyl)-ethyl. [00295] Li some embodiment, ZD is SO2NH and R9 is an optionally substituted C1-6 cycloaliphatic. In several examples, ZD is SO2NH and R9 is an optionally substituted C1-6 cycloalkyl. In several examples, ZD is SO2NH and R9 is C1-6 cycloalkyl. In one embodiment, ZD is SO2NH and R9 is cyclobutyl. In one embodiment, ZD is SO2NH and R9 is cyclopentyl. In one embodiment, ZD is SO2NH and R9 is cyclohexyl. [00296] In some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally substituted straight or branchedC1-6 aliphatic or an optionally substituted cycloaliphatic. In some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally substituted straight or branched C1-6 aliphatic. In some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally substituted straight or branchedC1-6 alkyl or an optionally substituted straight or branchedC1-6 alkenyl. In one embodiments, ZD is SO2N(CH3) and R9 is methyl. In one embodiments, ZD is SO2N(CH3) and R9 is n-propyl. In one embodiments, ZD is SO2N(CH3) and R9 is n-butyl. In one embodiments, ZD is SO2N(CH3) and R» is cyclohexyl. In one embodiments, ZD is SO2N(CH3) and R9 is allyl. In one embodiments, ZD is SO2N(CH3) and R9 is CH2CH2OH. In one embodiments, ZD is SO2N(CH3) and R9 is CH2CH(OH)CH2OH. In one embodiments, ZD is SO2N(CH2CH2CH3) and R9 is cyclopropylmethyl. [00297] In one embodiment, ZD is CH2NHSO2 and R9 is methyl. In one embodiment, ZD is CH2N(CH3)SO2 and R9 is methyl. [00298] In some embodiments, ZD is SO2 and R9 is an optionally substituted C1-6 straight or branched aliphatic or an optionally substituted 3-8 membered heterocyclic, having 1, 2, or 3 R1ng members selected from the group consisting of nitrogen, oxygen, sulfur, SO, or SO2. In some embodiments, ZD is SO2 and R9 is straight or branchedC1-6 alkyl or 3-8 membered heterocycloaliphatic each of which is optionally substituted with 1,2, or 3 of oxo, halo, hydroxyl, or an optionally substituted group selected from C1-6 aliphatic, carbonyl, amino, and carboxy. In one embodiment, ZD is SO2 and R9 is methyl. In some embodiments, ZD is SO2 and examples of R9 include [00299] In some embodiments, RD2 is H, hyckoxyl, halo, C1-6 aikyi, C1-6 alkoxy, C1-6 cycloalkyl, or NH2- In several examples, RD2 is H, halo, C1-4 alkyl, or C1-4 alkoxy. Examples of RD2 include H, F, Cl, methyl, esthyl, and naethoxy. [00300] In some embodiments, the present invention provides compounds of formula (I1-A) or formula (I'-B): wherein R1, R2, R3, R3, R4, and n are defined above. [00301] In some embodiments, R1 is an optionally substituted aryl. In several examples, R1 is phenyl optionally substituted with 1, 2, or 3 of halo, OH, -O(C1-6 aliphatic), amino, C1-6 aliphatic, C3-7 cycloaliphatic, 3-8 membered heterocycloaliphatic, C6-10 aryl, or 5-8 membered heteroaryl. In some embodiments, R1 is phenyl optionally substituted with alkoxy, halo, or amino. In one embodiment, R1 is phenyl. In one embodiment, R1 is phenyl substituted with Cl, methoxy, ethoxy, or dimethylamino. [00302] In some embodiments, R2 is hydrogen. In some embodiments, R2 is optionally substitutedC1-6 aliphatic. [00303] In some embodiments, R3, R'3, and the carbon atom to which they are attached form an optionally substituted C3-8 cycloaliphatic or an optionally substituted 3-8 membered heterocycloaliphatic. In some embodiments, R3, R'3, and the carbon atom to which they are attached form an optionally substituted C3-8 cycloalkyl. In one example, R3, R'3, and the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted. In one example, R3, R'3, and the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In several examples, R3, R'3, and the carbon atom to which they are attached is cyclopropyl. [00304] In some embodiments, R4 is an optionally substituted aryl or an optionally substituted heteroaryl. In some embodiments, R4 is an optionally substituted phenyl. In several embodiments, R4 is phenyl fused to a 3,4,5, or 6 membered heterocyclic having 1, 2, or 3 R1ng membered selected from oxygen, sulfur and nitrogen. In several embodiments, R4 is O' ^-^ , wherein T is defined above. In several examples, T is -CH2-. [00305] Alternative embodiments of R1, R2, R3, R'3, R4, and n in formula (I'-A) or formula (T-B) are as defined for formula (I), formula (I1), and embodiments thereof. [00306] Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below. SYNTHETIC SCHEMES [00308] Compounds of the invention may be preparec'. by known methods or as illustrated in the examples. In one instance wherein R1 is aryl or he eroaryl, the compounds of \| [00313] ReferR1ng to Scheme I, a nitR1le of formula i in alkylated (step a) with a dihalo-alrphatic in the presence of a base such as, for example, 50% sodium hydroxide and, optionally, a phase transfer reagent such as, for example, benzyltR1eihylaminonium chloR1de- (BTEAC), to produce the corresponding alkylated nitR1le (not shown) which on hydrolysis produces the acid ii. Compounds of formula ii are converted to the icid chloR1de iii with a suitable reagent such as, for example, thionyl chloR1de/DMF. Reaction of the acid chloR1de iii with an aminopyR1dine, wherein X is a halo, of formula iv (step c) produces the amide of formula v. Reaction of the amide v with an optionally substituted boronic acid deR1vative (step d) in the presence of a catalyst such as, for example, palladium acetate or dichloro-[l,l- bis(diphervylphosphino) ferrocene] palladium(IT) (Pd(dppf)Cl2 ), provides compounds of the invention wherein R1 is aryl, heteroaryl, or cycloalkenyl. The boronic acid deR1vatives vi are commercially available or may be prepared by known methods such as reaction of an aryl bromide with a diborane ester in the presence of a coupling reagent such as, for example, palladium acetate as descnDea in me examples. [00314] In another instance where one R1 is aryl and mother R1 is an aliphatic, alkoxy, cycloaliphatic, or heterocycloaliphatic, compounds of the invention can be prepared as descR1bed in steps a, b, and c of Scheme I using an appropR1ately substituted aminopyR1dine such as R2HN 5 where X is halo and Q is C1-6 aliphatic, aryl, heteroaryl, or 3 to 10 membered cycloaliphatic or heterocycloaliphatic as a substitute for the aminopyR1dine of formula iv. FORMULATIONS, ADMINISTRATIONS. AND USES Pharmaceutically acceptable compositions [00315] Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions compR1se any of the compounds as descR1bed herein, and optionally compR1se a pharmaceutically acceptable carR1er, adjuvant or vehicle. In certain embodiments, these compositions optionally further compR1se one or more additional therapeutic agents. [00316] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropR1ate, as a pharmaceutically acceptable deR1vative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable deR1vative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or deR1vative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise descR1bed herein, or a metabolite or residue thereof. [00317] As used herein the term pharmaccutically acceptable salt refres to. those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irR1tation, allergic response and the like, and are commensurate with a reasonable benofit/R1sk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitoR1ly active metabolite or residue thereof. [00318] Pharmaceutically acceptable salts are well kr.own in the art. For example, S. M. Berge, et ah descR1be pharmaceutically acceptable salts in detail in /. Pharmaceutical Sciences, 1977, 66,1-19, incorporated herein by reference. Pharme ceutically acceptable salts of the compounds of this invention include those deR1ved from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloR1c acid, hydrobromic acid, phosphoR1c acid, sulfuR1c acid and perchloR1c acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaR1c acid, citR1c acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-p lenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiccyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts deR1ved from appropR1ate bases include alkali metal, alkaline earth metal, ammonium and N^Ci^alkyl^ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropR1ate, nontoxic ammonium, quaternary ammon um, and amine cations formed using counteR1ons such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [00319] As descR1bed above, the pharmaceutically ace sptable compositions of the present invention additionally compR1se a pharmaceutically acceptable carR1er, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubR1cants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. SwarbR1ck and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which is incorporated by reference herein, disclose vaR1ous carR1ers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carR1er medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleteR1ous manner with any other compo:ient(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of mateR1als which can serve as pharmac jutically acceptable carR1ers include, but are not limited to, ion exchangers, alumina, aluminum s tearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceR1de mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloR1de, zinc salts, colloidal silica, magnesium tR1silicate, polyvinyl pyrrolidone, polyacryiates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its deR1vatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipieni s such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflowei oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffeR1ng agents such as magne sium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; R1nger's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubR1cants such as sodium lauryl sulfate and magnesium stearate, as well as coloR1ng agents, releasing agents, coating agents, sweetening, flavoR1ng and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Uses of compounds and pharmaceutical!? acceptable compositions [00320] In yet another aspect, the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter acti vity. In certain embodiments, the present invention provides a method of treating s condition, dis&asc, or disorder implicated by a deficiency of ABC transporter activity, the method compR1sing administeR1ng a composition compR1sing a compound of formulae ([, II, III, FV, V-A, V-B, I', I'-A, and I'-B) to a subject, preferably a mammal, in need thereof. [00321] In certain preferred embodiments, the preset, t invention provides a method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-FibR1nolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hyperoholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, MucopolysacchaR1doses, Sandhof/Tay-Sachs, CR1gler-Najjar type II, PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwaifism, Myleoperoxidase deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MaR1e Tooth syndrome, Perlizaeus-Merzbacher disease neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lat&ral 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 enc Hereditary Creutzfeldt-Jakob disease (due to PR1on 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, compR1sing the step of administeR1ng to said mammal an effective amount of a composition compR1sing a compound of formulae (I, II, HE, IV, V-A, V-B, I1,1'-A, and I'-B), or a preferred embodiment thereof as set forth above. [00322] According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis compR1sing the step of administeR1ng to said mammal a composition compR1sing the step of administeR1ng to said mammal an effective amount of a composition compR1sing a compound of formulae (I, II HI, IV, V-A, V-B, I', I'-A, and I'-B), or a preferred embodiment thereof as set forth above. [00323] According to the invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the seveR1ty of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-FibR1nolysis 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, MucopolysacchaR1doses, Sandhof/Tay-Sach;, CR1gler-Najjar typeII, PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis GDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MaR1e 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, Dentatorabal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encuphalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scbjsinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome. [00324] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the seveR1ty of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-FibR1nolysis 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, MucopolysacchaR1doses, Sandhof/Tay-Sachs, CR1gler-Najjar type n, PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis: mperfecta, Hereditary hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neui:ophyseal DI, Neprogenic DI,,Charcot-MaR1e 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 muscu; ar atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encsphalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Sch sinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome. [00325] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the seveR1ty of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physic illy discrete unit of agent appropR1ate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be; decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a vaR1ety of factors including the disorder being treated and the seveR1ty of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. [00326] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parentera[lly, intracistemally, intravaginally, intrapeR1toneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the seveR1ty of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 6.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00327] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solveats, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene giycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and seszme oils), glycerol, .tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoR1ng, and perfuming agents. [00328] Injectable preparations, for example, steR1le injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The steR1le injectable preparation may also be a steR1le injectable solution, suspension or emulsion in a nontoxic parenteral y 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, R1nger's solution, U.S.P. md isotonic sodium chloR1de solution. In addition, steR1le, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglyceR1des. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00329] The injectable formulations can be steR1lized, for example, by filtration through a bacteR1al-retaining filter, or by incorporating steR1lizing agents in the form of steR1le solid compositions which can be dissolved or dispersed in steR1le water or other steR1le injectable medium pR1or to use. [00330] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous mateR1al with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matR1ces of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly(anhydR1des). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00331] Compositions for rectal or vaginal administration are preferably suppositoR1es which can be prepared by mixing the compounds of this invention with suitable non-irR1tating excipients or carR1ers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00332] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carR1er such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulos 3, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubR1cants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also compR1se buffeR1ng agents. [00333] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose: or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteR1c coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeR1c substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00334] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteR1c coatings, release controlling coatings and other coatings well known in the pharmaceutical form .dating art. In such solid dosage forms the active compound may be admixed with at least or e inert diluent such as sucrose, lactose or starch. Such dosage forms may also compR1se, as is normal practice, additional substances other than inert diluents, e.g., tableting lubR1cants and other tableting aids such a magnesium stearate and macrocrystalline cellulose. In the cj.se of capsules, tablets and pills, the dosage forms may also compR1se buffeR1ng agents. They raay optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeR1c substances and waxes. [00335] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under steR1le conditions with a pharmaceutically acceptable carR1er and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matR1x or gel. [00336] As descR1bed generally above, the compounds; of the invention are useful as modulators of ABC transporters. Thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the seveR1ty of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder. Wh ;n hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as an "ABC transporter-mediated disease, condition or disorder".. Accordingly, in another aspect, the present invention provides a method for treating or lessening the seveR1ty of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state. [00337] The activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods descR1bed ge nerally in the art and in the Examples herein. [00338] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, pR1or to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropR1ate for the disease, or condition, being treated". [00339] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition compR1sing that therapeutic agent as the only active agsnt. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition compR1sing that agent as the only tnerapeuucaliy active agent. [00340] The compounds of this invention or pharmacoutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device compR1sing a compound of the present invention as descR1bed generally above, and in classes and subclasses herein, and a carR1er suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition compR1sing a compound of the present invention as descR1bed generally above, and in classes and subclasses herein, and a carR1er suitable for coatir. g said implantable device. Suitable coatings and the general preparation of coated implantable devices are descR1bed in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeR1c mateR1als such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilioone, polysaccaR1des, polyethylene glycol, phospholipids or combinations thereof to impat controlled release characteR1stics in the composition. [00341] Another aspect of the invention relates to modulating ABC transporter activity in a biological sample or a patient (e.g., in vitro or in vivo), which method compR1ses administeR1ng to the patient, or contacting said biological sample with a compound of formula I or a composition compR1sing said compound.. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied mateR1al obtained from a mammal or extracts thereof; and blood, saliva, uR1ne, feces, semen, tears, or other body fluids or extracts thereof. [00342] Modulation of ABC transporter activity in a biological sample is useful for a vaR1ety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biolagical and pathological phenomena; and the comparative evaluation of new modulators of ABC transporters. [00343] In yet another embodiment, a method of modulating activity of an anion channel in vitro or in vivo, is provided compR1sing the step of contacting said channel with a compound of formulae (I, II, III, IV, V-A, V-B, I', I'-A, and I'-B). In preferred embodiments, the anion channel is a chloR1de channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloR1de channel. [00344] 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, compR1sing the step of contacting said cell with a compound of formula (I, II, III, IV, V-A, V- B, I', I'-A, and I'-B). The term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity. In preferred embodiments, said functional ABC transporter is CFTR. [00345] According to another preferred embodiment, the activity of the ABC transporter is measured by measuR1ng the transmembrane voltage potential. Means for measuR1ng 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. [00346] The optical membrane potential assay utilizes voltage-sensitive FRET sensors descR1bed by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single ce Us" 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 measuR1ng fluorescence changes such as the Voltage/Ion Probe Reader (VDPR) (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). [00347] 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 n membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistR1bute 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. [00348] In another aspect the present invention provides a kit for use in measuR1ng the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo compR1sing (i) a composition compR1sing a compound of form ila (I, II, III, IV, V-A, V-B, I', I'-A, and I'-B) or any of the above embodiments; and (ii) instractions for a.) contacting the composition with the biological sample and b.) measuR1ng activity of said ABC transporter or a fragment thereof. In one embodiment, the kit further compR1ses instructions for a.) contacting an additional composition with the biological sample; fa.) measuR1ng the activity qf said ABC transporter or a fragment thereof in the presence of said additional cDmpound, and c.) compaR1ng the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I, II, III, IV, V- A, V-B, I', I'-A, and I'-B). In preferred embodiments, the kit is used to measure the density of [00349] BenzyltR1ethylamrhomum chloR1de (0.025 equivalents) and the appropR1ate dihalo compound (2.5 equivalents) were added to a substituted phenyl acetonitR1le. The mixture was heated at 10 °C and men 50% sodium hydroxide (10 equivalents) was slowly added to the mixture. The reaction was stirred at 70 °C for 12-24 hours to ensure complete formation of the cycloalkyl moiety and then heated at 130 °C for 24-48 hours to ensure complete conversion from the nitR1le to the carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted with ethyl acetate and then dichloromethane three times each to remove side products. The basic aqueous solution was acidified with concentrated hydrochloR1c acid to pH less than one and the precipitate which begsn to form at pH 4 was filtered and washed with 1 M hydrochloR1c acid two times. The soli 1 mateR1al was dissolved in dichloromethane and extracted two times with 1M hydrochloR1c acid and one time with a saturated aqueous solution of sodium chloR1de. The organic solution was dR1ed over sodium sulfate and evaporated to dryness to give the cycloalkylcarboxylic add. [00350] A mixture of benzo[l,3]dioxole-5-acetonitR1le; (5.10 g, 31.7 mmol), 1- bromo-2-chloro-ethane (9.00 mL, 109 mmol), and benzyltR1ethylarationium chloR1de (0.181 g, 0.795 mmol) was heated at 70 °C and then 50% (wt./wt.) aqueous sodium hydroxide (26 mL) was slowly added to the mixture. The reaction was stirred at 70 °C for 18 hours and then heated at 130 °C for 24 hours. The dark brown reaction mixture was diluted with water (400 mL) and extracted once with an equal volume of ethyl acetate and once with an equal volume of dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloR1c acid to pH less than one and the precipitate filtered and washed with 1 M hydrochloR1c acid. The solid mateR1al was dissolved in dichloromethane (400 mL) and extracted twice with equal volumes of 1 M hydrochloR1c acid and once with a saturated aqueous solution of sodium chloR1de. The organic solution was dR1ed over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%) ESI-MS m/z calc. ^06.1, found 207.1 (M+l)+. Retention time of 2.37 minutes. 1HNMR (400 MHz, DMSO-d6) 8 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H). [00351] Sodium hydroxide (50% aqueous solution, 7.4 equivalents) was slowly added to a mixture of the appropR1ate phenyl acetonitR1le, benzyltR1ethylammonium chloR1de (1.1 equivalents), and the appropR1ate dihalo compound (2.3 equivalents) at 70 °C. The mixture was stirred overnight at 70 °C and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dR1ed over sodium sulfate and evaporated to dryness to give the crude cyclopropanecarbonitR1le, which was used directly in the next step. [00352] The crude cyciopropanecarbonitR1le was heatsd at reflux in 10% aqueous sodium hydroxide (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloR1c acid. The precipitated solid was filtered to give the cyclopropanecarboxylic acid as a white solid. [00353] Step a: 2,2-Difluoro-benzo[ l,3]dioxole -5-carboxylic acid methyl ester A solution of 545romo-2,2-difluoro-benzo[l,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(tR1phenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, :5.00 mmol] in methanol (20 mL) containing acetonitR1le (30 mL) and tR1ethylamine (10 mL) was; stirred under a carbon monoxide atmosphere (55 PSI) at 75 °C (oil bath temperature) for 15 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was puR1fied by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5- carboxylic acid methyl ester (11.5 g), which was used directly in the next step. [00354] Step b: (2,2-Difluoro-benzo[l,3]dioxol-5-yl)-methanol Crude 2,2-difluoro-benzo[l,33dioxole-5-carboxylk acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was slowly added to a suspension of lithium aluminum hydR1de (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 °C. The mixture was then warmed to room temperature. After being stirred at room temperature for 1 hour, the reaction mixture was cooled to 0 °C and treated with water (4.1 g), followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and washed with THF. The combined filtrate was evaporated to drynes;, and the residue was puR1fied by silica gel column chromatography to give (2,2-difluoro-benzo[l,3]dioxol-5-yl)- methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil. [00355] Stepc: 5-Chloromethyl-2,2-difluoro-benzo[],3]dioxole Thionyl chloR1de (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro- benzo[l,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromettane (200 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature and the evaporated to dryness. The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 mL) and the organic layer was dR1ed over socium sulfate, filtered, and evaporated to dryness to give crude 5-chloromethyl'2,2-difluoro-be:izo[l,3]dioxole (4.4 g) which was used directly in the next step. [00356] Stepd: (2,2-Difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[l ,3]dioxole (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice aR1d extracted with ethyl acetate (300 mL). The organic layer was dR1ed over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le (3.3 g) which was used directly in the next step. [00357] Step e: l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitR1le Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le, benzyltR1ethylammonium chloR1de (3.00 g, 15.3 mmoi), and l-bromo-2-chioroeihane (4.9 g, 38 mmol) at 70 °C. The mixture was stirred overnight at 70 °C before the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dR1ed over sodium sulfate and evaporated to dryness to give crude l-(2,2-difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitR1le, which was used directly in the next step. [00358] Step f: l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropaneca:bonitR1le (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloR1c acid. The precipitated solid was filtered to give l-(2,2-difluoro- benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.2, found 243.3 (M+l)+;1H NMR (CDC13) 5 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mal) in CH3CN (700 mL) was added CH3I (111 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25 °C overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1- chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCI3) 5 7.22 (d, J = 7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H). [00360] Stepb: 4-Bromomethyl-l-chloro-2-methoxy-benzene To a solution of l-chloro-2-methoxy-4-methyl-benzene 150 g, 0.32 mol) in CCI4 (350 mL) was added NBS (57.2 g, 0.32 mol) and ABBN (10 g, 60 mtnol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was puR1fied by column chromatography on silica gel (Petroleum Ether/12tOAc = 20:1) to give 4- bromomethyl-l-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCI3) 5 7.33- 7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H). [00361] Step c: 2-(4-Chloro-3-methoxyphenyl)acetonitR1le To a solution of 4-bromomethyI-l-chIoro-2-methoxy-benzene (68.5 g, 0.29 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60 °C overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with bR1ne, dried over Na2SO4 and puR1fied by column chromatography on silica gel (Petroleum Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitR1]e (25 g, 48%). XH NMR (400 MHz, CDCl3) 8 7.36 (d, j= 8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDC13) 8 155.4, 130.8, 129.7,122.4,120.7,117.5,111.5, 56.2, 23.5. [00362] BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3- methoxyphenyl)acetonitR1le (12 g, 66 mmol) in DCM (120 mL) at -78 °C under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice-water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL x 3). The combined organic layers were washed with water, bR1ne, dried over Na2SO4, and concentrated under vacuum to give (4-chloro- 3-hydroxy-phenyl)-acetonitR1le (9.3 g, 85%). 1H NMR (300 MHz, CDC13) 5 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, j= 2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H). [00363] Step a: l-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester To a solution of l-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) at room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and bR1ne, dR1ed over anhydrous Na2SO4 and evaporated under vacuum to give l-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53.5 g, 99%). 1HNMR (CDC13,4OO MHz) 5 7.25-7.27 (m, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (m, 2 H), 1.15 (m, 2 H). [00364] Step b: l-(3-Chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester To a solution of l-(4-methoxy-phenyl)-cyclopropanecar Doxylic acid methyl ester (30.0 g, 146 mmol) and MOMC1 (29.1 g, 364 mmol) in CS2 (300 mL) was added TiCl4 (8.30 g, 43.5 mmol) at 5 °C. The reaction mixture was heated at 30 °C for 1 day and poured into ice- water. The mixture was extracted with CH2C12 (150 mL x 3). The combined organic extracts were evaporated under vacuum to give crude l-(3-chloromethyl-4-methoxy-phenyl)- cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further puR1fication. [00365] Stepc: l-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester To a suspension of crude l-(3-chloromethyl-4-metlioxy-phenyl)- cyclopropanecarboxylic acid methyl ester (20.0 g) in water (350 mL) was added Bu4NBr (4.0 g) and Na2CO3 (90.0 g, 0.85 mol) at room temperature. The reaction mixture was heated at 65 °C overnight. The resulting solution was acidified with aq. HC1 (2 mol/L) and extracted with EtOAc (200 mL x 3). The organic layer was washed with bR1ne, dR1ed over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which WE s puR1fied by column (Petroleum Ether/EtOAc 15:1) to give l-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 39%). 1H NMR (CDC13,400 MHz) 5 7.23-7.26 (m, 2 H), 6.83 (d, J = 8.0 Hz, 1 H), 4.67 (s, 2 H), 3.86 (s, 3 H), 3.62 (s, 3 H), 1.58 (q j= 3.6 Hz, 2 H), 1.14-1.17 (m, 2 H). [00366] Step d: l-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy- phenyl]cyclopropane-carboxylic acid methyl ester To a solution of l-(3-hydroxymethyl-4-methoxy-plienyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH2C12 (100 mL) were added imidazole (5.8 g, 85 mmol) and TBSC1 (7.6 g, 51 mmol) at room temperature. The mixtuie was stirred overnight at room temperature. The mixture was washed with bR1ne, dR1ed over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was puR1fied by column (Petroleum Ether/EtOAc 30:1) to give l-[3-(^rf-butyl-dimethyl-silanyloxymethyl)-4-mcthoxy-phenyl]- cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). 1H NMR (CDC13,400 MHz)  7.44- 7.45 (m, 1 H), 7.19 (dd, J- 2.0, 8.4Hz, 1 H), 6.76 (d, 7= 8.4Hz, 1 H), 4.75 (s, 2H), 3.81 (s, 3 H), 3.62 (s, 3 H), 1.57-1.60 (m, 2H), 1.15-1.18 (m, 2 H), 0.96 (s, 9 H), 0,11 (s, 6 H). [00367] Step e: l-(3-Hydroxymemyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid To a solution of l-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]- cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a solution of LiOH.H2O (1.50 g, 35.7 mmol) in water (10 mL) a: 0 °C. The reaction mixture was stirred overnight at 40 °C. MeOH was removed by evaporation under vacuum. AcOH (1 mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with b"nn'e,''dR1ed over"anhydrous Na2SO4 and evaporated under vacuum to provide l-(3- hydroxymemyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g). [00368] To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 mL) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 niL) at -78 °C. The mixture was stirred for 15 minutes, treated with a solution of 3-fluoro-4-mothoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at -78 °C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dR1ed and evaporated under reduced pressure to give crude product, which was puR1fied by column chromatography (Petroleum Ether/EtOAc 10:1) to afford 2-(3-fluoro-4-methoxyphenyl)acetonitR1le (5.0 g, 58%). 1H NMR (400 MHz, CDC13) 5 7.02-7.05 (m, 2 H), 6.94 (t, j= 8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67 (s, 2 H). 13C NMR (100 MHz, CDCI3) 5 152.3,147.5, 123.7,122.5,117.7, 115.8,113.8, 56.2, 22.6. [00369] To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at -78 °C. The mixture was stirred for 10 minutes, treated with a solution of 3-chloro-4-methoxy-benzaldehyde (1.65 g, 10 mmol) in THF (10 mL) dropwise, and continued to stir for 1.5 hours at -78 °C. To the cooled reaction mixture was added methanol (10 mL). The mixture was heate d at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were dR1ed and evaporated under reduced pressure to give crude product, which was puR1fied by column chromatography (Petroleum Ether/Et0Ac 10:1) to afford 2-(3-chloro-4- methoxyphenyl)acetonitR1le (1.5 g, 83%). 1H NMR (400 MBs, CDC13) 6 7.33 (d, /= 2.4 Hz, 1 H),7.20 (dd, J = 2.4, 8.4Hz, 1 H), 6.92 (d,j= 8.4Hz, 1 H), 2.91 (s,3H), 3.68 (s, 2H). 13C [00370] Step a: l-(4-Hydroxy-phenyl)-cyclopropinecarboxylic acid methyl ester To a solution of methyl l-(4-methoxyphenyl)cyclopropanecarboxylate (10.0 g, 48.5 mmol) in DCM (80 mL) was added EtSH (16 mL) under ice-water bath. The mixture was stirred at 0 oC for 20 min before A1C13 (19.5 g, 0.15 mmol) was added slowly at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated, and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were washed with H2O, bR1ne, dR1ed over Na2SO4 and evaporated under vacuum to give l-(4-hydroxy-phenyl)-cyclopropanecarbcxylic acid methyl ester (8.9 g, 95%). 1H NMR (400 MHz, CDCI3) § 7.20-7.17 (m, 2 H), 6.75-6.72 (m, 2 H), 5.56 (s, 1 H), 3.63 (s, 3 H), 1.60-1.57 (m, 2 H), 1.17-1.15 (m, 2H). [00371] Step b: l-(4-Hydroxy-3,5-cuiodo-phenyl)-cyclopropanecarboxylic acid methyl ester To a solution of l-(4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (8.9 g, 46 mmol) in CH3CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture wis concentrated and the residue was puR1fied by column chromatography on silica gel (Petroleum Ether/EtOAc 10:1) to give 1- (4-hydroxy-3,5-diiodo~phenyl)-cyclopropanecarboxylic acid muthyl ester (3.5 g, 18%). 1H NMR (400 MHz, CDC13) 5 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3 H), 1.59-1.56 (m, 2 H), 1.15- 1.12 (m, 2 H). [00372] Step c: l-[3,5-Diiodo-4-(2-methyI-allylo:ty)-phenyI]- cyclopropanecarboxylic acid methyl ester A mixture of l-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), K2CO3 (1.2 g, 8.6 mmol), Nal (0.1 g, 0.7 mmol) in acetone (20 ml.) was stirred at 20 °C overnight. The solid was filtered off and the filtrate was concentrated under vacuum to give l-I3,5-diiodo-4-(2-methyl-allyloxy)- phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 1H NMR (300 MHz, CDC13) 5 7.75 (s, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 4.38 (s, 2 H), 3.65 (s, 3 H), 1.98 (s, 3H), 1.62-1.58 (m, 2 H), 1.18-1.15 (m, 2 H). [00373] Step d: H3,3-Dimethyl-2,3-dihydro-benzofuran-5-yI)- cyclopropanecarboxylic acid methyl ester To a solution of 1 -[3,5-diiodo-4-(2-methyl-allyloxy )-phenyl]-cyclopropane- carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu3SnH (2.A g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated it reflux overnight. The reaction mixture was concentrated under vacuum and the residue was puR1fied by column chromatography on silica gel (Petroleum Ether/EtOAc 20:1) to give l-(33-dimethyl-2,3- dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 1HNMR (400 MHz, CDC13) 5 7,10-7.07 (m, 2 H), 6.71 (d, / = 8 Hz, 1 B), 4.23 (s, 2 H), 3.62 (s, 3 H), 1.58-1.54 (m, 2H), 1.34 (s,6H), 1.17-1.12 (m, 2 H). [00374] Step e: l-(3,3-Dimethyl-2,3-dihydrobens;ofuran-5- yl)cyclopropanecarboxylic acid To a solution of l-(3,3-dimel:hyl-2,3-dihydro-benzo::uran-5-yl)- cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 mL) was added LiOH (0.40 g, 9,5 mmol). The mixture was stirred at 40 °C overnight. HC1 (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The extracts were washed with bR1ne and dR1ed over Na2SO4- The solvent was removed under vaccum and the crude product was puR1fied by preparative HPLC to give l-(3,3-dimethyl-2,3- dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g? 4-l%). 1H NMR (400 MHz, CDCI3) 5 7.11-7.07 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H), 4.23 (s, 2 H), 1.66-1.63 (m, 2 H), 1.32 (s, 6 H), 1.26-1.23 (m, 2 H). To a solution of 3,4,5-tR1hydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 ml.) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0 °C. The mixture was acidified to pH ~ 2 by adding cone. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL x 3). The combined organic layers were dR1ed over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), vhich was used in the next step without further puR1fication. [00376] Step b: Methyl 7-methoxybenzo[d][l,3]d oxole-5-carboxylate To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 mL) was added CH2BrCl (34.4 g, 0.27 mol) and K2CO3 (75 g, 0.54 mol) at 80 °C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dR1ed over anhydrous Na2SCO4, and evaporated under reduced pressure to give the crude product, which was puR1fied by column chromatography on silica gel (Petroleum Ether/Ethyl Acetate = 10:1) to afford methyl 7-methoxybenzo[d][l,3]dioxole-5-carboxylate (12.6 g, 80%). 1HMR (400 MHz, CDCI3) 5 7.32 (s, 1 H), 7.2:1 (s, 1 H), 6.05 (s, 2 H), 3.93 (s, 3 H), 3.88 (s, 3 H). [00377] Step c:(7-Methoxybenzo[d][l,3]dioxol-5-yl)methanol To a solution of methyl 7-me1:hoxybenzo[d][l,3]dioxole-5-carboxylate (13.9 g, 0.040 moi) in THF (100 mL) was added LiAlrH4 (3.1 g, 0.080 mol) in portions at room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was cooled to 0 °C and treated with water (3.1 g) and NaOH: (10%, 3.1 mL) successively. The slurry was filtered off and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzo[d][l,3]dioxol-5-yl)methanol (7.2 g, 52%). 1H NMR (400 MHz, CDCI3) 5 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90 (s, 3 H). [00378] Stepd: 6-(ChloromethyI)-4-methoxybenzo[d][l,3Jdioxole To a solution of SOCI2 (150 mL) was added (7-methoxybenzo[d][l,3]dioxol-5- yl)methanol (9.0 g, 54 mmol) in portions at 0 °C. The mixture was stirred for 0.5 h. The excess SOC12 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO3 to pH ~ 7. The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dR1ed over anhydrous Na2SO4 and evaporated to give 6- (chloromethyl)-4-methoxybenzo[d][l,3]dioxole (10.2 g 94%). which was used in the next step without further puR1fication. 1H NMR (400 MHz, CDC13) 5 6.:58 (s, 1 H), 6.57 (s, 1 H), 5.98 (s, 2 H), 4.51 (s, 2 H), 3.90 (s, 3 H). [00379] Step e: 2-(7-Methoxybenzo[d][l,3]dioxol-5-yl)acetonitR1le To a solution of 6-(chloromethyl)-4-methoxybenzo[d][l,3]dioxole (10.2 g, 40 mmol) in DMSO (100 mL) was added NaCN (2.43 g, 50 mmol) at room temperature. The mixture was stirred for 3 h and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dR1ed over anhydrous Na2SO4 and evaporated to give the crude product, which was washed with ether to afford 2-(7- methoxybenzo[d][l,3]dioxol-5-yl)acetonitR1le (4.6 g, 45%). 1H NMR (400 MHz, CDC13) 5 6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 13C NMR (400 MHz, CDCI3) 5 148.9,143.4, 134.6,123.4,117.3,107.2,101.8, 101.3, 56.3, 23.1. [00380] Step a: l-[4-(2,2-Diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid To a stirred solution of l-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydR1de (6.7 g, 170 mmol, 60% in mineral oil) at 0 oC. After hydrogen evolution ceased, 2-brcmo-l,l-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 °C for 15 hours. The reaction mixture was poured onto ice (100 g) ar d extracted with CH2CI2. The combined organics were dR1ed over Na2SO4. The solvent was evaporated under vacuum to give crude l-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g), which was used directly in the next step without puR1fication. [00381] Step b: l-Benzofuran-5-yl-cyclopropan5carboxylic acid To a suspension of crude l-\|.4-(2,2-diethoxy-ethoxy)-phenyl]- cyclopropanecarboxylic acid (20 g, -65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at room temperature. The mixture was heated at reflux (140 °C) for 1 hour before it was cooled to room temperature and decanted from the PPA. The solvent was evaporated under vacuum to obtain the crude product, which was puR1fied by preparative HPLC to provide l-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 1H NMR (400 MHz, DMSO-d6) 5 12.25 (br s, 1 H), 7.95 (d, 7 = 2.8 Hz, 1 H), 7.56 (d, 7= 2.0 Hz, 1 H), 7.47 (d, 7= 11.6 Hz, 1 H), 7.25 (dd, 7= 2.4,11.2 Hz, 1 H), 6.89 (d, 7= 1.6 Hz, 1 H), 1.47 1.44 (m, 2 H), 1.17-1.14 (m, 2 TT) [00382] To a solution of l-(benzofuran-5-yl)cyclopropanecarboxylic acid (700 mg, 3.47 mmol) in MeOH (10 mL) was added PtO2 (140 mg, 23%) at room temperature. The stirred reaction mixture was hydrogenated under hydrogen (1 ami) at 10 °C for 3 days. The reaction mixture was filtered. The solvent was evaporated under vacuum to afford the crude product, which was puR1fied by preparative HPLC to give l-(2,:5-dihydrobenzofuran-5- yl)cyclopropanecarboxylic acid (330 mg, 47%). 1H NMR (400 MHz, CDC13) 5 7.20 (s, 1 H), 7.10 (d, 7= 10.8 Hz, 1 H), 6.73 (d, 7= 11.2 Hz, 1 H), 4.57 (t, 7= 11.6 Hz, 2 H), 3.20 (t, 7= 11.6 Hz, 2H), 1.67-1.63 (m, 2 H), 1.25-1.21 (m, 2H). To a solution of benzo[l,3]dioxol-5-yl-acetonitR1le (0.50 g, 3.1 mmol) in CH2C12 (15 mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at -78 °C under N2. The mixture was slowly warmed to room temperature and stirred overnight. H2O (10 mL) was added to quench the reaction and the CH2C12 layer was separated. The aqueous phase was extracted with CH2C12 (2 x 7 mL). The combined organics were washed with bR1ne, dR1ed over Na2SO4 and puR1fied by column chromatography on silica gel (Petroleum Ether/EtOAc 5:1) to give (3,4-dihydroxy- phenyl)-acetomtR1Te (0.25 g, 54%) as a white solid. 'H NMR (DMSO-d6,400 MHz) 5 9.07 (s, 1 H), 8.95 (s, 1 H), 6.68-6.70 (m, 2 H), 6.55 (dd, /= 8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H). [00384] Step b: 2-(2,2-Dimethylbenzo[d][l,3]dioxol-5-yl)acetonitR1le To a solution of (3,4-dihydroxy-phenyl)-acetonitR1le (0.2 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, bR1ne, and dR1ed over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was puR1fied by coluR1n chromatography on silica gel (Petroleum Ether/EtOAc 10:1) to give 2-(2,2-dimethylbenzo[d][l,3]dioxol-5-yl)acetonitR1le (40 mg, 20%). ]H NMR (CDC13,400 MHz) 5 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H). [00385] Step a: (4-Chloro-3-hydroxy-phenyl)ace1onitR1le BBr3 (16.6 g, 66 mmol) was slowly added to a solut on of 2-(4-chloro-3- methoxyphenyl)acetonitR1le (12 g, 66 mmol) in DCM (120 mL) at -78 °C under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated, and the aqueous layer was extracted with DCM (40 mL x 3). The combined organic layers were washed with water, bR1ne, dR1ed over Na2SO4, and concentrated under vacuum to give (4-chloro- 3-hydroxy-phenyl)-acetomtR1le (9.3 g, 85%). 1H NMR (300 MHz, CDC13) 5 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H). [00386] Step b: 2-(3-(Benzyloxy)-4-chloropheny] )acetonitR1le To a solution of (4-chloro-3-hydroxy~phenyl)acetonitR1le (6.2 g, 37 mmol) in CH3CN (80 mL) was added K2CO3 (10.2 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated under vacuum. The residue was puR1fied by columr. chromatography on silica gel (Petroleum EtherTEthyl Acetate 50:1) to give 2-(3-(benzyloxy)-4-chlorophenyl)acetonitR1le (5.6 [00387] Step a: 6-Methylquinoxaline To a solution of 4-methylbenzene-l,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80 °C for 2 hoars and evaporated under vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H NMR (300 MHz, CDC13) 5 8.77 (dd, J = 1.5,7.2 Hz, 2 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.87 (s, 1 H), 7.60 (dd, J = 1.5, 8.4 Hz, 1 H), 2.59 (s, 3 H). [00388] Step b: 6-Bromomethylquinoxaline To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCI4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL x 5). The extracts were concentrated under vacuum. The o:-ganics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDC13) 5 8.85-8.87 (m, 2 H), 8.10-8.13 (m, 2 H), 7.82 (dd, J = 2.1, 8.7 Hz, lH),4.70(s,2H). [00389] Step c: 2-(Quinoxalin-6-yl)acetonitR1le To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50 °C for 3 hours and then concentrated under vacuum. Water (100 mL) jmd ethyl acetate (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with bR1ne, dR1ed over Na2 SO4 and concentrated under vacuum. The residue was puR1fied by silica gel column (Petroleum Ether/EtOAc 10:1) to give 2-(qumoxalm-6-yl)acetomtnle (7.9 g, 23% over two steps). 'H NMR (300 MHz, CDC13) 8 8.88-8.90 (m, 2 H), 8.12-8.18 (m, 2 H), 7.74 (dd, J = 2.1, 8.7 Irlz, 1 H), 4.02 (s, 2 H). MS (ESI) mfz (M+H)+ 170.0. [00390] Step a: 6-Bromomethylquinoline To a solution of 6-methylquinoline (2.15 g, 15.0 miaol) in CCI4 (30 mL) was added NBS (2.92 g, 16.5 tnmol) and benzoyl peroxide (BP, 0.36 g, l.:5 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, ths mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (30 mL x 5). The extracts were concentrated under vacuum to give crude 6-bromomethylquinoline (1.8 g), which was used directly in the next step. [00391] Stepb: 2-(Quinolin-6-yI)acetonitR1le To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50 °C for 3 hours and then concentrated under vacuum. Water (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with bR1ne, dR1ed over Na2SO4 and concentrated under vacuum. The combined crude product was puR1fied by column (Petroleum Ether/EtOAc 5:1) to give 2-(qmnolin-6-yl)acetonitR1le (0.25 g, 8% over two steps).1H NMR (300 MHz, CDCI3) 5 8.95 (dd, J = 1.5,4.2 Hz, 1 H), 8.12-8.19 (m, 2 H), 7.85 (s, 1 H), 7.62 (dd, J = 2.1, 8.7 Hz, 1 H), 7.46 (q, J = 4.2 Hz, 1 H), 3.96 (s, 2 H). MS (ESI) m/e (M+H)+ 169.0. P. 2-(23-Dihvdrobenzofb][ 1,41dioxin-6-vDacetonitR1le £00392] Step a: 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4- dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80 °C overnight and then poured into ice-water. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 3) and bR1ne (100 mL), dR1e d over Na2SO4 and concentrated to dryness. The residue was puR1fied by column (Petroleum Ether /Ethyl Acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDC13) 5 7.53 (dd, J = 1.8,7.2 Hz, 2 H), 6.84-6.87 (ra, 1 H), 4.22-4.34 (m, 6 H), 1.35(t,J=7.2Hz,3H). [00393] Step b: (2,3-Dihydro~benzo[l,4]dioxin-6-yl)-methanol To a suspension of LAH (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3- dihydro-benzo[l,4]dioxin-6-yl)-methanol (10.6 g). 1HNMR (200MHz, DMSO-de) 5 6.73-6.78 (m, 3 H), 5.02 (t, J - 5.7 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17-4.20 (m, 4 H). [00394] Step c: 6-Chloromethyl-2,3-dihydro-ben7;o[l,4]dioxine A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOC12 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with NaHCO3 (sat solution), water and bR1ne, dR1ed over Na2SCO4 and concentrated to dryness to obtain 6-chlorome:hyl-2,3-dihydro- benzo[l,4]dioxine (12 g, 88% over two steps), which was used directly in next step. [00395] Step d: 2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)acetonitR1le A mixture or 6-chlorornethyl-2,3-dihydro-benzo[l,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL x 4). The combined organic layers were washed with water (50 mL x 2) and bR1ne (50 mL), dR1ed over Na2SO4 and concentrated to dryness. The residue was puR1fied by column (Petroleum Ether\Ethyl Acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][l,4]dioxin-6* yl)acetonitR1le as a yellow oil (10.2 g, 86%). 'H-NMR (300 MHz, CDC13) 8 6.78-6.86 (m, 3 H), 4.25(s,4H),3.63(s,2H). [00396] Step a: 2,254,4-Tetrafluoro-4H-benzo[l,3]dioxine-6-carboxylicacid methyl ester A suspension of 6-bromo-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (4.75 g, 16.6 mmol) and Pd(PPh3)4 (950 mg, 8.23 mmol) in MeOH (20 mL), MeCN (30 mL) and Et3N (10 mL) was stirred under carbon monoxide atmosphere (55 psi) a1; 75 °C (oil bath temperature) overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was puR1fied by silica gel column (Petroleum Ether) to give 2,2,4,4-tetrafiuoro-4H- benzo[l,3]dioxine-6-carboxylic acid methyl ester (3.75 g, 85%). 1H NMR (CDC13, 300 MHz) 5 8.34 (s, 1 H), 8.26 (dd, J = 2.1, 8.7 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 3.96 (s, 3 H). [00397] Step b: (2,2,4,4-Tetrafluoro-4H-benzo[l,3]dioxin-6-yl)methanol To a suspension of LAH (2.14 g, 56.4 mmol) in dry THF (200 mL) was added dropwise a solution of 2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxiR1e-6-carboxylic acid methyl ester (7.50 g, 28.2 mmol) in dry THF (50 mL) at 0 °C. After being stirred at 0 °C for 1 h, the reaction mixture was treated with water (2.14 g) and 10% NaOH (2.14 mL). The slurry was filtered and washed with THF. The combined filtrates were evaporated to dryness to give the crude (2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-methanol (6.5 g), which was used directly in the next step. 1H NMR (CDMR, 300 MHz) 5 7.64 (s, 1 H), 7.57-7.(50 (m, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 4.75 (s, 2 H). [00398] Step c: 6-Chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine A mixture of (2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-methanol (6.5 g) in thionyl chloR1de (75 mL) was heated at reflux overnight. The resulting mixture was concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The aqueous layer was extracted with dichloromethane (50 mL x 3) The combined organic layers were dR1ed over Na2SO4, filtrated, and concentrated under reduced pressure to give 6- chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (6.2 g), which was used directly in the next step. 1H NMR (CDC13, 300 MHz) 8 7.65 (s, 1 H), 7.61 (del, J = 2.1, 8.7 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2 H). [00399] Step d: (2,2,4,4-Tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-acetonitR1le A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL x 3). The combined organic layers were dR1ed over anhydrous Na2SO4, and evaporated to give a crude product, which was puR1fied by silica gel column (Petroleum Ether/EtOAc 10:1) to give (2,2-difluoro- benzo[l,3]dioxol-5-yl)-acetonitR1le (4.5 g, 68% over 3 steps). 1H NMR (CDC13,300 MHz) 5 7.57-7.60 (m, 2 H), 7.20 (d, J = 8.7 Hz, 1 H), 3.82 (s, 2 H). [00400] Step a: (3-Hydroxyphenyl)acetonitR1le To a solution of (3-methoxyphenyl)acetonitR1le (150 g, 1.03 mol) in CH2C12 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at -70 °C. Th; mixture was stirred and wanned to room temperature slowly. Water (300 mL) was added at 0 °C. The resulting mixture was extracted with CH2C12. The combined organic layers were dR1ed over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was puR1fied by column (Petroleum Ether /EtOAc 10:1) to give (3-hydroxyphenyl)aceto[iitR1le (75.0 g, 55%). 1H NMR (CDC13,300 MHz) 5 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H). [00401] Step b: 2-(4H-Benzo[d][l,3]dioxin-7-yl)acetonitR1le To a solution of (3-hydroxyphenyl)acetonitrile (75.0 g, '3.56 mol) in toluene (750 mL) was added paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) at room temperature. The reaction mixture was heated at reflux for 40 minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with bR1ne, dR1ed over anhydrous Na2SO4 and evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H- benzo[d][l,3]dioxin-7-yl)acetonitR1le (4.7 g, 5%). 1H NMR (300 MHz, CDC13) 5 6.85-6.98 (m, 3 H), 5.25 (d, J = 3.0 Hz, 2 H), 4.89 (s, 2 H), 3.69 (s, 2 H). [00402] To a solution of (4-hydroxyphenyl)acetonitR1]e (17.3 g, 0.13 mol) in toluene (350 mL) were added paraformaldehyde (39.0 g, 0.43 mmol) and toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) at room temperature. The react on mixture was heated at reflux for 1 hour. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with bR1ne, dR1ed over Na2SO4 and evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H- benzo[d][l,33dioxin-6-yl)acetonitR1le (7.35 g, 32%). 1H NMR (400 MHz, CDCI3) 6 7.07-7.11 (m, 1 H), 6.95-6.95 (m, 1 H), 6.88 (d, J = 11.6 Hz, 1 H), 5.24 (s, 2 E), 4.89 (s, 2 H), 3.67 (s, 2 H). [00403] To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) ;it -78 °C. The mixture was stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmoR1 in THF(50mL) dropwise, and continued to stir far 1.5 hours at -78 °C. To the cooled reaction mixture was added methanol (50 mL). The nurture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dR1ed and evaporated under reduced pressure to give crude product, which was puR1fied by column chromatography (Petroleum Ether/EtOAc 10:1) to afford 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitR1l (5.0 g, 48%). 1H NMR (300 MHz, CDC13) 5 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). 13C NMR (75 MHz, CDC13) 5 149.6,148.6,136.8,128.8,128.8,1:28.2,127.5,127.5, 122.1, 120.9, 118.2,113.8, 112.2, 71.2, 56.2, 23.3. [00404] The following Table 2 contains a list of carboxylic acid building blocks that were commercially available, or prepared by one of the methods descR1bed above: [00405] Table 2: Carboxylic acid building blocks. [00406] Step a: 2,2-Dimethyl-N-(5-methyl-pyR1din-2-yl)-propionamide To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH2C12 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2- dimethyl-propionyl chloR1de (274 mL, 2.22 mol) at 0 °C under N2. The ice bath was removed and stirR1ng was continued at room temperature for 2 hours. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2C12 (3x). The combined organics were dR1ed over Na2SO4 and evaporated to afford 2,2- dimethyl-N-(5-methyl-pyR1din-2-yl)-propionamide (350 g), which was used in the next step without further puR1fication. 1H NMR (400 MHz, CDC13) 5 8.12 (d, 7= 8.4 Hz, 1 H), 8.06 (d, J = 1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J = 1.6, 8.4 Hz, 1 H), 2.27 (s, 1H), 1.30 (s, 9 H). [00407] Step b: 2,2-Dimethyl-.N-(5-methyl-l-oxy-pyR1din-2-yl)-propionamide To a stirred solution of 2,2-dimethyl-N-(5-niethyl-pyR1din-2-yl)-propionamide (100 g, 0.52 mol) in AcOH (500 mL) was added drop-wise 30% H2O2 (80 mL, 2.6 mol) at room temperature. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was evaporated under vacuum to obtain 2,2-dimethyl-JV-(5-methyl-l-oxy-pyR1din-2-yl)- propionamide (SO g, 85% puR1ty). 1H NMR (400 MHz, CDC13) 5 10.26 (br s, 1 H), 8.33 (d, / = 8.4 Hz, 1 H), 8.12 (s, 1 H), 7.17 (dd, J = 0.8, 8.8 Hz, 1 H), 2.28 (s, 1 H), 1.34 (s, 9 H). [00408] Step c: iV-(6-Chloro-5-methyl-pyR1din-2-yl)-2,2-dimethyl-propionamide To a stirred solution of 2,2-dimethyl-A-N-(5-methyl-l-oxy-pyR1din-2-yl)-propionamide (10 g, 48 mmol) in anhydrous CH2C12 (50 mL) was added Et3N (60 mL, 240 mmol) at room temperature. After being stirred for 30 min, POC13 (20 mL) was added drop-wise to the reaction mixture. The reaction was stirred at 50 °C for 15 hours. The reaction mixture was poured into ice (200 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2C12 (3x). The combined organics were dR1ed over Na2SO4. The solvent was evaporated under vacuum to obtain the crude product, which was puR1fied by chromatography (Petroleum Ether/EtOAc 100:1) to provide A/-(6-chloro-5-methyl-pyridin-2-yl)- 2,2-dimethyl- propionamide (0.5 g, 5%). 