AU2013205183A1 - Modulators of ATP-Binding Cassette transporters - Google Patents

Abstract

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.

Description

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS [00011 CLAIM OF PRIORITY [00021 The present patent application claims priority to U.S. provisional patent application serial no. 60/790,459, filed on April 7, 2006, which is hereby incorporated by reference in its entirety. [00031 TECHNICAL FIELD OF THE INVENTION [00041 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. 100051 BACKGROUND OF THE INVENTION [00061 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 multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP 1), 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. [00071 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. 100081 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 2 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. [00091 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. [0010] 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. [0011] 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. [00121 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 3 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. [00131 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*/2Cl~/K* co-transporter, Na*-K*-ATPase pump and the basolateral membrane K* channels, that are responsible for the uptake of chloride into the cell. [00141 These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na*-K*-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via C1~ channels, resulting in a vectorial transport. Arrangement of Na*/2Cl~/K co-transporter, Na*-K*-ATPase pump and the basolateral membrane K* channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride. [00151 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 Sj6gren's Syndrome. [00161 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 4 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 Sj6grens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the comeal endothelial cells and secretory glands surrounding the eye to increase comeal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sj6grens'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. [00171 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 5 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type I 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, II, 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 PAPP 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 x-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect). [00181 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. [00191 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. [00201 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. [00211 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 6 diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel. [00221 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. [00231 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. [00241 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. [00251 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. [00261 There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity. [0027] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal. [00281 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. [00291 There is a need for methods of treating CFTR-mediated diseases using such modulators of CFTR activity. [00301 There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal. [00311 SUMMARY OF THE INVENTION [00321 It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity, particularly CTFR activity. These compounds have the general formula I: 7 0o B N n( 2)1 A R1 I or a pharmaceutically acceptable salt thereof, wherein RI, R 2 , ring A, ring B, and n are defined below. [00331 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-Najj ar 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, neurophysiol, nephrogenic, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. [00341 DETAILED DESCRIPTION OF THE INVENTION [00351 I. DEFINITIONS [00361 As used herein, the following definitions shall apply unless otherwise indicated. [00371 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. [00381 The term "CFTR" as used herein means cystic fibrosis transmembrane conductance 8 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). [00391 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. [00401 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), Neurophysiol DI, Nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, 9 Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. [00411 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. [00421 As described herein, compounds of the invention may 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. [00431 As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below. [00441 As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 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, phospho, 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)carbonyll, nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylanino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-S02-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaiyloxy, 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, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl. [00451 As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 10 2-8 (e.g., 2-12, 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, phospho, 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 alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g., alkyl-S0 2 -, cycloaliphatic-S02-, or aryl-S02-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-S0 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl. [0046] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 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., aliphatic-SO2-, aliphaticamino-S02-, or cycloaliphatic

SO

2 -], 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, 11 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. [0047] As used herein, an "amido" encompasses both "aminocarbonyl" and "carbonylamino". These terms when used alone or in connection with another group refer to an amido group such as -N(Rx)-C(O)-R or -C(O)-N(RX) 2 , 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 alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido. [0048] As used herein, an "amino" group refers to -NRXRY wherein each of RX and R is independently hydrogen, aliphatic, 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. [0049] 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 groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more

C

4 .. carbocyclic moieties. An aryl is optionally substituted with one or more substituents including 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 ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; 12 (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-S02- or amino-S02-]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted. [00501 Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-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, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic) o-(alkyl))aryl. [00511 As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C14 alkyl group) that is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as an aralkyl group is benzyl. [00521 As used herein, an "aralkyl" group refers to an alkyl group (e.g., a CI.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, 13 (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00531 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. 100541 As used herein, a "carbocycle" or "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below. [00551 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, or ((aminocarbonyl)cycloalkyl)cycloalkyl. [00561 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. [00571 A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, 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, 14 hydroxy, mercapto, sulfonyl [e.g., alkyl-S0 2 - and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfanoyl, sulfamide, oxo, or carbamoyl. [0058] As used herein, the term "heterocycle" or "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below. [0059] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 1 0-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, 0, 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, 1-aza-bicyclo[2.2.2]octyl, 3-aza bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1 .0 3

'

7 ]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls. [00601 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, 0, or S). Monocyclic and bicyclic heterocycloaliphatics.are numbered according to standard chemical nomenclature. [00611 A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, 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, ((heterocyclo aliphatic) 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], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl, 15 sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0062] 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, 0, 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, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, IH indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl. [0063] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. [0064] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, 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. [0065] 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)carbonyl]; sulfonyl [e.g., 16 aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted. 100661 Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryll; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (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; (heterocycloaiphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryll; (alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl]. [00671 A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C 1 4 alkyl group) that is substituted with a heteroaryl group. "Aliphatic," "alkyl," and "heteroaryl" have been defined above. 100681 A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C 1 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 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.

17 [00691 As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi-, and tri cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined. 100701 As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicaliphatic 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-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3 azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3

,

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)carbonylamnino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [00711 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 and pivaloyl are examples of acyl groups. [00721 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. [00731 As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously. 100741 As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NRxRy or -NRX-CO-O-Rz, wherein RX and R have been defined above and Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic. [00751 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.

18 [00761 As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF 3 . 100771 As used herein, a "mercapto" group refers to -SH. [00781 As used herein, a "sulfo" group refers to -SO 3 H or -SO 3 Rx when used terminally or

-S(O)

3 - when used internally. [00791 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, R , and Rz have been defined above. [00801 As used herein, a "sulfonamide" 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, R, and Rz are defined above. [00811 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 aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like. 100821 As used herein a "sulfinyl" group refers to -S(O)-RX when used terminally and S(O)- when used internally, wherein RX has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like. [00831 As used herein, a "sulfonyl" group refers to-S(O) 2 -Rx when used terminally and -S(0) 2 - when used internally, wherein RX has been -defined above. Exemplary sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-, cycloaliphatic-S(0)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S(O)2-, (cycloaliphatic(amido(aliphatic)))-S(O)2-or the like. [00841 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. [00851 As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine. 100861 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)-. 100871 As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-0-alkyl-, wherein alkyl has been defined above. ' 100881 As used herein, a "carbonyl" refer to -C(O)-. 100891 As used herein, an "oxo" refers to =0.