1H NMR (400 MHz, CDC13) 5 8.09 (d, J = 8.0 Hz, 1 H), 7.94 (br s, 1 H), 7.55 (d, J = 8.4 Hz, 1H), 2.33 (s, 1 H), 1.30 (s, 9 H). [00409] Step d: 6-Chloro-5-methyl-pyR1din-2-ylamine To 7Y-(6-chloro-5-methyl-pyR1din-2-yl)- 2,2-dimethyl-prcpionamide (4.00 g, 17.7 mmol) was added 6 N HC1 (20 mL) at room temperature. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was basified with drop-wise addition of sat. NaHCO3 to pH 8-9, and then the mixture was extracted with CH2CL2 (3x). The organic phases were dR1ed over Na2SO4 and evaporated under vacuum to obtain the 6-chloro-5-metr yl-pyR1din-2-ylamine (900 mg, 36%). 1H NMR (400 MHz, CDCI3) 5 7.28 (d, / = 8.0 Hz, 1 H), 6.35 (d, / = 8.0 Hz, 1 H), 4.39 (br s, 2 H), 2.22 (s, 3 H). MS (ESI) m/z: 143 (M+H+). [00410] 2,6-Dichloro-3-(tR1fluoromethyl)pyR1dine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93 °C for 21h. The reaction was cooled to rt and extracted with EtOAc (100 mL x 3). The combined organic extracts were dR1ed over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was puR1fied by column chromatography on silica gel (2-20% EtOAc in petroleum ether as eluant) to give 6-chloro-5-(tR1fluoromethyl)pyR1din-2-amine (2.1 g, 46% yield). ]H NMR (400 MHz, DMSCMs) 5 7.69 (d, J = 8.4 Hz, 1 H), 7.13 (br s, 2 H), 6.43 (d, /= 8.4 Hz, 1 H). MS (ESI) m/z (M + H)+ 197.2 [00411] One equivalent of the appropR1ate carboxylic acid was placed in an oven- dR1ed flask under nitrogen. Thionyl chloR1de (3 equivalents) and a catalytic amount of N,N- dimethylformarnide was added and the solution was allowed to stir at 60 °C for 30 minutes. The excess thionyl chloR1de was removed under vacuum and the resulting solid was suspended in a minimum of anhydrous pyR1dine. This solution was slowly added to a stirred solution of one equivalent the appropR1ate aminoheterocycle dissolved in a minimun of anhydrous pyR1dine. The resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was evaporated to dryness, suspended in dichloromethane, and then extracted three times with IN NaOH. The organic layer was then dR1ed over sodium sulfate, evaporated to dryness, and then puR1fied by column chrornatography. [00412] 1 -Benzo[l,3]dioxol-5-yl-cyclopropanecarbo?:ylic acid (2.38 g, 11.5 mmol) was placed in an oven-dR1ed flask under nitrogen. Thionyl chloR1de (2.5 mL) and N,N- dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at 60 °C. The excess thionyl chloR1de was removed under vacuum and the resulting solid was suspended in 7 mL of anhydrous pyR1dine. This solution was then slowly added to a solution of 5-bromo-pyR1din-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 mL of anhydrous pyR1dine. The resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was then evaporated to dryness, suspended in 100 mL- of dichloromethane, and washed with three 25 mL portions of IN NaOH. The organic layer was dR1ed over sodium sulfate, evaporated to near dryness, and then puR1fied by silica gel column chromatography utlizing dichloromethane as the eluent to yield the pure product (3.46 g, 83%) ESI-MS m/z calc. 361.2, found 362.1 (M+l)+; Retention time 3.40 minutes.1]H NMR (400 MHz, DMSO-dg) 5 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H)5 7.10 (d, /= 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H). [00413] (l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven-dR1ed flask under nitrogen. Thionyl chloR1de (2.5 mL) and N,N- dimethylformamide (0.3 mL) were added and the solution was allowed to stir at 60 °C for 30 minutes. The excess thionyl chloR1de was removed under vacuum and the resulting solid was suspended in 5 mL of anhydrous pyR1dine. This solution was then slowly added to a solution of 6-bromopyR1din-2-amine (1.0 g, 5.8 mmol) suspended in 10 mL of anhydrous pyR1dine. The resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was then evaporated to dryness, suspended in 50 mL of dichloromethane, and washed with three 20 mL portions of IN NaOH. The organic layer was dR1ed over sodium sulfate, evaporated to near dryness, and then puR1fied by silica gel column chromatography utilizing dichloromethane containing 2.5 % tR1ethylamine as the eluent to yield the pure product. ESI-MS tn/z calc. 361.2, found 362.1 (M+l)+; Retention time 3.43 minutes. 1H NMR (400 MHz, DMS0-d6) 8 1.10-1.17 (m, 2H), 1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, / = 1.6 ] Iz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.73 (t, J= 8.0 Hz, 1H), 8.04 (d, J= 8.2 Hz, 1H), 8.78 (s, 1H). [00414] The compounds in the following Table 3 were prepared in a manner analogous to that descR1bed above: [00415] Table 3: Exemplary compounds synthesized i ccording to Preparations W andX. [00416] The appropR1ate aryl halide (1 equivalent) was dissolved in 1 mL of N,N- dimethylformamide (DMF) in a reaction tube. The appropR1ate borcnic acid (1.3 equivalents), 0.1 mL of an aqueous 2 M potassium carbonate solution (2 equivalents), and a catalytic amount of Pd(dppf)Cl2 (0.09 equivalents) were added and the reaction mixtire was. heated at 80 °C for three hours or at 150 °C for 5 min in the microwave. The resulting mateR1al was cooled to room temperature, filtered, and puR1fied by reverse-phase preparative liquid chromatography. [00417] l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (5-bromo-pyR1din- 2-yl)-amide (36.1 mg, 0.10 mmol) was dissolved in 1 mL of iV,JV-dimethylformamide in a reaction tube. 2,4-Dimethoxybenzeneboronic acid (24 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and a catalytic amount of Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80 °C for three hours. The resulting mateR1al was cooled to room temperature, filtered, and puR1fied by reverse-phase preparative liquid chromatography to yield the pure product as a tR1fluoroacetic acid salt. ESI-MS m/z calc. 418.2, found 419.0 (M+l)+. Retention time 3.18 minutes. lH NMR (400 MHz, CD3CN) 5 1.25-1.29 (m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H), 5.64-6.68 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.30 (d, / = 8.3 Hz, 1H), 7.96 (d, / = 8.9 Hz, 1H), 8.14 (dd, /= 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H). [00418] l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (6-bromo-pyR1din- 2-yl)-amide (36 mg, 0.10 mmol) was dissolved in 1 mL of N, Af-dimethylformarnide in a reaction tube. 4-(Dimethylamino)phenylboronic acid (21 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and (Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80 °C for three hours. The resulting mateR1al was cooled to room temperature, filtered, and puR1fied by reverse-phase preparative liquid chromatography to yield the pure product as a tR1fluoroacetic acid salt. ESL-MS m/z calc. 401.2, found 402.5 (M+l)+. Retention time 2.96 minutes. 'H NMR (400 MHz, CD3CN) 5 1.23-1.27 (m, 2H), 1.62-1.66 (m, 2H), 3.04 (s, 6H), 6.06 (s, 2H), 6.88-6.90 (m, 2H), 6.93-6.96 (m, III), 7.05-7.07 (m, 2H), 7.53- 7.56 (m, 1H), 7.77-7.81 (m, 3H), 7.84-7.89 (m, 1H), 8.34 (s, 1H). [00419] The following schemes were utilized to prep ire additional boronic esters which were not commercially available: A A. l-Methvl-4-f4-('4,4,5,5-tetramethvl-11312-dioxaboro]an-2-vI)phenvl]- sulfonylpiperazine [00420] Step a: l-(4-Bromophenylsulfonyl)-4-meth piperazine j A solution of 4-bromobenzene-l-sulfonyl chloR1de (256 mg, 1.00 mmol) in 1 mL of dichloromethane was slowly added to a vial (40 mL) containing 5 rnL of a saturated aqueous solution of sodium bicarbonate, dichloromethane (5 mL) and 1-meihylpiperazine (100 mg, 1.00 mmol). The reaction was stirred at room temperature overnight. The phases were separated and the organic layer was dR1ed over magnesium sulfate. Evaporation o: the solvent under reduced pressure provided the required product, which was used in the next step without further puR1fication. ESI-MS m/z calc. 318.0, found 318.9 (M+l)+. Retention time of 1.30 minutes. 1H NMR (300 MHZ CDCI3) 5 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, 1/ = 8.7 Hz, 2H), 3.03 (t, J = 4.2 Hz, 4H), 2.48 (t, / = 4.2 Hz, 4H), 2.26 (s, 3H). [00421] Step b: l-Methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- y])pheny]]sulfonyl-piperazine A 50 mL round bottom flask was charged with l-(4-bromophenyl-sulfonyl)-4- methylpiperazine (110 mg, 0.350 mmol), fos-(pinacolato)-diboron (93 mg, 0.37 mmol), palladium acetate (6 mg, 0.02 mmol), and potassium acetate (103 mg, 1.05 mmol) in N,N- dimethylformamide (6 mL). The mixture was degassed by gently bubbling argon through the solution for 30 minutes at room temperature. The mixture was then heated at 80 °C under argon until the reaction was complete (4 hours). The desired produci;, l-methyl-4-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-sulfonyl-piperazine, and the bi-aryl product, 4-(4- methylpiperazin-l-ylsulfonyl)-phenyl-phenylsulfonyl-4-methylpiperazine, were obtained in a ratio of 1:2 as indicated by LC/MS analysis. The mixture was used without further puR1fication. [00422] Step a: 4-Bromophenethyl-4-methylbenzenesulfonate To a 50 mL round-bottom flask was added p-bromophenethyl alcohol (1.0 g, 4.9 mmol), followed by the addition of pyR1dine (15 mL). To this clear solution was added, under argon,P-toluenesulfonyl chloR1de (TsCl) (1.4 g, 7.5 mmol) as a solid. The reaction mixture was purged with Argon and stirred at room temperature for 18 hours. The crude mixture was treated with IN HC1 (20 mL) and extracted with ethyl acetate (5 x 25 mL). The organic fractions were dR1ed over Na2SO4, filtered, and concentrated to yield 4-bromophenethyl-4- methylbenzenesulfonate (0.60 g, 35%) as a yellowish liquid. H-NMR (Acetone- d6, 300 MHz) 5 7.64 (d, J = 8.4 Hz, 2H), 7.40-7.37 (d, / = 8.7 Hz, 4H), 7.09 (d, / == 8.5 Hz, 2H), 4.25 (t, / = 6.9 Hz, 2H), 2.92 (t, J - 6.3 Hz, 2H), 2.45 (s, 3H). [00423] Step b: (4-Bromophenethyl)(methyl)sulfane To a 20 mL round-bottom flask were added 4-bromophenethyl 4- methylbenzenesulfonate (0.354 g, 0.996 mmol) and CH3SNa (0.10 £, 1.5 mmol), followed by the addition of THF (1.5 mL) and AT-methyl-2-pyrrolidinone (1.0 ml,). The mixture was stirred at room temperature for 48 hours, and then treated with a saturated aqueous solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate [4 x 10 mL), dR1ed over Na2SO4, filtered, and concentrated to yield (4-bromophenethyl) (met tiyl)sulfane (0.30 g crude) as a yellowish oil. 1H-NMR (CDC13, 300 MHz) 5 7.40 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 2.89-2.81 (m, 2H), 2.74-2.69 (m, 2H), 2.10 (s, 3H). [00424] Step c: l-Bromo-4-(2-methylsulfonyl)-ethylbjnzene To a 20 mL round-bottom flask were added (4-bromoph(!nethyl)-(methyl)sulfane (0.311g, 1.34 mmol) and Oxone (3.1 g, 0.020 mol), followed by the addition of a 1:1 mixture of acetone/water (10 mL). The mixture was vigorously stirred at room temperature for 20 hours, before being concentrated. The aqueous mixture was extracted with ethyl acetate (3 x 15 mL) and dichloromethane (3x10 mL). The organic fractions were combined, dR1ed with Na2SO4 filtered, and concentrated to yield a white semisolid. PuR1fication of the crude mateR1al by flash chromatography yielded l-bromo-4-(2-methylsulfonyl)-ethylbenzer e (0.283 g, 80%). 1H- NMR (DMSO-d6, 300 MHz) 5 7.49 (d, J- 8.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 3.43 (m, 2H), 2.99 (m, 2H), 2.97 (s, 3H). [00425] Step d: 4,4,5,5-Tetramethyl-2-(4-(2-(methylsulfonyl)ethyl)-phenyl)-l,3,2- dioxaboroliine 4,4,5,5-Tetramethyl-2-(4-(2-(methylsulfonyl)ethyl)phenyl)-1,3,2-dioxaborolane was prepared in the same manner as descR1bed above for l-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]sulfonyl-piperazine, Preparation AA. [00426] Step a: tert-Butyl-4-bromobenzylcarbamate Commercially available p-bromobenzylamine hydrochloride (1 g, 4 mmol) was treated with 10% aq. NaOH (5 mL). To the clear solution was added (Boc)2O (1.1 g, 4.9 mmol) dissolved in dioxane (10 mL). The mixture was vigorously stirred at room temperature for 18 hours. The resulting residue was concentrated, suspended in water (20 mL), extracted with ethyl acetate (4 x 20 mL), dR1ed overNa2SO4, filtered, andconcentiatedto yieldtert-butyl-4- bromobenzylcarbamate (1.23 g, 96%) as a white solid. 1H NMR (3 DO MHz, DMSO-d6) 6 7.48 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.07 (d, J = 6.3 Hz, 2H), 1.38 (s,9H). [00427] Step b: tert-Butyl-4-bromobenzyl(methyl)ca:bamate In a 60-mL vial, tert-butyl'4-broiR1obenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0j, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50 °C for 18 hours. The reaction mixture was filtered through a bed of celite and the celite v/as washed with methane! (2 x 20 mL) and dichloromethane (2 x 20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4 x 25 mL), dR1ed over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1HNMR (300 MHz, DMSO-d6) 5 7.53 (d, 7 = 8.1 Hz, 2H), 7.15 (d J= 8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H). [00428] Step c: tert-Butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzylmethylcarbarnate The coupling reaction was achieved in the same manner as descR1bed above for 1- methyI-4-[4-(4,4,5)5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-piperazine, Preparation AA. The Boc protecting group was removed after the coupling reaction by treating the crude reaction mixture with 0.5 mL of IN HC1 in diethyl ether for 18 hours before puR1fication by HPLC. [00429] Additional examples of the invention were prepared following the above procedure with non-substantial changes but using aryl boronic acids given in Table 4. [00430] Table 4: Additional exemplary compounds of formula I. (a.) The tsoc protecting group was remo\ea after me coupling reaction by treating the crude reaction mixture with 0.5 mL of IN HC1 in diethyl ether for 18 hours before puR1fication by HPLC. [00431] Further examples of the invention may be prepared by modification of intermediates as illustrated above. Compound DeR1vatization After Coupling: [00432] Step a: 4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic acid 4,4'-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in 20 mL AcOH and heated at 60 °C for lh. Solvent was evaporated and the resid'ue Was dR1ed under high vacuum. This mateR1al was used without further puR1fication. [00433] Step b: 6-(4-(Bis(4-methoxyphenyl)methylthio)phenyl)pyR1din-2-amine 4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic acid (10 nimol) and 2-amino-6- bromopyR1dine (1.73 g, 10 mmol) were dissolved in MeCN (40 roL) followed by addition of Pd(PPh3)4 (-50 mg) and aq. K2CO3 (1M, 22 mL). The reaction mixture was heated portion wise in a microwave oven (160 °C, 400 sec). The products were distR1buted between ethyl acetate and water. The organic layer was washed with water, bR1ne and dR1ed over MgSO4. Evaporation of the volatiles yielded an oil that was used without puR1fication in the next step. ESI-MS m/z calc. 428.0, found 429.1 (M+l). [00434] Stepc: l-(Benzo[d][l,3]dioxol-5-yl)-N-(6-(4-(bis(4- methoxyphenyl)methylthio)phenyl)-pyR1din-2-yl)cyclopropanecarboxamide 6-[(4,4'-DimethoxybenzhydRY)-4-thiophenyl]pyR1dir-2-ylamine (-10 mmol) and 1- benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in chloroform (25 mL) followed by the addition of TCPH (4.1 g, 12 mmol) and DIEA (5 mL, 30 mmol). The reaction mixture was heated at 65 °C for 48 h before the volatiles were removed under reduced pressure. The residue was transferred to a separatory funnel and distR1buted between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO3 (2 x 150 mL), water (1 x 150 mL), bR1ne (1 x 150 mL) and dR1ed over MgSO4. Evaporation of the solvent yielded crude l-(benzo[d][l,3]dioxol-5-yl)-iV-(6-(4-(bis(4- methoxyphenyl)-methylthio)phenyl)pyR1din-2-yl)cyclopropanecarboxamide as a pale oil. ESI- MS m/z calc. 616.0, found 617.0 (M+l) (HPLC puR1ty -85%, UV254 ran). [004351 Step d: 4-(6-(l-(Benzo[d][l,3]dioxol-5-yl)cyclopropane- j carboxamido)pyR1din~2-yl)benzenesulfomc acid l-(Benzo[d][l,3]dioxol-5-yl)-Ar-(6-(4-(bis(4-methoxyphenyl)methylthio)- phenyl)pyR1din-2-yl)cyclopropanecarboxamide (-8.5 mmol) was dissolved in AcOH (75 mL) followed by the addition of 30% H2O2 (10 mL). Additional hyc rogen peroxide (10 ml) was added 2h later. The reaction mixture was stirred at 35-45 °C overnight (-90% conversion, HPLC). The volume of reaction mixture was reduced to a third by evaporation (bath temperature below 40 °C). The reaction mixture was loaded directly onto a prep RP HPLC column (C-18) and puR1fied. Fractions with 4-(6-(l-(benzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)pyR1din-2-yl)benzenesulfonic acid were collected and evaporated (1.9 g, 43 %, cal. based on 4-mercaptophenylboromc acid). ESI-MS m/z calc. 438.0, found 438.9 (M+l). [00436] Step e: 4-(6-(l-(Benzo[d][l,3]dioxol-5 •yl)cyclopropane- carboxamido)pyR1din-2-yl)benzene- 1-sulfonyl chloR1de 4-(6-(l-(Benzo[d] [ 1,3]dioxol-5-yl)cyclopropaneca] boxamido)pyR1din-2- yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCI3 (30 mL) followed by the addition of SOC12 (3 mL) and DMF (100 fil). The reaction mixture was heated at 70-80 °C for 15min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+l). [00437] Step f: l-(Benzo[d][l,3]dioxol-5-yl)-N-(6-(4-(2-methylpyrrolidin-l- ylsulfonyl)phenyl)pyR1din-2-yl)cyclopropanecarboxamide 4-(6-(l-(Benzo[d][l,3]dioxol-5-yl)cyclopropanecaiboxamido)pyR1din-2-yl)benzene- 1-sulfonyl chloR1de (~ 35imol, 400/d solution in chloroform) was treated with 2- methylpyrrolidine followed by the addition of DIEA (100 /il). The reaction mixture was kept at room temperature for lh, concentrated, then diluted with DMSO (400/^1). The resulting solution was subjected to HPLC puR1fication. Fractions containing the desired mateR1al were combined and concentrated in vacuum centR1fuge at 40° C to provide the tR1fluoroacetic salt of target mateR1al (ESI-MS m/z calc. 505.0, found 505.9 (M+l), retention time 4.06 min). ]H NMR (250 MHz, DMSO-d6) 5 1.15 (m. 2H), 5 1.22 (d, 3H, J=6.3 Hz), 8 1.41-1.47 (m, 2H), 5 1.51 (m, 2H), 8 1.52-1.59 (m, 2H), 6 3.12 (m, 1H), 5 3.33 (m, 1H), 6 3.64 (m, 1H), 5 6.07 (s, 2H), 6 6.96-7.06 (m, 2H), 5 7.13 (d, 1H, J=1.3 Hz), 5 7.78 (d, 1H, J=8.2 Hz), S 7.88 (d, 2H, J=8.5 Hz), 5 7.94 (t, 1H, J=8.2 Hz), o 8.08 (d, IK, J=8.2 Hz), 5 8.16 (d, 2H, J=8.5 Hz), 5 8.53 (s, III). [00438] The compounds in the following table were synthesized as descR1bed above using commercially available amines. Additional exarr pies of the invention were prepared following the above procedure with non-substantial changes but using amines given in Table 5. [00439] Table 5: Additional exemplary compounds of formula I. [00440] To the starting amine (brown semisolid, 0.100 g, ~ 0.2 mmol, obtained by treatment of the corresponding f-butyloxycarbonyl deR1vative by treatment with IN HC1 in ether) was added dichloroethane (DCE) (1.5 mL), followed by the addition of pyR1dine (0.063 mL, 0778 mmol) and methansulfonyl chloR1de (0.03 mL, 0.4 mmol). The mixture was stirred at 65 °C for 3 hours. After this time, LC/MS analysis showed ~ 50 % conversion to the desired product. Two additional equivalents of pyR1dine and 1.5 equivalents of methansulfonyl chloR1de were added and the reaction was stirred for 2 hours. The residue was concentrated and puR1fied by HPLC to yield l~benzo[l,3]dioxol-5-yl-iV-[6-[4-[(methyl-methylsulfonyl- amino)methyl]phenyl]-2-pyR1dyl]-cyclopropane-l-carboxamide (0.020 g, 21% yield) as a white solid. ESI-MS m/z calc. 479.2, found 480.1 (M+l)+. FF.(J?)-l-(3-hydroxy-4-methoxyphenvl)-A^-(6-(4-(2-(hvdroxvR1ethvlVpyrrolidin-l- vlsulfonyl)phenyl)pvR1din-2-yl)cyclopropanecarboxamide [00441] (/?)-l-(3-(Benzyloxy)-4-methoxyphenyl)-iV (hydroxymethyl)pyrrolidin-l-ylsulfonyI)phenyl)pyR1din-2-yl)cycl()propanecarboxamide(28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added ana tne"reaction was stirred overnight under 1 atm of hydrogen. The catalyst was filtered off and the product was isolated by silica gel chromatography (50-80% EtOAc in hexane) to provide (R)-l-(3-hydroxy-4-methoxyphenyl)-N-(6-(4-(2-(hydrcoxymethyl)pyrrolidin-1- ylsulfonyl)phenyl)pyR1din-2-yl)cyclopropanecarboxamide (8 mg, 34%). ESI-MS mfz calc. 523.4, found 524.3 (M+l)+. Retention time of 3.17 minutes. [00442] 2-Ammo-5-phenylpyR1dine (CAS [33421 -40-8]) is C-l. GG. (R)-(l-(4-(6-AminopyR1din-2-yl)phenylsulfonvl'lpyrrolidin-2-yl) methanol hydrochloR1de (C-2) [00443] Step a: (R)-(l-(4-Bromophenylsulfonyl)])yrrolidin-2-yl)methanol To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2C12 (400 mL) and prrolidin-2- yl-methanol (53 g, 0.53 mol) was added a solution of 4-bromo-benzenesulfonyl chloR1de (127 g, 0.50 mol) in CH2C12 (100 mL). The reaction was stirred at 20 °C overnight. The organic phase was separated and dR1ed over Na2SO4. Evaporation of the solvent under reduced pressure provided (i?)-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methiinol (145 g, crude), which was used in the next step without further puR1fication. 1H NMR (CDC13,300 MHz) 5 7.66-7.73 (m, 4 H), 3.59-3.71 (m, 3 H), 3.43-3.51 (m, 1 H), 3.18-3.26 (m, 1 H) 1.680-1.88 (m, 3 H), 1.45-1.53 (m, 1 H). [00444] Step b: (R)-l-(4-Bromo-benzenesulfonyI)-2-(rert-butyl-dimethyl- silanyloxymethyl) pyrrolidine To a solution of [l-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (50.0 g, 0.16 mol) and lH-imidazole (21.3 g, 0.31 mol) in CH2C12 (500 itnL) was added tert- butylchlorodimethylsilane (35.5 g, 0.24 mol) in portions. After addition, the mixture was stirred for 1 hour at room temperature. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH2C12 (100 mL x 3). The combined organic layers were washed with bR1ne, dR1ed over Na2SO4-6 and evaporated under vacuum to give l-(4-bromo- benzenesulfonyl)-2-(tert-butyldimethylsilanyloxymethyl)pyrrolidine (68.0 g, 99%). :H NMR (300 MHz, CDC13) 5 7.63-7.71 (m, 4 H), 3.77-3.81 (m, 1 H), 3.51-3.63 (m, 2 H), 3.37-3.43 (m, 1 H), 3.02-3.07 (m, 1 H), 1.77-1.91 (m, 2 H), 1.49-1.57 (m, 2 H), 0.87 (s, 9 H), 0.06 (d, j= 1.8 Hz, 6 H). [00445] Step c: (R)-4-(2-((fcrt-butyldimethylsilyloxy)methyl)pyrrolidin-l- ylsulfonyl) phenylboronic acid To a solution of l-(4-bromo-benzenesulfonyl)-2-(tert-butyl-dimethyl- silanyloxymethyOpyrrolidine (12.9 g, 29.7 mmol) and B(O'Pr)3(8.4 g, 45 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 29.7 mL) at -70 °C. After addition, the mixture was warmed slowly to -10 °C and treated with HC1 (1M, 50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dR1ed over Na2SO4 and evaporated under vacuum. The organics were combined to give crude (R)-4-(2-((tert-butyJdimethylsilyloxy)methyl) pyrrolidin-1- . ylsulfonyl)phenylboronic acid (15.0 g), which was used directly in the next step. [00446] Step d: (6-{4-[2-(fert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidine-l- sulfonyl] phenyl}pyR1din-2-yl)carbamic acid tert-butyl ester To a solution of (6-bromo-pyR1din-2-yl)carbarnic acid tert-bnty\ ester (24.6 g, 90.0 mmol) in DMF (250 mL) were added (i?)-4-(2-((ter/-butyldimethylsilyloxy)-methyl) pyrrolidin- l-ylsulfonyl)phenylboronic acid (45.0 g), Pd(PPh.3)4 (10.4 g, 9.0 mmol), potassium carbonate (18.6 g, 135 mol) and water (200 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20 °C. The reaction mixture was then heated at 80 °C overnight. DMF was removed under vacuum. To the residue was added EtOAc (300 mL). The mixture was filtered through a pad of silica gel, which was washed with EtOAc (50 mL x 3). The combined organic extracts were evaporated under vacuum. The crude residue was puR1fied by column (Petroleum Ether/EtOAc 20:1) to give (6-{4-[2-(tert butyl-dimethyl- silan1yoxymethy pyrrolidine-1-sulfonyl} phenyl}pyR1din-2-yl)carbamic acid tert-butyl ester (22.2 g, 45% over 2-steps). 1H NMR (300 MHz, CDC13) 5 8.09 (d, J = 8.4 Hz, 2 H), 7.88-7.96 (m, 3 H), 8.09 (t, / = 7.8 Hz, 1 H),7.43-7.46 (m, 1 H), 7.38 (s, 1 H), 3.83-3,.88 (m, 1H), 3.64- 3.67 (m, 1 H), 3.53-3.59 (m, 1 H), 3.41-3.47 (m, 1 H), 3.08-3.16 (m, 1 H), 1.82-1.91 (m, 2 H), 1.67-1.69 (m, 1 H), 1,53-1.56 (m, 10 H), 0.89 (s, 9 H), 0.08 (d, J= 2.4 Hz, 6 H). [00447] Step e: {6~[4-(2~Hydroxyraethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din- 2-yl carbamic acid tert-buty ester A solution of crude (6-{4-[2-(tert-butyl-dimethyI-silanyloxymethyl)-pyrrolidine-l- sulfonyl]phenyl}-pyR1din-2-yl)carbamic acid tert-bntyl ester (22.2 g, 40.5 mmol) and TBAF (21.2 g, 81.0 mmol) in DCM (300 mL) was stirred at room temperature overnight. The mixture was washed with bR1ne (100 mL x 3), dR1ed over Na2SO4 and evaporated under vacuum to give {6-[4-(2-hydroxymethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din-2-yl}carbamic acid tert-bntyl ester (15.0 g, 86%), which was used directly in the next step. [00448] Step f: (R)-(l-(4-(6-AminopyR1din-2-yl)phenylsulfonyl)-pyrrolidin-2-yl) methanol hydrochloR1de (C-2) A solution of {6-[4-(2-hydroxymethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din-2- yl}carbamic acid tert-butyl ester (15.0 g, 34.6 mmol) in HCI/MeOH (50 mL, 2M) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated under vacuum and washed with EtOAc to give (i?)-(l-(4-(6-aminopyR1din-2- yl)phenylsulfonyl)pyrrolidin-2-yl) methanol hydrochloR1de (C-2; 11.0 g, 86%). !H NMR (300 MHz, DMSO-d6) 5 8.18 (d, /= 8.7 Hz, 2 H), 7.93-7.99 (m, 3 H), 7.31 (d, / = 7.2 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 3.53-3.57 (m, 2 H), 3.29-35 (m, 2 H), 3.05-3.13 (m, 1 H), 1.77-1.78 (m, 2 H), 1.40-1.45 (m, 2 H). MS (ESI) m/z (M+H)+ 334.2. HH. JV-(4-(6-AminopyR1dm-2-vI')benzyl)methanesulfonarnide(C-3") [00449] Step a: [6-(4-Cyano-phenyl)-pyR1din-2-yl]carbamic acid ferr-butyl ester A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyR1din-2- yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80 °C overnight. DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and bR1ne, dR1ed over Na2SO4, and concentrated to dryness. The residue was puR1fied by column (Petroleum Ether/EtOAc 50:1) on silica gel to give [6-(4-cyano-phenyl)-pyR1din-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR (300MHz, CDC13) 5 8.02-8.07 (m, 2 H), 7.95 (d, j= 8.4 Hz, 1 H), 7.71-7.79 (m, 3 H), 7.37- 7.44 (m, 2 H), 1.53 (s, 9 H). [00450] Step b: [6-(4-Aminomethyl-phenyl)-pyR1din-2-yl]-carbamic acid tert- butyl ester . A suspension of [6-(4-cyano-phenyl)-pyR1din-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50 °C for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyR1din-2-yl]-carbamic acid tert- butyl ester, which was used directly in next step. ]H NMR (300 MHz, CDC13) 5 7.83-7.92 (m, 3H), 7.70 (t, J = 7.8 Hz, 1H), 7.33-7.40 (m, 4 H), 3.92 (brs, 2 H), 1.53 (s, 9 H). [00451] Step c: {6-[4-(Methanesulfonylamino-methyl)-phenyl]-pyR1din-2- yl}carbamic acid terf-butyl ester To a solution of [6-(4-aminomemyI-phenyI)-pyR1din-2-yl]-carbamic acid terr-butyl ester (5.7 g 19 mmol) and Et3N (2.88 g, 29 inmol) in dichloromethane (50 mL) was added dropwise MsCl (2.7 g, 19 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 30 min, and then washed with water and bR1ne, dR1ed over Na2SO4 and concentrated to dryness. The residue was recrystallized with DCM/Petroleum Ether (1:3) to give (6-[4- (methanesulfonylamino-methyl)-phenyl]-pyR1din-2-yl}carbamic acid rert-butyl ester (4.0 g, 44% over two steps). 1H NMR (300 MHz, CDC13) 5 7.90-7.97 (m, 3 H), 7.75 (t, / = 8.4, 8.4 Hz, 1 H), 7.54-7.59 (m, 1 H), 7.38-7.44 (m, 3 H), 4.73 (br ,1 H), 4.37 (d, J = 6.0 Hz, 2 H), 2.90 (s, 3 H), 1.54 (s, 9 H). [00452] Step d: N-(4-(6-AmiR1opyR1din-2-yl)benzyl)methane-sulfonamide (C-3) A mixture of {6-[4-(methanesuli7onylamino-methyl)-phenyl]-pyR1din-2-yl) carbamic acid tert-butyl ester (11 g, 29 mmol) in HCl/MeOH (4M, 300 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was filtered and washed with ether to give iV-(4-(6-aminopyR1din-2-yl)benzyl)methane sulfonamide (C-3) (7.6 g, 80%) 1H NMR (300 MHz, DMSO-d6) 5 14.05 (br s, 1 H), 8.24 (br s, 2 H), 7.91-7.98 (m, 3 H), 7.70 (t, J = 6.0 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 6.9 Hz, 1 H), 6.96 (d, J = 9 Hz, 1 H), 4.23 (d, J = 5.7 Hz, 2 H), 2.89 (s, 3 H). MS (ESI) m/z (M+H)+: 278.0, II. 4-(6-AminopvR1din-2-yl)-//-m.ethvlbenzenesulfonamidehydrochloR1de(C-4) [00453] Step a: 4-Bromo-N-methyl-benzenesulfonamide To a mixture of sat aq. NaHCO3 (42 g, 0.5 mol), CH2C12 (400 mL) and methylamine (51.7 g, 0.5 mol, 30% in methanol) was added a solution of 4-bromo-benzenesulfonyl chloR1de (127 g, 0.5 mol) in CH2C12 (100 mL). The reaction was stirred at 20 °C overnight. The organic phase was separated and dR1ed over Na2SO4. Evaporation of the solvent under reduced pressure provided the 4-bromo-A7-methyl-benzenesulfonamide (121 g, crude), which was used in the next step without further puR1fication. !H NMR (CDC13,300 MHz) 5 7.64-7.74 (m, 4 H), 4.62-4.78 (m, 1H), 2.65 (d, J = 5.4 Hz, 3 H). [00454] Step b: 4-(iV-Methylsulfamoyl)phenylboronic acid To a solution of 4-bromo-A^-methyl-benzene sulfonamide (24.9 g, 0.1 mol) and BtO'P)3 (28.2 g, 0.15 mol) in THF (200 mL) was added n-BuLi (100 mL, 0.25 mol) at -70 °C. The mixture was slowly warmed to 0 °C, then 10% HC1 solution was added until pH 3-4. The resulting mixture was extracted with EtOAc. The organic layer was dR1ed over Na2SO4, and evaporated under reduced pressure to give 4-(iV-methylsulfarnoyl)phenylboronic acid (22.5 g, 96%), which was used in the next step without further puR1fication. 1H NMR (DMSO-c6, 300 MHz) 5 8.29 (s, 2 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 2.36 (d, J = 5.1 Hz, 3 H). [00455] Step c: tert-Butyl 6-(4-(iV-methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate To a solution of 4-(N-methylsulfamoyl)phenylboronic acid (17.2 g, 0.08 mol) and (6- bromo-pyR1din-2-yl)carbamic acid terf-butyl ester (21.9 g, 0.08 mol) in DMF (125 mL) and H2O (125 mL) were added Pd(PPh3)4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g, 0.12 mol). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20 °C. The reaction mixture was then heated at 80 °C for 16 h. The mixture was evaporated under reduced pressure, then poured into H2O, and. extracted with EtOAc. The organic phase was dR1ed over Na2SO4, and was evaporated under reduced pressure to give tert-butyl 6-(4-(N- methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate (21 g, 58%), which was used in the next step without further puR1fication. [00456] Step d: 4-(6-AminopyR1din-2-yl)-AT-methylbenzenesulfonamide hydrochloR1de To a solution of terr-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate (8.5 g, 23.4 mmol) in MeOH (10 mL) was added HCl/MeOH (2M, 50 mL) at room temperature. The suspension was stirred at room temperature overnight. The solid product was collected by filtration, washed with MeOH, and dR1ed to give 4-(6-aminopyR1dm-2-yl)-iV- methylbenzenesulfonamide hydrochloR1de (5.0 g, 71%). 1H NMR (300 Hz, DMSO-d6) 5 8.12 (d, /= 8.4 Hz, 2 H), 7.91-7.96 (m, 3 H), 7.58-7.66 (m, 1 H), 7.31-7.53 (m, 1 H), 7.27 (d, J = 6.6, 1 H), 6.97 (d, J = 9.0,1 H), 2.43 (d, J = 4.8 Hz, 3 H). MS (ESI) m/z (M+H)+ 264.0. [00457] The compounds in the following table were synthesized as descR1bed above using commercially available or previously descR1bed carboxylic acids and amines. [00458] Table 6: Additional exemplary compounds of formula I. [00459] Physical data for examples of the invention are given in Table 7. [00460] Additional exemplary compounds 164-388, as shown in Table 1, can also be prepared using appropR1ate starting mateR1als and methods exemplified for the previously descR1bed compounds. [00461] Table?: Physical data for exemplary compounds. ASSAYS Assays for Detecting and MeasuR1ng AF508-CFTR Correction Properties of Compounds JJ. Membrane potential optical methods for assaying AF508-CFTR modulation properties of compounds [00462] The optical membrane potential assay utilized voltage-sensitive FRET sensors descR1bed 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 measuR1ng 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). [00463] 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 redistR1bute 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. 1. Identification of Correction Compounds [00464] To identify small molecules that correct the trafficking defect associated with DF508-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" AF5O8-CFTR. The cells were subsequently R1nsed 3X with Krebs R1ngers solution and loaded with the voltage-sensitive dyes. To activate AF508- CFTR, 10 M forskolin and the CFTR potentiator, genistein (20 uM), were added along with Cl"-free medium to each well. The addition of Cl"-free medium promoted Cl efflux in response to AF508-CFTR activation and the resulting membrane depolaR1zation was optically monitored using the FRET-based voltage-sensor dyes. 2. Identification of Potentiator Compounds [00465] To identify potentiators of AF508-CFTR, a double-addition HTS assay format was developed. DuR1ng the first addition, a Cl'-free medium with or without test compound was added to each well. After 22 sec, a second addition of CF-free medium containing 2 -10 JJM forskolin was added to activate AF508-CFTR. The extracellular Cl" concentration following both additions was 28 mM, which promoted Cl" efflux in response to AF508-CFTR activation and the resulting membrane depolaR1zation was optically monitored using the FRET-based voltage-sensor dyes.3 Solutio?isBath Solution #1: (in mM) NaCl [00467] NIH3T3 mouse fibroblasts stably expressing AF5O8-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 °C in 5% CO2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamme, 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 matR1gel- coated plates and cultured for 2 hrs at 37 °C before cultuR1ng 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 hoursElectrophysiological Assays for assaying AF508-CFTR [00468] Using chamber expeR1ments were performed on polaR1zed epithelial cells expressing AF508-CFTR to further characteR1ze the AF508-CFTR modulators identified in the optical assays. FRTAF508-CFrR epithelial 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 BioengineeR1ng, 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 KQJ 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 AF508-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). 2. Identification of Correction Compounds [00469] Typical protocol utilized abasolateral to apical membrane Cl" concentration gradient. To set up this gradient, normal R1nger was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl" concentration gradient across the epithelium. All expeR1ments were performed with intact monolayers. To fully activate AF5O8-CFTR, forskolin (10 M) and the PDE inhibitor, IBMX (100 M), were applied followed by the addition of the CFTR potentiator, genistein (50 M). [00470] As observed in other cell types, incubation at low temperatures of FRT cells stably expressing AF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 M of the test compound for 24 hours at 37°C and were subsequently washed 3X pR1or 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. 5= Identification of Potentiator Compounds. [00471] Typical protocol utilized a basolateral to apical membrane Cl" concentration gradient. To set up this gradient, normal R1ngers was used on the basolateral membrane and was permeabilized with nystatin (360 g/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl" concentration gradient across the epithelium. All expeR1ments were performed 30 min after nystatin permeabilization. Forskolin (10 M) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative AF508-CFTR potentiators was compared to that of the known potentiator, genistein. 4. Solutions [00472] Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FRT^508'01™) were used for Ussing chamber expeR1ments for the putative AF5O8-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% CO2in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 jug/ml streptomycin. PR1or to use for characteR1zing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the AF5O8-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. [00473] The macroscopic AF508-CFTR current (IAFSOS) in temperature- and test compound-corrected NIH3T3 cells stably expressing AF508-CFTR were monitored using the perforated-patch, whole-cell recording. BR1efly, voltage-clamp recordings of IAFSOS were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Tnc,5 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 MO when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for Cl" (Eci) at room temperature was -28 mV. All recordings had a seal resistance > 20 GQ and a seR1es resistance using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath contained rate of 2 ml/min using a gravity-dR1ven perfusion system. 7. Identification of Correction Compounds [00474] To determine the activity of correction compounds for increasing the density of functional AF508-CFTR in the plasma membrane, we used the above-descR1bed perforated-patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 10 M forskolin and 20 M 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 AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 uM 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). PR1or to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preineubation with 10 M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls. 8. Identification of Potentiator Compounds [00475] The ability of AF508-CFTR potentiators to increase the macroscopic AF508-CFTR Cl" current (IAFSOS) in NIH3T3 cells stably expressing AF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in I^KSOS with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and duR1ng potentiator application was around -30 mV, which is the calculated EQ (-28 mV). [00476] NIH3T3 mouse fibroblasts stably expressing AF5O8-CFTR are used for whole-cell recordings. The cells are maintained at 37 °C in 5% CO2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, -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 measuR1ng the activity of correctors. 11. Single-chminel recordings [00477] The single-channel actdivities of temperature-corrected AF508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. BR1efly, 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 fabR1cated from Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MQ, when filled with the extracellular solution. The AF5O8-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 peR1fused using a gravity-dR1ven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1-2 sec. To maintain AF508-CFTR activity duR1ng the rapid peR1fusion, 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. [00478] Channel activity was analyzed from membrane patches containing active channels. The maximum number of simultaneous openings determined the number of active channels duR1ng the course of an expeR1ment. To determine the single-channel current amplitude, the data recorded from 120 sec of AF5O8-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 (Po) were determined from 120 sec of channel activity. The Po was determined using the Bio-Patch software or from the relationship Po = M(N), where I = mean current, i = single-channel current amplitude, and N = number of active channels in patch. [00479] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 °C in 5% CO2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutarnine, 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. [00480] The exemplified compounds of Table 1 have an activity with a range of about 100 nM and 20 M as measured using the assays descR1bed hereinabove. The exemplified compounds of Table 1 are found to be sufficiently efficacious as measured using the assays descR1bed hereinabove. OTHER EMBODIMENTS [00481] It is to be understood that while the invention has been descR1bed in conjunction with the detailed descR1ption thereof, the foregoing descR1ption is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyR1dyl R1ng; Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C3_6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; Each R3 and R'3 together with the carbon atom to which they are attached form an optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic; Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and Each n is 1,2, 3 or 4. 2. The compound according to claim 1, wherein one R1 that is attached to 5- or 6- position of. the pyR1dyi R1ng is aryl or heteroaryl, each optionally substituted, with 1, 2, or 3 of R ; wherein RD is -ZDR9; wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O- , -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, - NRESO2-, or -NRESO2NRE-; each R9 is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 3. The compound according to claim 2, wherein the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is phenyl optionally substituted with 1, 2, or 3 of RD. 4. The compound according to claim 3, wherein the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is a phenyl optionally substituted with 1 RD, wherein RD is -Z1^; each ZD is independently a bond or an optionally substituted branched or straight C]_ aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -O-, - NHC(O)-, -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -NRESO2-, -SO2NH-, -SO2NRE-, -NH-, or - C(O)O-. 5. The compound according to claim 2, wherein one carbon unit of ZD is replaced by -O-, - NHC(O)-, -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -SO-, -NRESO2-, -SO2NH-, -SO2NRB-, - NH-, or -C(O)O-. 6. The compound according to claim 4, wherein R9 is independently an optionally substituted aliphatic,.an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, H, or halo. 7. The compound according to claim 2, wherein the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is heteroaryl optionally substituted with 1,2, or 3 of RD. 8. The compound according to claim 7, wherein one R2 attached to the 5- or 6- position of the pyR1dyl R1ng is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 1 of RD, wherein RD is -ZDR9; each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -O-, -NHC(O)-, -C(O)NRE-, -SO2-, -NHSCV, -NHC(O)-, -NRESO2-, -SO2NH-, -SO2NRE-, -NH-, or -C(O)O-. 9. The compound according to claim 7, wherein one carbon unit of ZD is replaced by -O-, - NHC(OK -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -SO-, -NRESO2-, -SO2NH-, -SO2NRE-, - NH-, or -C(O)O-. 10. The compound according to claim 8, wherein R9 is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, H, or halo. 11. The compound according to claim 1, wherein R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is: D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy, and amino; and RD is defined above. 12. The compound according to claim 11, D is OH, an optioally substituted C1-6 aliphatic, an optionally substituted C3-Cg cycloaliphatic, an optionally substituted alkoxy, or an optionally substituted amino. wherein each of A and B is independently H, an optionally substituted Cl-6 aliphatic, an optionally substituted C3-C8 cycloaliphatic, or A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. 14. The compound according to claim 1, wherein R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is: Each of A and B is independently H, an optionally substituted C\.6 aliphatic, an optionally substituted C3-C8 cycloaliphatic; or A and B, taken together, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. 15. The compound according to claim 13, wherein A is H and B is C1-6 aliphatic optionally substituted with 1,2, or 3 of halo, oxo, alkyl, hydroxy, hydroxyallcyl, alkoxyalkyl, and an optionally substituted heterocycloaliphatic. 16. The compound according to claim 13, wherein A and B, taken together with the nitrogen atom to which they are attached, form an optionally substituted 3-7 membered heterocycloaliphatic R1ng. 17. The compound according to claim 16, wherein A and B, taken together with the nitrogen atom to which they are attached, form an optionally substituted pyrrolidinyl, pipeR1dinyl, morpholinyl, or piperazinyl. 18. The compound according to claim 16, wherein the heterocycloaliphatic R1ng is optionally substituted with 1, 2, or 3 of halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy. 19. The compound according to claim 1, wherein one Rt that is attached to the 5- or 6- position of the pyR1dyl R1ng is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1,2, or 3 of RD; wherein RD is -ZDRg; wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRBNRE-, ~CO2-, - OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, ~NRENRE-, -NRECO-, -S-, -SO-, -SO2-, - NRE-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, - NO2, -CN, -CF3, or -OCF3; and each RE is independently hydrogen, an optionally substituted Ci_ s aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 20. The compound according to claim 19, wherein one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloaliphatic. 21. The compound according to claim 20, wherein one R1 that is attached to the 5- or 6- position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloalkyl or an optionally substituted C3-Cs cycloalkenyl. 23. The compound according to claim 1, wherein R2 is hydrogen. 24. The compound according to claim 1, wherein R3 and R3 together with the carbon atom to which they are attached form an unsubstituted C3.7 cycloaliphatic or an unsubstituted heterocycloaliphatic. 25. The compound according to claim 24, wherein R3 and R'3 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl. 26. The compound according to claim 1, wherein R4 is an aryl or heteroaryl optionally substituted with 1, 2, or 3 of -ZcRg, wherein each Zc is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, -OCO-, -NRCCO2-, -O-, -NRCCONRC-, -OCONRC-, -NRCNRC-, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, - SO2NRC-, -NRCSO2-, or -NRCSO2NRC-; each R8 is independently Rc, halo, -OH, -NH2, -NO2, - CN, or -OCF3; and each R is independently an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 27. The compound according to claim 26, wherein R4 is an aryl optionally substituted with 1, 2, or 3 of ZCR8. 28. The compound according to claim 27, wherein R4 is an optionally substituted phenyl. 29. The compound according to claim 26, wherein R4 is a heteroaryl optionally substituted with 1,2, or 3 of-ZCR8. 30. The compound according to claim 26, wherein R4 is one selected from or a pharmaceutically acceptable salt thereof, wherein RD is -ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O- , ~NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, -NRES02-,or-NRES02NRE-; R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; Each RE is independently hydrogen, an optionally substituted C1-6 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; R2 is C1-4 aliphatic, C1-6 cycloaliphatic, phenyl, or heteroaryl, each of which is optionally substituted, or R2 is hydrogen; R3 and R'3 together with the carbon atom to which they are attached form a C3-7 cycloaliphatic or a C3-7 heterocycloaliphatic, each of which is optionally substituted with 1,2, or 3 of -ZBR7, wherein each ZB is independently a bond, or an optionally substituted branched or straight C1.4 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -OCO-, -NRBCO2-, -O- , -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -NRB-, -SO2NRB-, - NRBSO2-, or -NRBSO2NRB-; Each R7is independently RB, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; Each RB is independently hydrogen, an optionally substituted C1-6 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R4 is an aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 of -ZcRg, wherein each Zc is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, -OCO-, -NRCCO2-, -O- , -NRCCONRC-, -OCONRC-, -NRCNRC-, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -SO2NRC-, - NRCSO2-, or -NRCSO2NRC-; Each R8 is independently Rc, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; and Each Rc is independently an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 32. The compound according to claim 31, wherein Z is independently a bond or an optionally substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -SO2-, -CONRE-, -NRESO2-, or -SO2NRE-. 33. The compound according to claim 32, wherein ZD is an optionally substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -SO2-. 34. The compound according to claim 31, wherein Rp is an optionally substituted heteroaryl or an optionally substituted heterocycloaliphatic. 35. The compound according to claim 33, wherein R9 is an optionally substituted heterocycloaliphatic having 1 or 2 nitrogen atoms and R9 attaches directly to -SO2- via one R1ng nitrogen. 36. The compound according to claim 1, wherein said compound has formula V-A or formula V-B: or a pharmaceutically acceptable salt thereof, wherein: T is an optionally substituted C1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by -CO-, -CS-, -COCO-, -SO2-, -B(OH)-, or -B(O(C1-6 Each of R11 and R1" is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy; RD1 is attached to carbon number 3" or 4"; each RD1 and RD2 is -ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straightC1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, ~SO2-, -NRE-, - SO2NRE-, -NRESO2-, or -NRESO2NRE-; R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; or RD1 and RD2, taken together with atoms to which they are attached, form a 3-8 membered saturated, partially unsaturated, or aromatic R1ng with up to 3 R1ng members independently selected from the group consisting of O, NH, NRE, and S; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 37. The compound according to claim 36, wherein up to two methylene units of T are optionally substituted by -CO-, -CS-, -B(OH), or -B(O(C1-6 alkyl). 38. The compound according to claim 36, wherein T is an optionally substituted chain selected from the group consisting of -CH2- and -CH2CH2-. 39. The compound according to claim 36, wherein T is optionally substituted by -ZER1o; wherein each ZB is independently a bond or an optionally substituted branched or straightC1-6 aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced by -CO-, -CS-, -CONRF-, -CONRFNRF~, -CO2-, -OCO-, -NRFCO2-, -O-, -NRFCONRF-, - OCONRF-, -NRFNRF-, -NRFCO-, -S-, -SO-, -SO2-, -NRF-, -SO3NRF-, -NRFSO2-, or - NRFSO2NRF-; R10is independently RF, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; each RF is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 40. The compound according to claim 39, wherein T is optionally substituted by F, Cl, C1-6 alkyl, C3_8 cycloalkyl, phenyl, naphthyl, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), -O-phenyl, or C3-8 spiroaliphatic. 42. The compound according to claim 41, wherein T is selected from the group consisting of -CH2-, -CF2-, and -C(CH3)2-. 43. The compound according to claim 36, wherein ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -CO-, -SO-, -SO2-, -CO2-, -OCO-, -CONRE-, -NRECO-, NRECO2-, -O-, -NRESO2-,or-SO2NRE-. 44. The compound according to claim 36, wherein RD1 is -ZDRci, wherein R9 is halo, -OH, - NH2, -CN, -CF3, -OCF3, or an optionally substituted group selected from the group consisting of C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, Q5-10 aryl, and 5-10 membered heteroaryl. 45. The compound according to claim 44, wherein R9 is F, Cl, -OH, -CN, -CF3, or -OCF3. 46. The compound according to claim 44, wherein R9 is selected from the group consisting ofC1-6 straight or branched alkyl or C2-6 straight or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE. 47. The compound according to claim 44, wherein R9 is C3-8 cycloaliphatic optionally substituted by 1 or 2 substituents independently selected from the group consisting of RB, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE. 48. The compound according to claim 47, wherein R9 is cyclopropy.l, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 49. The compound according to claim 44, wherein R9 is a 3-8 membered heterocyclic with 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NRE, and S; wherein said heterocyclic is optionally substituted by 1 or 2 substituents independently selected from the group RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and ~CONRBRE. 50. The compound according to claim 49, wherein R9 is an optionally substituted 3-8 membered heterocyclic is The compound according to claim 49, wherein R9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i- propyl, f-butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(O)NH2, -CH2O(C1-6 alkyl), - CH2CH2OCC(C1-6 alkyl), and -C(O)(C1-6 alkyl). 52. The compound according to claim 44, wherein R9 is 5-8 membered heteroaryl with 1 or two R1ng atom independently selected from the group consisting of O, S, and NRE; wherein said heteroaryl is optionally substituted by 1 or 2 substituents independently selected from the group RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -C0NRERE. 53. The compound according to claim 52, wherein R9 is 54. The compound according to claim 52, wherein R9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting, of F, Cl, methyl, ethyl, z-propyl, t- butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(0)NH2, -CH2OC1-6 alkyl), -CH2CH2O(C1-6 alkyl), and -CCO)(C1-6 alkyl). 55. The compound according to claim 36, wherein RD1 and RD2, taken together with carbons to which they are attached, form an optionally substituted 3-8 membered saturated, partially unsaturated, or aromatic R1ng with 0-2 R1ng atoms independently selected from the group consisting of O, NH, NRE, and S. 56. The compound according to claim 55, wherein Rm and RD2, taken together with phenyl containing carbon atoms 3" and 4", is 57. The compound according to claim 55, wherein RD1 and RD2, taken together with phenyl containing carbon atoms 3" and 4", is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and - CONRERE. 58. The compound according to claim 36, wherein RD2 is selected from the group consisting of H, C1-6 aliphatic, halo, -CN, -NH2, -CH2NH2, -OH, -O(Cl6 aliphatic), -CH2OH, -SO2(C1-6 aliphatic), -KH-SO2(C1-6 aliphatic), -C(O)O(C1-6 aliphatic), -C(O)OH, -NHC(O)(C1-6 aliphatic), -C(O)NH2, -C(O)NH(C1-6 aliphatic), and -C(O)N(C1-6 aliphatic)2. or a pharmaceutically acceptable salt thereof, wherein: one of G1 and G2 is N and the other of Gi and G2 is CH; Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R1 is an optionally substituted aryl or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyR1dyl R1ng; Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C1-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; Each R3 and R'3 together with the carbon atom to which they are attached form an optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic; Each R4 is an optionally substituted aryi or an optionally substituted heteroaryl; and Each nisi, 2,3, or 4. 60. The compound according to claim 59, wherein the compound has formula (I'-A) or formula (I'-B). or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R'3, R4, and n are defined above. 61. A compound according to any one of claims 1-59, wherein the compound is selected from Table 1. 62. A pharmaceutical composition compR1sing: (i) a compound according to any one of claims 1-61; and (ii) a pharmaceutically acceptable carR1er. 63. The composition according to claim 62, optionally further compR1sing a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutR1tional agent. 64. A method according to modulating ABC transporter activity compR1sing the step of contacting said ABC transporter with a compound of formula (I) or formula (I1): wnerem: one of G1 and G2 is a nitrogen, and the other is a carbon; each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyR1dyl R1ng; each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; each R3 and R3 together with the carbon atom to which they are attached form an optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic; each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and each n is 1-4. 65. The method according to claim 64, wherein the ABC transporter is CFTR. 66. A method of treating or lessening the seveR1ty of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibR1nolysis 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, mucopolysacchaR1doses, Sandhof/Tay-Sachs, CR1gler-Najjar type II, polyendocR1nopathy/hypeR1nsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, pR1mary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-MaR1e 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 pR1on protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, said method compR1sing the step of administeR1ng to said patient an effective amount of a compound of formula I or formula I1 according to any oe of claims 1-61. 67. A kit for use in measuR1ng the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, compR1sing: (i) a composition compR1sing a compound of formula (I) or formula (I1) according to any one of claims 1-61; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuR1ng activity of said ABC transporter or a fragment thereof. 68. The kit according to claim 67, further compR1sing instructions for a) contacting an additional composition with the biological sample; b) measuR1ng the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c) compaR1ng the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I) or formula (I'). 69. The kit according to claim 68, wherein the kit is used to measure the density of CFTR. Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

Full Text

HETEROCYCLIC MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[00100] The present application claims the benefit under 3 5 U.S .C. § 119 of
United States Provisional Application No. 60/734,506, filed on November 8, 2005, United
States Provisional Application No. 60/754,086, filed on December 27, 2005, and United States
Provisional Application No. 60/802,458, filed on May 22, 2006, the entire contents of each of
the above applications being incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[00101] The present invention relates to modulators of ATP-Binding Cassette
("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane
Conductance 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
[00102] ABC transporters are a family of membrane transporter proteins that
regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and
xenobiotics, as well as anions. 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 multi-drug resistance proteins (like the MDR1-P glycoprotein,
or the multi-drug resistance protein, MRP1), defending malignant cancer cells against
chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into
7 families based on their sequence identity and function.
[00103] ABC transporters regulate a variety of important physiological roles
within the body and provide defense against harmful environmental compounds. Because of
this, they represent important potential drug targets for the treatment of diseases associated with
defects in the transporter, prevention of drug transport out of the target cell, and intervention in
other diseases in which modulation of ABC transporter activity may be beneficial.
[00104] One member of the ABC transporter family commonly associated with
disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in a variety of
cells types, including absorptive and secretory epithelia cells, where it regulates anion flux
across the membrane, as well as the activity of other ion channels and proteins. In epithelia
cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport

throughout the body, including respiratory and digestive tissue. CFTR is composed of
approximately 1480 amino acids that encode a protein made up of a tandem repeat of
transmembrane domains, each containing six transmembrane helices and a nucleotide binding
domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain
with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
[00105] The gene encoding 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 causes mutations in
CFTR resulting in Cystic Fibrosis ("CF"), the most common fatal genetic disease in humans.
Cystic Fibrosis affects approximately one in every 2,500 infants 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 debilitating and fatal effects of CF, including chronic lung
disease.
[00106] In patients with cystic fibrosis, mutations in CFTR endogenously
expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance
in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced
mucus accumulation in the lung and the accompanying microbial infections that ultimately
cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from
gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In
addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among
females with cystic fibrosis. 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.
[00107] 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). To date, > 1000 disease causing
mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/). The
most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid
sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately
70% of the cases of cystic fibrosis and is associated with a severe disease.

[00108] The deletion of residue 508 in AF508-CFTR prevents the nascent protein
from folding correctly. This results in the inability of the mutant protein to exit the ER, and
traffic to the plasma membrane. As a result, the number of channels present in the membrane is
far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking,
the mutation results in defective channel gating. Together, the reduced number of channels in
the membrane and the defective gating lead to reduced anion transport across epithelia leading
to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies
have shown, however, that the reduced numbers of AF508-CFTR in the membrane are
functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-
528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In
addition to AF508-CFTR, other disease causing mutations in CFTR that result in defective
trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion
secretion and modify disease progression and/or severity.
[00109] 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+/2C17K+ co-transporter, Na+-K+-ATPase pump and the basolateral
membrane K+ channels, that are responsible for the uptake of chloride into the cell.
[00110] 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 basoiateral 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+/2C17K+ 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.
[00111] In addition to Cystic Fibrosis, 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 (COPD), dry eye disease, and Sjo"gren's
Syndrome.

[00112] 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 Sjogrens'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. Sjogrens'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.
[0.0113] As discussed above, it is believed that the deletion of residue 508 in
AF508-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)]. The diseases associated with the first class of ER malfunction are

Cystic fibrosis (due to misfolded AF508-CFTR as discussed above), Hereditary emphysema
(due to al-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 p-
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
hypoparathyroidism (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 al-Antitrypsin (PiZ variant), Congenital hyperthyroidism,
Osteogenesis imperfecta (due to Type I, n, IV procollagen), Hereditary hypofibrinogenemia
(due to Fibrinogen), ACT deficiency (due to al-Antichymotrypsin), Diabetes insipidus (DI),
Neurophyseal DI (due to Vasopvessin 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 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 (due to
lysosomal cc-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing
defect).
[00114] In addition to up-regulation of CFTR activity, reducing anion secretion
by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which
epithelial water transport is dramatically increased as a result of secretagogue activated chloride
transport. The mechanism involves elevation of cAMP and stimulation of CFTR.
[00115] 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, impaired growth and death.
[00116] 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:

[00117] Secretory diarrheas are also a dangerous condition in patients of acquired
immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16
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.
[00118] 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.
[00119] The most common diarrhea 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 cryptosporidium, giardia lamblia, and salmonella,
among others.
[00120] 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.
[00121] 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.
[00122] There is a need for method of treating ABC transoter mediated
diseases using such modulators of ABC transporter activity.
[00123] There is a need for methods of modulating an ABC transporter activity in
an ex vivo cell membrane of a mammal.
[00124] 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.
[00125] There is a need for methods of treating CFTR-mediated diseases using
such modulators of CFTR activity.
[00126] There is a need for methods of modulating CFTR activity in an ex vivo
cell membrane of a mammal.

SUMMARY OF THE INVENTION
[00127] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter
activity. These compounds have the general formula (I):

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R3, R4, and n are
described herein.
[00128] These compounds and pharmaceutically acceptable compositions are
useful for treating or lessening the severity of a variety of diseases, disorders, or conditions,
including, but not limited to, 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-Najjar type H,
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, amyotropnic lateral sclerosis, progressive
supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as
Huntingdon, 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, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
[00129] As used herein, the following definitions shall apply unless otherwise
indicated.