19 [00901 As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(RP) 2 , wherein RP is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino. [00911 As used herein, an "aminoalkyl" refers to the structure (RX) 2 N-alkyl-. [00921 As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-. [00931 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 -NR CO-NR - or -NRX-CS-NRY- when used internally, wherein RX, R , and RZ have been defined above. [00941 As used herein, a "guanidine" group refers to the structure N=C(N(RXRY))N(RXRY) or -NRX-C(=NR)NRXRY wherein RX and R have been defined above. [00951 As used herein, the term "amidino" group refers to the structure C=(NRx)N(RxRY) wherein RX and RY have been defined above. [0096] 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. [00971 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 carbon atom. [00981 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 of the chemical structure. Alkylcarboxy (e.g., alkyl-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. [00991 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 -[CH 2 ]v-, where v is 1-12. 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 -[CQQ]-. where each Q is independently a hydrogen or an aliphatic group; however, Q shall 20 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. [001001 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 RI, R 2 , and R 3 , and other variables contained in formulae described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables RI, R 2 , and R3, 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, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, 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, oxo, alkoxy, 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, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy groups can form a ring together with the atom(s) to which they are bound. [001011 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. [001021 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 21 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. [001031 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, surface 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. [001041 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 1 4 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents. [001051 Compounds of the present invention are useful modulators of ABC transporters and are useful in the treatment of ABC transporter mediated diseases. [001061 II. COMPOUNDS [001071 A. Generic Compounds [001081 The present invention relates to compounds of formula I useful as modulators of ABC transporter activity: 22 No (RPO A R 1 or a pharmaceutically acceptable salt thereof. [001091 R, is -ZAR 4 , wherein each ZA is independently a bond or an optionally substituted branched or straight CI-6 aliphatic chain wherein up to two carbon units of Z^ are optionally and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -CO 2 -, -OCO-, NRACO 2 -, -O-,~-NRACONRA-, -OCONRA-, -NRANR -, -NRACO-, -S-, -SO-, -S02-, -NRA-, -SO 2 NR-, -NRASO2-, or -NRASO 2 NRA-. Each R 4 is independently R^, halo, -OH, -NH 2 , -NO 2 , -CN, or

-OCF

3 . Each RA is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00110] R2 is -ZBRs, wherein each ZB is independently a bond or an optionally substituted branched or straight C 1 .6 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2 -OCO-, NRBCO 2 -, BBB B_ B B_ -0-, -NR CONR-, -OCONRB-, -NRBNR -, -NRBCO-, -S-, -SO-, -SO 2 -, -NR -, -SO 2 NRB

-NRBSO

2 -, or -NRBS0 2 NRB-. Each R 5 is independently RB, halo, -OH, -NH 2 , -NO 2 , -CN, CF 3 , or -OCF 3 . Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle. 1001111 Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, 0, and S. 1001121 Ring B is a group having formula Ia:

R'

3

N

23 Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-3 and each R 3 and R' 3 is independently -ZcR 6 , where each Zc is independently a bond or an optionally substituted branched or straight CI- 6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRc-, -CONRCNRc-, -CO 2 -, -OCO-, NRcCO 2 -, -0-, -NRCCONRC-, -OCONRc-, -NRcNRc-, -NRcCO-, -S-, -SO-, -SO 2 -, -NRC-, -SO 2 NRC_,

-NRCSO

2 -, or -NRCSO 2 NRC-. Each R 6 is independently Rc, halo, -OH, -NH 2 , -NO 2 , -CN, or

-OCF

3 . Each Rc is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle. Furthermore, R' 3 and an adjacent R 3 group, together with the atoms to which they are attached, form an optionally substituted heterocycle. [001131 n is 1-3. [001141 However, in several embodiments, when ring A is unsubstituted cyclopentyl, n is 1, R 2 is 4-chloro, and R, is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6 dichlorophenyl(carbonyl))-3-methyl-1H-indol- 5 -yl; and when ring A is unsubstituted cyclopentyl, n is 0, and Ri is hydrogen, then ring B is not 0 N HN N 00 / K or 0 OH N 0-1 [001151 B. Specific Compounds [001161 1. R_ Group [001171 R, is -ZAR 4 , wherein each ZA is independently a bond or an optionally substituted branched or straight Ci- 6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -C0 2 -, -OCO-, - 24

NRACO

2 -, -O-, -NRACONRA, -OCONRA-, -NRANRA-, -NRACO-, -S-, -50-, -SO 2 -, -NRA-, -SO 2 NRA-,

-NRASO

2 -, or -NRASO 2 NRA-. Each R 4 is independently RA, halo, -OH, -NH 2 , -NO 2 , -CN, or

-OCF

3 . Each RA is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [00118] In several embodiments,

R

1 . is -ZAR 4 , wherein each ZA is independently a bond or an optionally substituted branched or straight C 1

-

6 aliphatic chain and each R 4 is hydrogen. [001191 In other embodiments, R, is -ZA R 4 , wherein each ZA is a bond and each R 4 is hydrogen. [00120] 2. R2 Group [00121] Each R 2 is independently -ZBRs, wherein each ZB is independently a bond or an optionally substituted branched or straight C 1

-

6 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNR B_

CO

2 -, -OCO-, -NRBCO 2 -, -O-, -NRBCONR-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -S02-, -NR B-, -SO 2 NRB-, -NR BSO 2 -, or -NRBSO 2 NRB-. Each R 5 is independently RB, halo, -OH, NH 2 ,

-NO

2 , -CN, -CF 3 , or -OCF 3 . Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle or heteroaryl. [001221 In several embodiments, R 2 is an optionally substituted aliphatic. For example, R 2 is an optionally substituted branched or straight C 1

.