[00130] 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 vitro. 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.
[00131] The term "CFTR" as used herein means cystic fibrosis transmembrane
conductance regulator or a mutation thereof capable of regulator activity, including, but not
limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for
CFTR mutations).
[00132] The term "modulating" as used herein means increasing or decreasing,
e.g. activity, by a measurable amount. Compounds that modulate ABC Transporter activity,
such as CFTR activity, by increasing the activity of the ABC Transporter, e.g., a CFTR anion
channel, are called agonists. Compounds that modulate ABC Transporter activity, such as
CFTR activity, by decreasing the activity of the ABC Transporter, e.g., CFTR anion channel,
are called antagonists. An agonist interacts with an ABC Transporter, such as CFTR anion
channel, to increase the ability of the receptor to transduce an intracellular signal in response to
endogenous ligand binding. An antagonist interacts with an ABC Transporter, such as CFTR,
and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to
decrease the ability of the receptor to transduce an intracellular signal in response to
endogenous ligand binding.
[00133] The phrase "treating or reducing the severity of an ABC Transporter
mediated disease" refers both to treatments for diseases that are directly caused by ABC
Transporter and/or CFTR activities and alleviation of symptoms of diseases not directly caused
by ABC Transporter and/or CFTR anion channel activities. Examples of diseases whose
symptoms may be affected by ABC Transporter and/or CFTR activity include, but are not
limited to, 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-Najjar 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

D1, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases
such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive
supranudear 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, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
[00134] For purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and
Physics, 75th Ed. Additionally, general principles of organic chemistry are described in
"Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and
"March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley
& Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[00135] For purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and
Physics, 75th Ed. Additionally, general principles of organic chemistry are described in
"Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and
"March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley
& Sons, New York: 2001.
[00136] As used herein the term "aliphatic' encompasses the terms alkyl, alkenyl,
alkynyl, each of which being optionally substituted as set forth below.
[00137] As used herein, an "alkyl" group refers to a saturated aliphatic
hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be
straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An
alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as
halo, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g.,
heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano,
amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino], amino [e.g., aliphaticamino,
cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphaticsulfonyl], sulfinyl,

sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,
cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some
examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl,
and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydfoxyalkyl,
aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkylsulfonylamino)alkyl),
aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, cyanoalkyl, or haloalkyl.
[00138] As used herein, an "alkenyl" group refers to an aliphatic carbon group
that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl
group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but
are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be
optionally substituted with one or more substituents such as halo, cycloaliphatic,
heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, acyl [e.g.,
aliphaticcarbonyl, cycloaliphaticcarbonyl, arylcarbonyl, heterocycloaliphaticcarbonyl or
heteroarylcarbonyl], amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino
alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino, or
aliphaticsulfonylamino], sulfonyl [e.g., alkylsulfonyl, cycloaliphaticsulfonyl, or arylsulfonyl],
sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,
cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
[00139] As used herein, an "alkynyl" group refers to an aliphatic carbon group
that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl
group can be straight or branched. Examples of an alkynyl group include, but are not limited to,
propargyl and butynyl. An alkynyl group can be optionally substituted with one or more
substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,
heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g.,
aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or
cycloaliphaticsulfinyl], sulfonyl [e.g., aliphaticsulfonyl, aliphaticaminosulfonyl, or
cycloaliphaticsulfonyl], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino,

arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino,
heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea,
thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,
heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or
(heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.
[00140] As used herein, an "amido" encompasses both "aminocarbonyl" and
"carbonylamino". These terms when used alone or in connection with another group refers to
an amido group such as N(RXRY)-C(O)- or RYC(O)-N(RX)- when used terminally and -C(O)- .
N(RX)- or -N(RX)-C(O)- when used internally, wherein Rx and RY are defined below.
Examples of amido groups include alkylamido (such as alkylcarbonylamino or
alkylcarbonylamino), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido,
(heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or
cycloalkylamido.
[00141] As used herein, an "amino" group refers to -NR R wherein each of R
and RY is independently hydrogen, alkyl, cycloaliphatic, (cycloaliphatic)aliphatic, aryl,
araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,
sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl,
or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally
substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When
the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -
NRX-. Rx has the same meaning as defined above.
[00142] As used herein, an "aryl" group used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic (e.g., phenyl); bicyclic (e.g.,
indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl
tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the
monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring
system is aromatic. The bicyclic and tricyclic ring systems include benzofused 2-3 membered
carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more Co,.
8 carbocyclic moieties. An aryl is optionally substituted with one or more substituents including
aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic;

heterocycloaJiphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy;
(heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a
benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [ e.g., aliphaticcarbonyl;
(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g.,
aliphaticsulfinyl or cycloaliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanylj; cyano; halo;
hydroxy; mercapto, sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively,
an aryl can be unsubstituted.
[00143] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-,
di (such as p,/n-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,
(((alkylamino)alkyl)aminocarbonyl)aryl, (allcyJcarbony2)aminoaryl, (arylaminocarbonyl)aryl,
and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or
((dialkyi)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,
(aminosulfony])aryl]; (alkylsulfony])aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl;
(hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;
(((alkylsulfonyl)amino)alkyl)aryl;((heterocycloaliphatic)carbony])aryl;
((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl;
(trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-w-cyanoaryl; p-halo-»?-aminoaryl;
or(m-(heterocycloaliphatic)-0-(alkyl))aryl.
[00144] As used herein, an "araliphatic" such as an "aralkyl" group refers to an
aliphatic group (e.g., aC1-4 alkyl group) that is substituted with an aryi group. "Aliphatic,"
"alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is
benzyl.
[00145] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C1-4
alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined
above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one
or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl,
hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or
cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl,
alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido

[e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl,
mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[00146] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9,10, or 11)
membered structures that form two rings, wherein the two rings have at least one atom in
common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g.,
bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
[00147] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl"
group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.
[00148] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic
mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,
bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl,
azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. A "cycloalkenyl" group, as used
herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or
more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-
enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl,
cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl
group can be optionally substituted with one or more substituents such as aliphatic [e.g., alkyl,
alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic,
(heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy,
(heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy,
aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,
(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or
(heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or
alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,
(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl,
or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl
and arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea,

thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[00149] As used herein, "cyclic moiety" includes cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, each of which has been defined previously.
[00150] As used herein, the term "heterocycloaliphatic" encompasses a
heterocycloalkyl group and a heterocycloalkeny] group, each of which being optionally
substituted as set forth below.
[00151] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered
mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring
structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations
thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl,
tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl,
morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl,
octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,
octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-
bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03>7]nonyl. A monocycbc heterocycloalkyl
group can be fused with a phenyl moiety such as tetrahydroisoquinoline. A
"heterocycloalkenyl" group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-
membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds,
and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and
bicycloheteroaliphatics are numbered according to standard chemical nomenclature.
[00152] A heterocycloalkyl or heterocycloalkenyl group can be optionally
substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkyny.l],
cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic,
aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy,
(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g.,
(aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)
aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino,
(heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-,
alkoxycaibonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo,
hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl],

sulfanyl [e.g., alkylsulfanylj, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[00153] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or
tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a
heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is
aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A
heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a
benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic
moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolmyl, orisoquinolinyl). Some examples of heteroaryl are azetidinyl,
pyridyl, IH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl,
benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole,
benzo[l,3]dioxole, benzo[b]furyl, benzol>}thiophenyl, indazolyl, benzimidazolyl,
benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cirmolyl, phthalazyl, quinazolyl, quinoxalyl,
isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[00154] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-
pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-
thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or
1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical
nomenclature.
[00155] Without limitation, bicyclic heteroaryls include indolizyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo [b]jfuryl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl,
indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl,
benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl,
quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to
standard chemical nomenclature.
[00156] A heteroaryl is optionally substituted with one or more substituents such
as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy, aryloxy; heteroaryloxy; (araliphatic)oxy;
(heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or
heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g.,
aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl;

or (heteroaraliphatic)carbonylj; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonylj; sulfinyl
[e.g., aliphaticsulfmyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto;
sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be
imsubstituted.
[00157] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl
[e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl
and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amitio)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
(((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and
((alkylcarbonyl)amino)heteroaryi]; (cyanoaikyl)heteroatyl; (alkoxy)heteroaryl;
(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,
(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl;
(hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl;
(((alkylsulfonyl)araino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl;
(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl, and
(haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
[00158] A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein,
refers to an aliphatic group (e.g., a C1-4 alkyl group) that is substituted with a heteroaryl group.
"Aliphatic," "alkyl," and "heteroaryl" have been defined above.
[00159] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a
C1-4 alkyl group) that is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" have
been defined above. A heteroaralkyl is optionally substituted with one or more substitueuis
such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl),
alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,
heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy,
aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylarnino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[00160] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl,
cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined
previously.
[00161] As used herein, an "acyl" group refers to a formyl group or RX-C(O)-
(such as -alkyl-C(O)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have been
defined previously. Acetyl andpivaloyl are examples of acyl groups.
t
[00162] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a
heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally

substituted as previously defined.
[00163] As used herein, an "alkoxy" group refers to an alkyl-O- group where
"alkyl" has been defined previously.
[00164] As used herein, a "carbamoyl" group refers to a group having the
structure -O-CO-NRXRY or -NRX-CO-O-RZ wherein Rx and Ry have been defined above and
Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[00165] As used herein, a "carboxy" group refers to -COOH, -COORX, -OC(O)H,
-OC(O)RX when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal
group.
[00166] As used herein, a "haloaliphatic" group refers to an aliphatic group
substituted with 1, 2, or 3 halogen. For instance, the term haloalkyl includes the group -CF3.
[00167] As used herein, a "mercapto" group refers to -SH.
[00168] As used herein, a "sulfo" group refers to -SO3H or -SO3RX when used
terminally or -S(O)3- when used internally.
[00169] As used herein, a "sulfamide" group refers to the structure -NRX-S(O)2-
NRYRZ when used terminally and -NRX-S(O)2-NRY- when used internally, wherein Rx, RY, and
Rz have been defined above.
[00170] As used herein, a "sulfamoyl" group refers to the structure -S(O)2-NRXRY
or -NRX-S(O)2-RZ when used terminally; or -S(O)2-NRX- or -NRX -S(O)2- when used
internally, wherein Rx, RY, and Rz are defined above.

[00171] As used herein a "sulfanyl" group refers to -S-Rx when used terminally
and -S- when used internally, wherein Rx has been defined above. Examples of sulfanyls
include alkylsulfanyl.

[00172] As used herein a "sulfinyl" group refers to -S(O)-R when used
terminally and -S(O)- when used internally, wherein Rx has been defined above.
[00173] As used herein, a "sulfonyl" group refers to-S(O)2-RX when used
terminally and -S(O)2- when used internally, wherein Rx has been defined above.
[00174] As used herein, a "sulfoxy" group refers to -O-SO-RX or -SO-O-RX,
when used terminally and -O-S(O)- or -S(O)-O- when used internally, where Rx has been
defined above.
[00175] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine,
bromine or iodine.
[00176] As used herein, an "alkoxycarbonyl," which is encompassed by the term
carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-
[00177] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-
alkyl-, wherein alkyl has been defined above.
[00178] As used herein, a "carbonyl" refer to -C(O)-.
[00179] As used herein, an "oxo" refers to =O.
[00180] As used herein, an "aminoalkyl" refers to the structure (Rx RY)N-alkyl-.
[00181] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.
[00182] As used herein, a "urea" group refers to the structure -NRX-CO-NRYRZ
and a "thiourea" group refers to the structure -NRX-CS~NRYRZ when used terminally and -NRX-
CO-NRY- or -NRX-CS-NRY- when used internally, wherein Rx, RY, and Rz have been defined
above.
[00183] As used herein, a "guanidino" group refers to the structure -N=C(N (R
RY))N(RXRY) wherein Rx and RY have been defined above.
[00184] As used herein, the term "amidino" group refers to the structure -
C=(NRX)N(RXRY) wherein Rx and RY have been defined above.
[00185] In general, the term "vicinal" refers to the placement of substituents on a
group that includes two or more carbon atoms, wherein the substituents are attached to adjacent
carbon atoms.
[00186] In general, the term "geminal" refers to the placement of substituents on a
group that includes two or more carbon atoms,- wherein the substituents are attached to the same

[00187] The terms "terminally" and "internally" refer to the location of a group
within a substituent. A group is terminal when the group is present at the end of the substituent
not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RxO(O)C-alkyl is an
example of a carboxy group used terminally. A group is internal when the group is present in
the middle of a substituent to at the end of the substituent bound to the rest of the chemical
structure. Alkylcarboxy (e.g., alkyI-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-
C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.
[00188] As used herein, the term "amidino" group refers to the structure
-C=(NRX)N(RXRY) wherein Rx and RYhave been defined above.
[00189] As used herein, "cyclic group" includes mono-, bi-, and tri-cyclic ring
systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has
been previously defined.
[00190] As used herein, a "bridged bicyclic ring system" refers to a bicyclic
heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are
bridged. Examples of bridged bicyclic ring systems include, but are not limited to,
adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo(2.2.2]octyl, bicyclo[3.3.1]nonyl,
bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-
bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system
can be optionally substituted with one or more substituents such as alkyl (including
carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,
cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy,
aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,
arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino,
cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl,
sulfamide, oxo, or carbamoyl.
[00191] As used herein, an "aliphatic chain" refers to a branched or straight
aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic
chain has the structure -[CH2]v-, where v is 1-6. A branched aliphatic chain is a straight
aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain

has the structure--[CHO]v- where Q is hydrogen or an aliphatic group; however, Q shall be an
aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl
chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
[00192] The phrase "optionally substituted" is used interchangeably with the
phrase "substituted or unsubstituted." As described herein, compounds of the invention can
optionally be substituted with one or more substituents, such as are illustrated generally above,
or as exemplified by particular classes, subclasses, and species of the invention. As described
herein, the variables R1, R2, R3, and R4, and other variables contained therein formulae I
encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific
groups for the variables R1, R2, R3, and R4, and other variables contained therein can be
optionally substituted with one or more substituents described herein. Each substituent of a
specific group is further optionally substituted with one to three of halo, cyano, oxoalkoxy,
hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted
with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo,
cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example,
the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to
three of halo, cyano, allcoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are
bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with
the atom(s) to which they are bound.
[00193] In general, the term "substituted," whether preceded by the term
"optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the
radical of a specified substituent. Specific substituents are described above in the definitions
and below in the description of compounds and examples thereof. Unless otherwise indicated,
an optionally substituted group can have a substituent at each substitutable position of the
group, and when more than one position in any given structure can be substituted with more
than one substituent selected from a specified group, the substituent can be either the same or
different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to
another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share
one common atom. As one of ordinary skill in the art will recognize, combinations of
substituents envisioned by this invention are those combinations that result in the formation of
stable or chemically feasible compounds.
[00194] The phrase "up to", as used herein, refers to zero or any integer number
that is equal or less than the number following the phrase. For example, "up to 3" means any
one of 0,1, 2, and 3.

[00195] The phrase "stable or chemically feasible," as used herein, refers to
compounds that are not substantially altered when subjected to conditions to allow for their
production, detection, and preferably their recovery, purification, and use for one or more of the
purposes disclosed herein. In some embodiments, 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.
[00196] As used herein, an effective amount is defined as the amount required to
confer a therapeutic effect on the treated patient, and is typically determined based on age,
suiface area, weight, and condition of the patient. The interrelationship of dosages for animals
and humans (based on milligrams per meter squared of body surface) is described by Freireich
et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately
determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy
Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a
mammal, including a human.
[00197] Unless otherwise stated, structures depicted herein are also meant to
include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational))
forms of the structure; for example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the
scope of the invention. Additionally, 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 hydrogen by deuterium or tritium, or the replacement of a carbon by a C- or
uC-enriched carbon are within the scope of this invention. Such compounds are useful, for
example, as analytical tools or probes in biological assays.
COMPOUNDS
[001983 Compounds of the present invention are useful modulators of ABC
transporters and are useful in the treatment of ABC transport mediated diseases.
A. Generic Compounds
[00199] The present invention includes a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:
Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally
substituted 3 to 10 membered heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl or
alkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, or hydroxy;
provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally
substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted
heteroaryl attached to the 5- or 6- position of the pyridyl ring;
Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally
substituted C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted
heteroaryl;
Each R3 and R'3 together with the carbon atom to which they are attached form an
optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and
Each n is 1,2,3 or 4.
[00200] In another aspect, the present invention includes compounds of formula

or a pharmaceutically acceptable salt thereof,
wherein:
one of G1 and G2 is a nitrogen, and the other is a carbon; and
R1, R2, R3, R'3, R4, and n are defined above.
Specific Embodiments
A. Substituent Ri
[00201] Each R1 is independently an optionally substituted C1-6 aliphatic, an

optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10
membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic,
carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo,
or hydroxy.
[00202] In some embodiments, one R1 is an optionally substituted C1-6 aliphatic.
In several examples, one R1 is an optionally substituted C1_6 alkyl, an optionally substituted C2-6
alkenyl, or an optionally substituted C2-6 alkynyl. In several examples, one R1 is C1.6 alkyl, C2-6
alkenyl, or C2-6 alkynyl.
[00203] In several embodiments, one R1 is an aryl or heteroaryl with 1,2, or 3
substituents. In several examples, one R1 is a monocyclic aryl or heteroaryl. In several
embodiments, R1 is an aryl or heteroaryl with 1, 2, or 3 substituents. In several examples, R1 is
a monocyclic aryl or heteroaryl.
[00204] In several embodiments, at least one R1 is an optionally substituted aryl
or an optionally substituted heteroaryl and R1 is bonded to the core structure at the 6 position on
the pyR1dine R1ng.
[00205] In several embodiments, at least one R1 is an optionally substituted aryl
or an optionally substituted heteroaryl and R1 is bonded to the core structure at the 5 position on
the pyR1dine R1ng.
[00206] In several embodiments, one R1 is phenyl with up to 3 substituents. In
several embodiments, Rj is phenyl with up to 3 substituents.
[00207] In several embodiments, one R1 is a heteroaryl R1ng with up to 3
substituents. In certain embodiments, one R1 is a monocyclic heteroaryl R1ng with up to 3
substituents. In other embodiments, one R1 is a bicyclic heteroaryl R1ng with up to 3
substituents. In several embodiments, R1 is a heteroaryl R1ng with up to 3 substituents. In
certain embodiments, R1 is a monocyclic heteroaryl R1ng with up to 3 substituents. In other
embodiments, B.x is a bicyclic heteroaryl R1ng with up to 3 substituents.
[00208] In several embodiments, one R1 is carboxy [e.g., hydroxycarbonyl or
alkoxycarbonyl]. Or, one R1 is amido [e.g., aminocarbonyl]. Or, one R1 is amino. Or, is halo.
Or, is cyano. Or, hydroxyl.
[00209] In some embodiments, R1 is hydrogen, methyl, ethyl, i-propyl, t-butyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F, Cl, methoxy, ethoxy, i-propoxy, t-
butoxy, CF3, OCF3, CN, hydroxyl, or amino. In several examples, R1 is hydrogen, methyl,

methoxy, F, CF3 or OCF3. In several examples, R1 can be hydrogen. Or, R1 can be methyl. Or,
R1 can be CF3. Or, R1 can be methoxy.
[00210] In several embodiments, R1 is substituted with no more than three
substituents selected from halo, oxo, or optionally substituted aliphatic, cycloaliphatic,
heterocycloaliphatic, amino [e.g., (aliphatic)aminoj, amido [e.g., aminocarbonyl,
((aliphatic)amino)carbonyl, and ((aliphatic)2amino)carbonyl], carboxy [e.g., alkoxycarbonyl and
hydroxycarbonyl], sulfamoyl [e.g., aminosulfonyl, ((aliphatic)2amino)sulfonyl,
((cycloaliphatic)aliphatic)aminosulfonyl, and ((cycloaliphatic)amino)sulfonyl], cyano, alkoxy,
aryl, heteroaryl [e.g., monocyclic heteroaryl and bicycloheteroaryl], sulfonyl [e.g.,
aliphaticsulfonyl or (heterocycloaliphatic)sulfonyl], sulfinyl [e.g., aliphaticsulfinyl], aroyl,
heteroaroyl, or heterocycloaliphaticcarbonyl.
[00211] In several embodiments, R1 is substituted with halo. Examples of R1
substituents include F, Cl, and Br. In several examples, R1 is substituted with F.
[00212] In several embodiments, R1 is substituted with an optionally substituted
aliphatic. Examples of R1 substituents include optionally substituted alkoxyaliphatic,
heterocycloaliphatic, aminoalkyl, hydroxyalkyl, (heterocycloalkyl)aliphatic,
alkylsulfonylaliphatic, alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic,
alkylaminoaliphatic, or alkylcarbonylaliphatic.
[00213] In several embodiments, R1 is substituted with an optionally substituted
amino. Examples of R1 substituents include aliphaticcarbonylamino, aliphaticamino, arylamino,
or aliphaticsulfonylamino.
[00214] In several embodiments, R1 is substituted with a sulfonyl. Examples of
R1 substituents include heterocycloaliphaticsulfonyl, aliphatic sulfonyl, alphaticaminosulfony!,
aminosulfonyl, aliphaticcarbonylaminosulfonyl, alkoxyalkylheterocycloalkylsulfonyl,
alkylheterocycloalkylsulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl,
(heterocycloalkyl)alkylaminosulfonyl, and heterocycloalkylsulfonyl.
[00215] In several embodiments, R1 is substituted with carboxy. Examples of R1
substituents include alkoxycarbonyl and hydroxycarbonyl.
[00216] In several embodiments R1 is substituted with amido. Examples of R1
substituents include alkylaminocarbonyl, aminocarbonyl, ((aliphatic)2amino)carbonyl, and
[((aliphatic)aminoaliphatic)amino]carbonyl.
[00217] In several embodiments, R1 is substituted with carbonyl. Examples of R1

substituents include arylcarbonyl, cycloaliphaticcarbonyl, heterocycloaliphaticcarbonyl, and
heteroarylcarbonyi.
[00218] In some embodiments, R1 is hydrogen. In some embodiments, R1 is -
ZAR5, wherein each ZA is independently a bond or an optionally substituted branched or straight
C1-6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently
replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -CO2-, -OCO-, -NRACO2-, -O-, -
NRACONRA-, -OCONRA-, -NRANRA-7 -NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, -
NRASO2-, or -NRASO2NRA-. Each R5 is independently RA, halo, -OH, -NH2, -NO2, -CN, -CF3,
or -OCF3. Each RA is independently a C1-8 aliphatic group, a cycloaliphatic, a
heterocycloaliphatic, an aryl, or a heteroaryl, each of which is optionally substituted with 1, 2,
or 3 of Ru. Each RD is -ZDR9, wherein each ZD is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are
optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-,
-NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -
SO2NRE-, -NRESO2-, or -NRESO2NRE-. Each R9is independently RE, halo, -OH, -NH2, -NO2, -
CN, -CF3, or -OCF3. Each RE is independently hydrogen, an optionally substituted C1-8
aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
[00219] In some embodiments, each RD is independently -ZDR9; wherein each ZD
can independently be a bond or an optionally substituted branched or straight C1-6 aliphatic
chain wherein up to two carbon units of ZD are optionally and independently replaced by -O-, -
NHC(O)-, -C(O)NRE-, -SO,-, -NHSO3-, -NHC(O)-, -NRESO2-, -SO2NH-, -SO2NRE-, -NH-, or -
C(O)O-. In some embodiments, one carbon unit of ZD is replaced by -O-. Or, by -NHC(O)-.
Or, by -C(O)NRE-. Or, by -SO2-. Or, by NHSO2-. Or, by -NHC(O)-. Or, by -SO-. Or, by -
NRESO2-. Or, by -SO2NH-. Or, by -SO2NRE-. Or, by -NH-. Or, by -C(O)O-.
[00220] In some embodiments, R9 is hydrogen. In some embodiments, R9 is
independently an optionally substituted aliphatic. In some embodiments, R9 is an optionally
substituted cycloaliphatic. Or, is an optionally substituted heterocycloaliphatic. Or, is an
optionally substituted aryl. Or, is an optionally substituted heteroaryl. Or, halo.
[00221] In some embodiments, one R1 is aryl or heteroaryl, each optionally
substituted with 1,2, or 3 of RD, wherein RD is defined above.
[00222] In several embodiments, one R1 is carboxy [e.g., hydroxycarbonyl or
alkoxycarbonyl]. Or, one R1 is amido [e.g., aminocarbonyl]. Or, one R1 is amino. Or, is halo.

[00223] In some embodiments, one R1 that is attached to 5- or 6- position of the
pyR1dyl R1ng is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of RD, wherein RD is
defined above. In some embodiments, the one R1 attached to the 5- or 6- postion of the pyR1dyl
R1ng is phenyl optionally substituted with 1, 2, or 3 of RD, wherein RD is defined above. In some
embodiments, the one R1 attached to the 5- or 6- position of the pyR1dyl R1ng is heteroaryl
optionally substituted with 1, 2, or 3 of RD. In several embodiments, the one R1 attached to the
5- or 6- position of the pyR1dyl R1ng is 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom
independently selected from the group consisting of oxygen, nitrogen and sulfur. In other
embodiments, the 5 or 6 membered heteroaryl is substituted with 1 RD.
[00224] In some embodiments, one R1 attached to the 5- or 6- position of the
pyR1dyl R1ng is a phenyl substituted with 1 RD. In some embodiments, one R1 attached to the 5-
or 6- position of the pyR1dyl R1ng is a phenyl substituted with 2 RD. In some embodiments, one
R1 attached to the 5- or 6- position of the pyR1dyl R1ng is a phenyl substituted with 3 RD.
[00225] In several embodiments, R1 is:

W1 is -C(O)-, -SO2-, or -CH-2-;
D is H, hydroxyl, or an optionally substituted group selected from aliphatic,
cycloaliphatic, alkoxy, and amino; and
RD is defined above.
[00226] In several embodiments, W2 is -C(O)-. Or, W1 is -SO2-. Or, W1 is -CH2-.
[00227] In several embodiments, D is OH. Or, D is an optionally substituted C1-6
aliphatic or an optionally substituted C3-C8 cycloaliphatic. Or, D is an optionally substituted
alkoxv. Or, D is an optionally substituted amino.

wherein each" of A and B is independently H, an optionally substituted C1-6 aliphatic,
an optionally substituted C3-C8 cycloaliphatic, or
A and B, taken together, form an optionally substituted 3-7 membered
heterocycloaliphatic R1ng.
[00229] In several embodiments, A is H and B is an optionally substituted C1-6
aliphatic. In several embodiments, B is substituted with 1, 2, or 3 substituents. Or, both, A and
B, are H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, dialkyamino, or an optionally substituted group selected from cycloaliphatic,
heterocycloaliphatic, aryl, and heteroaryl.
[00230] In several embodiments, A is H and B is an optionally substituted C1-6
aliphatic. Or, both, A and B, are H. Exemplary substituents include oxo, alkyl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, and an optionally substituted heterocycloaliphatic.
[00231] In several embodiments, B is C1-6 alkyl, optionally substituted with oxo,
alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, or an optionally substituted group selected
from cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl. In several embodiments, B is
substituted with oxo, C1-6 alkyl, hydroxy, hydroxy-(C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1.
6)alkyl, C3_8 cycloaliphatic, 3-8 membered heterocycloaliphatic, phenyl, and 5-10 membered
heteroaryl. In one example, B is C1-6 alkyl substituted with optionally substituted phenyl.
[00232] In several embodiments, A and B, taken together, form an optionally
substituted 3-7 membered heterocycloaliphatic R1ng. In several examples, the
heterocycloaliphatic R1ng is optionally substituted with 1,2, or 3 substituents. Exemplary such
R1ngs include optionally substituted pyrrolidinyl, pipeR1dinyl, morpholinyl, and piperazinyl.
Exemplary substituents on such R1ngs include halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, acyl (e.g., alkylcarbonyl), amino, amido, and carboxy. In some embodiments, the
substituent is halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or
carboxy.
[00233] In several embodiments, RD is hydrogen, halo, or an optionally
substituted group selected from aliphatic, cycloaliphatic, amino, hydroxy, alkoxy, carboxy,
amido, carbonyl, cyano, aryl, or heteroaryl. In several examples, RD is hydrogen, halo, an
optionally substituted C1-6 aliphatic, or an optionally substituted alkoxy. In several examples,
RD is hydrogen, F, Cl, an optionally substituted C1-6 alkyl, or an optionally substituted -O(C1-6
alkyl). Examples of RD include hydrogen, F, Cl, methyl, ethyl, i-propyl, r-butyl, -OMe, -OEt, i-
propoxy, t-butoxy, CF3, or -OCF3. In some examples, RDis hydrogen, F, methyl, methoxy, CF3,

W1 is -C(O)-, -SO2-, or -CH2-;
Each of A and B is independently H, an optionally substituted C1-6 aliphatic, an
optionally substituted C3-C8 cycloaliphatic; or
A and B, taken together, form an optionally substituted 3-7 membered
heterocycloaliphatic R1ng.
[00235] In some embodiments, one R1 that is attached to the 5- or 6- position of
the pyR1dyl R1ng is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1, 2,
or 3 of RD; wherein RD is -ZDR9; wherein each ZD is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are
optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-,
-NRECO2-, -O-, -NRECONRE-, -OCOKRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -
SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, -NO2, -
CN, -CF3, or -OCF3; and each RE is independently hydrogen, an optionally substituted C1-8
aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
[00236] In several examples, one R1 that is attached to the 5- or 6- position of the
pyR1dyl R1ng is an optionally substituted C3-C8 cycloaliphatic.
[00237] In some embodiments, one R1 that is attached to the 5- or 6- position of
the pyR1dyl R1ng is an optionally substituted C3-C8 cycloalkyl or an optionally substituted C3-C8 -
cycloalkenyl.
[00238] In several embodiments, one R1 that is attached to the 5- or 6- position of
the pyR1dyl R1ng is C3-C8 cycloalkyl or C3-Cs cycloalkenyl. Examples of cycloalkyl and
cycloalkenyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,- cycloheptyl,

B. Substituent R2
[00241] Each R2 can be hydrogen. Each R2 can be an optionally substituted group
selected from C1-6 aliphatic, C3-6 cycloaliphatic, phenyl, and heteroaryi.
[00242] In several embodiments, R2 is aC1-6 aliphatic optionally substituted with
1, 2, or 3 halo, C1-2 aliphatic, or alkoxy. In several examples, R2 can be substituted methyl,
ethyl, propyl, or butyl. In several examples, R1 can be methyl, ethyl, propyl, or butyl.
[00243] In several embodiments, R2 is hydrogen.
C. Substituents R3 and R1
[00244] Each R3 and R'3 together with the carbon atom to which they are attached
form a C3-7 cycloaliphatic or a heterocycloaliphatic, each of which is optionally substituted with
1,2, or 3 substituents.
[00245] In several embodiments, R3 and R'3 together with the carbon atom to
which they are attached form a C3.7 cycloaliphatic or a C3.7 heterocycloaliphatic, each of which
is optionally substituted with 1,2, or 3 of -ZBR7, wherein each ZB is independently a bond, or an
optionally substituted branched or straight C1-4 aliphatic chain wherein up to two carbon units of
ZB are optionally and independently replaced by -CO-, -CS-, -CONR8-, -CONRBNRB-, -CO2-, -
OCO-, -NRBCO2~, -O~, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO~, -S-, -SO-, -SO2-, -
NRB-, -SO2NRB-, -NRBSO2-, or -NRBSO2NRB-; each R7is independently RB, halo, -OH, -NH2, -
NO2, -CN, -CF3, or -OCF3; and each RB is independently hydrogen, an optionally substituted C1.
8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryi.
[00246] In several embodiments, R3 and R'3 together with the carbon atom to
which they are attached form a 3, 4, 5, or 6 membered cycloaliphatic that is optionally
substituted with 1, 2, or 3 substituents. In several examples, R3, R'3, and the carbon atom to
which they are attached form an optionally substituted cyclopropyl group. In several alternative

examples, R3, R'3, and the carbon atom to which they are attached form an optionally substituted
cyclobutyl group. In several other examples, R3, Rr3, and the carbon atom to which they are
attached form an optionally substituted cyclopentyl group. In other examples, R3, R'3) and the
carbon atom to which they are attached form an optionally substituted cyclohexyl group. In
more examples, R3 and R'3 together with the carbon atom to which they are attached form an
unsubstituted cyclopropyl.
[00247] In several embodiments, R3 and R'3 together with the carbon atom to
which they are attached form a 5, 6, or 7 membered optionally substituted heterocycloaliphatic.
In other examples, R3, R'3 and the carbon atom to which they are attached form an optionally
substituted tetrahydropyranyl group.
[00248] In some embodiments, R3 and R'3 together with the carbon atom to which
they are attached form an unsubstituted C3.7 cycloaliphatic or an unsubstituted
heterocycloaliphatic. In several examples, R3 and R'3 together with the carbon atom to which
they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an
unsubstituted cyclohexyl.
D. Substituent R4
[00249] Each R4 is independently an optionally substituted aryl or an optionally
substituted heteroaryl.
[00250] In several embodiments, R4 is an aryl having 6 to 10 members (e.g., 7 to
10 members) optionally substituted with 1, 2, or 3 substituents. Examples of R4 include
optionally substituted benzene, naphthalene, or indene. Or, examples of R4 can be optionally
substituted phenyl, optionally substituted naphthyl, or optionally substituted indenyl.
[00251] In several embodiments, R4 is an optionally substituted heteroaryi.
Examples of R4 include monocyclic and bicyclic heteroaryl, such a benzofused R1ng system in
which the phenyl is fused with one or two 4-8 membered heterocycloaliphatic groups.
[00252] In some embodiments, R4 is an aryl or heteroaryl, each optionally
substituted with 1, 2, or 3 of -ZCR8. In some embodiments, R4 is an aryl optionally substituted
with 1, 2, or 3 of -ZcRg. In some embodiments, R4 is phenyl optionally substituted with 1, 2, or
3 of -ZcRg. Or, R4 is a heteroaryl optionally substituted with 1, 2, or 3 of -ZCR8. Each Zc is
independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain
wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -
CONRC-, -CONRCNRC-, -CO2-, -OCO-, -NRCCO2-, -O-, -NRcCONRc-,-OCONRc-, -NRCNRC-
, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -SO2NRC-, -KRCSO2-, or -NRCSO2NRC-. Each R8is

independently Rc, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OGF3. Each Rc is independently
hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic,
an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally
substituted heteroaryl.
[00253] In some embodiments, two occurrences of —ZCR8, taken together with
carbons to which they are attached, form a 4-8 membered saturated, partially saturated, or
aromatic R1ng with up to 3 R1ng atoms independently selected from the group consisting of O,
NH, NRC, and S; wherein Rc is defined herein.
[00254] In several embodiments, R4 is one selected from

E. Exemplary Compound Families
[00255] In several embodiments, R1 is an optionally substituted cyclic group that
is attached to the core structure at the 5 or 6 position of the pyR1dine R1ng.
[00256] In several examples, R1 is an optionally substituted aryl that is attached to
the 5 position of the pyR1dine R1ng. In other examples, R1 is an optionally substituted aryl that is
attached to the 6 position of the pyR1dine R1ng.
[00257] In more examples, R1 is an optionally substituted heteroaryl that is

attached to the 5 position of the pyR1dine R1ng. In still other examples, R1 is an optionally
substituted heteroaryl that is attached to the 6 position of the pyR1dine R1ng.
[00258] In other embodiments, R1 is an optionally substituted cycloaliphatic or an
optionally substituted heterocycloaliphatic that is attached to the pyR1dine R1ng at the 5 or 6
position.
[00259] Accordingly, another aspect of the present invention provides compounds
of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R'3, and R4 are
defined in formula I.
[00260] In some embodiments, each R1 is aryl or heteroaryl optionally substituted
with 1, 2, or 3 of RD, wherein RD is -ZDRc,, wherein each ZD is independently a bond or an
optionally substituted branched or straightC1-6 aliphatic chain wherein up to two carbon units of
ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, ~CONRENRE-, -CO2-, -
OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -
NRB-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, -
NO2, -CN, -CF3) or -OCF3; each RE is independently hydrogen, an optionally substituted C1-8
aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic. an optionally substituted aryl. or an optionally substituted heteroaryl.
[00261] In some embodiment, each R1 is cycloaliphatic or heterocycloaliphatic
optionally substituted with 1, 2, or 3 of RD; wherein RD is defined above.
[00262] Another aspect of the present invention provides compounds of formula

or a pharmaceutically acceptable salt thereof, wherein R1 R2) R3, R'3, and R4 are
defined in formula I.
[00263] In some embodiments, each R1 is aryl or heteroaryl optionally substituted
with 1,2, or 3 of RD, wherein RD is -ZDR9, wherein each ZD is independently a bond or an
optionally substituted branched or straight Ci.6 aliphatic chain wherein up to two carbon units of
ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -
OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -
NRE-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, -
NO2, -CN, -CF3, or -OCF3; each RE is independently hydrogen, an optionally substituted C1-8
aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycioaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
[00264] In some embodiments, each R1 is cycloaliphatic or heterocycioaliphatic
optionally substituted with 1, 2, or 3 of RD; wherein RD is defined above.
[00265] In another aspect, the present invention includes compounds of formula

or a pharmaceutically acceptable salt thereof, wherein R2, R3, R'3, and R4 are defined
in formula I.
[00266] RD is -ZDR9; wherein each ZD is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are
optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-,
-NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -
SO2NRE-, -NRESO2-, or -NRESO2NRE-.
[00267] R9 is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3.
[00268] Each RE is independently hydrogen, an optionally substituted C1-8
aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycioaliphatic, an optionally substituted aryl,.or an optionally substituted heteroaryl.

[00269] In several embodiments, ZD is independently a bond or is an optionally
substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is optionally
replaced by -SO2-, -CONRE-, - NRESO2-, or -SO2NRE-. For example, ZD is an optionally
substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is optionally
replaced by -SO2-. In other examples, Rg is an optionally substituted heteroaryl or an optionally
substituted heterocycloaliphatic. In additional examples, R9 is an optionally substituted
heterocycloaliphatic having 1-2 nitrogen atoms, and R9 attaches directly to -SO2- via a R1ng
nitrogen.
[00270] In another aspect, the present invention includes compounds of formula
V-A or formula V-B:

or a pharmaceutically acceptable salt thereof,
wherein:
T is an optionally substituted C1-2 aliphatic chain, wherein each of the carbon units is
optionally and independently replaced by --CO-, -CS-, -COCO-, -SO2-, -B(OH)-, or -B(O(C1-6
alkyl))s
Each of R1' and R1" is independently a bond or an optionally substituted C1-6
aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally
substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered
heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy;
RD1 is attached to carbon 3" or 4";
each RD1 and RD2 is -ZDRg, wherein each ZD is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are
optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-,
-NRECO2-, -O-, -NRECONRE-, -OCONRE~, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -
SO2NRE-, -NRESO2-, or -NRESO2NRE-;
R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3;

or RD1 and RD2 , taken together with atoms to which they are attached, form a 3-8
membered saturated, partially unsaturated, or aromatic R1ng with up to 3 R1ng members
independently selected from the group consisting of O, NH, NRE, and S; and
each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl.
[00271] In some embodiments, T is an optionally substituted -CH2-. In some
other embodiments, T is an optionally substituted -CH2CH2-.
[00272] In some embodiments, T is optionally substituted by -ZBR10; wherein
each Z is independently a bond or an optionally substituted branched or straight C1-6 aliphatic
chain wherein up to two carbon units of ZE are optionally and independently replaced by -CO-, -
CS-, -CONRF-, -CONRFNRF-, -CO2-, -OCO-, -NRFCO2-, -O-, -NRFCONRF-, -OCONRF-, -
INRFNRF-, -NRFCO-, -S-, -SO-, -SO2-, -NRF-, -SO2NRF-, -NRFSO2-, or -NRFSO2NRF-; R1o is
independently RF halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; each RF is independently
hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic,
an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally
substituted heteroaryl. In one example, ZE is -O-.
[00273] In some embodiments, R10 can be an optionally substituted C1-6 alkyl, an
optionally substituted C2.6 alkenyl, an optionally substituted C3-7 cycloaliphatic, or an optionally
substituted C6-10 aryl- In one embodiment, R1o is methyl, ethyl, z-propyl, or /-butyl.
[00274] In some embodiments, up to two carbon units of T are optionally
substituted by -CO-, -CS-, -B(OH)-, or -B(O(C1-6 alkyl)-.
[00275] In some embodiments, T is selected from the group consisting of -CH2-, -

CH2-. Or,Tis-CF2-. Or, T is-C(CH3)2-.
[00276] In some embodiments, each of R1' and R1" is hydrogen. In some
embodiments, each of R1' and R1" is independently -ZAR5j wherein each ZA is independently a
bond or an optionally substituted branched or straight Cj.6 aliphatic chain wherein up to two
carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, -
CONRANRA-, -CO2-, -OCO-, -NRACO2-, -O-, -NRACONRA-, -OCONRA-, -NRANRA-, -
NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, -NRASO2-, or -NRASO2NRA-. Each R5 is
independently RA, halo, -OH, -NH2, -NO2, -CN, -CF3> or -OCF3. Each RA is independently an
optionally substituted group selected from C1-8 aliphatic group, a cycloaliphatic, a
heterocycloaliphatic, an ary], and a heteroaryl.
[00277] In some embodiments, R1' is selected from the group consisting of H, C1-6
aliphatic, halo, CF3, CHF2, -O(C1-6 aliphatic), C3-C5 cycloalkyl, or C4-C6 heterocycloalkyl
containing one oxygen atom. In some embodiments, R11 is selected from the group consisting of
H, methyl, ethyl, z'-propyl, t-butyl, F. Cl, CF3, CHF2, ~OCH3, -OCH2CH3, -O-(i-propyl), or -O-
(f-butyl). More preferably, R11 is H. Or, R1' is methyl. Or, ethyl. Or, CF3.
[00278] In some embodiments, R1" is selected from the group consisting of H, C1-
6 aliphatic, halo, CF3, CHF2, and -O(C1-6 aliphatic). In some embodiments, R1" is selected from
the group consisting of H, methyl, ethyl, i-propyl, f-butyl, F. Cl, CF3, CHF2, -OCH3, -
OCH2CH3, -O-(i-propyl), or -O-(t-butyl). More preferably, R1" is H. Or, R1" is methyl. Or,
ethyl. Or, CF3.
[00279] In some embodiments, RD1 is attached to carbon 3" or 4", and is -ZDR9,
wherein each ZD is independently a bond or an optionally substituted branched or straight Q-6
aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced
by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-, -NRECONRE-, -
OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, -NRESO2-, or -
NRESO2NRE-. In yet some embodiments, ZD is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally
replaced by -CO-, -SO-, -SO2-, -COO-, -OCO-, -CONRE-, -NRECO-, NRECO2-, -O-, -NRESO2-
, or -SO2NRE-. In some embodiments, one carbon unit of ZD is optionally replaced by -CO-.
Or, by-SO-. Or,by-SO2-. Or,by-COO-. Or,by-OCO-. Or, by -CONRE-. Or, by-NRECO-.
Or,by-NRECO2-. Or,by-O-. Or, by-NRESO2-. Or, by-SO2NRE-.
[00280] In several embodiments, R9 is hydrogen, halo, -OH, -NH2, -CN, -CF3, -
OCF3) or an optionally substituted group selected from the group consisting of C1-6 aliphatic, C3.

8 cycloaliphatic, 3-8 membered heterocycloaliphatic, Cw aryU and 5-10 membered heteroaryl.
In several examples, R9 is hydrogen, F, Cl, -OH, -CN, -CF3, or -OCF3. In some embodiments,
R is C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C6-10 aryl, and 5-10
membered heteroaryl, each of which is optionally substituted by 1 or 2 substituents
independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -
COORE, and -CONRERE. In several examples, Rg is optionally substituted by 1 or 2
substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i-
propyl, t-butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(O)NH2, -CH2O(C1-6 alkyl), -
CH2CH2O(C1-6 alkyl), and -C(O)(C1-6 alkyl).
[00281] In one embodiment, R is hydrogen. In some embodiments, R9 is
selected from the group consisting of C1-6 straight or branched alkyl or C2-6 straight or branched
alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents
independently selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -
COORE, and -CONRERE.
[00282] In other embodiments, R9 is C3-8 cycloaliphatic optionally substituted by
1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, -OH, -
NRERE, -ORE, -COORE, and -CONRERE. Examples of cycloaliphatic include but are not
limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[00283] In yet other embodiments, R9 is a 3-8 membered heterocyclic with 1 or 2
heteroatoms independently selected from the group consisting of O, NH, NRE, and S; wherein
said heterocyclic is optionally substituted by 1 ox 2 substituents independently selected from the
group RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE. Example of 3-8
membered heterocyclic include but are not limited to

[00285] In some embodiments, RD1 and RD2, taken together with carbons to which
they are attached, form an optionally substituted 4-8 membered saturated, partially unsaturated,
or aromatic R1ng with 0-2 R1ng atoms independently selected from the group consisting of O,
NH, NRE, and S. Examples of Rm and RD2, taken together with phenyl containing carbon
atoms 3" and 4", include but are not limited to

[00286] In some embodiments, RD2 is selected from the group consisting of H, RE,
halo, -OH, -(CH2)rNRERE, -(CH2)r-ORE, -SO2-RE, -NRE-SO2-RE, -SO2NRERE, -C(O)RE, -
C(O)ORE, -OC(O)ORE, -NREC(O)ORE, and -C(O)NRERE; wherein r is 0,1, or 2. In other
embodiments, RD2 is selected from the group consisting of H, C1-6 aliphatic, halo, -CN, -NH2, -
NH(C1-6 aliphatic), -N(C1-6 aliphatic)2, -CH2-N(C1-6 aliphatic)2, -CH2-NH(C1-6 aliphatic), -
CH2NH2, -OH, -O(C1-6 aliphatic), -CH2OH, -CH2-O(C,-6 aliphatic), -SO2(C1-6 aliphatic), -N(C1-6
aliphatic)-SO2(C1-6 aliphatic), -NH-SO2(C1-6 aliphatic), -SO2NH2, -SO2NH(C1-6 aliphatic), -
SO2N(C1-6 aliphatic)2, -C(O)(C1-6 aliphatic), ~C(O)O(C1-6 aliphatic), -C(O)OH, ~OC(O)O(C1-6
aliphatic), -NHC(O)(C1-6 aliphatic), -NHC(O)O(C1-6 aliphatic), -N(C1-6 a]iphatic)C(O)O(C1-6
aliphatic), -C(O)NH2, and -C(O)N(C1-6 aliphatic)2. In several examples, RD2 is selected from
the group consisting of H, C1-6 aliphatic, halo, -CN, -NH2, -CH2NH2, -OH, -O(C1-6 aliphatic), -
CH2OH, -SO2(C1-6 aliphatic), -NH-SO2(C1-6 aliphatic), -C(O)O(C1-6 aliphatic), -C(O)OH, -
NHC(O)(C1-6 aliphatic), -C(O)NH2, -C(O)NH(C1-6 aliphatic), and -C(O)N(C1-6 aliphatic)2. For
examples, RD2 is selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, t-
butyl, F, Cl, CN, -NH2, -CH2NH2, -OH, -OCH3, -O-ethyl, -O-(i-propyl), -0-(n-propyl), -

CH2OH, -SO2CH3, -NH-SO2CH3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OH, -NHC(O)CH3, -
C(O)NH2, and -C(O)N(CH3)2. In one embodiment, RD2 is hydrogen. In another embodiment,
RD2 is methyl. Or, RM is ethyl. Or, RD2 is F. Or, RD2 is Cl. Or, -OCH3.
[00287] In one embodiment, the present invention provides compounds of

[00289] In one embodiment, R1 is selected from the group consisting of H,C1-6
aliphatic, halo, CF3, CHF2, -O(C1-6 aliphatic), C3-C5 cycloalkyl, or C4-C6 heteiocycloalkyl
containing one oxygen atom. Exemplary embodiments include H, methyl, ethyl, i-propyl, t-
butyl, F. Cl, CF3, CHF2, -OCH3, -OCH2CH3, -O-(i-propyl), -O-(r-butyl), cyclopropyl, or
oxetanyl. More preferably, R3'is H. Or, R1'is methyl. Or, ethyl. Or, CF3. Or, oxetanyl.
[00290] In one embodiment, Rm is Z°R9, wherein ZD is selected from CONH,
NHCO, SO2NH, SO2N(C1-6 alkyl), NHSO2, CH2NHSO2, CH2N(CH3)SO2, CH2NHCO, COO,
SO2, or CO. In one embodiment, Rm is Z0R9, wherein ZD is selected from CONH, SO2NH,
SO2N(C1-6 alkyl), CH2NHSO2, CH2N(CH3)SO2, CH2NHCO, COO, SO2, or CO.
[08291] lit one embodiment, ZD is COO and R9 is K. In one embodiment, ZP is
COO and R9 is an optionally substituted straight or branched C1-6 aliphatic. In one embodiment,
ZD is COO and R9 is an optionally substituted straight or branched C1-6 alkyl. In one
embodiment, ZD is COO and R9 is C1-6 alkyl. In one embodiment, ZD is COO and R9 is methyl.
[00292] In one embodiment, ZD is CONH and R9 is H. In one embodiment, ZD is
CONH and R9 is an optionally substituted straight or branched C1-6 aliphatic. In one
embodiment, ZD is CONH and R9 is straight or branched C1-6 alkyl. In one embodiment, ZD is
CONH and R9 is methyl. In one embodiment, ZD is CONH and R9 is an optionally substituted
straight or branched C1-6 alkyl. In one embodiment, In one embodiment, ZD is CONH and R9 is
2-(dimethylamino)-ethyl.

[00293] In some embodiments, ZD is CH2NHCO and R9 is an optionally
substituted straight or branched C1-6 aliphatic or an optionally substituted alkoxy. In some
embodiments, ZD is CH2NHCO and R9 is straight or branched C1-6 alkyl optionally substituted
with halo, oxo, hydroxyl, or an optionally substituted group selected from aliphatic, cyclic, aryl,
heteroaryl, alkoxy, amino, carboxyl, or carbonyl. In one embodiment, ZD is CH2NHCO and R9
is methyl. In one embodiment, ZD is CH2NHCO and R9 is CF3. In one embodiment, ZD is
CH2NHCO and R9 is t-butoxy.
[00294] In one embodiment, ZD is SO2NH and R9 is H. In some embodiments, ZD
is SO2NH and R9 is an optionally substituted straight or branchedC1-6 aliphatic. In some
embodiments, ZD is SO2NH and R9 is is straight or branched C1-6 alkyl optionally substituted
with halo, oxo, hydroxyl, or an optionally substituted group selected fromC1-6 aliphatic, 3-8
membered cyclic, C6-10 aryl, 5-8 membered heteroaryl, alkoxy, amino, amido, carboxyl, or
carbonyl. In one embodiment, 7? is SO2NH and R9 is methyl. In one embodiment, Zp is
SO2NH and R9 is ethyl. In one embodiment, ZD is SO2NH and R9 is i-propyl. In one
embodiment, ZD is SO2NH and R9 is f-butyl. In one embodiment, ZD is SO2NH and R9 is 3,3-
dimethylbutyl. In one embodiment, ZD is SO2NH and R9 is CH2CH2OH. In one embodiment,
ZD is SO2NH and R9 is CH(CH3)CH2OH. In one embodiment, ZD is SO2NH and R9 is
CH2CH(CH3)OH. In one embodiment, ZD is SO2NH and R9 is CH(CH2OH)2. In one
embodiment, ZD is SO2NH and R9 is CH2CH(OH)CH2OH. In one embodiment, ZD is SO2NH
and R9 is CH2CH(OH)CH2CH3. In one embodiment, ZD is SO2NH and R9 is C(CH3)2CH2OH.
In one embodiment, ZD is SO2NH and R9 is CH(CH2CH3)CH2OH. In one embodiment, ZD is
SO2NH and R9 is CH2CH2OCH2CH2OH. In one embodiment, ZD is SO2NH and R9 is
C(CH3)(CH2OH)2. In one embodiment, ZD is SO2NH and R9 is CH2CH(OH)CH2C(O)OH. In
one embodiment, ZD is SO2NH and R9 is CH2CH2N(CH3)2. In one embodiment, ZD is SO2NH
and R9 is CH2CH2NHC(O)CH3. In one embodiment, ZD is SO2NH and R9 is
CH(CH(CH3)2)CH2OH. In one embodiment, ZD is SO2NH and R9 is CH(CH2CH2CH3)CH2OH.
In one embodiment, ZD is SO2NH and R9 is 1-tetrahydrofuryl-methyl. In one embodiment, Z
is SO2NH and R9 is furylmethyl. In one embodiment, ZD is SO2NH and R9 is (5-methylfuryl)-
methyl. In one embodiment, ZD is SO2NH and R9 is 2-pyrrolidinylethyl. In one embodiment,
ZD is SO2NH and R9 is 2-(l-methylpyrrolidinyl)-ethyl. In one embodiment, ZD is SO2NH and
R9 is 2-(4-morpholinyl)-ethyl. In one embodiment, ZD is SO2KH and R9 is 3-(4-morpholinyl)-
propyl. In one embodiment, ZD is SO2NH and R9 is C(CH2CH3)(CH2OH)2. In one
embodiment, ZD is SO2NH and R9 is 2-(lH-imidazol-4-yl)ethyl. In one embodiment, ZD is
SO2NH and R9 is 3-(lH-imidazol-l-yl)-propyl. In one embodiment, ZD is SO2NH and R9 is 2-

(2-pyR1dinyl)-ethyl.
[00295] Li some embodiment, ZD is SO2NH and R9 is an optionally substituted
C1-6 cycloaliphatic. In several examples, ZD is SO2NH and R9 is an optionally substituted C1-6
cycloalkyl. In several examples, ZD is SO2NH and R9 is C1-6 cycloalkyl. In one embodiment,
ZD is SO2NH and R9 is cyclobutyl. In one embodiment, ZD is SO2NH and R9 is cyclopentyl. In
one embodiment, ZD is SO2NH and R9 is cyclohexyl.
[00296] In some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally
substituted straight or branchedC1-6 aliphatic or an optionally substituted cycloaliphatic. In
some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally substituted straight or
branched C1-6 aliphatic. In some embodiments, ZD is SO2N(C1-6 alkyl) and R9 is an optionally
substituted straight or branchedC1-6 alkyl or an optionally substituted straight or branchedC1-6
alkenyl. In one embodiments, ZD is SO2N(CH3) and R9 is methyl. In one embodiments, ZD is
SO2N(CH3) and R9 is n-propyl. In one embodiments, ZD is SO2N(CH3) and R9 is n-butyl. In
one embodiments, ZD is SO2N(CH3) and R» is cyclohexyl. In one embodiments, ZD is
SO2N(CH3) and R9 is allyl. In one embodiments, ZD is SO2N(CH3) and R9 is CH2CH2OH. In
one embodiments, ZD is SO2N(CH3) and R9 is CH2CH(OH)CH2OH. In one embodiments, ZD is
SO2N(CH2CH2CH3) and R9 is cyclopropylmethyl.
[00297] In one embodiment, ZD is CH2NHSO2 and R9 is methyl. In one
embodiment, ZD is CH2N(CH3)SO2 and R9 is methyl.
[00298] In some embodiments, ZD is SO2 and R9 is an optionally substituted C1-6
straight or branched aliphatic or an optionally substituted 3-8 membered heterocyclic, having 1,
2, or 3 R1ng members selected from the group consisting of nitrogen, oxygen, sulfur, SO, or SO2.
In some embodiments, ZD is SO2 and R9 is straight or branchedC1-6 alkyl or 3-8 membered
heterocycloaliphatic each of which is optionally substituted with 1,2, or 3 of oxo, halo,
hydroxyl, or an optionally substituted group selected from C1-6 aliphatic, carbonyl, amino, and
carboxy. In one embodiment, ZD is SO2 and R9 is methyl. In some embodiments, ZD is SO2
and examples of R9 include

[00299] In some embodiments, RD2 is H, hyckoxyl, halo, C1-6 aikyi, C1-6 alkoxy,
C1-6 cycloalkyl, or NH2- In several examples, RD2 is H, halo, C1-4 alkyl, or C1-4 alkoxy.
Examples of RD2 include H, F, Cl, methyl, esthyl, and naethoxy.
[00300] In some embodiments, the present invention provides compounds of
formula (I1-A) or formula (I'-B):

wherein R1, R2, R3, R3, R4, and n are defined above.
[00301] In some embodiments, R1 is an optionally substituted aryl. In several
examples, R1 is phenyl optionally substituted with 1, 2, or 3 of halo, OH, -O(C1-6 aliphatic),
amino, C1-6 aliphatic, C3-7 cycloaliphatic, 3-8 membered heterocycloaliphatic, C6-10 aryl, or 5-8
membered heteroaryl. In some embodiments, R1 is phenyl optionally substituted with alkoxy,
halo, or amino. In one embodiment, R1 is phenyl. In one embodiment, R1 is phenyl substituted
with Cl, methoxy, ethoxy, or dimethylamino.
[00302] In some embodiments, R2 is hydrogen. In some embodiments, R2 is
optionally substitutedC1-6 aliphatic.
[00303] In some embodiments, R3, R'3, and the carbon atom to which they are
attached form an optionally substituted C3-8 cycloaliphatic or an optionally substituted 3-8
membered heterocycloaliphatic. In some embodiments, R3, R'3, and the carbon atom to which
they are attached form an optionally substituted C3-8 cycloalkyl. In one example, R3, R'3, and
the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
or cycloheptyl, each of which is optionally substituted. In one example, R3, R'3, and the carbon
atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. In several examples, R3, R'3, and the carbon atom to which they are attached is
cyclopropyl.
[00304] In some embodiments, R4 is an optionally substituted aryl or an
optionally substituted heteroaryl. In some embodiments, R4 is an optionally substituted phenyl.
In several embodiments, R4 is phenyl fused to a 3,4,5, or 6 membered heterocyclic having 1, 2,
or 3 R1ng membered selected from oxygen, sulfur and nitrogen. In several embodiments, R4 is
O' ^-^ , wherein T is defined above. In several examples, T is -CH2-.
[00305] Alternative embodiments of R1, R2, R3, R'3, R4, and n in formula (I'-A) or
formula (T-B) are as defined for formula (I), formula (I1), and embodiments thereof.
[00306] Exemplary compounds of the present invention include, but are not
limited to, those illustrated in Table 1 below.

SYNTHETIC SCHEMES
[00308] Compounds of the invention may be preparec'. by known methods or as
illustrated in the examples. In one instance wherein R1 is aryl or he eroaryl, the compounds of
|

[00313] ReferR1ng to Scheme I, a nitR1le of formula i in alkylated (step a) with a
dihalo-alrphatic in the presence of a base such as, for example, 50% sodium hydroxide and,
optionally, a phase transfer reagent such as, for example, benzyltR1eihylaminonium chloR1de-
(BTEAC), to produce the corresponding alkylated nitR1le (not shown) which on hydrolysis
produces the acid ii. Compounds of formula ii are converted to the icid chloR1de iii with a
suitable reagent such as, for example, thionyl chloR1de/DMF. Reaction of the acid chloR1de iii
with an aminopyR1dine, wherein X is a halo, of formula iv (step c) produces the amide of
formula v. Reaction of the amide v with an optionally substituted boronic acid deR1vative (step
d) in the presence of a catalyst such as, for example, palladium acetate or dichloro-[l,l-
bis(diphervylphosphino) ferrocene] palladium(IT) (Pd(dppf)Cl2 ), provides compounds of the
invention wherein R1 is aryl, heteroaryl, or cycloalkenyl. The boronic acid deR1vatives vi are
commercially available or may be prepared by known methods such as reaction of an aryl
bromide with a diborane ester in the presence of a coupling reagent such as, for example,

palladium acetate as descnDea in me examples.
[00314] In another instance where one R1 is aryl and mother R1 is an aliphatic,
alkoxy, cycloaliphatic, or heterocycloaliphatic, compounds of the invention can be prepared as
descR1bed in steps a, b, and c of Scheme I using an appropR1ately substituted aminopyR1dine such
as R2HN 5 where X is halo and Q is C1-6 aliphatic, aryl, heteroaryl, or 3 to 10 membered
cycloaliphatic or heterocycloaliphatic as a substitute for the aminopyR1dine of formula iv.
FORMULATIONS, ADMINISTRATIONS. AND USES
Pharmaceutically acceptable compositions
[00315] Accordingly, in another aspect of the present invention, pharmaceutically
acceptable compositions are provided, wherein these compositions compR1se any of the
compounds as descR1bed herein, and optionally compR1se a pharmaceutically acceptable carR1er,
adjuvant or vehicle. In certain embodiments, these compositions optionally further compR1se
one or more additional therapeutic agents.
[00316] It will also be appreciated that certain of the compounds of present
invention can exist in free form for treatment, or where appropR1ate, as a pharmaceutically
acceptable deR1vative or a prodrug thereof. According to the present invention, a
pharmaceutically acceptable deR1vative or a prodrug includes, but is not limited to,
pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or deR1vative
which upon administration to a patient in need is capable of providing, directly or indirectly, a
compound as otherwise descR1bed herein, or a metabolite or residue thereof.
[00317] As used herein the term pharmaccutically acceptable salt refres to.
those salts which are, within the scope of sound medical judgment, suitable for use in contact
with the tissues of humans and lower animals without undue toxicity, irR1tation, allergic
response and the like, and are commensurate with a reasonable benofit/R1sk ratio. A
"pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of
this invention that, upon administration to a recipient, is capable of providing, either directly or
indirectly, a compound of this invention or an inhibitoR1ly active metabolite or residue thereof.
[00318] Pharmaceutically acceptable salts are well kr.own in the art. For example,
S. M. Berge, et ah descR1be pharmaceutically acceptable salts in detail in /. Pharmaceutical
Sciences, 1977, 66,1-19, incorporated herein by reference. Pharme ceutically acceptable salts of

the compounds of this invention include those deR1ved from suitable inorganic and organic acids
and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an
amino group formed with inorganic acids such as hydrochloR1c acid, hydrobromic acid,
phosphoR1c acid, sulfuR1c acid and perchloR1c acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaR1c acid, citR1c acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include
adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,
lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-p lenylpropionate, phosphate,
picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiccyanate, p-
toluenesulfonate, undecanoate, valerate salts, and the like. Salts deR1ved from appropR1ate bases
include alkali metal, alkaline earth metal, ammonium and N^Ci^alkyl^ salts. This invention
also envisions the quaternization of any basic nitrogen-containing groups of the compounds
disclosed herein. Water or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium,
potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts
include, when appropR1ate, nontoxic ammonium, quaternary ammon um, and amine cations
formed using counteR1ons such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate,
loweralkyl sulfonate and aryl sulfonate.
[00319] As descR1bed above, the pharmaceutically ace sptable compositions of the
present invention additionally compR1se a pharmaceutically acceptable carR1er, adjuvant, or
vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle,
dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying
agents, preservatives, solid binders, lubR1cants and the like, as suited to the particular dosage
form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B.
Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical
Technology, eds. J. SwarbR1ck and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the
contents of each of which is incorporated by reference herein, disclose vaR1ous carR1ers used in
formulating pharmaceutically acceptable compositions and known techniques for the
preparation thereof. Except insofar as any conventional carR1er medium is incompatible with
the compounds of the invention, such as by producing any undesirable biological effect or

otherwise interacting in a deleteR1ous manner with any other compo:ient(s) of the
pharmaceutically acceptable composition, its use is contemplated to be within the scope of this
invention. Some examples of mateR1als which can serve as pharmac jutically acceptable carR1ers
include, but are not limited to, ion exchangers, alumina, aluminum s tearate, lecithin, serum
proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic
acid, or potassium sorbate, partial glyceR1de mixtures of saturated vegetable fatty acids, water,
salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloR1de, zinc salts, colloidal silica, magnesium tR1silicate,
polyvinyl pyrrolidone, polyacryiates, waxes, polyethylene-polyoxypropylene-block polymers,
wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its deR1vatives such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipieni s such as cocoa butter and
suppository waxes; oils such as peanut oil, cottonseed oil; safflowei oil; sesame oil; olive oil;
corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as
ethyl oleate and ethyl laurate; agar; buffeR1ng agents such as magne sium hydroxide and
aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; R1nger's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubR1cants such as
sodium lauryl sulfate and magnesium stearate, as well as coloR1ng agents, releasing agents,
coating agents, sweetening, flavoR1ng and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of the formulator.
Uses of compounds and pharmaceutical!? acceptable compositions
[00320] In yet another aspect, the present invention provides a method of treating
a condition, disease, or disorder implicated by ABC transporter acti vity. In certain
embodiments, the present invention provides a method of treating s condition, dis&asc, or
disorder implicated by a deficiency of ABC transporter activity, the method compR1sing
administeR1ng a composition compR1sing a compound of formulae ([, II, III, FV, V-A, V-B, I',
I'-A, and I'-B) to a subject, preferably a mammal, in need thereof.
[00321] In certain preferred embodiments, the preset, t invention provides a
method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-FibR1nolysis deficiencies, such as Protein C deficiency, Type 1 hereditary
angioedema, Lipid processing deficiencies, such as Familial hyperoholesterolemia, Type 1
chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell
disease/Pseudo-Hurler, MucopolysacchaR1doses, Sandhof/Tay-Sachs, CR1gler-Najjar type II,

PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwaifism, Myleoperoxidase
deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary
emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic
DI, Charcot-MaR1e Tooth syndrome, Perlizaeus-Merzbacher disease neurodegenerative diseases
such as Alzheimer's disease, Parkinson's disease, Amyotrophic lat&ral 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 enc Hereditary Creutzfeldt-Jakob disease (due to PR1on 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, compR1sing the step of
administeR1ng to said mammal an effective amount of a composition compR1sing a compound of
formulae (I, II, HE, IV, V-A, V-B, I1,1'-A, and I'-B), or a preferred embodiment thereof as set
forth above.
[00322] According to an alternative preferred embodiment, the present invention
provides a method of treating cystic fibrosis compR1sing the step of administeR1ng to said
mammal a composition compR1sing the step of administeR1ng to said mammal an effective
amount of a composition compR1sing a compound of formulae (I, II HI, IV, V-A, V-B, I', I'-A,
and I'-B), or a preferred embodiment thereof as set forth above.
[00323] According to the invention an "effective amount" of the compound or
pharmaceutically acceptable composition is that amount effective for treating or lessening the
seveR1ty of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-FibR1nolysis 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, MucopolysacchaR1doses, Sandhof/Tay-Sach;, CR1gler-Najjar typeII,
PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase
deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis GDG type 1, Hereditary
emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic
DI, Charcot-MaR1e 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, Dentatorabal
pallidoluysian, and Myotonic dystrophy, as well as Spongiform encuphalopathies, such as
Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scbjsinker disease, secretory
diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye
disease, and Sjogren's Syndrome.
[00324] The compounds and compositions, according to the method of the present
invention, may be administered using any amount and any route of administration effective for
treating or lessening the seveR1ty of one or more of Cystic fibrosis, Hereditary emphysema,
Hereditary hemochromatosis, Coagulation-FibR1nolysis 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, MucopolysacchaR1doses, Sandhof/Tay-Sachs,
CR1gler-Najjar type n, PolyendocR1nopathy/HypeR1nsulemia, Diabetes mellitus, Laron dwarfism,
Myleoperoxidase deficiency, PR1mary hypoparathyroidism, Melanoma, Glycanosis CDG type 1,
Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis: mperfecta, Hereditary
hypofibR1nogenemia, ACT deficiency, Diabetes insipidus (DI), Neui:ophyseal DI, Neprogenic
DI,,Charcot-MaR1e 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 muscu; ar atrophy, Dentatorubal
pallidoluysian, and Myotonic dystrophy, as well as Spongiform encsphalopathies, such as
Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Sch sinker disease, secretory
diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye
disease, and Sjogren's Syndrome.
[00325] The exact amount required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the seveR1ty of the infection, the
particular agent, its mode of administration, and the like. The compounds of the invention are
preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
The expression "dosage unit form" as used herein refers to a physic illy discrete unit of agent
appropR1ate for the patient to be treated. It will be understood, however, that the total daily usage
of the compounds and compositions of the present invention will be; decided by the attending
physician within the scope of sound medical judgment. The specific effective dose level for any
particular patient or organism will depend upon a vaR1ety of factors including the disorder being
treated and the seveR1ty of the disorder; the activity of the specific compound employed; the

specific composition employed; the age, body weight, general health, sex and diet of the patient;
the time of administration, route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in combination or coincidental
with the specific compound employed, and like factors well known in the medical arts. The
term "patient", as used herein, means an animal, preferably a mammal, and most preferably a
human.
[00326] The pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally, parentera[lly, intracistemally,
intravaginally, intrapeR1toneally, topically (as by powders, ointments, or drops), bucally, as an
oral or nasal spray, or the like, depending on the seveR1ty of the infection being treated. In
certain embodiments, the compounds of the invention may be administered orally or
parenterally at dosage levels of about 6.01 mg/kg to about 50 mg/kg and preferably from about
1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain
the desired therapeutic effect.
[00327] Liquid dosage forms for oral administration include, but are not limited
to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other solveats, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene giycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and seszme oils), glycerol,
.tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoR1ng, and perfuming agents.
[00328] Injectable preparations, for example, steR1le injectable aqueous or
oleaginous suspensions may be formulated according to the known art using suitable dispersing
or wetting agents and suspending agents. The steR1le injectable preparation may also be a steR1le
injectable solution, suspension or emulsion in a nontoxic parenteral y 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, R1nger's solution, U.S.P. md isotonic sodium chloR1de
solution. In addition, steR1le, fixed oils are conventionally employed as a solvent or suspending
medium. For this purpose any bland fixed oil can be employed including synthetic mono- or
diglyceR1des. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00329] The injectable formulations can be steR1lized, for example, by filtration
through a bacteR1al-retaining filter, or by incorporating steR1lizing agents in the form of steR1le
solid compositions which can be dissolved or dispersed in steR1le water or other steR1le injectable
medium pR1or to use.
[00330] In order to prolong the effect of a compound of the present invention, it is
often desirable to slow the absorption of the compound from subcutaneous or intramuscular
injection. This may be accomplished by the use of a liquid suspension of crystalline or
amorphous mateR1al with poor water solubility. The rate of absorption of the compound then
depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline
form. Alternatively, delayed absorption of a parenterally administered compound form is
accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot
forms are made by forming microencapsule matR1ces of the compound in biodegradable
polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer
and the nature of the particular polymer employed, the rate of compound release can be
controlled. Examples of other biodegradable polymers include poly (orthoesters) and
poly(anhydR1des). Depot injectable formulations are also prepared by entrapping the compound
in liposomes or microemulsions that are compatible with body tissues.
[00331] Compositions for rectal or vaginal administration are preferably
suppositoR1es which can be prepared by mixing the compounds of this invention with suitable
non-irR1tating excipients or carR1ers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at ambient temperature but liquid at body temperature and therefore melt in
the rectum or vaginal cavity and release the active compound.
[00332] Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is mixed with at least
one inert, pharmaceutically acceptable excipient or carR1er such as sodium citrate or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and
silicic acid, b) binders such as, for example, carboxymethylcellulos 3, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating
agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i)
lubR1cants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form

may also compR1se buffeR1ng agents.
[00333] Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose: or milk sugar as well as
high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets,
dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteR1c
coatings and other coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a
delayed manner. Examples of embedding compositions that can be used include polymeR1c
substances and waxes. Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using, such excipients as lactose or milk sugar as well as
high molecular weight polethylene glycols and the like.
[00334] The active compounds can also be in microencapsulated form with one or
more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteR1c coatings, release controlling
coatings and other coatings well known in the pharmaceutical form .dating art. In such solid
dosage forms the active compound may be admixed with at least or e inert diluent such as
sucrose, lactose or starch. Such dosage forms may also compR1se, as is normal practice,
additional substances other than inert diluents, e.g., tableting lubR1cants and other tableting aids
such a magnesium stearate and macrocrystalline cellulose. In the cj.se of capsules, tablets and
pills, the dosage forms may also compR1se buffeR1ng agents. They raay optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s)
only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeR1c substances and
waxes.
[00335] Dosage forms for topical or transdermal administration of a compound of
this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays,
inhalants or patches. The active component is admixed under steR1le conditions with a
pharmaceutically acceptable carR1er and any needed preservatives or buffers as may be required.
Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the
scope of this invention. Additionally, the present invention contemplates the use of transdermal
patches, which have the added advantage of providing controlled delivery of a compound to the
body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux of the compound across

the skin. The rate can be controlled by either providing a rate controlling membrane or by
dispersing the compound in a polymer matR1x or gel.
[00336] As descR1bed generally above, the compounds; of the invention are useful
as modulators of ABC transporters. Thus, without wishing to be bound by any particular
theory, the compounds and compositions are particularly useful for treating or lessening the
seveR1ty of a disease, condition, or disorder where hyperactivity or inactivity of ABC
transporters is implicated in the disease, condition, or disorder. Wh ;n hyperactivity or
inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder, the
disease, condition, or disorder may also be referred to as an "ABC transporter-mediated disease,
condition or disorder".. Accordingly, in another aspect, the present invention provides a method
for treating or lessening the seveR1ty of a disease, condition, or disorder where hyperactivity or
inactivity of an ABC transporter is implicated in the disease state.
[00337] The activity of a compound utilized in this invention as a modulator of an
ABC transporter may be assayed according to methods descR1bed ge nerally in the art and in the
Examples herein.
[00338] It will also be appreciated that the compounds and pharmaceutically
acceptable compositions of the present invention can be employed in combination therapies,
that is, the compounds and pharmaceutically acceptable compositions can be administered
concurrently with, pR1or to, or subsequent to, one or more other desired therapeutics or medical
procedures. The particular combination of therapies (therapeutics or procedures) to employ in a
combination regimen will take into account compatibility of the desired therapeutics and/or
procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same disorder (for example, an
inventive compound may be administered concurrently with another agent used to treat the
same disorder), or they may achieve different effects (e.g., control of any adverse effects). As
used herein, additional therapeutic agents that are normally administered to treat or prevent a
particular disease, or condition, are known as "appropR1ate for the disease, or condition, being
treated".
[00339] The amount of additional therapeutic agent present in the compositions of
this invention will be no more than the amount that would normally be administered in a
composition compR1sing that therapeutic agent as the only active agsnt. Preferably the amount
of additional therapeutic agent in the presently disclosed compositions will range from about
50% to 100% of the amount normally present in a composition compR1sing that agent as the

only tnerapeuucaliy active agent.
[00340] The compounds of this invention or pharmacoutically acceptable
compositions thereof may also be incorporated into compositions for coating an implantable
medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
Accordingly, the present invention, in another aspect, includes a composition for coating an
implantable device compR1sing a compound of the present invention as descR1bed generally
above, and in classes and subclasses herein, and a carR1er suitable for coating said implantable
device. In still another aspect, the present invention includes an implantable device coated with
a composition compR1sing a compound of the present invention as descR1bed generally above,
and in classes and subclasses herein, and a carR1er suitable for coatir. g said implantable device.
Suitable coatings and the general preparation of coated implantable devices are descR1bed in US
Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeR1c mateR1als such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone,
polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings
may optionally be further covered by a suitable topcoat of fluorosilioone, polysaccaR1des,
polyethylene glycol, phospholipids or combinations thereof to impat controlled release
characteR1stics in the composition.
[00341] Another aspect of the invention relates to modulating ABC transporter
activity in a biological sample or a patient (e.g., in vitro or in vivo), which method compR1ses
administeR1ng to the patient, or contacting said biological sample with a compound of formula I
or a composition compR1sing said compound.. The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts thereof; biopsied mateR1al obtained from a
mammal or extracts thereof; and blood, saliva, uR1ne, feces, semen, tears, or other body fluids or
extracts thereof.
[00342] Modulation of ABC transporter activity in a biological sample is useful
for a vaR1ety of purposes that are known to one of skill in the art. Examples of such purposes
include, but are not limited to, the study of ABC transporters in biolagical and pathological
phenomena; and the comparative evaluation of new modulators of ABC transporters.
[00343] In yet another embodiment, a method of modulating activity of an anion
channel in vitro or in vivo, is provided compR1sing the step of contacting said channel with a
compound of formulae (I, II, III, IV, V-A, V-B, I', I'-A, and I'-B). In preferred embodiments,
the anion channel is a chloR1de channel or a bicarbonate channel. In other preferred
embodiments, the anion channel is a chloR1de channel.