6 aliphatic chain. In other examples, R 2 is an optionally substituted branched or straight C 1

-

6 alkyl chain, an optionally substituted branched or straight C 2

-

6 alkenyl chain, or an optionally substituted branched or straight C 2 -6 alkynyl chain. In alternative embodiments, R 2 is a branched or straight C 1

-

6 aliphatic chain that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. For example, R 2 is a branched or straight C 1

-

6 alkyl that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof: In still other examples, R2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is 25 optionally substituted with 1-3 of halo, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic, or heterocycloaliphatic. In still other examples, R 2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is unsubstituted. [001231 In several other embodiments, R 2 is an optionally substituted branched or straight

C

1

.

5 alkoxy. For example, R 2 is a C 1

.

5 alkoxy that is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof. In other examples, R 2 is a methoxy, ethoxy, propoxy, butoxy, or pentoxy, each of which is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof. [001241 In other embodiments, R 2 is hydroxy, halo, or cyano. [001251 In several embodiments,

R

2 is -ZBR 5 , and 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 -C(O)-, -0-, -S-, -S(O) 2 -, or -NH-, and R 5 is Ra, halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3 , and RB is hydrogen or aryl. [00126] In several embodiments, two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle. For example, two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle, either of which is fused to the phenyl of formula I, wherein the carbocycle or heterocycle has formula Ib: Z2 .

Z

3 Ib [00127] Each of ZI, Z 2 , Z 3 , Z 4 , and Z 5 is independently a bond, -CR 7

R'

7 -, -C(O)-, -NR 7 -, or -0-; each R 7 is independently -ZDRs, wherein each ZD is independently a bind or an optionally substituted branched or straight C t-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONR D-, -C0 2 -, -OCO-, NRDCO 2 -, -O-, -NRDCONRD-, -OCONRD-, -NRDNRD-, -NRDCO-, -S-, -SO-, -SO 2 -, -NRD-, -SO 2 NRD_

-NRDSO

2 -, or -NRDSO 2 NRD-. Each R8 is independently RD, halo, -OH, -NH 2 , -NO 2 , -CN, CF 3 , or -OCF 3 . Each RD is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally 26 substituted heteroaryl. Each R'7 is independently hydrogen, optionally substituted C1, aliphatic, hydroxy, halo, cyano, nitro, or combinations thereof. Alternatively, any two adjacent R 7 groups together with the atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring, such as an optionally substituted cyclobutyl ring, or any two R 7 and R' 7 groups together with the atom or atoms to which they are attached form an optionally substituted 3-7 membered carbocyclic ring or a heterocarbocyclic ring. [001281 In several other examples, two adjacent R 2 groups form an optionally substituted carbocycle. For example, two adjacent R 2 groups form an optionally substituted 5-7 membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof. In another example, two adjacent R 2 groups form a 5-6 membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof. In still another example, two adjacent R 2 groups form an unsubstituted 5-7 membered carbocycle. [001291 In alternative examples, two adjacent R 2 groups form an optionally substituted heterocycle. For instance, two adjacent R 2 groups form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatoms independently selected from N, 0, and S. In several examples, two adjacent R2 groups form an optionally substituted 5-6 membered heterocycle having 1-2 oxygen atoms. In other examples, two adjacent R 2 groups form an unsubstituted 5-7 membered heterocycle having 1-2 oxygen atoms. In other embodiments, two adjacent R 2 groups form a ring selected from: H F2C XA1 XA2 XA3 XA4 XA5 XA6 0 O N H XA7 XA8 XA9 XA10 XA1 1 XA12 H 0I N CI N . O MeO N XA13 XA14 XA15 XA16 XA17 XA18 27 H O N N ,N a and XA19 XA20 XA21 [001301 In alternative examples, two adjacent R 2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle, and a third R 2 group is attached to any chemically feasible position on the phenyl of formula I. For instance, an optionally substituted carbocycle or an optionally substituted heterocycle, both of which is formed by two adjacent R 2 groups; a third R 2 group; and the phenyl of formula I form a group having formula Ic: Z__Z, R2 Z3 Z41Z 5 Ic [001311 Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 has been defined above in formula lb, and R 2 has been defined above in formula I. [001321 In several embodiments, each R2 group is independently selected from hydrogen, halo,

-OCH

3 , -OH, -CH 2 OH, -CH 3 , and -OCF 3 , and/or two adjacent R2 groups together with the atoms to which they are attached form H \ XA1 XA2 XA3 XA4 XA5 XA6 HH 0 1 ,I0 0 1 N H XA7 XA8 XA9 XA10 XA11 XA12 28 0 OL0 ~~ NI N ,4 , OI , 0 MeO OH XA13 XA14 XA15 XA16 XA17 XA18 H O afL N N'N N \ N ,and . XA19 XA20 XA21 [001331 In other embodiments, R 2 is at least one selected from hydrogen, halo, methoxy, phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy, and methyl. [001341 In some embodiments, two adjacent R 2 groups, together with the atoms to which they are attached, form

F

2 CIIJ ,or 0 C XA1 XA2 [001351 3. Ring A [001361 Ring A is an optionally substituted 3-7 membered--monocyclic ring having 0-3 heteroatoms selected from N, 0, and S. [001371 In several embodiments, ring A is an optionally substituted 3-7 membered monocyclic cycloaliphatic. For example, ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy,

C

1

-

5 aliphatic, or combinations thereof. [001381 In other embodiments, ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic. For example, ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic having 1-2 heteroatoms independently selected from N, 0, and S. In other examples, ring A is tetrahydrofuran-yl, tetrahydro-2H-pyran-yl, pyrrolidone-yl, or piperidine-yl, each of which is optionally substituted. [001391 In still other examples, ring A is selected from 7 (Rs)q (Ra)q R8)q (Rs)g XB1 XB2 XB3 XB4 XB5 29 RHqR~ R8)q HR8)q XB6 XB7 XB8 XB9 H RS)q (R8)q (R8)q (RB)q SNHN XB10 XB11 XB12 XB13 (Raq S(R)q)q 0 XB14 XB15 XB16 XB17 (R8)q (R8)q HN (R 8 )q andH(R XB1 XB19 XB20 XB21 [001401 Each R 8 is independently

-ZER

9 , wherein each ZE is independently a bond or an optionally substituted branched or straight C 1

..

5 aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced by -CO-, -CS-, -CONRE-, -C02-, -OCO-,

-NRECO

2 -, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO 2 -, -NRE_,

-SO

2 NRE-, -NRESO 2 -, or -NRESO 2 NRE-, each R 9 is independently RE, -OH, -NH 2 , -NO 2 , CN,

-CF

3 , oxo, or -OCF 3 . Each RE is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [001411 q is 0-5. [001421 In other embodiments, ring A is one selected from -XCI XC2 XC3 XC4 XC5 and XC6 XC4 30 [001431 In several embodiments, ring A is [001441 4. Ring B [00145] Ring B is a group having formula Ia:

R'

3 (R3)p Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-3. [001461 Each R 3 and R' 3 is independently -ZcR 6 , where each Zc is independently a bond or an optionally substituted branched or straight C 1 .. 6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by -CO-, -CS-, -CONRc-, -CONRCNRc-, -CO 2 -, -OCO-, -NRCCO 2 -, -O-, -NRcCONRc-, -OCONRc-, -NRcNRc , -NRcCO-, -S-, -SO-, -SO 2 -, -NRc-, -SO 2 NRc-, -NRcS02-, or -NRcSO 2 NRc-. Each R 6 is independently Rc, halo, -OH, -NH 2 , -NO2, -CN, or -OCF 3 . Each Rc is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle, or R' 3 and an adjacent R 3 , i.e., attached to the 2 position of the indole of formula la, together with the atoms to which they are attached form an optionally substituted heterocycle. [00147] In several embodiments, ring B is

R'

3 R' 3 N R 3 3N (R2o)q N I o 3)p (3)p 3) r(R3)p-1 [001481 wherein q is 0-3 and each R 20 is -ZGR 2 1 , where each ZG is independently a bond or an optionally substituted branched or straight C.

5 aliphatic chain wherein up to two carbon units of ZG are optionally and independently replaced by -CO-, -CS-, -CONR-, -C02-, -OCO-, -NRGCO 2 - , -OCONRG-. -NRG R G-, -NRCO-, -S-, -SO-, -So2-, -NRG

-

, -SO2NRG-, -NR'SO2-, or -NRGS02NRG-. Each R21 is independently RG, halo, -OH, -NH2, - 31

NO

2 , -CN, or -OCF 3 . Each RG is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. [001491 For example, ring B is HH N H H N (R20)q \3)/ (Ra)p ,Ror [001501 In several embodiments, R' 3 is hydrogen and R 3 is attached to the 2, 3, 4, 5, 6, or 7 position of the indole of formula Ia. In several other examples, R 3 is attached to the 2 or 3 position of the indole of formula Ia, and R 3 is independently an optionally substituted aliphatic. For instance, R 3 is an optionally substituted acyl group. In several instances, R 3 is an optionally substituted (alkoxy)carbonyl. In other instances, R 3 is (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl, or (butoxy)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. In other instances, R 3 is an optionally substituted (aliphatic)carbonyl. For example, R 3 is an optionally substituted (alkyl)carbonyl that is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. .In other-examples, R 3 is (methyl)carbonyl, (ethyl)carbonyl, (propyl)carbonyl, or (butyl)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. [001511 In several embodiments, R 3 is an optionally substituted (cycloaliphatic)carbonyl or an optionally substituted (heterocycloaliphatic)carbonyl. In several examples, R 3 is an optionally substituted (C 3

..

7 cycloaliphatic)carbonyl. For example, R 3 is a (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is optionally substituted with aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof. In several alternative examples, R 3 is an optionally substituted (heterocycloaliphatic)carbonyl. For example, R 3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N, 0, and S. In other examples, R 3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N and 0. In still other examples, R 3 is an optionally substituted 4-7 membered monocyclic (heterocycloaliphatic)carbonyl having 1 3 heteroatoms independently selected from N and 0. Alternatively, R 3 is (piperidine-1 yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, or (morpholine-4-yl)carbonyl, (piperazine-1- 32 yl)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or aliphatic. [001521 In still other instances, R 3 is optionally substituted (aliphatic)amido such as (aliphatic(amino(carbonyl)) that is attached to the 2 or 3 position on the indole ring of formula Ia. In some embodiments, R 3 is an optionally substituted (alkyl(amino))carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia. In other embodiments, R 3 is an optionally substituted straight or branched (aliphatic(amino))carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia. In several examples, R 3 is (N,N dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. [00153] In other embodiments,

R

3 is an optionally substituted (alkoxy)carbonyl. For example, R 3 is (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl, or (butoxy)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. In several instances, R3 is an optionally substituted straight or branched CI.6 aliphatic. For example, R 3 is an optionally substituted straight or branched C1-6 alkyl. In other examples, R 3 is independently an optionally substituted methyl, ethyl, propyl, butyl, isopropyl, or tertbutyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or combination thereof. In other embodiments, R3 is an optionally substituted C 3

.