[00344] 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,
compR1sing the step of contacting said cell with a compound of formula (I, II, III, IV, V-A, V-
B, I', I'-A, and I'-B). The term "functional ABC transporter" as used herein means an ABC
transporter that is capable of transport activity. In preferred embodiments, said functional ABC
transporter is CFTR.
[00345] According to another preferred embodiment, the activity of the ABC
transporter is measured by measuR1ng the transmembrane voltage potential. Means for
measuR1ng 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.
[00346] The optical membrane potential assay utilizes voltage-sensitive FRET
sensors descR1bed by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage
sensing by fluorescence resonance energy transfer in single ce Us" 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 measuR1ng fluorescence changes such as the Voltage/Ion Probe Reader
(VDPR) (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).
[00347] 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 n membrane potential (Vm) cause
the negatively charged DiSBAC2(3) to redistR1bute 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.
[00348] In another aspect the present invention provides a kit for use in measuR1ng
the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo
compR1sing (i) a composition compR1sing a compound of form ila (I, II, III, IV, V-A, V-B, I',
I'-A, and I'-B) or any of the above embodiments; and (ii) instractions for a.) contacting the
composition with the biological sample and b.) measuR1ng activity of said ABC transporter or a
fragment thereof. In one embodiment, the kit further compR1ses instructions for a.) contacting

an additional composition with the biological sample; fa.) measuR1ng the activity qf said ABC
transporter or a fragment thereof in the presence of said additional cDmpound, and c.)
compaR1ng the activity of the ABC transporter in the presence of the additional compound with
the density of the ABC transporter in the presence of a composition of formula (I, II, III, IV, V-
A, V-B, I', I'-A, and I'-B). In preferred embodiments, the kit is used to measure the density of

[00349] BenzyltR1ethylamrhomum chloR1de (0.025 equivalents) and the
appropR1ate dihalo compound (2.5 equivalents) were added to a substituted phenyl acetonitR1le.
The mixture was heated at 10 °C and men 50% sodium hydroxide (10 equivalents) was slowly
added to the mixture. The reaction was stirred at 70 °C for 12-24 hours to ensure complete
formation of the cycloalkyl moiety and then heated at 130 °C for 24-48 hours to ensure
complete conversion from the nitR1le to the carboxylic acid. The dark brown / black reaction
mixture was diluted with water and extracted with ethyl acetate and then dichloromethane three
times each to remove side products. The basic aqueous solution was acidified with concentrated
hydrochloR1c acid to pH less than one and the precipitate which begsn to form at pH 4 was
filtered and washed with 1 M hydrochloR1c acid two times. The soli 1 mateR1al was dissolved in
dichloromethane and extracted two times with 1M hydrochloR1c acid and one time with a
saturated aqueous solution of sodium chloR1de. The organic solution was dR1ed over sodium
sulfate and evaporated to dryness to give the cycloalkylcarboxylic add.

[00350] A mixture of benzo[l,3]dioxole-5-acetonitR1le; (5.10 g, 31.7 mmol), 1-
bromo-2-chloro-ethane (9.00 mL, 109 mmol), and benzyltR1ethylarationium chloR1de (0.181 g,
0.795 mmol) was heated at 70 °C and then 50% (wt./wt.) aqueous sodium hydroxide (26 mL)
was slowly added to the mixture. The reaction was stirred at 70 °C for 18 hours and then heated

at 130 °C for 24 hours. The dark brown reaction mixture was diluted with water (400 mL) and
extracted once with an equal volume of ethyl acetate and once with an equal volume of
dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloR1c acid
to pH less than one and the precipitate filtered and washed with 1 M hydrochloR1c acid. The
solid mateR1al was dissolved in dichloromethane (400 mL) and extracted twice with equal
volumes of 1 M hydrochloR1c acid and once with a saturated aqueous solution of sodium
chloR1de. The organic solution was dR1ed over sodium sulfate and evaporated to dryness to give
a white to slightly off-white solid (5.23 g, 80%) ESI-MS m/z calc. ^06.1, found 207.1 (M+l)+.
Retention time of 2.37 minutes. 1HNMR (400 MHz, DMSO-d6) 8 1.07-1.11 (m, 2H), 1.38-1.42
(m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).

[00351] Sodium hydroxide (50% aqueous solution, 7.4 equivalents) was slowly
added to a mixture of the appropR1ate phenyl acetonitR1le, benzyltR1ethylammonium chloR1de (1.1
equivalents), and the appropR1ate dihalo compound (2.3 equivalents) at 70 °C. The mixture was
stirred overnight at 70 °C and the reaction mixture was diluted with water (30 mL) and extracted
with ethyl acetate. The combined organic layers were dR1ed over sodium sulfate and evaporated
to dryness to give the crude cyclopropanecarbonitR1le, which was used directly in the next step.
[00352] The crude cyciopropanecarbonitR1le was heatsd at reflux in 10% aqueous
sodium hydroxide (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was washed
with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloR1c acid.
The precipitated solid was filtered to give the cyclopropanecarboxylic acid as a white solid.

[00353] Step a: 2,2-Difluoro-benzo[ l,3]dioxole -5-carboxylic acid methyl ester
A solution of 545romo-2,2-difluoro-benzo[l,3]dioxole (11.8 g, 50.0 mmol) and
tetrakis(tR1phenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, :5.00 mmol] in methanol (20 mL)
containing acetonitR1le (30 mL) and tR1ethylamine (10 mL) was; stirred under a carbon
monoxide atmosphere (55 PSI) at 75 °C (oil bath temperature) for 15 hours. The cooled
reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was
puR1fied by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5-
carboxylic acid methyl ester (11.5 g), which was used directly in the next step.
[00354] Step b: (2,2-Difluoro-benzo[l,3]dioxol-5-yl)-methanol
Crude 2,2-difluoro-benzo[l,33dioxole-5-carboxylk acid methyl ester (11.5 g)
dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was slowly added to a suspension of
lithium aluminum hydR1de (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 °C. The
mixture was then warmed to room temperature. After being stirred at room temperature for 1
hour, the reaction mixture was cooled to 0 °C and treated with water (4.1 g), followed by
sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and

washed with THF. The combined filtrate was evaporated to drynes;, and the residue was
puR1fied by silica gel column chromatography to give (2,2-difluoro-benzo[l,3]dioxol-5-yl)-
methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil.
[00355] Stepc: 5-Chloromethyl-2,2-difluoro-benzo[],3]dioxole
Thionyl chloR1de (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro-
benzo[l,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromettane (200 mL) at 0 °C. The
resulting mixture was stirred overnight at room temperature and the evaporated to dryness.
The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100
mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with
dichloromethane (150 mL) and the organic layer was dR1ed over socium sulfate, filtered, and
evaporated to dryness to give crude 5-chloromethyl'2,2-difluoro-be:izo[l,3]dioxole (4.4 g)
which was used directly in the next step.
[00356] Stepd: (2,2-Difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le
A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[l ,3]dioxole (4.4 g) and
sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was stirred at room
temperature overnight. The reaction mixture was poured into ice aR1d extracted with ethyl
acetate (300 mL). The organic layer was dR1ed over sodium sulfate and evaporated to dryness to
give crude (2,2-difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le (3.3 g) which was used directly in
the next step.
[00357] Step e: l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitR1le
Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of
crude (2,2-difluoro-benzo[l,3]dioxol-5-yl)-acetonitR1le, benzyltR1ethylammonium chloR1de (3.00
g, 15.3 mmoi), and l-bromo-2-chioroeihane (4.9 g, 38 mmol) at 70 °C. The mixture was stirred
overnight at 70 °C before the reaction mixture was diluted with water (30 mL) and extracted
with ethyl acetate. The combined organic layers were dR1ed over sodium sulfate and evaporated
to dryness to give crude l-(2,2-difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitR1le, which
was used directly in the next step.
[00358] Step f: l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic
acid
l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropaneca:bonitR1le (crude from the last
step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled
reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2

with 2M hydrochloR1c acid. The precipitated solid was filtered to give l-(2,2-difluoro-
benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four
steps). ESI-MS m/z calc. 242.2, found 243.3 (M+l)+;1H NMR (CDC13) 5 7.14-7.04 (m, 2H),
6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).

To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mal) in CH3CN (700 mL) was
added CH3I (111 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25 °C
overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-
chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCI3) 5 7.22 (d, J =
7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
[00360] Stepb: 4-Bromomethyl-l-chloro-2-methoxy-benzene
To a solution of l-chloro-2-methoxy-4-methyl-benzene 150 g, 0.32 mol) in CCI4
(350 mL) was added NBS (57.2 g, 0.32 mol) and ABBN (10 g, 60 mtnol). The mixture was
heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was
puR1fied by column chromatography on silica gel (Petroleum Ether/12tOAc = 20:1) to give 4-
bromomethyl-l-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCI3) 5 7.33-
7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).
[00361] Step c: 2-(4-Chloro-3-methoxyphenyl)acetonitR1le
To a solution of 4-bromomethyI-l-chIoro-2-methoxy-benzene (68.5 g, 0.29 mol) in
C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). The mixture was stirred at 60 °C
overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was
extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with
bR1ne, dried over Na2SO4 and puR1fied by column chromatography on silica gel (Petroleum
Ether/EtOAc 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitR1]e (25 g, 48%). XH NMR
(400 MHz, CDCl3) 8 7.36 (d, j= 8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H).
13C NMR (100 MHz, CDC13) 8 155.4, 130.8, 129.7,122.4,120.7,117.5,111.5, 56.2, 23.5.

[00362] BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-
methoxyphenyl)acetonitR1le (12 g, 66 mmol) in DCM (120 mL) at -78 °C under N2. The
reaction temperature was slowly increased to room temperature. The reaction mixture was
stirred overnight and then poured into ice-water. The organic layer was separated and the
aqueous layer was extracted with DCM (40 mL x 3). The combined organic layers were
washed with water, bR1ne, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-
3-hydroxy-phenyl)-acetonitR1le (9.3 g, 85%). 1H NMR (300 MHz, CDC13) 5 7.34 (d, J = 8.4 Hz,
1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, j= 2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H).

[00363] Step a: l-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester
To a solution of l-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50.0 g, 0.26
mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) at
room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was
removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic layer was
washed with sat. aq. NaHCO3 (100 mL) and bR1ne, dR1ed over anhydrous Na2SO4 and
evaporated under vacuum to give l-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl
ester (53.5 g, 99%). 1HNMR (CDC13,4OO MHz) 5 7.25-7.27 (m, 2 H), 6.85 (d, J = 8.8 Hz, 2
H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (m, 2 H), 1.15 (m, 2 H).
[00364] Step b: l-(3-Chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl ester
To a solution of l-(4-methoxy-phenyl)-cyclopropanecar Doxylic acid methyl ester
(30.0 g, 146 mmol) and MOMC1 (29.1 g, 364 mmol) in CS2 (300 mL) was added TiCl4 (8.30 g,
43.5 mmol) at 5 °C. The reaction mixture was heated at 30 °C for 1 day and poured into ice-
water. The mixture was extracted with CH2C12 (150 mL x 3). The combined organic extracts

were evaporated under vacuum to give crude l-(3-chloromethyl-4-methoxy-phenyl)-
cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without
further puR1fication.
[00365] Stepc: l-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl ester
To a suspension of crude l-(3-chloromethyl-4-metlioxy-phenyl)-
cyclopropanecarboxylic acid methyl ester (20.0 g) in water (350 mL) was added Bu4NBr (4.0 g)
and Na2CO3 (90.0 g, 0.85 mol) at room temperature. The reaction mixture was heated at 65 °C
overnight. The resulting solution was acidified with aq. HC1 (2 mol/L) and extracted with
EtOAc (200 mL x 3). The organic layer was washed with bR1ne, dR1ed over anhydrous Na2SO4
and evaporated under vacuum to give crude product, which WE s puR1fied by column (Petroleum
Ether/EtOAc 15:1) to give l-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl ester (8.0 g, 39%). 1H NMR (CDC13,400 MHz) 5 7.23-7.26 (m, 2 H), 6.83 (d, J =
8.0 Hz, 1 H), 4.67 (s, 2 H), 3.86 (s, 3 H), 3.62 (s, 3 H), 1.58 (q j= 3.6 Hz, 2 H), 1.14-1.17 (m, 2
H).
[00366] Step d: l-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy-
phenyl]cyclopropane-carboxylic acid methyl ester
To a solution of l-(3-hydroxymethyl-4-methoxy-plienyl)-cyclopropanecarboxylic
acid methyl ester (8.0 g, 34 mmol) in CH2C12 (100 mL) were added imidazole (5.8 g, 85 mmol)
and TBSC1 (7.6 g, 51 mmol) at room temperature. The mixtuie was stirred overnight at room
temperature. The mixture was washed with bR1ne, dR1ed over anhydrous Na2SO4 and evaporated
under vacuum to give crude product, which was puR1fied by column (Petroleum Ether/EtOAc
30:1) to give l-[3-(^rf-butyl-dimethyl-silanyloxymethyl)-4-mcthoxy-phenyl]-
cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). 1H NMR (CDC13,400 MHz)  7.44-
7.45 (m, 1 H), 7.19 (dd, J- 2.0, 8.4Hz, 1 H), 6.76 (d, 7= 8.4Hz, 1 H), 4.75 (s, 2H), 3.81 (s, 3
H), 3.62 (s, 3 H), 1.57-1.60 (m, 2H), 1.15-1.18 (m, 2 H), 0.96 (s, 9 H), 0,11 (s, 6 H).
[00367] Step e: l-(3-Hydroxymemyl-4-methoxy-phenyl)-cyclopropanecarboxylic
acid
To a solution of l-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-
cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a
solution of LiOH.H2O (1.50 g, 35.7 mmol) in water (10 mL) a: 0 °C. The reaction mixture was
stirred overnight at 40 °C. MeOH was removed by evaporation under vacuum. AcOH (1
mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed

with b"nn'e,''dR1ed over"anhydrous Na2SO4 and evaporated under vacuum to provide l-(3-
hydroxymemyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).

[00368] To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 mL) was
added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 niL) at -78 °C. The mixture was
stirred for 15 minutes, treated with a solution of 3-fluoro-4-mothoxy-benzaldehyde (8.00 g, 51.9
mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at -78 °C. To the cooled
reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30
minutes. Solvent of the reaction mixture was removed to give a crude product, which was
dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The
combined organic layers were dR1ed and evaporated under reduced pressure to give crude
product, which was puR1fied by column chromatography (Petroleum Ether/EtOAc 10:1) to
afford 2-(3-fluoro-4-methoxyphenyl)acetonitR1le (5.0 g, 58%). 1H NMR (400 MHz, CDC13) 5
7.02-7.05 (m, 2 H), 6.94 (t, j= 8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67 (s, 2 H). 13C NMR (100 MHz,
CDCI3) 5 152.3,147.5, 123.7,122.5,117.7, 115.8,113.8, 56.2, 22.6.

[00369] To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added
a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at -78 °C. The mixture was stirred for
10 minutes, treated with a solution of 3-chloro-4-methoxy-benzaldehyde (1.65 g, 10 mmol) in
THF (10 mL) dropwise, and continued to stir for 1.5 hours at -78 °C. To the cooled reaction
mixture was added methanol (10 mL). The mixture was heate d at reflux for 30 minutes.
Solvent of the reaction mixture was removed to give a crude product, which was dissolved in
water (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined
organic layers were dR1ed and evaporated under reduced pressure to give crude product, which
was puR1fied by column chromatography (Petroleum Ether/Et0Ac 10:1) to afford 2-(3-chloro-4-
methoxyphenyl)acetonitR1le (1.5 g, 83%). 1H NMR (400 MBs, CDC13) 6 7.33 (d, /= 2.4 Hz, 1
H),7.20 (dd, J = 2.4, 8.4Hz, 1 H), 6.92 (d,j= 8.4Hz, 1 H), 2.91 (s,3H), 3.68 (s, 2H). 13C

[00370] Step a: l-(4-Hydroxy-phenyl)-cyclopropinecarboxylic acid methyl ester
To a solution of methyl l-(4-methoxyphenyl)cyclopropanecarboxylate (10.0 g, 48.5
mmol) in DCM (80 mL) was added EtSH (16 mL) under ice-water bath. The mixture was
stirred at 0 oC for 20 min before A1C13 (19.5 g, 0.15 mmol) was added slowly at 0 °C. The
mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice-water, the
organic layer was separated, and the aqueous phase was extracted with DCM (50 mL x 3). The
combined organic layers were washed with H2O, bR1ne, dR1ed over Na2SO4 and evaporated
under vacuum to give l-(4-hydroxy-phenyl)-cyclopropanecarbcxylic acid methyl ester (8.9 g,
95%). 1H NMR (400 MHz, CDCI3) § 7.20-7.17 (m, 2 H), 6.75-6.72 (m, 2 H), 5.56 (s, 1 H), 3.63
(s, 3 H), 1.60-1.57 (m, 2 H), 1.17-1.15 (m, 2H).
[00371] Step b: l-(4-Hydroxy-3,5-cuiodo-phenyl)-cyclopropanecarboxylic acid
methyl ester
To a solution of l-(4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
(8.9 g, 46 mmol) in CH3CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture was
stirred at room temperature for 1 hour. The reaction mixture wis concentrated and the residue
was puR1fied by column chromatography on silica gel (Petroleum Ether/EtOAc 10:1) to give 1-
(4-hydroxy-3,5-diiodo~phenyl)-cyclopropanecarboxylic acid muthyl ester (3.5 g, 18%). 1H
NMR (400 MHz, CDC13) 5 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3 H), 1.59-1.56 (m, 2 H), 1.15-
1.12 (m, 2 H).
[00372] Step c: l-[3,5-Diiodo-4-(2-methyI-allylo:ty)-phenyI]-
cyclopropanecarboxylic acid methyl ester
A mixture of l-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl
ester (3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), K2CO3 (1.2 g, 8.6 mmol),
Nal (0.1 g, 0.7 mmol) in acetone (20 ml.) was stirred at 20 °C overnight. The solid was filtered

off and the filtrate was concentrated under vacuum to give l-I3,5-diiodo-4-(2-methyl-allyloxy)-
phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 1H NMR (300 MHz, CDC13) 5
7.75 (s, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 4.38 (s, 2 H), 3.65 (s, 3 H), 1.98 (s, 3H), 1.62-1.58 (m,
2 H), 1.18-1.15 (m, 2 H).
[00373] Step d: H3,3-Dimethyl-2,3-dihydro-benzofuran-5-yI)-
cyclopropanecarboxylic acid methyl ester
To a solution of 1 -[3,5-diiodo-4-(2-methyl-allyloxy )-phenyl]-cyclopropane-
carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu3SnH (2.A g, 8.4
mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated it reflux overnight. The reaction
mixture was concentrated under vacuum and the residue was puR1fied by column
chromatography on silica gel (Petroleum Ether/EtOAc 20:1) to give l-(33-dimethyl-2,3-
dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 1HNMR
(400 MHz, CDC13) 5 7,10-7.07 (m, 2 H), 6.71 (d, / = 8 Hz, 1 B), 4.23 (s, 2 H), 3.62 (s, 3 H),
1.58-1.54 (m, 2H), 1.34 (s,6H), 1.17-1.12 (m, 2 H).
[00374] Step e: l-(3,3-Dimethyl-2,3-dihydrobens;ofuran-5-
yl)cyclopropanecarboxylic acid
To a solution of l-(3,3-dimel:hyl-2,3-dihydro-benzo::uran-5-yl)-
cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 mL) was added LiOH
(0.40 g, 9,5 mmol). The mixture was stirred at 40 °C overnight. HC1 (10%) was added slowly
to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The
extracts were washed with bR1ne and dR1ed over Na2SO4- The solvent was removed under
vaccum and the crude product was puR1fied by preparative HPLC to give l-(3,3-dimethyl-2,3-
dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g? 4-l%). 1H NMR (400 MHz,
CDCI3) 5 7.11-7.07 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H), 4.23 (s, 2 H), 1.66-1.63 (m, 2 H), 1.32 (s,
6 H), 1.26-1.23 (m, 2 H).

To a solution of 3,4,5-tR1hydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and
Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 ml.) and aqueous NaOH solution
(25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature
for 6 h before it was cooled to 0 °C. The mixture was acidified to pH ~ 2 by adding cone.
H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL x 3). The combined
organic layers were dR1ed over anhydrous Na2SO4 and evaporated under reduced pressure to
give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), vhich was used in the next step
without further puR1fication.
[00376] Step b: Methyl 7-methoxybenzo[d][l,3]d oxole-5-carboxylate
To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in
acetone (500 mL) was added CH2BrCl (34.4 g, 0.27 mol) and K2CO3 (75 g, 0.54 mol) at 80 °C.
The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room
temperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced
pressure, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed
with water, dR1ed over anhydrous Na2SCO4, and evaporated under reduced pressure to give the
crude product, which was puR1fied by column chromatography on silica gel (Petroleum
Ether/Ethyl Acetate = 10:1) to afford methyl 7-methoxybenzo[d][l,3]dioxole-5-carboxylate
(12.6 g, 80%). 1HMR (400 MHz, CDCI3) 5 7.32 (s, 1 H), 7.2:1 (s, 1 H), 6.05 (s, 2 H), 3.93 (s,
3 H), 3.88 (s, 3 H).
[00377] Step c:(7-Methoxybenzo[d][l,3]dioxol-5-yl)methanol
To a solution of methyl 7-me1:hoxybenzo[d][l,3]dioxole-5-carboxylate (13.9 g, 0.040
moi) in THF (100 mL) was added LiAlrH4 (3.1 g, 0.080 mol) in portions at room temperature.
The mixture was stirred for 3 h at room temperature. The reaction mixture was cooled to 0 °C
and treated with water (3.1 g) and NaOH: (10%, 3.1 mL) successively. The slurry was filtered
off and washed with THF. The combined filtrates were evaporated under reduced pressure to
give (7-methoxy-benzo[d][l,3]dioxol-5-yl)methanol (7.2 g, 52%). 1H NMR (400 MHz, CDCI3)
5 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90 (s, 3 H).
[00378] Stepd: 6-(ChloromethyI)-4-methoxybenzo[d][l,3Jdioxole
To a solution of SOCI2 (150 mL) was added (7-methoxybenzo[d][l,3]dioxol-5-
yl)methanol (9.0 g, 54 mmol) in portions at 0 °C. The mixture was stirred for 0.5 h. The excess
SOC12 was evaporated under reduced pressure to give the crude product, which was basified
with sat. aq. NaHCO3 to pH ~ 7. The aqueous phase was extracted with EtOAc (100 mL x 3).

The combined organic layers were dR1ed over anhydrous Na2SO4 and evaporated to give 6-
(chloromethyl)-4-methoxybenzo[d][l,3]dioxole (10.2 g 94%). which was used in the next step
without further puR1fication. 1H NMR (400 MHz, CDC13) 5 6.:58 (s, 1 H), 6.57 (s, 1 H), 5.98 (s,
2 H), 4.51 (s, 2 H), 3.90 (s, 3 H).
[00379] Step e: 2-(7-Methoxybenzo[d][l,3]dioxol-5-yl)acetonitR1le
To a solution of 6-(chloromethyl)-4-methoxybenzo[d][l,3]dioxole (10.2 g, 40 mmol)
in DMSO (100 mL) was added NaCN (2.43 g, 50 mmol) at room temperature. The mixture was
stirred for 3 h and poured into water (500 mL). The aqueous phase was extracted with EtOAc
(100 mL x 3). The combined organic layers were dR1ed over anhydrous Na2SO4 and evaporated
to give the crude product, which was washed with ether to afford 2-(7-
methoxybenzo[d][l,3]dioxol-5-yl)acetonitR1le (4.6 g, 45%). 1H NMR (400 MHz, CDC13) 5 6.49
(s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 13C NMR (400 MHz, CDCI3) 5 148.9,143.4,
134.6,123.4,117.3,107.2,101.8, 101.3, 56.3, 23.1.

[00380] Step a: l-[4-(2,2-Diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid
To a stirred solution of l-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl
ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydR1de (6.7 g, 170 mmol, 60%
in mineral oil) at 0 oC. After hydrogen evolution ceased, 2-brcmo-l,l-diethoxy-ethane (16.5 g,
84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 °C for
15 hours. The reaction mixture was poured onto ice (100 g) ar d extracted with CH2CI2. The
combined organics were dR1ed over Na2SO4. The solvent was evaporated under vacuum to give
crude l-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g), which was used
directly in the next step without puR1fication.
[00381] Step b: l-Benzofuran-5-yl-cyclopropan5carboxylic acid

To a suspension of crude l-|.4-(2,2-diethoxy-ethoxy)-phenyl]-
cyclopropanecarboxylic acid (20 g, -65 mmol) in xylene (100 mL) was added PPA (22.2 g,
64.9 mmol) at room temperature. The mixture was heated at reflux (140 °C) for 1 hour before it
was cooled to room temperature and decanted from the PPA. The solvent was evaporated
under vacuum to obtain the crude product, which was puR1fied by preparative HPLC to provide
l-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 1H NMR (400 MHz, DMSO-d6) 5
12.25 (br s, 1 H), 7.95 (d, 7 = 2.8 Hz, 1 H), 7.56 (d, 7= 2.0 Hz, 1 H), 7.47 (d, 7= 11.6 Hz, 1 H),
7.25 (dd, 7= 2.4,11.2 Hz, 1 H), 6.89 (d, 7= 1.6 Hz, 1 H), 1.47 1.44 (m, 2 H), 1.17-1.14 (m, 2
TT)

[00382] To a solution of l-(benzofuran-5-yl)cyclopropanecarboxylic acid (700
mg, 3.47 mmol) in MeOH (10 mL) was added PtO2 (140 mg, 23%) at room temperature. The
stirred reaction mixture was hydrogenated under hydrogen (1 ami) at 10 °C for 3 days. The
reaction mixture was filtered. The solvent was evaporated under vacuum to afford the crude
product, which was puR1fied by preparative HPLC to give l-(2,:5-dihydrobenzofuran-5-
yl)cyclopropanecarboxylic acid (330 mg, 47%). 1H NMR (400 MHz, CDC13) 5 7.20 (s, 1 H),
7.10 (d, 7= 10.8 Hz, 1 H), 6.73 (d, 7= 11.2 Hz, 1 H), 4.57 (t, 7= 11.6 Hz, 2 H), 3.20 (t, 7= 11.6
Hz, 2H), 1.67-1.63 (m, 2 H), 1.25-1.21 (m, 2H).

To a solution of benzo[l,3]dioxol-5-yl-acetonitR1le (0.50 g, 3.1 mmol) in CH2C12 (15
mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at -78 °C under N2. The mixture was slowly
warmed to room temperature and stirred overnight. H2O (10 mL) was added to quench the
reaction and the CH2C12 layer was separated. The aqueous phase was extracted with CH2C12 (2
x 7 mL). The combined organics were washed with bR1ne, dR1ed over Na2SO4 and puR1fied by
column chromatography on silica gel (Petroleum Ether/EtOAc 5:1) to give (3,4-dihydroxy-

phenyl)-acetomtR1Te (0.25 g, 54%) as a white solid. 'H NMR (DMSO-d6,400 MHz) 5 9.07 (s, 1
H), 8.95 (s, 1 H), 6.68-6.70 (m, 2 H), 6.55 (dd, /= 8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H).
[00384] Step b: 2-(2,2-Dimethylbenzo[d][l,3]dioxol-5-yl)acetonitR1le
To a solution of (3,4-dihydroxy-phenyl)-acetonitR1le (0.2 g, 1.3 mmol) in toluene (4
mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol).
The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the
solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with
NaHCO3 solution, H2O, bR1ne, and dR1ed over Na2SO4. The solvent was evaporated under
reduced pressure to give a residue, which was puR1fied by coluR1n chromatography on silica gel
(Petroleum Ether/EtOAc 10:1) to give 2-(2,2-dimethylbenzo[d][l,3]dioxol-5-yl)acetonitR1le (40
mg, 20%). ]H NMR (CDC13,400 MHz) 5 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).

[00385] Step a: (4-Chloro-3-hydroxy-phenyl)ace1onitR1le
BBr3 (16.6 g, 66 mmol) was slowly added to a solut on of 2-(4-chloro-3-
methoxyphenyl)acetonitR1le (12 g, 66 mmol) in DCM (120 mL) at -78 °C under N2. The
reaction temperature was slowly increased to room temperature. The reaction mixture was
stirred overnight and then poured into ice and water. The organic layer was separated, and the
aqueous layer was extracted with DCM (40 mL x 3). The combined organic layers were
washed with water, bR1ne, dR1ed over Na2SO4, and concentrated under vacuum to give (4-chloro-
3-hydroxy-phenyl)-acetomtR1le (9.3 g, 85%). 1H NMR (300 MHz, CDC13) 5 7.34 (d, J = 8.4 Hz,
1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H).
[00386] Step b: 2-(3-(Benzyloxy)-4-chloropheny] )acetonitR1le
To a solution of (4-chloro-3-hydroxy~phenyl)acetonitR1le (6.2 g, 37 mmol) in CH3CN
(80 mL) was added K2CO3 (10.2 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The mixture was
stirred at room temperature overnight. The solids were filtered off and the filtrate was
evaporated under vacuum. The residue was puR1fied by columr. chromatography on silica gel
(Petroleum EtherTEthyl Acetate 50:1) to give 2-(3-(benzyloxy)-4-chlorophenyl)acetonitR1le (5.6

[00387] Step a: 6-Methylquinoxaline
To a solution of 4-methylbenzene-l,2-diamine (50.0 g, 0.41 mol) in isopropanol
(300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room
temperature. The reaction mixture was heated at 80 °C for 2 hoars and evaporated under
vacuum to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. 1H
NMR (300 MHz, CDC13) 5 8.77 (dd, J = 1.5,7.2 Hz, 2 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.87 (s, 1
H), 7.60 (dd, J = 1.5, 8.4 Hz, 1 H), 2.59 (s, 3 H).
[00388] Step b: 6-Bromomethylquinoxaline
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCI4 (80 mL) was
added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room
temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was
evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50
mL x 5). The extracts were concentrated under vacuum. The o:-ganics were combined and
concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the
next step. 1H NMR (300 MHz, CDC13) 5 8.85-8.87 (m, 2 H), 8.10-8.13 (m, 2 H), 7.82 (dd, J =
2.1, 8.7 Hz, lH),4.70(s,2H).
[00389] Step c: 2-(Quinoxalin-6-yl)acetonitR1le
To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL)
was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50 °C for
3 hours and then concentrated under vacuum. Water (100 mL) jmd ethyl acetate (100 mL) were
added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organics were washed with bR1ne, dR1ed over Na2 SO4 and concentrated under
vacuum. The residue was puR1fied by silica gel column (Petroleum Ether/EtOAc 10:1) to give

2-(qumoxalm-6-yl)acetomtnle (7.9 g, 23% over two steps). 'H NMR (300 MHz, CDC13) 8
8.88-8.90 (m, 2 H), 8.12-8.18 (m, 2 H), 7.74 (dd, J = 2.1, 8.7 Irlz, 1 H), 4.02 (s, 2 H). MS (ESI)
mfz (M+H)+ 170.0.

[00390] Step a: 6-Bromomethylquinoline
To a solution of 6-methylquinoline (2.15 g, 15.0 miaol) in CCI4 (30 mL) was added
NBS (2.92 g, 16.5 tnmol) and benzoyl peroxide (BP, 0.36 g, l.:5 mmol) at room temperature.
The mixture was heated at reflux for 2 hours. After cooling, ths mixture was evaporated under
vacuum to give a yellow solid, which was extracted with Petroleum Ether (30 mL x 5). The
extracts were concentrated under vacuum to give crude 6-bromomethylquinoline (1.8 g), which
was used directly in the next step.
[00391] Stepb: 2-(Quinolin-6-yI)acetonitR1le
To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was
added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50 °C for 3
hours and then concentrated under vacuum. Water (50 mL) and ethyl acetate (50 mL) were
added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organics were washed with bR1ne, dR1ed over Na2SO4 and concentrated under
vacuum. The combined crude product was puR1fied by column (Petroleum Ether/EtOAc 5:1) to
give 2-(qmnolin-6-yl)acetonitR1le (0.25 g, 8% over two steps).1H NMR (300 MHz, CDCI3) 5
8.95 (dd, J = 1.5,4.2 Hz, 1 H), 8.12-8.19 (m, 2 H), 7.85 (s, 1 H), 7.62 (dd, J = 2.1, 8.7 Hz, 1 H),
7.46 (q, J = 4.2 Hz, 1 H), 3.96 (s, 2 H). MS (ESI) m/e (M+H)+ 169.0.
P. 2-(23-Dihvdrobenzofb][ 1,41dioxin-6-vDacetonitR1le

£00392] Step a: 2,3-Dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester
To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-
dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at
room temperature. The resulting mixture was stirred at 80 °C overnight and then poured into
ice-water. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers
were washed with water (200 mL x 3) and bR1ne (100 mL), dR1e d over Na2SO4 and concentrated
to dryness. The residue was puR1fied by column (Petroleum Ether /Ethyl Acetate 50:1) on silica
gel to obtain 2,3-dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR
(300 MHz, CDC13) 5 7.53 (dd, J = 1.8,7.2 Hz, 2 H), 6.84-6.87 (ra, 1 H), 4.22-4.34 (m, 6 H),
1.35(t,J=7.2Hz,3H).
[00393] Step b: (2,3-Dihydro~benzo[l,4]dioxin-6-yl)-methanol
To a suspension of LAH (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a
solution of 2,3-dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF
(10 mL) at 0 °C under N2. The mixture was stirred at room temperature for 1 h and then
quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The
precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-
dihydro-benzo[l,4]dioxin-6-yl)-methanol (10.6 g). 1HNMR (200MHz, DMSO-de) 5 6.73-6.78
(m, 3 H), 5.02 (t, J - 5.7 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17-4.20 (m, 4 H).
[00394] Step c: 6-Chloromethyl-2,3-dihydro-ben7;o[l,4]dioxine
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOC12 (10
mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic
layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3).
The combined organic layers were washed with NaHCO3 (sat solution), water and bR1ne, dR1ed
over Na2SCO4 and concentrated to dryness to obtain 6-chlorome:hyl-2,3-dihydro-
benzo[l,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
[00395] Step d: 2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)acetonitR1le

A mixture or 6-chlorornethyl-2,3-dihydro-benzo[l,4]dioxine (12.5 g, 67.7 mmol)
and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was
poured into water (150 mL) and then extracted with dichloromethane (50 mL x 4). The
combined organic layers were washed with water (50 mL x 2) and bR1ne (50 mL), dR1ed over
Na2SO4 and concentrated to dryness. The residue was puR1fied by column (Petroleum
Ether\Ethyl Acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][l,4]dioxin-6*
yl)acetonitR1le as a yellow oil (10.2 g, 86%). 'H-NMR (300 MHz, CDC13) 8 6.78-6.86 (m, 3 H),
4.25(s,4H),3.63(s,2H).

[00396] Step a: 2,254,4-Tetrafluoro-4H-benzo[l,3]dioxine-6-carboxylicacid
methyl ester
A suspension of 6-bromo-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (4.75 g, 16.6
mmol) and Pd(PPh3)4 (950 mg, 8.23 mmol) in MeOH (20 mL), MeCN (30 mL) and Et3N (10
mL) was stirred under carbon monoxide atmosphere (55 psi) a1; 75 °C (oil bath temperature)
overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The
residue was puR1fied by silica gel column (Petroleum Ether) to give 2,2,4,4-tetrafiuoro-4H-
benzo[l,3]dioxine-6-carboxylic acid methyl ester (3.75 g, 85%). 1H NMR (CDC13, 300 MHz) 5
8.34 (s, 1 H), 8.26 (dd, J = 2.1, 8.7 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 3.96 (s, 3 H).
[00397] Step b: (2,2,4,4-Tetrafluoro-4H-benzo[l,3]dioxin-6-yl)methanol
To a suspension of LAH (2.14 g, 56.4 mmol) in dry THF (200 mL) was added
dropwise a solution of 2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxiR1e-6-carboxylic acid methyl ester
(7.50 g, 28.2 mmol) in dry THF (50 mL) at 0 °C. After being stirred at 0 °C for 1 h, the reaction
mixture was treated with water (2.14 g) and 10% NaOH (2.14 mL). The slurry was filtered and
washed with THF. The combined filtrates were evaporated to dryness to give the crude
(2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-methanol (6.5 g), which was used directly in the

next step. 1H NMR (CDMR, 300 MHz) 5 7.64 (s, 1 H), 7.57-7.(50 (m, 1 H), 7.58 (d, J = 8.7 Hz,
1 H), 4.75 (s, 2 H).
[00398] Step c: 6-Chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine
A mixture of (2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-methanol (6.5 g) in
thionyl chloR1de (75 mL) was heated at reflux overnight. The resulting mixture was
concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The
aqueous layer was extracted with dichloromethane (50 mL x 3) The combined organic layers
were dR1ed over Na2SO4, filtrated, and concentrated under reduced pressure to give 6-
chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (6.2 g), which was used directly in the
next step. 1H NMR (CDC13, 300 MHz) 8 7.65 (s, 1 H), 7.61 (del, J = 2.1, 8.7 Hz, 1 H), 7.15 (d, J
= 8.4 Hz, 1 H), 4.60 (s, 2 H).
[00399] Step d: (2,2,4,4-Tetrafluoro-4H-benzo[l,3]dioxin-6-yl)-acetonitR1le
A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[l,3]dioxine (6.2 g) and
NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was stirred at room temperature for 2 h. The
reaction mixture was poured into ice and extracted with EtOAc (50 mL x 3). The combined
organic layers were dR1ed over anhydrous Na2SO4, and evaporated to give a crude product,
which was puR1fied by silica gel column (Petroleum Ether/EtOAc 10:1) to give (2,2-difluoro-
benzo[l,3]dioxol-5-yl)-acetonitR1le (4.5 g, 68% over 3 steps). 1H NMR (CDC13,300 MHz) 5
7.57-7.60 (m, 2 H), 7.20 (d, J = 8.7 Hz, 1 H), 3.82 (s, 2 H).