6 cycloaliphatic. Exemplary embodiments include cyclopropyl, 1-methyl cycloprop-1-yl, etc. In other examples, p is 2 and the two R 3 substituents are attached to the indole of formula Ia at the 2,4- or 2,6- or 2,7- positions. Exemplary embodiments include 6 F, 3-(optionally substituted C- 6 aliphatic or C 3

.

6 cycloaliphatic); 7-F-2-(-(optionally substituted C .

6 aliphatic or C 3

.

6 cycloaliphatic)), 4F-2-(optionally substituted CI-6 aliphatic or

C

3

.

6 cycloaliphatic); 7-CN-2-(optionally substituted C 1

.

6 aliphatic or C 3 .6 cycloaliphatic); 7 Me-2-(optionally substituted C1.

6 aliphatic or C 3

.

6 cycloaliphatic) and 7-OMe-2-(optionally substituted CI-6 aliphatic or C 3

-

6 cycloaliphatic). [00154] In several embodiments, R3 is hydrogen. In several instances, R3 is an optionally substituted straight or branched C1- 6 aliphatic. In other embodiments, R3 is an optionally substituted C 3

.

6 cycloaliphatic. [001551 In several embodiments, R3 is one selected from: -H, -CH 3 , -CH 2 OH, -CH 2

CH

3 , -CH 2

CI

2 OH, -CH 2

CH

2

CH

3 , -NH 2 , halo, -OCH 3 , -CN, -CF 3

,

33

-C(O)OCH

2

CH

3 , -S(O) 2

CH

3 , -CH 2

NH

2 , -C(O)NH 2 , OH O OH N N O H H H 0 0 0 0 0 0 OH F ll I 0o ~C2CH3 OH -\- Ak N NH_\ -o

~CONH

2 ~ HOH OH 00 OH\ 0 A OH 0- -OH NH NH 2 0O 0 A- N H - OEt OH O H H _N~ 0 0a L 34 H N ON NON H N N aN A' _JC H 0 ~O 0

-

-

C O 2 H [001561 In another embodiment, two adjacent R 3 groups form [00157] In several embodiments,

R'

3 is independently -ZcR 6 , where 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-, -CO 2 -, -OCO-, -NRcCO 2 -, -O-, -NRcCONRc-, -OCONRc-, NRcNRC-, NRcCO-, -S-, -SO-, -SO2-, -NRc-, -SO 2 NRC-, -NRcSO 2 -, or -NRcSO 2 NRc. Each R 6 is independently RC, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 . Each Rc is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl. In one embodiment, each Rc is hydrogen, C1- 6 aliphatic, or C 3

-

6 cycloaliphatic, wherein either of the aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH substituents. In another embodiment, Rc is hydrogen, or C 1

-

6 alkyl optionally substituted with up to 4 -OH substituents. [001581 For example, in many embodiments,

R'

3 is is independently -ZcR 6 , where each ZC is independently a bond or an optionally substituted branched or straight C 1

.

6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -C(O)-, -C(O)NRc-, -C(O)O-, -NRcC(O)O-, -0-, -NRcS(O)2-, or -NRc-. Each R 6 is independently Rc, -OH, or -NH 2 . Each Rc is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl. In one embodiment, each Rc is hydrogen, C 1

.

6 aliphatic, or C 3

-

6 cycloaliphatic, 35 wherein either of the aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH substituents. In another embodiment, Rc is hydrogen, or C 1

.

6 alkyl optionally substituted with up to 4 -OH substituents. [001591 In other embodiments,

R'

3 is hydrogen or

R

3 1 R32 OH [001601 wherein R 3 1 is H or a C 1

..

2 aliphatic that is optionally substituted with 1-3 of halo, OH, or combinations thereof. R 32 is -L-R 33 , wherein L is a bond, -CH 2 -, -CH 2 0-, CH 2

NHS(O)

2 -,

-CH

2 C(O)-, -CH 2 NHC(O)-, or -CH 2 NH-; and R 33 is hydrogen, or C 1

..

2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally subsitututed with I of -OH,

-NH

2 , or -CN. For example, in one embodiment,

R

31 is hydrogen and R 32 is C 1

-

2 aliphatic optionally substituted with -OH, -NH 2 , or -CN. [001611 In several embodiments, R' 3 is independently selected from one of the following: -H, -CH 3 , -CH 2

CH

3 , -C(O)CH 3 , -CH 2

CH

2 OH, -C(O)OCH 3 , 0 (CH 2 H OH vtC2OH 1 --- OH O NH-Me OMe < .NHCOCH 3 -- CO 2 H, OH OH -OH OHH NH N H 2 OH N H -\N2 O - CONHMe 0 OEt CO2 NH 2 N O OH \'IC2H OH NHCOMe -\ CN NH -\ '- CONMe 2 OH OH HO

CO

2 H N O CO 2 H OH 0 OH 4 NHSO 2 Me NHCO 2 Me NHC2Me NNH OH OH OH Nz:N 36 OH H -\ OH OH-' N OHX N OH NC~~ OH O A-- N -H0j O ,,NHC0 2 fflu OH OH 0 OHO2 0 0 H" -O N NO A-\ NHSO 2 Et -- N O N N OH OH 0 NHH OH N- , and 0 [001621 5. n term [001631 n is 1-3. [001641 In several embodiments, n is 1. In other embodiments, n is 2. In still other embodiments, n is 3. [001651 C. Exemplary compounds of the present invention Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

37 Table 1: Exemplary compounds of the present invention. 1 2 3 H N 0 NO 45 6 0OH 00 < O NH H <N F 7 8 9 10 11 12 NH N >Q~--N\ LAHF)%oL0 I N~ 38 13 14 ;P F .HN NH NH0 0K)DK H 16 1718 0 H.1H 0 JA0- ~ ID 0< N 2 23 24 F 0 N F 0 N F>(o* ~ Ax:) N <m 39 25 26 27 (01 0 28 29 30 H Cc y 0: :: , HN 0 < ~ 0=