[00400] Step a: (3-Hydroxyphenyl)acetonitR1le
To a solution of (3-methoxyphenyl)acetonitR1le (150 g, 1.03 mol) in CH2C12 (1000
mL) was added BBr3 (774 g, 3.09 mol) dropwise at -70 °C. Th; mixture was stirred and
wanned to room temperature slowly. Water (300 mL) was added at 0 °C. The resulting
mixture was extracted with CH2C12. The combined organic layers were dR1ed over anhydrous
Na2SO4, filtered, and evaporated under vacuum. The crude residue was puR1fied by column
(Petroleum Ether /EtOAc 10:1) to give (3-hydroxyphenyl)aceto[iitR1le (75.0 g, 55%). 1H NMR
(CDC13,300 MHz) 5 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H).
[00401] Step b: 2-(4H-Benzo[d][l,3]dioxin-7-yl)acetonitR1le

To a solution of (3-hydroxyphenyl)acetonitrile (75.0 g, '3.56 mol) in toluene (750
mL) was added paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate
(10.7 g, 56.0 mmol) at room temperature. The reaction mixture was heated at reflux for 40
minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL)
were added. The organic layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined organics were washed with bR1ne, dR1ed over anhydrous Na2SO4 and
evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H-
benzo[d][l,3]dioxin-7-yl)acetonitR1le (4.7 g, 5%). 1H NMR (300 MHz, CDC13) 5 6.85-6.98 (m,
3 H), 5.25 (d, J = 3.0 Hz, 2 H), 4.89 (s, 2 H), 3.69 (s, 2 H).

[00402] To a solution of (4-hydroxyphenyl)acetonitR1]e (17.3 g, 0.13 mol) in
toluene (350 mL) were added paraformaldehyde (39.0 g, 0.43 mmol) and toluene-4-sulfonic
acid monohydrate (2.5 g, 13 mmol) at room temperature. The react on mixture was heated at
reflux for 1 hour. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate
(150 mL) were added. The organic layer was separated and the aqueous layer was extracted
with ethyl acetate. The combined organics were washed with bR1ne, dR1ed over Na2SO4 and
evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H-
benzo[d][l,33dioxin-6-yl)acetonitR1le (7.35 g, 32%). 1H NMR (400 MHz, CDCI3) 6 7.07-7.11
(m, 1 H), 6.95-6.95 (m, 1 H), 6.88 (d, J = 11.6 Hz, 1 H), 5.24 (s, 2 E), 4.89 (s, 2 H), 3.67 (s, 2
H).

[00403] To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 mL) was
added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) ;it -78 °C. The mixture was
stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g,

51.9 mmoR1 in THF(50mL) dropwise, and continued to stir far 1.5 hours at -78 °C. To the
cooled reaction mixture was added methanol (50 mL). The nurture was heated at reflux for 30
minutes. Solvent of the reaction mixture was removed to give a crude product, which was
dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The
combined organic layers were dR1ed and evaporated under reduced pressure to give crude
product, which was puR1fied by column chromatography (Petroleum Ether/EtOAc 10:1) to
afford 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitR1l (5.0 g, 48%). 1H NMR (300 MHz,
CDC13) 5 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). 13C
NMR (75 MHz, CDC13) 5 149.6,148.6,136.8,128.8,128.8,1:28.2,127.5,127.5, 122.1, 120.9,
118.2,113.8, 112.2, 71.2, 56.2, 23.3.
[00404] The following Table 2 contains a list of carboxylic acid building blocks
that were commercially available, or prepared by one of the methods descR1bed above:
[00405] Table 2: Carboxylic acid building blocks.

[00406] Step a: 2,2-Dimethyl-N-(5-methyl-pyR1din-2-yl)-propionamide
To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous
CH2C12 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2-
dimethyl-propionyl chloR1de (274 mL, 2.22 mol) at 0 °C under N2. The ice bath was removed
and stirR1ng was continued at room temperature for 2 hours. The reaction was poured into ice
(2000 g). The organic layer was separated and the remaining aqueous layer was extracted with
CH2C12 (3x). The combined organics were dR1ed over Na2SO4 and evaporated to afford 2,2-
dimethyl-N-(5-methyl-pyR1din-2-yl)-propionamide (350 g), which was used in the next step
without further puR1fication. 1H NMR (400 MHz, CDC13) 5 8.12 (d, 7= 8.4 Hz, 1 H), 8.06 (d, J
= 1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J = 1.6, 8.4 Hz, 1 H), 2.27 (s, 1H), 1.30 (s, 9 H).
[00407] Step b: 2,2-Dimethyl-.N-(5-methyl-l-oxy-pyR1din-2-yl)-propionamide
To a stirred solution of 2,2-dimethyl-N-(5-niethyl-pyR1din-2-yl)-propionamide (100
g, 0.52 mol) in AcOH (500 mL) was added drop-wise 30% H2O2 (80 mL, 2.6 mol) at room
temperature. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was
evaporated under vacuum to obtain 2,2-dimethyl-JV-(5-methyl-l-oxy-pyR1din-2-yl)-

propionamide (SO g, 85% puR1ty). 1H NMR (400 MHz, CDC13) 5 10.26 (br s, 1 H), 8.33 (d, / =
8.4 Hz, 1 H), 8.12 (s, 1 H), 7.17 (dd, J = 0.8, 8.8 Hz, 1 H), 2.28 (s, 1 H), 1.34 (s, 9 H).
[00408] Step c: iV-(6-Chloro-5-methyl-pyR1din-2-yl)-2,2-dimethyl-propionamide
To a stirred solution of 2,2-dimethyl-A-N-(5-methyl-l-oxy-pyR1din-2-yl)-propionamide
(10 g, 48 mmol) in anhydrous CH2C12 (50 mL) was added Et3N (60 mL, 240 mmol) at room
temperature. After being stirred for 30 min, POC13 (20 mL) was added drop-wise to the
reaction mixture. The reaction was stirred at 50 °C for 15 hours. The reaction mixture was
poured into ice (200 g). The organic layer was separated and the remaining aqueous layer was
extracted with CH2C12 (3x). The combined organics were dR1ed over Na2SO4. The solvent was
evaporated under vacuum to obtain the crude product, which was puR1fied by chromatography
(Petroleum Ether/EtOAc 100:1) to provide A/-(6-chloro-5-methyl-pyridin-2-yl)- 2,2-dimethyl-
propionamide (0.5 g, 5%). 1H NMR (400 MHz, CDC13) 5 8.09 (d, J = 8.0 Hz, 1 H), 7.94 (br s, 1
H), 7.55 (d, J = 8.4 Hz, 1H), 2.33 (s, 1 H), 1.30 (s, 9 H).
[00409] Step d: 6-Chloro-5-methyl-pyR1din-2-ylamine
To 7Y-(6-chloro-5-methyl-pyR1din-2-yl)- 2,2-dimethyl-prcpionamide (4.00 g, 17.7
mmol) was added 6 N HC1 (20 mL) at room temperature. The mixture was stirred at 80 °C for
12 hours. The reaction mixture was basified with drop-wise addition of sat. NaHCO3 to pH 8-9,
and then the mixture was extracted with CH2CL2 (3x). The organic phases were dR1ed over
Na2SO4 and evaporated under vacuum to obtain the 6-chloro-5-metr yl-pyR1din-2-ylamine (900
mg, 36%). 1H NMR (400 MHz, CDCI3) 5 7.28 (d, / = 8.0 Hz, 1 H), 6.35 (d, / = 8.0 Hz, 1 H),
4.39 (br s, 2 H), 2.22 (s, 3 H). MS (ESI) m/z: 143 (M+H+).

[00410] 2,6-Dichloro-3-(tR1fluoromethyl)pyR1dine (5.00 g, 23.2 mmol) and 28%
aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93
°C for 21h. The reaction was cooled to rt and extracted with EtOAc (100 mL x 3). The
combined organic extracts were dR1ed over anhydrous Na2SO4 and evaporated under vacuum to
give the crude product, which was puR1fied by column chromatography on silica gel (2-20%
EtOAc in petroleum ether as eluant) to give 6-chloro-5-(tR1fluoromethyl)pyR1din-2-amine (2.1 g,

46% yield). ]H NMR (400 MHz, DMSCMs) 5 7.69 (d, J = 8.4 Hz, 1 H), 7.13 (br s, 2 H), 6.43
(d, /= 8.4 Hz, 1 H). MS (ESI) m/z (M + H)+ 197.2

[00411] One equivalent of the appropR1ate carboxylic acid was placed in an oven-
dR1ed flask under nitrogen. Thionyl chloR1de (3 equivalents) and a catalytic amount of N,N-
dimethylformarnide was added and the solution was allowed to stir at 60 °C for 30 minutes.
The excess thionyl chloR1de was removed under vacuum and the resulting solid was suspended
in a minimum of anhydrous pyR1dine. This solution was slowly added to a stirred solution of one
equivalent the appropR1ate aminoheterocycle dissolved in a minimun of anhydrous pyR1dine.
The resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was evaporated
to dryness, suspended in dichloromethane, and then extracted three times with IN NaOH. The
organic layer was then dR1ed over sodium sulfate, evaporated to dryness, and then puR1fied by
column chrornatography.

[00412] 1 -Benzo[l,3]dioxol-5-yl-cyclopropanecarbo?:ylic acid (2.38 g, 11.5
mmol) was placed in an oven-dR1ed flask under nitrogen. Thionyl chloR1de (2.5 mL) and N,N-
dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at
60 °C. The excess thionyl chloR1de was removed under vacuum and the resulting solid was
suspended in 7 mL of anhydrous pyR1dine. This solution was then slowly added to a solution of
5-bromo-pyR1din-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 mL of anhydrous pyR1dine.
The resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was then
evaporated to dryness, suspended in 100 mL- of dichloromethane, and washed with three 25 mL
portions of IN NaOH. The organic layer was dR1ed over sodium sulfate, evaporated to near
dryness, and then puR1fied by silica gel column chromatography utlizing dichloromethane as the
eluent to yield the pure product (3.46 g, 83%) ESI-MS m/z calc. 361.2, found 362.1 (M+l)+;

Retention time 3.40 minutes.1]H NMR (400 MHz, DMSO-dg) 5 1.06-1.21 (m, 2H), 1.44-1.51
(m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H)5 7.10 (d, /= 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 2H), 8.34
(s, 1H), 8.45 (s, 1H).

[00413] (l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol)
was placed in an oven-dR1ed flask under nitrogen. Thionyl chloR1de (2.5 mL) and N,N-
dimethylformamide (0.3 mL) were added and the solution was allowed to stir at 60 °C for 30
minutes. The excess thionyl chloR1de was removed under vacuum and the resulting solid was
suspended in 5 mL of anhydrous pyR1dine. This solution was then slowly added to a solution of
6-bromopyR1din-2-amine (1.0 g, 5.8 mmol) suspended in 10 mL of anhydrous pyR1dine. The
resulting mixture was allowed to stir for 15 hours at 110 °C. The mixture was then evaporated to
dryness, suspended in 50 mL of dichloromethane, and washed with three 20 mL portions of IN
NaOH. The organic layer was dR1ed over sodium sulfate, evaporated to near dryness, and then
puR1fied by silica gel column chromatography utilizing dichloromethane containing 2.5 %
tR1ethylamine as the eluent to yield the pure product. ESI-MS tn/z calc. 361.2, found 362.1
(M+l)+; Retention time 3.43 minutes. 1H NMR (400 MHz, DMS0-d6) 8 1.10-1.17 (m, 2H),
1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, / = 1.6 ] Iz, 1H), 7.33 (d, J = 7.6 Hz,
1H), 7.73 (t, J= 8.0 Hz, 1H), 8.04 (d, J= 8.2 Hz, 1H), 8.78 (s, 1H).
[00414] The compounds in the following Table 3 were prepared in a manner
analogous to that descR1bed above:
[00415] Table 3: Exemplary compounds synthesized i ccording to Preparations W
andX.

[00416] The appropR1ate aryl halide (1 equivalent) was dissolved in 1 mL of N,N-
dimethylformamide (DMF) in a reaction tube. The appropR1ate borcnic acid (1.3 equivalents),
0.1 mL of an aqueous 2 M potassium carbonate solution (2 equivalents), and a catalytic amount
of Pd(dppf)Cl2 (0.09 equivalents) were added and the reaction mixtire was. heated at 80 °C for
three hours or at 150 °C for 5 min in the microwave. The resulting mateR1al was cooled to room
temperature, filtered, and puR1fied by reverse-phase preparative liquid chromatography.

[00417] l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (5-bromo-pyR1din-
2-yl)-amide (36.1 mg, 0.10 mmol) was dissolved in 1 mL of iV,JV-dimethylformamide in a
reaction tube. 2,4-Dimethoxybenzeneboronic acid (24 mg, 0.13 mmol), 0.1 mL of an aqueous 2
M potassium carbonate solution, and a catalytic amount of Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol)
were added and the reaction mixture was heated at 80 °C for three hours. The resulting mateR1al
was cooled to room temperature, filtered, and puR1fied by reverse-phase preparative liquid
chromatography to yield the pure product as a tR1fluoroacetic acid salt. ESI-MS m/z calc. 418.2,
found 419.0 (M+l)+. Retention time 3.18 minutes. lH NMR (400 MHz, CD3CN) 5 1.25-1.29
(m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H), 5.64-6.68 (m, 2H), 6.92 (d,
J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.30 (d, / = 8.3 Hz, 1H), 7.96 (d, / = 8.9 Hz, 1H), 8.14 (dd,
/= 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H).

[00418] l-Benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (6-bromo-pyR1din-
2-yl)-amide (36 mg, 0.10 mmol) was dissolved in 1 mL of N, Af-dimethylformarnide in a reaction
tube. 4-(Dimethylamino)phenylboronic acid (21 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M
potassium carbonate solution, and (Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol) were added and the
reaction mixture was heated at 80 °C for three hours. The resulting mateR1al was cooled to room
temperature, filtered, and puR1fied by reverse-phase preparative liquid chromatography to yield
the pure product as a tR1fluoroacetic acid salt. ESL-MS m/z calc. 401.2, found 402.5 (M+l)+.
Retention time 2.96 minutes. 'H NMR (400 MHz, CD3CN) 5 1.23-1.27 (m, 2H), 1.62-1.66 (m,
2H), 3.04 (s, 6H), 6.06 (s, 2H), 6.88-6.90 (m, 2H), 6.93-6.96 (m, III), 7.05-7.07 (m, 2H), 7.53-
7.56 (m, 1H), 7.77-7.81 (m, 3H), 7.84-7.89 (m, 1H), 8.34 (s, 1H).
[00419] The following schemes were utilized to prep ire additional boronic esters
which were not commercially available:
A A. l-Methvl-4-f4-('4,4,5,5-tetramethvl-11312-dioxaboro]an-2-vI)phenvl]-
sulfonylpiperazine

[00420] Step a: l-(4-Bromophenylsulfonyl)-4-meth piperazine
j
A solution of 4-bromobenzene-l-sulfonyl chloR1de (256 mg, 1.00 mmol) in 1 mL of
dichloromethane was slowly added to a vial (40 mL) containing 5 rnL of a saturated aqueous
solution of sodium bicarbonate, dichloromethane (5 mL) and 1-meihylpiperazine (100 mg, 1.00
mmol). The reaction was stirred at room temperature overnight. The phases were separated and
the organic layer was dR1ed over magnesium sulfate. Evaporation o: the solvent under reduced
pressure provided the required product, which was used in the next step without further
puR1fication. ESI-MS m/z calc. 318.0, found 318.9 (M+l)+. Retention time of 1.30 minutes. 1H

NMR (300 MHZ CDCI3) 5 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, 1/ = 8.7 Hz, 2H), 3.03 (t, J = 4.2
Hz, 4H), 2.48 (t, / = 4.2 Hz, 4H), 2.26 (s, 3H).
[00421] Step b: l-Methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
y])pheny]]sulfonyl-piperazine
A 50 mL round bottom flask was charged with l-(4-bromophenyl-sulfonyl)-4-
methylpiperazine (110 mg, 0.350 mmol), fos-(pinacolato)-diboron (93 mg, 0.37 mmol),
palladium acetate (6 mg, 0.02 mmol), and potassium acetate (103 mg, 1.05 mmol) in N,N-
dimethylformamide (6 mL). The mixture was degassed by gently bubbling argon through the
solution for 30 minutes at room temperature. The mixture was then heated at 80 °C under argon
until the reaction was complete (4 hours). The desired produci;, l-methyl-4-[4-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-sulfonyl-piperazine, and the bi-aryl product, 4-(4-
methylpiperazin-l-ylsulfonyl)-phenyl-phenylsulfonyl-4-methylpiperazine, were obtained in a
ratio of 1:2 as indicated by LC/MS analysis. The mixture was used without further puR1fication.

[00422] Step a: 4-Bromophenethyl-4-methylbenzenesulfonate
To a 50 mL round-bottom flask was added p-bromophenethyl alcohol (1.0 g, 4.9
mmol), followed by the addition of pyR1dine (15 mL). To this clear solution was added, under
argon,P-toluenesulfonyl chloR1de (TsCl) (1.4 g, 7.5 mmol) as a solid. The reaction mixture was
purged with Argon and stirred at room temperature for 18 hours. The crude mixture was treated
with IN HC1 (20 mL) and extracted with ethyl acetate (5 x 25 mL). The organic fractions were
dR1ed over Na2SO4, filtered, and concentrated to yield 4-bromophenethyl-4-
methylbenzenesulfonate (0.60 g, 35%) as a yellowish liquid. H-NMR (Acetone- d6, 300 MHz)

5 7.64 (d, J = 8.4 Hz, 2H), 7.40-7.37 (d, / = 8.7 Hz, 4H), 7.09 (d, / == 8.5 Hz, 2H), 4.25 (t, / =
6.9 Hz, 2H), 2.92 (t, J - 6.3 Hz, 2H), 2.45 (s, 3H).
[00423] Step b: (4-Bromophenethyl)(methyl)sulfane
To a 20 mL round-bottom flask were added 4-bromophenethyl 4-
methylbenzenesulfonate (0.354 g, 0.996 mmol) and CH3SNa (0.10 £, 1.5 mmol), followed by
the addition of THF (1.5 mL) and AT-methyl-2-pyrrolidinone (1.0 ml,). The mixture was stirred
at room temperature for 48 hours, and then treated with a saturated aqueous solution of sodium
bicarbonate (10 mL). The mixture was extracted with ethyl acetate [4 x 10 mL), dR1ed over
Na2SO4, filtered, and concentrated to yield (4-bromophenethyl) (met tiyl)sulfane (0.30 g crude)
as a yellowish oil. 1H-NMR (CDC13, 300 MHz) 5 7.40 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz,
2H), 2.89-2.81 (m, 2H), 2.74-2.69 (m, 2H), 2.10 (s, 3H).
[00424] Step c: l-Bromo-4-(2-methylsulfonyl)-ethylbjnzene
To a 20 mL round-bottom flask were added (4-bromoph(!nethyl)-(methyl)sulfane
(0.311g, 1.34 mmol) and Oxone (3.1 g, 0.020 mol), followed by the addition of a 1:1 mixture of
acetone/water (10 mL). The mixture was vigorously stirred at room temperature for 20 hours,
before being concentrated. The aqueous mixture was extracted with ethyl acetate (3 x 15 mL)
and dichloromethane (3x10 mL). The organic fractions were combined, dR1ed with Na2SO4
filtered, and concentrated to yield a white semisolid. PuR1fication of the crude mateR1al by flash
chromatography yielded l-bromo-4-(2-methylsulfonyl)-ethylbenzer e (0.283 g, 80%). 1H-
NMR (DMSO-d6, 300 MHz) 5 7.49 (d, J- 8.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 3.43 (m, 2H),
2.99 (m, 2H), 2.97 (s, 3H).
[00425] Step d: 4,4,5,5-Tetramethyl-2-(4-(2-(methylsulfonyl)ethyl)-phenyl)-l,3,2-
dioxaboroliine
4,4,5,5-Tetramethyl-2-(4-(2-(methylsulfonyl)ethyl)phenyl)-1,3,2-dioxaborolane was
prepared in the same manner as descR1bed above for l-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)phenyl]sulfonyl-piperazine, Preparation AA.

[00426] Step a: tert-Butyl-4-bromobenzylcarbamate
Commercially available p-bromobenzylamine hydrochloride (1 g, 4 mmol) was
treated with 10% aq. NaOH (5 mL). To the clear solution was added (Boc)2O (1.1 g, 4.9 mmol)
dissolved in dioxane (10 mL). The mixture was vigorously stirred at room temperature for 18
hours. The resulting residue was concentrated, suspended in water (20 mL), extracted with
ethyl acetate (4 x 20 mL), dR1ed overNa2SO4, filtered, andconcentiatedto yieldtert-butyl-4-
bromobenzylcarbamate (1.23 g, 96%) as a white solid. 1H NMR (3 DO MHz, DMSO-d6) 6 7.48
(d, J = 8.4 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.07 (d, J = 6.3 Hz, 2H),
1.38 (s,9H).
[00427] Step b: tert-Butyl-4-bromobenzyl(methyl)ca:bamate
In a 60-mL vial, tert-butyl'4-broiR1obenzylcarbamate (1.25 g, 4.37 mmol) was
dissolved in DMF (12 mL). To this solution was added Ag2O (4.0j, 17 mmol) followed by the
addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50 °C for 18 hours. The
reaction mixture was filtered through a bed of celite and the celite v/as washed with methane! (2
x 20 mL) and dichloromethane (2 x 20 mL). The filtrate was concentrated to remove most of
the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This
mixture was extracted with ethyl acetate (4 x 25 mL), dR1ed over Na2SO4, and the solvent was
evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil.
1HNMR (300 MHz, DMSO-d6) 5 7.53 (d, 7 = 8.1 Hz, 2H), 7.15 (d J= 8.4 Hz, 2H), 4.32 (s,
2H), 2.74 (s, 3H), 1.38 (s, 9H).
[00428] Step c: tert-Butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)benzylmethylcarbarnate

The coupling reaction was achieved in the same manner as descR1bed above for 1-
methyI-4-[4-(4,4,5)5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-piperazine,
Preparation AA. The Boc protecting group was removed after the coupling reaction by treating
the crude reaction mixture with 0.5 mL of IN HC1 in diethyl ether for 18 hours before
puR1fication by HPLC.
[00429] Additional examples of the invention were prepared following the above
procedure with non-substantial changes but using aryl boronic acids given in Table 4.
[00430] Table 4: Additional exemplary compounds of formula I.

(a.) The tsoc protecting group was remo\ea after me coupling reaction by
treating the crude reaction mixture with 0.5 mL of IN HC1 in diethyl ether for 18 hours before
puR1fication by HPLC.
[00431] Further examples of the invention may be prepared by modification of
intermediates as illustrated above.
Compound DeR1vatization After Coupling:

[00432] Step a: 4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic acid
4,4'-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid
(1.54 g, 10 mmol) were dissolved in 20 mL AcOH and heated at 60 °C for lh. Solvent was

evaporated and the resid'ue Was dR1ed under high vacuum. This mateR1al was used without
further puR1fication.
[00433] Step b: 6-(4-(Bis(4-methoxyphenyl)methylthio)phenyl)pyR1din-2-amine
4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic acid (10 nimol) and 2-amino-6-
bromopyR1dine (1.73 g, 10 mmol) were dissolved in MeCN (40 roL) followed by addition of
Pd(PPh3)4 (-50 mg) and aq. K2CO3 (1M, 22 mL). The reaction mixture was heated portion wise
in a microwave oven (160 °C, 400 sec). The products were distR1buted between ethyl acetate
and water. The organic layer was washed with water, bR1ne and dR1ed over MgSO4. Evaporation
of the volatiles yielded an oil that was used without puR1fication in the next step. ESI-MS m/z
calc. 428.0, found 429.1 (M+l).
[00434] Stepc: l-(Benzo[d][l,3]dioxol-5-yl)-N-(6-(4-(bis(4-
methoxyphenyl)methylthio)phenyl)-pyR1din-2-yl)cyclopropanecarboxamide
6-[(4,4'-DimethoxybenzhydRY)-4-thiophenyl]pyR1dir-2-ylamine (-10 mmol) and 1-
benzo[l,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) were dissolved in
chloroform (25 mL) followed by the addition of TCPH (4.1 g, 12 mmol) and DIEA (5 mL, 30
mmol). The reaction mixture was heated at 65 °C for 48 h before the volatiles were removed
under reduced pressure. The residue was transferred to a separatory funnel and distR1buted
between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5%
NaHCO3 (2 x 150 mL), water (1 x 150 mL), bR1ne (1 x 150 mL) and dR1ed over MgSO4.
Evaporation of the solvent yielded crude l-(benzo[d][l,3]dioxol-5-yl)-iV-(6-(4-(bis(4-
methoxyphenyl)-methylthio)phenyl)pyR1din-2-yl)cyclopropanecarboxamide as a pale oil. ESI-
MS m/z calc. 616.0, found 617.0 (M+l) (HPLC puR1ty -85%, UV254 ran).
[004351 Step d: 4-(6-(l-(Benzo[d][l,3]dioxol-5-yl)cyclopropane-
j
carboxamido)pyR1din~2-yl)benzenesulfomc acid
l-(Benzo[d][l,3]dioxol-5-yl)-Ar-(6-(4-(bis(4-methoxyphenyl)methylthio)-
phenyl)pyR1din-2-yl)cyclopropanecarboxamide (-8.5 mmol) was dissolved in AcOH (75 mL)
followed by the addition of 30% H2O2 (10 mL). Additional hyc rogen peroxide (10 ml) was
added 2h later. The reaction mixture was stirred at 35-45 °C overnight (-90% conversion,
HPLC). The volume of reaction mixture was reduced to a third by evaporation (bath
temperature below 40 °C). The reaction mixture was loaded directly onto a prep RP HPLC
column (C-18) and puR1fied. Fractions with 4-(6-(l-(benzo[d][l,3]dioxol-5-
yl)cyclopropanecarboxamido)pyR1din-2-yl)benzenesulfonic acid were collected and evaporated

(1.9 g, 43 %, cal. based on 4-mercaptophenylboromc acid). ESI-MS m/z calc. 438.0, found
438.9 (M+l).
[00436] Step e: 4-(6-(l-(Benzo[d][l,3]dioxol-5 •yl)cyclopropane-
carboxamido)pyR1din-2-yl)benzene- 1-sulfonyl chloR1de
4-(6-(l-(Benzo[d] [ 1,3]dioxol-5-yl)cyclopropaneca] boxamido)pyR1din-2-
yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCI3 (30 mL) followed by the
addition of SOC12 (3 mL) and DMF (100 fil). The reaction mixture was heated at 70-80 °C for
15min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The
residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation
immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+l).
[00437] Step f: l-(Benzo[d][l,3]dioxol-5-yl)-N-(6-(4-(2-methylpyrrolidin-l-
ylsulfonyl)phenyl)pyR1din-2-yl)cyclopropanecarboxamide
4-(6-(l-(Benzo[d][l,3]dioxol-5-yl)cyclopropanecaiboxamido)pyR1din-2-yl)benzene-
1-sulfonyl chloR1de (~ 35imol, 400/d solution in chloroform) was treated with 2-
methylpyrrolidine followed by the addition of DIEA (100 /il). The reaction mixture was kept at
room temperature for lh, concentrated, then diluted with DMSO (400/^1). The resulting solution
was subjected to HPLC puR1fication. Fractions containing the desired mateR1al were combined
and concentrated in vacuum centR1fuge at 40° C to provide the tR1fluoroacetic salt of target
mateR1al (ESI-MS m/z calc. 505.0, found 505.9 (M+l), retention time 4.06 min). ]H NMR (250
MHz, DMSO-d6) 5 1.15 (m. 2H), 5 1.22 (d, 3H, J=6.3 Hz), 8 1.41-1.47 (m, 2H), 5 1.51 (m, 2H),
8 1.52-1.59 (m, 2H), 6 3.12 (m, 1H), 5 3.33 (m, 1H), 6 3.64 (m, 1H), 5 6.07 (s, 2H), 6 6.96-7.06
(m, 2H), 5 7.13 (d, 1H, J=1.3 Hz), 5 7.78 (d, 1H, J=8.2 Hz), S 7.88 (d, 2H, J=8.5 Hz), 5 7.94 (t,
1H, J=8.2 Hz), o 8.08 (d, IK, J=8.2 Hz), 5 8.16 (d, 2H, J=8.5 Hz), 5 8.53 (s, III).
[00438] The compounds in the following table were synthesized as descR1bed
above using commercially available amines. Additional exarr pies of the invention were
prepared following the above procedure with non-substantial changes but using amines given in
Table 5.
[00439] Table 5: Additional exemplary compounds of formula I.

[00440] To the starting amine (brown semisolid, 0.100 g, ~ 0.2 mmol, obtained by
treatment of the corresponding f-butyloxycarbonyl deR1vative by treatment with IN HC1 in
ether) was added dichloroethane (DCE) (1.5 mL), followed by the addition of pyR1dine (0.063
mL, 0778 mmol) and methansulfonyl chloR1de (0.03 mL, 0.4 mmol). The mixture was stirred at
65 °C for 3 hours. After this time, LC/MS analysis showed ~ 50 % conversion to the desired
product. Two additional equivalents of pyR1dine and 1.5 equivalents of methansulfonyl chloR1de
were added and the reaction was stirred for 2 hours. The residue was concentrated and puR1fied
by HPLC to yield l~benzo[l,3]dioxol-5-yl-iV-[6-[4-[(methyl-methylsulfonyl-
amino)methyl]phenyl]-2-pyR1dyl]-cyclopropane-l-carboxamide (0.020 g, 21% yield) as a white
solid. ESI-MS m/z calc. 479.2, found 480.1 (M+l)+.
FF.(J?)-l-(3-hydroxy-4-methoxyphenvl)-A^-(6-(4-(2-(hvdroxvR1ethvlVpyrrolidin-l-
vlsulfonyl)phenyl)pvR1din-2-yl)cyclopropanecarboxamide

[00441] (/?)-l-(3-(Benzyloxy)-4-methoxyphenyl)-iV (hydroxymethyl)pyrrolidin-l-ylsulfonyI)phenyl)pyR1din-2-yl)cycl()propanecarboxamide(28 mg,
0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added

ana tne"reaction was stirred overnight under 1 atm of hydrogen. The catalyst was filtered off
and the product was isolated by silica gel chromatography (50-80% EtOAc in hexane) to
provide (R)-l-(3-hydroxy-4-methoxyphenyl)-N-(6-(4-(2-(hydrcoxymethyl)pyrrolidin-1-
ylsulfonyl)phenyl)pyR1din-2-yl)cyclopropanecarboxamide (8 mg, 34%). ESI-MS mfz calc.
523.4, found 524.3 (M+l)+. Retention time of 3.17 minutes.
[00442] 2-Ammo-5-phenylpyR1dine (CAS [33421 -40-8]) is C-l.
GG. (R)-(l-(4-(6-AminopyR1din-2-yl)phenylsulfonvl'lpyrrolidin-2-yl) methanol
hydrochloR1de (C-2)

[00443] Step a: (R)-(l-(4-Bromophenylsulfonyl)])yrrolidin-2-yl)methanol
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2C12 (400 mL) and prrolidin-2-
yl-methanol (53 g, 0.53 mol) was added a solution of 4-bromo-benzenesulfonyl chloR1de (127 g,
0.50 mol) in CH2C12 (100 mL). The reaction was stirred at 20 °C overnight. The organic phase
was separated and dR1ed over Na2SO4. Evaporation of the solvent under reduced pressure
provided (i?)-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methiinol (145 g, crude), which was
used in the next step without further puR1fication. 1H NMR (CDC13,300 MHz) 5 7.66-7.73 (m, 4
H), 3.59-3.71 (m, 3 H), 3.43-3.51 (m, 1 H), 3.18-3.26 (m, 1 H) 1.680-1.88 (m, 3 H), 1.45-1.53
(m, 1 H).

[00444] Step b: (R)-l-(4-Bromo-benzenesulfonyI)-2-(rert-butyl-dimethyl-
silanyloxymethyl) pyrrolidine
To a solution of [l-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (50.0 g,
0.16 mol) and lH-imidazole (21.3 g, 0.31 mol) in CH2C12 (500 itnL) was added tert-
butylchlorodimethylsilane (35.5 g, 0.24 mol) in portions. After addition, the mixture was stirred
for 1 hour at room temperature. The reaction was quenched with water (200 mL) and the
separated aqueous layer was extracted with CH2C12 (100 mL x 3). The combined organic layers
were washed with bR1ne, dR1ed over Na2SO4-6 and evaporated under vacuum to give l-(4-bromo-
benzenesulfonyl)-2-(tert-butyldimethylsilanyloxymethyl)pyrrolidine (68.0 g, 99%). :H NMR
(300 MHz, CDC13) 5 7.63-7.71 (m, 4 H), 3.77-3.81 (m, 1 H), 3.51-3.63 (m, 2 H), 3.37-3.43 (m,
1 H), 3.02-3.07 (m, 1 H), 1.77-1.91 (m, 2 H), 1.49-1.57 (m, 2 H), 0.87 (s, 9 H), 0.06 (d, j= 1.8
Hz, 6 H).
[00445] Step c: (R)-4-(2-((fcrt-butyldimethylsilyloxy)methyl)pyrrolidin-l-
ylsulfonyl) phenylboronic acid
To a solution of l-(4-bromo-benzenesulfonyl)-2-(tert-butyl-dimethyl-
silanyloxymethyOpyrrolidine (12.9 g, 29.7 mmol) and B(O'Pr)3(8.4 g, 45 mmol) in dry THF
(100 mL) was added dropwise n-BuLi (2.5 M in hexane, 29.7 mL) at -70 °C. After addition,
the mixture was warmed slowly to -10 °C and treated with HC1 (1M, 50 mL). The organic
layer was separated and the aqueous layer was extracted with ethyl acetate. The combined
organic layers were dR1ed over Na2SO4 and evaporated under vacuum. The organics were
combined to give crude (R)-4-(2-((tert-butyJdimethylsilyloxy)methyl) pyrrolidin-1-
. ylsulfonyl)phenylboronic acid (15.0 g), which was used directly in the next step.
[00446] Step d: (6-{4-[2-(fert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidine-l-
sulfonyl] phenyl}pyR1din-2-yl)carbamic acid tert-butyl ester
To a solution of (6-bromo-pyR1din-2-yl)carbarnic acid tert-bnty\ ester (24.6 g, 90.0
mmol) in DMF (250 mL) were added (i?)-4-(2-((ter/-butyldimethylsilyloxy)-methyl) pyrrolidin-
l-ylsulfonyl)phenylboronic acid (45.0 g), Pd(PPh.3)4 (10.4 g, 9.0 mmol), potassium carbonate
(18.6 g, 135 mol) and water (200 mL). The resulting mixture was degassed by gently bubbling
argon through the solution for 5 minutes at 20 °C. The reaction mixture was then heated at 80
°C overnight. DMF was removed under vacuum. To the residue was added EtOAc (300 mL).
The mixture was filtered through a pad of silica gel, which was washed with EtOAc (50 mL x
3). The combined organic extracts were evaporated under vacuum. The crude residue was
puR1fied by column (Petroleum Ether/EtOAc 20:1) to give (6-{4-[2-(tert butyl-dimethyl-

silan1yoxymethy pyrrolidine-1-sulfonyl} phenyl}pyR1din-2-yl)carbamic acid tert-butyl ester
(22.2 g, 45% over 2-steps). 1H NMR (300 MHz, CDC13) 5 8.09 (d, J = 8.4 Hz, 2 H), 7.88-7.96
(m, 3 H), 8.09 (t, / = 7.8 Hz, 1 H),7.43-7.46 (m, 1 H), 7.38 (s, 1 H), 3.83-3,.88 (m, 1H), 3.64-
3.67 (m, 1 H), 3.53-3.59 (m, 1 H), 3.41-3.47 (m, 1 H), 3.08-3.16 (m, 1 H), 1.82-1.91 (m, 2 H),
1.67-1.69 (m, 1 H), 1,53-1.56 (m, 10 H), 0.89 (s, 9 H), 0.08 (d, J= 2.4 Hz, 6 H).
[00447] Step e: {6~[4-(2~Hydroxyraethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din-
2-yl carbamic acid tert-buty ester
A solution of crude (6-{4-[2-(tert-butyl-dimethyI-silanyloxymethyl)-pyrrolidine-l-
sulfonyl]phenyl}-pyR1din-2-yl)carbamic acid tert-bntyl ester (22.2 g, 40.5 mmol) and TBAF
(21.2 g, 81.0 mmol) in DCM (300 mL) was stirred at room temperature overnight. The mixture
was washed with bR1ne (100 mL x 3), dR1ed over Na2SO4 and evaporated under vacuum to give
{6-[4-(2-hydroxymethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din-2-yl}carbamic acid tert-bntyl
ester (15.0 g, 86%), which was used directly in the next step.
[00448] Step f: (R)-(l-(4-(6-AminopyR1din-2-yl)phenylsulfonyl)-pyrrolidin-2-yl)
methanol hydrochloR1de (C-2)
A solution of {6-[4-(2-hydroxymethyl-pyrrolidine-l-sulfonyl)-phenyl]pyR1din-2-
yl}carbamic acid tert-butyl ester (15.0 g, 34.6 mmol) in HCI/MeOH (50 mL, 2M) was heated at
reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated under
vacuum and washed with EtOAc to give (i?)-(l-(4-(6-aminopyR1din-2-
yl)phenylsulfonyl)pyrrolidin-2-yl) methanol hydrochloR1de (C-2; 11.0 g, 86%). !H NMR (300
MHz, DMSO-d6) 5 8.18 (d, /= 8.7 Hz, 2 H), 7.93-7.99 (m, 3 H), 7.31 (d, / = 7.2 Hz, 1 H), 7.03
(d, J = 8.7 Hz, 1 H), 3.53-3.57 (m, 2 H), 3.29-35 (m, 2 H), 3.05-3.13 (m, 1 H), 1.77-1.78 (m, 2
H), 1.40-1.45 (m, 2 H). MS (ESI) m/z (M+H)+ 334.2.
HH. JV-(4-(6-AminopyR1dm-2-vI')benzyl)methanesulfonarnide(C-3")