F

0 <I-IIIN Z, 00. L-/-o 0H 0 H (~1RJ4 N HF 0 0 34 35 36 -40 -37 38 39 0 x~AN 0 tNcJD+H 0&% 40 -41 42 FH HH 00 HH FFA0 FF 46 44 45

H~

-41 49 50 00 0~ 0~0 F 00C 42 61 62 63 FN N H sOJD C 67 68 69 H H H \-p 43 73 74 75 Ho H jOH NHN O0 O OO FH H 79 F 0 8 0 0 H < o o' *

F

0 0 F__ _ 0I __ 44 85 8687 89 90 HH HH C0 H N O 91 92 93 b NJ H-0 NH --- ol l isN 45 97989 H o 103 104 105 ,D-Z H 10 107 108 0 H Ho 00 H0 zA H 0

N

-46 Ho- yZ OHH 0-NH 112 113 -114 115 -116 117 NL\H H 0 =<~~ N C / H 118 1-19 120 F N 0

F

-47 12l 122 -- 23 H 0 F H < HI 130 131 12 0 F F :W

H

-48 133 34135 H '1 HH

F

0 0 139 140 141 00 142 143 144 0 H01 N 0N 142FF 14314 49 145 146 147 Cl H H N

-O

N-< 0 N r r-o0 < NH .H 60 50 157 15815 H 0 HF 16 16 162~j f_ H H 16306 6 HHO HHC0 0 H N H -N 0 Y,- H NN O0 FF ~1 6~~3 16 7 16 8 HN F F F H \....Op QAKXD':JY:r)Y/+ 51 169 170 17 HN O NN H-N H Nc N F N HH H 175176 177 FF N:ON H .

H H 17p N 8 MNo F< F>0- 0 N 0 0 A:6+ 0V0 H < 0 0~J

'~-H

52 181 18 183 H F N N) N + H 0 + H~ 0$ 84185 N0 186 HN 0~.-I- HN 0: N F$ H (111 i 187188 189 H.N 190 191 192 53 193 194195 0. 0 0H 196 197 198 H& H NF> ' 0 0A HoH &Y e~ 0NH 00 0<I Q 54 2050 207 0; HNDI/+~ Fr N HH 0 218 209 210 NN 00 217 21 219 oH OHO o 0 + 223 224 222 H o 0]~j N 0 x NyA-/ X~~)4J 56 229 230 231 OO OH OH NN F 00 X H 235 233 237 0 H HH -- 238 239 240 00 57 241 242243 Ho * N <0 1 < O H 24 ~2~~ 45~ 246 H H F O N 244 248 249 20 25 252 HH F O JC/ NC[ p NH _ H HH o ~ F IO 58 253 254255

H

0 / 0 0/ 0- Q% HK~fL 256 -257 JL258 FO f Hf H 259 26 N6 F HNXII 0 <H 262 263 261 r 0 H 00 H <~ 2 ~> K~ ~ NNX ~N 59 265 266 267 *N 0 HNH p " 271 272c ), 0 00( 0

(

0 ywm - 60 273 27 275 H F 0 F 0 -276 277 278 HH ~~0 27 28 281 HH 282283 281 H H F 0 F 0 JiJOi2F-- 61 285 286 287 HH F0 lrr.~ft N~HN NCN c~ P' N F HN HO 21 2892 293 HN I F N p 111 N/H 00 FA0 FI F 62 297 298 299 H 05 o OH N F 0 -- 00 -301 -302 0 00 HoH 14 NF F 0O >( >( CL 0 HO F 4 FX0 III. SUBGENERIC COMPOUNDS OF THE PRESENT INVENTION [00166] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ic: 63 No nRP A R 1 Ic or a pharmaceutically acceptable salt thereof. 1001671 R 1 , R 2 , and ring A are defined above in formula I, and ring B, R 3 and p are defined in formula Ia. Furthermore, when ring A is unsubstituted cyclopentyl, n is 1, R 2 is 4-chloro, and R, is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6 dichlorophenyl(carbonyl))- 3 -methyl-iH-indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0, and R, is hydrogen, then ring B is not 0 N HN N O ,or 0 OH NN [001681 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Id: 0 No n(RP O A R1 Id or a pharmaceutically acceptable salt thereof. [001691 R 1 , R 2 , and ring A are defined above in formula I, and ring B, R 3 and p are defined in formula Ia. [001701 However, when R, is H, n is 0, ring A is an unsubstituted cyclopentyl, and ring B is an indole-5-yl substituted with 1-2 of R 3 , then each R 3 is independently -ZGR 12, where each ZG is independently a bond or an unsubstituted branched or straight CI-6 aliphatic chain wherein up to two carbon units of ZG are optionally and independently replaced by -CS-, - 64 CONRGNRG-, -CO 2 -, -OCO-, -NRGCO 2 -, -0-, -NRGCONRG-, -OCONRG-, -NRNR-, -S-, SO-, -SO2-, -NRG-,

-SO

2 NR-, -NRGSO 2 -, or -NRGSO 2 NRC-, each R 12 is independently RG, halo, -OH, -NH 2 , NO 2 , -CN, or -OCF 3 , and each RG is independently hydrogen, an unsubstituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an unsubstituted aryl, or an optionally substituted heteroaryl; or any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle. Futhermore, when R, is H, n is 1, R 2 is 4-chloro, ring A is an unsubstituted cyclopentyl, and ring B is an indole-5-yl substituted with 1-2 of R 3 , then each R 3 is independently -Z R 22 , where each ZH is independently a bond or an unsubstituted branched or straight C 1

..

3 aliphatic chain wherein up to two carbon units of ZH are optionally and independently replaced by CS-, -CONRHNR H, -CO 2 -, -OCO-,

-NRHCO

2 -, -O-, -NRHCONRH-, -OCONR"-, -NR NR -, -S-, -SO-, -SO 2 -, -NRH_, -SO2 NR H_

-NRHSO

2 -, or -NRHSO 2 NRH-, each R 2 2 is independently RH, halo, -OH, -NH 2 , -NO 2 , -CN, or

-OCF

3 , and each RH is independently hydrogen, a substituted C 4 alkyl, an optionally substitituted C 2 _6 alkenyl, an optionally substituted C 2

.

6 alkynyl, an optionally substituted C 4 alkenyl, an optionally substituted C 4 alkynyl, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted heteroaryl, an unsubstituted phenyl, or a mono-substituted phenyl, or any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle. [001711 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula II: 2z1 R2 O / 3 A R 1 P(R 3 )

II

or a pharmaceutically acceptable salt thereof. [001721 R 1 , R 2 , and ring A are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are defined above in formula Lb. [001731 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ila: 65 z2-z, R2 Z1 0A Z4- z 5 A. A R, PAR) Ila or a pharmaceutically acceptable salt thereof [00174] R 1 , R 2 , and ring A are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Zi, Z 2 , Z 3 , Z4, and Z 5 are defined above in formula lb. [001751 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ib: z2-z, R2

Z

3 0 ( Z 4 -~ Z 5 N - A zj N

R'

3 I~b or a pharmaceutically acceptable salt thereof. [001761 R 1 , R 2 , and ring A, are defined above in formula I; R 3 , R' 3 , and p are defined above in formula Ia; and Zi, Z 2 , Z 3 , Z 4 , and Zs are defined above in formula lb. [001771 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ic: (R2)n R R's IIc or a pharmaceutically acceptable salt thereof [001781 R 1 , R 2 and n are defined above in formula 1; and R 3 , R' 3 , and p are defined in formula Ia. [001791 Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ild: 66 R2 R's R2 NR3 N H (R3)0-2 Ild or a pharmaceutically acceptable salt thereof. [00180] Both R 2 groups, together with the atoms to which they are attached form a group selected from: 0 I

F

2 KJ XA1 XA2 XA3 XA4 XA5 XA6 H 0 O N XA7 XA8 XA9 XA10 XA11 XA12 N , ,s, OMeO OH XA13 XA14 XA15 XA16 XA17 XA18 H XA19 XA20 XA21 [001811 R' 3 is independently selected from one of the following: -H-, -CH 3 , -CH 2

CH

3 , -C(O)CH 3 , -CH 2

CH

2 OH, -C(O)OCH 3 ,O OH 2OH 0 OH

OHN

67 O - NHMe - OMe NHCOCHs CO 2 H OH OH OH NH NH C OH Nj A -\-- CONHMe O 4 OEt 4 NH 2 N^- O-, OH '-,CO 2 H OH 4 NHCOMe ,0CN NH -C CONMe 2 OH 3 OH H NHSO2Me

CO

2 H N4OH

CO

2 H O OH 0 OH

NHSO

2 Me 4 NHCO 2 Me NHCOMe NH OH OH OH Nz:4 OH OH OH 0 HOH -NHCO 2 tBu OHN N HS H, H _ OH H 9OH 0 N NHSOEt .. S N N 0 0 H N N', / , and O ; and each R 3 is independently selected from -H, -CH 3 , -CH 2 OH, -CH 2

CH

3 , -CH 2

CH

2 OH, -CH 2

CH

2

CH

3 , -NH 2 , halo, OCH 3 , -CN, -CF 3 , -C(O)OCH 2

CH

3 , -S(O) 2

CH

3 , -CH 2

NH

2 , -C(O)NH 2 , OH OH HH

HN

68 0 OH j N0 0 0 A N 4NJ", AN" O H H H 0K OH 0 0 0 00 NC A IN 0~ C0 2

CH

3 OH / NH NH jN 0 0 II.

'CONH

2 HH 0 OH OH 0 OHo 0 -OH 0 OH N H N - IH QEt OH ~ ~ N OH H H 0 o 0o H Q N No NN I I ICN NO 69 0 NH N O 0 OH and [00182] IV. GENERIC SYNTHETIC SCHEMES [001831 The compounds of formulae (I, Ic, Id, II, Ila, Ilb, lIc, and IlId) may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of formulae (I, Ic, Id, II, Ila, IIb, IIc, and lId) are provided below in Schemes 1-22 below. [00184] Preparation of the compounds of the invention is achieved by the coupling of a ring B amine with a ring A carboxylic acid as illustrated in Scheme 1. [00185] Scheme 1:

(R

2 )n XH A H c (R 2 )n B A / R 1a

(R

2 )n O 1b H_ py. H K> a) SOCl 2 , DMF (cat.), DCM; b) R 1 -N , pyr.; c) RI-N , HATU, TEA, DCM/DMF. [00186] Referring to Scheme 1, the acid la may be converted to the corresponding acid chloride Ib using thionyl chloride in the presence of a catalystic amount of dimethylformamide. Reaction of the acid chloride with the amine RJN-G provides compounds of the invention I. Alternatively, the acid la may be directly coupled to the amine using known coupling reagents such as, for example, HATU in the presence of triethylamine. [00187] Preparation of the acids l a may be achieved as illustrated in Scheme 2. Scheme 2: 70 nA A C1 Br 0 -~ ab ~ - OH (R(R2) (R2)n1 2b la 2a a) NaOH, BTEAC; b) NaOH, A [001881 Referring to Scheme 2, the nitrile 2a reacts with a suitable bromochloroalkane in the presence of sodium hydroxide and a phase tranfer catalyst such as butyltriethylammonium chloride to provide the intermediate 2b. Hydrolysis of the nitrile of 2b provides the acid 1 a. In some instances, isolation of the intermediate 2b is unnecessary. [001891 The phenylacetonitriles 2a are commercially available or may be prepared as illustrated in Scheme 3. Scheme 3 Br a