[00449] Step a: [6-(4-Cyano-phenyl)-pyR1din-2-yl]carbamic acid ferr-butyl ester
A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyR1din-2-
yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3
(10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80 °C overnight.
DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200
mL). The mixture was washed with water and bR1ne, dR1ed over Na2SO4, and concentrated to
dryness. The residue was puR1fied by column (Petroleum Ether/EtOAc 50:1) on silica gel to
give [6-(4-cyano-phenyl)-pyR1din-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR
(300MHz, CDC13) 5 8.02-8.07 (m, 2 H), 7.95 (d, j= 8.4 Hz, 1 H), 7.71-7.79 (m, 3 H), 7.37-
7.44 (m, 2 H), 1.53 (s, 9 H).
[00450] Step b: [6-(4-Aminomethyl-phenyl)-pyR1din-2-yl]-carbamic acid tert-
butyl ester .
A suspension of [6-(4-cyano-phenyl)-pyR1din-2-yl]carbamic acid tert-butyl ester (7.0
g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated
under H2 (50 psi.) at 50 °C for 6 h. The catalyst was filtered off and the filtrate was
concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyR1din-2-yl]-carbamic acid tert-
butyl ester, which was used directly in next step. ]H NMR (300 MHz, CDC13) 5 7.83-7.92 (m,
3H), 7.70 (t, J = 7.8 Hz, 1H), 7.33-7.40 (m, 4 H), 3.92 (brs, 2 H), 1.53 (s, 9 H).
[00451] Step c: {6-[4-(Methanesulfonylamino-methyl)-phenyl]-pyR1din-2-
yl}carbamic acid terf-butyl ester
To a solution of [6-(4-aminomemyI-phenyI)-pyR1din-2-yl]-carbamic acid terr-butyl
ester (5.7 g 19 mmol) and Et3N (2.88 g, 29 inmol) in dichloromethane (50 mL) was added
dropwise MsCl (2.7 g, 19 mmol) at 0 °C. The reaction mixture was stirred at this temperature
for 30 min, and then washed with water and bR1ne, dR1ed over Na2SO4 and concentrated to
dryness. The residue was recrystallized with DCM/Petroleum Ether (1:3) to give (6-[4-
(methanesulfonylamino-methyl)-phenyl]-pyR1din-2-yl}carbamic acid rert-butyl ester (4.0 g, 44%
over two steps). 1H NMR (300 MHz, CDC13) 5 7.90-7.97 (m, 3 H), 7.75 (t, / = 8.4, 8.4 Hz, 1 H),
7.54-7.59 (m, 1 H), 7.38-7.44 (m, 3 H), 4.73 (br ,1 H), 4.37 (d, J = 6.0 Hz, 2 H), 2.90 (s, 3 H),
1.54 (s, 9 H).
[00452] Step d: N-(4-(6-AmiR1opyR1din-2-yl)benzyl)methane-sulfonamide (C-3)
A mixture of {6-[4-(methanesuli7onylamino-methyl)-phenyl]-pyR1din-2-yl) carbamic
acid tert-butyl ester (11 g, 29 mmol) in HCl/MeOH (4M, 300 mL) was stirred at room
temperature overnight. The mixture was concentrated to dryness. The residue was filtered and

washed with ether to give iV-(4-(6-aminopyR1din-2-yl)benzyl)methane sulfonamide (C-3) (7.6 g,
80%) 1H NMR (300 MHz, DMSO-d6) 5 14.05 (br s, 1 H), 8.24 (br s, 2 H), 7.91-7.98 (m, 3 H),
7.70 (t, J = 6.0 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 6.9 Hz, 1 H), 6.96 (d, J = 9 Hz, 1
H), 4.23 (d, J = 5.7 Hz, 2 H), 2.89 (s, 3 H). MS (ESI) m/z (M+H)+: 278.0,
II. 4-(6-AminopvR1din-2-yl)-//-m.ethvlbenzenesulfonamidehydrochloR1de(C-4)

[00453] Step a: 4-Bromo-N-methyl-benzenesulfonamide
To a mixture of sat aq. NaHCO3 (42 g, 0.5 mol), CH2C12 (400 mL) and methylamine
(51.7 g, 0.5 mol, 30% in methanol) was added a solution of 4-bromo-benzenesulfonyl chloR1de
(127 g, 0.5 mol) in CH2C12 (100 mL). The reaction was stirred at 20 °C overnight. The organic
phase was separated and dR1ed over Na2SO4. Evaporation of the solvent under reduced pressure
provided the 4-bromo-A7-methyl-benzenesulfonamide (121 g, crude), which was used in the next
step without further puR1fication. !H NMR (CDC13,300 MHz) 5 7.64-7.74 (m, 4 H), 4.62-4.78
(m, 1H), 2.65 (d, J = 5.4 Hz, 3 H).
[00454] Step b: 4-(iV-Methylsulfamoyl)phenylboronic acid
To a solution of 4-bromo-A^-methyl-benzene sulfonamide (24.9 g, 0.1 mol) and
BtO'P)3 (28.2 g, 0.15 mol) in THF (200 mL) was added n-BuLi (100 mL, 0.25 mol) at -70 °C.
The mixture was slowly warmed to 0 °C, then 10% HC1 solution was added until pH 3-4. The
resulting mixture was extracted with EtOAc. The organic layer was dR1ed over Na2SO4, and
evaporated under reduced pressure to give 4-(iV-methylsulfarnoyl)phenylboronic acid (22.5 g,
96%), which was used in the next step without further puR1fication. 1H NMR (DMSO-c6, 300
MHz) 5 8.29 (s, 2 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 2.36 (d, J = 5.1 Hz, 3
H).
[00455] Step c: tert-Butyl 6-(4-(iV-methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate

To a solution of 4-(N-methylsulfamoyl)phenylboronic acid (17.2 g, 0.08 mol) and (6-
bromo-pyR1din-2-yl)carbamic acid terf-butyl ester (21.9 g, 0.08 mol) in DMF (125 mL) and H2O
(125 mL) were added Pd(PPh3)4 (9.2 g, 0.008 mol) and K2CO3 (16.6 g, 0.12 mol). The resulting
mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20 °C.
The reaction mixture was then heated at 80 °C for 16 h. The mixture was evaporated under
reduced pressure, then poured into H2O, and. extracted with EtOAc. The organic phase was
dR1ed over Na2SO4, and was evaporated under reduced pressure to give tert-butyl 6-(4-(N-
methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate (21 g, 58%), which was used in the next step
without further puR1fication.
[00456] Step d: 4-(6-AminopyR1din-2-yl)-AT-methylbenzenesulfonamide
hydrochloR1de
To a solution of terr-butyl 6-(4-(N-methylsulfamoyl)phenyl)pyR1din-2-ylcarbamate
(8.5 g, 23.4 mmol) in MeOH (10 mL) was added HCl/MeOH (2M, 50 mL) at room temperature.
The suspension was stirred at room temperature overnight. The solid product was collected by
filtration, washed with MeOH, and dR1ed to give 4-(6-aminopyR1dm-2-yl)-iV-
methylbenzenesulfonamide hydrochloR1de (5.0 g, 71%). 1H NMR (300 Hz, DMSO-d6) 5 8.12
(d, /= 8.4 Hz, 2 H), 7.91-7.96 (m, 3 H), 7.58-7.66 (m, 1 H), 7.31-7.53 (m, 1 H), 7.27 (d, J = 6.6,
1 H), 6.97 (d, J = 9.0,1 H), 2.43 (d, J = 4.8 Hz, 3 H). MS (ESI) m/z (M+H)+ 264.0.
[00457] The compounds in the following table were synthesized as descR1bed
above using commercially available or previously descR1bed carboxylic acids and amines.
[00458] Table 6: Additional exemplary compounds of formula I.

[00459] Physical data for examples of the invention are given in Table 7.
[00460] Additional exemplary compounds 164-388, as shown in Table 1, can also
be prepared using appropR1ate starting mateR1als and methods exemplified for the previously
descR1bed compounds.
[00461] Table?: Physical data for exemplary compounds.

ASSAYS
Assays for Detecting and MeasuR1ng AF508-CFTR Correction Properties of Compounds
JJ. Membrane potential optical methods for assaying AF508-CFTR modulation properties
of compounds
[00462] The optical membrane potential assay utilized voltage-sensitive FRET
sensors descR1bed 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 measuR1ng 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).
[00463] 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 redistR1bute 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.
1. Identification of Correction Compounds
[00464] To identify small molecules that correct the trafficking defect associated
with DF508-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" AF5O8-CFTR. The cells were subsequently R1nsed
3X with Krebs R1ngers solution and loaded with the voltage-sensitive dyes. To activate AF508-
CFTR, 10 M forskolin and the CFTR potentiator, genistein (20 uM), were added along with
Cl"-free medium to each well. The addition of Cl"-free medium promoted Cl efflux in response
to AF508-CFTR activation and the resulting membrane depolaR1zation was optically monitored
using the FRET-based voltage-sensor dyes.
2. Identification of Potentiator Compounds

[00465] To identify potentiators of AF508-CFTR, a double-addition HTS assay
format was developed. DuR1ng the first addition, a Cl'-free medium with or without test
compound was added to each well. After 22 sec, a second addition of CF-free medium
containing 2 -10 JJM forskolin was added to activate AF508-CFTR. The extracellular Cl"
concentration following both additions was 28 mM, which promoted Cl" efflux in response to
AF508-CFTR activation and the resulting membrane depolaR1zation was optically monitored
using the FRET-based voltage-sensor dyes.3 Solutio?isBath Solution #1: (in mM) NaCl

[00467] NIH3T3 mouse fibroblasts stably expressing AF5O8-CFTR are used for
optical measurements of membrane potential. The cells are maintained at 37 °C in 5% CO2 and
90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamme,
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 matR1gel-
coated plates and cultured for 2 hrs at 37 °C before cultuR1ng 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 hoursElectrophysiological Assays for assaying AF508-CFTR

[00468] Using chamber expeR1ments were performed on polaR1zed epithelial cells
expressing AF508-CFTR to further characteR1ze the AF508-CFTR modulators identified in the
optical assays. FRTAF508-CFrR epithelial 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
BioengineeR1ng, 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 KQJ 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
AF508-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).
2. Identification of Correction Compounds
[00469] Typical protocol utilized abasolateral to apical membrane Cl"
concentration gradient. To set up this gradient, normal R1nger was used on the basolateral
membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH
7.4 with NaOH) to give a large Cl" concentration gradient across the epithelium. All
expeR1ments were performed with intact monolayers. To fully activate AF5O8-CFTR, forskolin
(10 M) and the PDE inhibitor, IBMX (100 M), were applied followed by the addition of the
CFTR potentiator, genistein (50 M).
[00470] As observed in other cell types, incubation at low temperatures of FRT
cells stably expressing AF508-CFTR increases the functional density of CFTR in the plasma
membrane. To determine the activity of correction compounds, the cells were incubated with
10 M of the test compound for 24 hours at 37°C and were subsequently washed 3X pR1or 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.
5= Identification of Potentiator Compounds.
[00471] Typical protocol utilized a basolateral to apical membrane Cl"
concentration gradient. To set up this gradient, normal R1ngers was used on the basolateral
membrane and was permeabilized with nystatin (360 g/ml), whereas apical NaCl was replaced
by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl" concentration
gradient across the epithelium. All expeR1ments were performed 30 min after nystatin
permeabilization. Forskolin (10 M) and all test compounds were added to both sides of the
cell culture inserts. The efficacy of the putative AF508-CFTR potentiators was compared to that
of the known potentiator, genistein.
4. Solutions

[00472] Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FRT^508'01™)
were used for Ussing chamber expeR1ments for the putative AF5O8-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% CO2in Coon's modified Ham's F-12 medium
supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 jug/ml streptomycin. PR1or
to use for characteR1zing the potentiator activity of compounds, the cells were incubated at 27 °C
for 16 - 48 hrs to correct for the AF5O8-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.

[00473] The macroscopic AF508-CFTR current (IAFSOS) in temperature- and test
compound-corrected NIH3T3 cells stably expressing AF508-CFTR were monitored using the
perforated-patch, whole-cell recording. BR1efly, voltage-clamp recordings of IAFSOS were
performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon
Instruments Tnc,5 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 MO when filled with the
intracellular solution. Under these recording conditions, the calculated reversal potential for Cl"
(Eci) at room temperature was -28 mV. All recordings had a seal resistance > 20 GQ and a
seR1es resistance using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon
Instruments Inc.). The bath contained rate of 2 ml/min using a gravity-dR1ven perfusion system.
7. Identification of Correction Compounds
[00474] To determine the activity of correction compounds for increasing the

density of functional AF508-CFTR in the plasma membrane, we used the above-descR1bed
perforated-patch-recording techniques to measure the current density following 24-hr treatment
with the correction compounds. To fully activate AF508-CFTR, 10 M forskolin and 20 M
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 AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on
CFTR current density, the cells were incubated with 10 uM 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). PR1or to
recording, the cells were washed 3X with extracellular recording medium to remove any
remaining test compound. Preineubation with 10 M of correction compounds significantly
increased the cAMP- and genistein-dependent current compared to the 37°C controls.
8. Identification of Potentiator Compounds
[00475] The ability of AF508-CFTR potentiators to increase the macroscopic
AF508-CFTR Cl" current (IAFSOS) in NIH3T3 cells stably expressing AF508-CFTR was also
investigated using perforated-patch-recording techniques. The potentiators identified from the
optical assays evoked a dose-dependent increase in I^KSOS with similar potency and efficacy
observed in the optical assays. In all cells examined, the reversal potential before and duR1ng
potentiator application was around -30 mV, which is the calculated EQ (-28 mV).

[00476] NIH3T3 mouse fibroblasts stably expressing AF5O8-CFTR are used for
whole-cell recordings. The cells are maintained at 37 °C in 5% CO2 and 90 % humidity in

Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine
serum, 1 X NEAA, -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 measuR1ng the activity of correctors.
11. Single-chminel recordings
[00477] The single-channel actdivities of temperature-corrected AF508-CFTR
stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using
excised inside-out membrane patch. BR1efly, 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 fabR1cated from Corning Kovar Sealing #7052
glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MQ, when
filled with the extracellular solution. The AF5O8-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 peR1fused using a
gravity-dR1ven microperfusion system. The inflow was placed adjacent to the patch, resulting in
complete solution exchange within 1-2 sec. To maintain AF508-CFTR activity duR1ng the
rapid peR1fusion, 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.
[00478] Channel activity was analyzed from membrane patches containing active channels. The maximum number of simultaneous openings determined the number of
active channels duR1ng the course of an expeR1ment. To determine the single-channel current
amplitude, the data recorded from 120 sec of AF5O8-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 (Po) were determined from 120 sec of channel
activity. The Po was determined using the Bio-Patch software or from the relationship Po =
M(N), where I = mean current, i = single-channel current amplitude, and N = number of active
channels in patch.

[00479] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for
excised-membrane patch-clamp recordings. The cells are maintained at 37 °C in 5% CO2 and
90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutarnine,
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.
[00480] The exemplified compounds of Table 1 have an activity with a range of
about 100 nM and 20 M as measured using the assays descR1bed hereinabove. The
exemplified compounds of Table 1 are found to be sufficiently efficacious as measured using
the assays descR1bed hereinabove.
OTHER EMBODIMENTS
[00481] It is to be understood that while the invention has been descR1bed in
conjunction with the detailed descR1ption thereof, the foregoing descR1ption is intended to
illustrate and not limit the scope of the invention, which is defined by the scope of the appended
claims. Other aspects, advantages, and modifications are within the scope of the following
claims.

Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally
substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy,
provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl
attached to the 5- or 6- position of the pyR1dyl R1ng;
Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally
substituted C3_6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted
heteroaryl;
Each R3 and R'3 together with the carbon atom to which they are attached form an
optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and
Each n is 1,2, 3 or 4.
2. The compound according to claim 1, wherein one R1 that is attached to 5- or 6- position
of. the pyR1dyi R1ng is aryl or heteroaryl, each optionally substituted, with 1, 2, or 3 of R ; wherein
RD is -ZDR9; wherein each ZD is independently a bond or an optionally substituted branched or
straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and
independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-
, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, -
NRESO2-, or -NRESO2NRE-; each R9 is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or
-OCF3; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group,
an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl.

3. The compound according to claim 2, wherein the one R1 attached to the 5- or 6- position
of the pyR1dyl R1ng is phenyl optionally substituted with 1, 2, or 3 of RD.
4. The compound according to claim 3, wherein the one R1 attached to the 5- or 6- position
of the pyR1dyl R1ng is a phenyl optionally substituted with 1 RD, wherein RD is -Z1^; each ZD is
independently a bond or an optionally substituted branched or straight C]_ aliphatic chain
wherein up to two carbon units of ZD are optionally and independently replaced by -O-, -
NHC(O)-, -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -NRESO2-, -SO2NH-, -SO2NRE-, -NH-, or -
C(O)O-.
5. The compound according to claim 2, wherein one carbon unit of ZD is replaced by -O-, -
NHC(O)-, -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -SO-, -NRESO2-, -SO2NH-, -SO2NRB-, -
NH-, or -C(O)O-.
6. The compound according to claim 4, wherein R9 is independently an optionally
substituted aliphatic,.an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, H, or
halo.
7. The compound according to claim 2, wherein the one R1 attached to the 5- or 6- position
of the pyR1dyl R1ng is heteroaryl optionally substituted with 1,2, or 3 of RD.
8. The compound according to claim 7, wherein one R2 attached to the 5- or 6- position of
the pyR1dyl R1ng is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom selected from the
group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 1 of
RD, wherein RD is -ZDR9; each ZD is independently a bond or an optionally substituted branched
or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and
independently replaced by -O-, -NHC(O)-, -C(O)NRE-, -SO2-, -NHSCV, -NHC(O)-, -NRESO2-,
-SO2NH-, -SO2NRE-, -NH-, or -C(O)O-.
9. The compound according to claim 7, wherein one carbon unit of ZD is replaced by -O-, -
NHC(OK -C(O)NRE-, -SO2-, -NHSO2-, -NHC(O)-, -SO-, -NRESO2-, -SO2NH-, -SO2NRE-, -
NH-, or -C(O)O-.
10. The compound according to claim 8, wherein R9 is independently an optionally
substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, H, or
halo.

11. The compound according to claim 1, wherein R1 that is attached to the 5- or 6- position
of the pyR1dyl R1ng is:

D is H, hydroxyl, or an optionally substituted group selected from aliphatic,
cycloaliphatic, alkoxy, and amino; and
RD is defined above.
12. The compound according to claim 11, D is OH, an optioally substituted C1-6 aliphatic, an
optionally substituted C3-Cg cycloaliphatic, an optionally substituted alkoxy, or an optionally
substituted amino.

wherein each of A and B is independently H, an optionally substituted Cl-6
aliphatic, an optionally substituted C3-C8 cycloaliphatic, or
A and B, taken together, form an optionally substituted 3-7 membered
heterocycloaliphatic R1ng.
14. The compound according to claim 1, wherein R1 that is attached to the 5- or 6- position
of the pyR1dyl R1ng is:

Each of A and B is independently H, an optionally substituted C\.6 aliphatic, an
optionally substituted C3-C8 cycloaliphatic; or
A and B, taken together, form an optionally substituted 3-7 membered
heterocycloaliphatic R1ng.
15. The compound according to claim 13, wherein A is H and B is C1-6 aliphatic optionally
substituted with 1,2, or 3 of halo, oxo, alkyl, hydroxy, hydroxyallcyl, alkoxyalkyl, and an
optionally substituted heterocycloaliphatic.
16. The compound according to claim 13, wherein A and B, taken together with the nitrogen
atom to which they are attached, form an optionally substituted 3-7 membered
heterocycloaliphatic R1ng.
17. The compound according to claim 16, wherein A and B, taken together with the nitrogen
atom to which they are attached, form an optionally substituted pyrrolidinyl, pipeR1dinyl,
morpholinyl, or piperazinyl.
18. The compound according to claim 16, wherein the heterocycloaliphatic R1ng is optionally
substituted with 1, 2, or 3 of halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
amino, amido, or carboxy.
19. The compound according to claim 1, wherein one Rt that is attached to the 5- or 6-
position of the pyR1dyl R1ng is cycloaliphatic or heterocycloaliphatic, each optionally substituted
with 1,2, or 3 of RD; wherein RD is -ZDRg; wherein each ZD is independently a bond or an
optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of
ZD are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRBNRE-, ~CO2-, -
OCO-, -NRECO2-, -O-, -NRECONRE-, -OCONRE-, ~NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -
NRE-, -SO2NRE-, -NRESO2-, or -NRESO2NRE-; each R9is independently RE, halo, -OH, -NH2, -
NO2, -CN, -CF3, or -OCF3; and each RE is independently hydrogen, an optionally substituted Ci_
s aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
20. The compound according to claim 19, wherein one R1 that is attached to the 5- or 6-

position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloaliphatic.
21. The compound according to claim 20, wherein one R1 that is attached to the 5- or 6-
position of the pyR1dyl R1ng is an optionally substituted C3-C8 cycloalkyl or an optionally
substituted C3-Cs cycloalkenyl.

23. The compound according to claim 1, wherein R2 is hydrogen.
24. The compound according to claim 1, wherein R3 and R3 together with the carbon atom
to which they are attached form an unsubstituted C3.7 cycloaliphatic or an unsubstituted
heterocycloaliphatic.

25. The compound according to claim 24, wherein R3 and R'3 together with the carbon atom
to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or
an unsubstituted cyclohexyl.
26. The compound according to claim 1, wherein R4 is an aryl or heteroaryl optionally
substituted with 1, 2, or 3 of -ZcRg, wherein each Zc is independently a bond or an optionally
substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of Zc are
optionally and independently replaced by -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, -OCO-,
-NRCCO2-, -O-, -NRCCONRC-, -OCONRC-, -NRCNRC-, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -
SO2NRC-, -NRCSO2-, or -NRCSO2NRC-; each R8 is independently Rc, halo, -OH, -NH2, -NO2, -
CN, or -OCF3; and each R is independently an optionally substituted C1-8 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl.
27. The compound according to claim 26, wherein R4 is an aryl optionally substituted with
1, 2, or 3 of ZCR8.
28. The compound according to claim 27, wherein R4 is an optionally substituted phenyl.
29. The compound according to claim 26, wherein R4 is a heteroaryl optionally substituted
with 1,2, or 3 of-ZCR8.
30. The compound according to claim 26, wherein R4 is one selected from

or a pharmaceutically acceptable salt thereof, wherein
RD is -ZDR9, wherein each ZD is independently a bond or an optionally substituted
branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and
independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-, -NRECO2-, -O-
, ~NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO2-, -NRE-, -SO2NRE-,
-NRES02-,or-NRES02NRE-;
R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3;
Each RE is independently hydrogen, an optionally substituted C1-6 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl;
R2 is C1-4 aliphatic, C1-6 cycloaliphatic, phenyl, or heteroaryl, each of which is
optionally substituted, or R2 is hydrogen;
R3 and R'3 together with the carbon atom to which they are attached form a C3-7
cycloaliphatic or a C3-7 heterocycloaliphatic, each of which is optionally substituted with 1,2, or
3 of -ZBR7, wherein each ZB is independently a bond, or an optionally substituted branched or
straight C1.4 aliphatic chain wherein up to two carbon units of ZB are optionally and
independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -OCO-, -NRBCO2-, -O-
, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -NRB-, -SO2NRB-, -
NRBSO2-, or -NRBSO2NRB-;
Each R7is independently RB, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3;
Each RB is independently hydrogen, an optionally substituted C1-6 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl;
Each R4 is an aryl or heteroaryl, each of which is optionally substituted with 1, 2, or
3 of -ZcRg, wherein each Zc is independently a bond or an optionally substituted branched or
straight C1-6 aliphatic chain wherein up to two carbon units of Zc are optionally and
independently replaced by -CO-, -CS-, -CONRC-, -CONRCNRC-, -CO2-, -OCO-, -NRCCO2-, -O-
, -NRCCONRC-, -OCONRC-, -NRCNRC-, -NRCCO-, -S-, -SO-, -SO2-, -NRC-, -SO2NRC-, -
NRCSO2-, or -NRCSO2NRC-;
Each R8 is independently Rc, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; and
Each Rc is independently an optionally substituted C1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl.

32. The compound according to claim 31, wherein Z is independently a bond or an
optionally substituted branched or straightC1-6 aliphatic chain wherein one carbon unit of ZD is
optionally replaced by -SO2-, -CONRE-, -NRESO2-, or -SO2NRE-.
33. The compound according to claim 32, wherein ZD is an optionally substituted branched
or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by -SO2-.
34. The compound according to claim 31, wherein Rp is an optionally substituted heteroaryl
or an optionally substituted heterocycloaliphatic.
35. The compound according to claim 33, wherein R9 is an optionally substituted
heterocycloaliphatic having 1 or 2 nitrogen atoms and R9 attaches directly to -SO2- via one R1ng
nitrogen.
36. The compound according to claim 1, wherein said compound has formula V-A or
formula V-B:

or a pharmaceutically acceptable salt thereof,
wherein:
T is an optionally substituted C1-2 aliphatic chain, wherein each of the carbon units is
optionally and independently replaced by -CO-, -CS-, -COCO-, -SO2-, -B(OH)-, or -B(O(C1-6
Each of R11 and R1" is an optionally substituted C1-6 aliphatic, an optionally
substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered
cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy,
amido, amino, halo, or hydroxy;
RD1 is attached to carbon number 3" or 4";
each RD1 and RD2 is -ZDR9, wherein each ZD is independently a bond or an optionally
substituted branched or straightC1-6 aliphatic chain wherein up to two carbon units of ZD are
optionally and independently replaced by -CO-, -CS-, -CONRE-, -CONRENRE-, -CO2-, -OCO-,
-NRECO2-, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, ~SO2-, -NRE-, -
SO2NRE-, -NRESO2-, or -NRESO2NRE-;

R9is independently RE, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3;
or RD1 and RD2, taken together with atoms to which they are attached, form a 3-8
membered saturated, partially unsaturated, or aromatic R1ng with up to 3 R1ng members
independently selected from the group consisting of O, NH, NRE, and S; and
each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl.
37. The compound according to claim 36, wherein up to two methylene units of T are
optionally substituted by -CO-, -CS-, -B(OH), or -B(O(C1-6 alkyl).
38. The compound according to claim 36, wherein T is an optionally substituted chain
selected from the group consisting of -CH2- and -CH2CH2-.
39. The compound according to claim 36, wherein T is optionally substituted by -ZER1o;
wherein each ZB is independently a bond or an optionally substituted branched or straightC1-6
aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced
by -CO-, -CS-, -CONRF-, -CONRFNRF~, -CO2-, -OCO-, -NRFCO2-, -O-, -NRFCONRF-, -
OCONRF-, -NRFNRF-, -NRFCO-, -S-, -SO-, -SO2-, -NRF-, -SO3NRF-, -NRFSO2-, or -
NRFSO2NRF-; R10is independently RF, halo, -OH, -NH2, -NO2, -CN, -CF3, or -OCF3; each RF is
independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or
an optionally substituted heteroaryl.
40. The compound according to claim 39, wherein T is optionally substituted by F, Cl, C1-6
alkyl, C3_8 cycloalkyl, phenyl, naphthyl, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), -O-phenyl, or C3-8
spiroaliphatic.

42. The compound according to claim 41, wherein T is selected from the group consisting of
-CH2-, -CF2-, and -C(CH3)2-.
43. The compound according to claim 36, wherein ZD is independently a bond or an
optionally substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is

optionally replaced by -CO-, -SO-, -SO2-, -CO2-, -OCO-, -CONRE-, -NRECO-, NRECO2-, -O-,
-NRESO2-,or-SO2NRE-.
44. The compound according to claim 36, wherein RD1 is -ZDRci, wherein R9 is halo, -OH, -
NH2, -CN, -CF3, -OCF3, or an optionally substituted group selected from the group consisting of
C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, Q5-10 aryl, and 5-10
membered heteroaryl.
45. The compound according to claim 44, wherein R9 is F, Cl, -OH, -CN, -CF3, or -OCF3.
46. The compound according to claim 44, wherein R9 is selected from the group consisting
ofC1-6 straight or branched alkyl or C2-6 straight or branched alkenyl; wherein said alkyl or
alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group
consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE.
47. The compound according to claim 44, wherein R9 is C3-8 cycloaliphatic optionally
substituted by 1 or 2 substituents independently selected from the group consisting of RB, oxo,
halo, -OH, -NRERE, -ORE, -COORE, and -CONRERE.
48. The compound according to claim 47, wherein R9 is cyclopropy.l, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl.
49. The compound according to claim 44, wherein R9 is a 3-8 membered heterocyclic with 1
or 2 heteroatoms independently selected from the group consisting of O, NH, NRE, and S;
wherein said heterocyclic is optionally substituted by 1 or 2 substituents independently selected
from the group RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and ~CONRBRE.
50. The compound according to claim 49, wherein R9 is an optionally substituted 3-8
membered heterocyclic is

The compound according to claim 49, wherein R9 is optionally substituted by 1 or 2
substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i-
propyl, f-butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(O)NH2, -CH2O(C1-6 alkyl), -
CH2CH2OCC(C1-6 alkyl), and -C(O)(C1-6 alkyl).
52. The compound according to claim 44, wherein R9 is 5-8 membered heteroaryl with 1 or
two R1ng atom independently selected from the group consisting of O, S, and NRE; wherein said

heteroaryl is optionally substituted by 1 or 2 substituents independently selected from the group
RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -C0NRERE.
53. The compound according to claim 52, wherein R9 is

54. The compound according to claim 52, wherein R9 is optionally substituted by 1 or 2
substituents independently selected from the group consisting, of F, Cl, methyl, ethyl, z-propyl, t-
butyl, -CH2OH, -CH2CH2OH, -C(O)OH, -C(0)NH2, -CH2OC1-6 alkyl), -CH2CH2O(C1-6 alkyl),
and -CCO)(C1-6 alkyl).
55. The compound according to claim 36, wherein RD1 and RD2, taken together with carbons
to which they are attached, form an optionally substituted 3-8 membered saturated, partially
unsaturated, or aromatic R1ng with 0-2 R1ng atoms independently selected from the group
consisting of O, NH, NRE, and S.
56. The compound according to claim 55, wherein Rm and RD2, taken together with phenyl
containing carbon atoms 3" and 4", is

57. The compound according to claim 55, wherein RD1 and RD2, taken together with phenyl
containing carbon atoms 3" and 4", is optionally substituted by 1 or 2 substituents independently
selected from the group consisting of RE, oxo, halo, -OH, -NRERE, -ORE, -COORE, and -
CONRERE.

58. The compound according to claim 36, wherein RD2 is selected from the group consisting
of H, C1-6 aliphatic, halo, -CN, -NH2, -CH2NH2, -OH, -O(Cl6 aliphatic), -CH2OH, -SO2(C1-6
aliphatic), -KH-SO2(C1-6 aliphatic), -C(O)O(C1-6 aliphatic), -C(O)OH, -NHC(O)(C1-6 aliphatic),
-C(O)NH2, -C(O)NH(C1-6 aliphatic), and -C(O)N(C1-6 aliphatic)2.

or a pharmaceutically acceptable salt thereof,
wherein:
one of G1 and G2 is N and the other of Gi and G2 is CH;
Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an
optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or
hydroxy, provided that at least one R1 is an optionally substituted aryl or an optionally
substituted heteroaryl attached to the 5- or 6- position of the pyR1dyl R1ng;
Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally
substituted C1-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted
heteroaryl;
Each R3 and R'3 together with the carbon atom to which they are attached form an
optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R4 is an optionally substituted aryi or an optionally substituted heteroaryl; and
Each nisi, 2,3, or 4.
60. The compound according to claim 59, wherein the compound has formula (I'-A) or
formula (I'-B).

or a pharmaceutically acceptable salt thereof,
wherein R1, R2, R3, R'3, R4, and n are defined above.

61. A compound according to any one of claims 1-59, wherein the compound is selected
from Table 1.
62. A pharmaceutical composition compR1sing:
(i) a compound according to any one of claims 1-61; and
(ii) a pharmaceutically acceptable carR1er.
63. The composition according to claim 62, optionally further compR1sing a mucolytic agent,
a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR
modulator, or a nutR1tional agent.
64. A method according to modulating ABC transporter activity compR1sing the step of
contacting said ABC transporter with a compound of formula (I) or formula (I1):

wnerem:
one of G1 and G2 is a nitrogen, and the other is a carbon;
each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally
substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy,
provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl
attached to the 5- or 6- position of the pyR1dyl R1ng;
each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted
C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl;
each R3 and R3 together with the carbon atom to which they are attached form an
optionally substituted C3.7 cycloaliphatic or an optionally substituted heterocycloaliphatic;
each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and
each n is 1-4.
65. The method according to claim 64, wherein the ABC transporter is CFTR.
66. A method of treating or lessening the seveR1ty of a disease in a patient, wherein said
disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis,
coagulation-fibR1nolysis 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, mucopolysacchaR1doses, Sandhof/Tay-Sachs, CR1gler-Najjar type II,
polyendocR1nopathy/hypeR1nsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase
deficiency, pR1mary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital
hyperthyroidism, osteogenesis imperfecta, hereditary hypofibR1nogenemia, ACT deficiency,
Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-MaR1e 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 pR1on protein processing defect), Fabry disease, Straussler-Scheinker syndrome,
COPD, dry-eye disease, or Sjogren's disease, said method compR1sing the step of administeR1ng
to said patient an effective amount of a compound of formula I or formula I1 according to any
oe of claims 1-61.
67. A kit for use in measuR1ng the activity of an ABC transporter or a fragment thereof in a
biological sample in vitro or in vivo, compR1sing:
(i) a composition compR1sing a compound of formula (I) or formula (I1) according to
any one of claims 1-61; and
(ii) instructions for:
a) contacting the composition with the biological sample; and
b) measuR1ng activity of said ABC transporter or a fragment thereof.
68. The kit according to claim 67, further compR1sing instructions for
a) contacting an additional composition with the biological sample;
b) measuR1ng the activity of said ABC transporter or a fragment thereof in the
presence of said additional compound, and
c) compaR1ng the activity of the ABC transporter in the presence of the additional
compound with the density of the ABC transporter in the presence of a composition of formula
(I) or formula (I').
69. The kit according to claim 68, wherein the kit is used to measure the density of CFTR.

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators
of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance
Regulator ("CFTR"). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds
of the present invention.

Documents:

01897-kolnp-2008-abstract.pdf

01897-kolnp-2008-claims.pdf

01897-kolnp-2008-correspondence others.pdf

01897-kolnp-2008-description complete.pdf

01897-kolnp-2008-form 1.pdf

01897-kolnp-2008-form 3.pdf

01897-kolnp-2008-form 5.pdf

01897-kolnp-2008-gpa.pdf

01897-kolnp-2008-international publication.pdf

01897-kolnp-2008-international search report.pdf

01897-kolnp-2008-pct priority document notification.pdf

01897-kolnp-2008-pct request form.pdf

1897-KOLNP-2008-(10-04-2014)-ASSIGNMENT.pdf

1897-KOLNP-2008-(10-04-2014)-CLAIMS.pdf

1897-KOLNP-2008-(10-04-2014)-CORRESPONDENCE.pdf

1897-KOLNP-2008-(10-04-2014)-DESCRIPTION (COMPLETE).pdf

1897-KOLNP-2008-(10-04-2014)-FORM-13.pdf

1897-KOLNP-2008-(10-04-2014)-FORM-2.pdf

1897-KOLNP-2008-(10-04-2014)-OTHERS.pdf

1897-KOLNP-2008-(10-04-2014)-PA.pdf

1897-KOLNP-2008-(17-04-2014)-ANNEXURE TO FORM 3.pdf

1897-KOLNP-2008-(17-04-2014)-CORRESPONDENCE.pdf

1897-KOLNP-2008-(17-04-2014)-PETITION UNDER RULE 137.pdf

1897-KOLNP-2008-ASSIGNMENT.pdf

1897-KOLNP-2008-CANCELLED PAGES.pdf

1897-KOLNP-2008-CORRESPONDENCE.pdf

1897-KOLNP-2008-DECISION.pdf

1897-KOLNP-2008-EXAMINATION REPORT.pdf

1897-KOLNP-2008-FORM 13.pdf

1897-KOLNP-2008-FORM 18-1.1.pdf

1897-KOLNP-2008-FORM 18.pdf

1897-KOLNP-2008-GPA.pdf

1897-KOLNP-2008-GRANTED-ABSTRACT.pdf

1897-KOLNP-2008-GRANTED-CLAIMS.pdf

1897-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE)-(PART 1).pdf

1897-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE)-(PART 2).pdf

1897-KOLNP-2008-GRANTED-FORM 1.pdf

1897-KOLNP-2008-GRANTED-FORM 2.pdf

1897-KOLNP-2008-GRANTED-FORM 3.pdf

1897-KOLNP-2008-GRANTED-LETTER PATENT.pdf

1897-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE-(PART 1).pdf

1897-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE-(PART 2).pdf

1897-KOLNP-2008-INTERNATIONAL PUBLICATION.pdf

1897-KOLNP-2008-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

1897-KOLNP-2008-OTHERS.pdf

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Patent Number

262900

Indian Patent Application Number

1897/KOLNP/2008

PG Journal Number

39/2014

Publication Date

26-Sep-2014

Grant Date

23-Sep-2014

Date of Filing

12-May-2008

Name of Patentee

VERTEX PHARMACEUTICALS INCORPORATED

Applicant Address

130 WAVERLY STREET CAMBRIDGE, MA

Inventors:

#	Inventor's Name	Inventor's Address
1	HADIDA RUAH SARA	2356 TORREY PINES #16, LA JOLLA, CA 92037
2	MILLER MARK	5075 LA JOLLA BLVD #9, SAN DIEGO, CA 92109
3	GROOTENHUIS PETER D. J.	4801 RIDING RIDGE ROAD, SAN DIEGO, CA 92130
4	BEAR BRIAN	5108 SPENCER CT., OCEANSIDE, CA 92057
5	MCCARTHY JASON	2274 CAROL VIEW DRIVE APT 112, CARDIFF BY THE SEA, CA 92007
6	ZHOU JINGLAN	4466 SHOREPOINTE WAY, SAN DIEGO, CA 92130
7	HAMILTON MATTHEW	24 MOCKINGBIRD ROAD, HACKETTSTOWN, NJ 07840

PCT International Classification Number

C07D 405/12

PCT International Application Number

PCT/US2006/043289

PCT International Filing date

2006-11-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/754086	2005-12-27	U.S.A.
2	60/802458	2006-05-22	U.S.A.
3	60/734506	2005-11-08	U.S.A.