CO

2 Me b OH (R2)n

(R

2 )n (R 2 )n 3a 3b 3c C C1 d CN

(R

2 )n

(R

2 )XCN 3d 2a a) Pd(PPh 3

)

4 , CO, MeOH; b) LiAlH 4 , THF; c) SOCl 2 ; d) NaCN [001901 Referring to Scheme 3, reaction of an aryl bromide 3a with carbon monoxide in the presence of methanol and tetrakis(triphenylphosphine)palladium (0) provides the ester 3b. Reduction of 3b with lithium aluminum hydride provides the alcohol 3c which is converted to the halide 3d with thionyl chloride. Reaction of 3d with sodium cyanide provides the nitrile 2a. [001911 Other methods of producing the nitrile 2a are illustrated in schemes 4 and 5 below. Scheme 4 71 H o a ' CN

(R

2 )n 4a

(R

2 )n 2a b d ~- OH ____ CI

/

(R

2 )n 3c

(R

2 )n 3d a) TosMIC; b) NaBH 4 , THF; c) SOC1 2 ; d) NaCN Scheme 5 a Br b NC

(R

2 )n

(R

2 )n

(R

2 )n 5a 5b 2a a) NBS, AIBN, CCl 4 ; b) NaCN, EtOH [001921 Preparation of Ri-N components is illustrated in the schemes that follow. A number of methods for preparing ring B compounds. wherein ring B is an indole have been reported. See for example Angew. Chem. 2005,44, 606; J. Am. Chem. Soc. 2005, 127, 5342,); J. Comb. Chem. 2005, 7, 130; Tetrahedron 2006, 62, 3439; J. Chem. Soc. Perkin Trans. 1, 2000, 1045. [001931 One method for preparing RIN 3 is illustrated in Scheme 6. Scheme 6 72 a I b 0 2 N NH 2 0 2 N NH2 O 2 N-NN' 0'R 3 H H 6a 6b 6c

NO

2

R

3

R

3 + N 0 2 N N

(R

3 )p 1 H

(R

3 )p-1 6d 6e d

NH

2

R

3

R

3 N H 2 N N

(R

3 )p- 1 ( ) H 6f 6g a) NaNO 2 , HCl, SnCl 2 ; b) NaOH, R 3

CH

2

C(O)R

3 , EtOH; c) H 3

PO

4 , toluene; d) H 2 , Pd-C, EtOH [001941 Referring to Scheme 6, a nitroaniline 6a is converted to the hydrazine 6b using nitrous acid in the presence of HCI and stannous chloride. Reaction of 6b with an aldehyde or ketone CH 3

C(O)R

3 provides the hydrazone 6c which on treatment with phophoric acid in toluene leads to a mixture of nitro indoles 6d and 6e. Catalytic hydrogenation in the presence of palladium on carbon provides a mixture of the amino indoles 6f and 6g which may be separated using know methods such as, for example, chromatography. [001951 An alternative method is illustrated in scheme 7. [001961 Scheme 7

NH

2 N R3 b (R3)p-1 (R3)p.1 H (R3)p H 7a 7b 7c (R3)p-R C : -R3 d0 2 N N R (R3)pP H H 7d 7e I (R3)p1 (R 3)p-1 R 3 I H N R 02H H 2 N't N 0 2 N NH 2 0 2 N N'NH 2 2N 'N R3 H H\ 7f 7g 7h 73 a) R 3 aCOCI, Et 3 N, CH 2

C

2 ; b) n-BuLi, THF; c) NaBH 4 , AcOH; d) KNO 3 , H 2

SO

4 ; e) DDQ, 1,4-dioxane; f) NaNO 2 , HCl, SnC1 2 .2H 2 0, H 2 0; g) MeCOR 3 , EtOH; h) PPA; i) Pd/C, EtOH or H2, Raney Ni, EtOH or MeOH [00197] [00198] Scheme 8 a b 0 2 NO2NN NO 2 ( 3 ) aRr 3 ) C 0 2 N / N0 2

H

2 N H N / H P(73 (R 3 ) a) HNO 3 , H 2

SC

4 ; b) Me 2 NCH(OMe) 2 , DMF; c) H 2 , Raney Ni, EtO [00199] Scheme 9 Br bBr

NH

2

NH

2 0 2 N NH 2 p(3) P(R3 (R 3 ) * TMS d e 0 2 N NH20N ,:'C) H 2 N- N

P(R

3 ) p R31 (R 3 ) H a) NBS, DMF; b) KNO 3 , H 2 S0 4 ; c) HC=-C-TMS, Pd(PPh 3

)

2 C1 2 , GuI, Et 3 N, toluene, H 2 0; d) CuT, DMF; e) H 2 , Raney Ni, MeOH [00200] Scheme 10 74

NO

2 R 3

CO

2 H a CO 2 H CO 2 H + b

NO

2 0 2 N

NO

2

R

3

R

3

NO

2 R3 NO 2 ~- C0 2 H ~ \ COEt C- 0 2 Hb CO2 CO separation b + NO 2 b NO2 0 2 N NO 2 I NO 2

NO

2

NO

2 R

CO

2 Et c0N CO 2 Et d H I NO 2

INO

2

H

2 N HN

CO

2 Et a) HNO 3 , H 2

SO

4 ; b) SOC1 2 ; EtOH; c) DMA, DMF; d) Raney Ni, H2, MeOH [002011 Scheme 11 \ CO 2 Et N CO 2 Et 0 2 N NO 2

-

2 N NO 2

(R

3 )p-. b EtO 2 C

H

2 N N H a) DMA, DMF; b) Raney Ni, H2, MeOH [00202] Scheme 12 RR3 a b

N

2 H3 02~ N 0 2 N H

R

3

R

3 R2 R 3 c R 3 02N N

H

2 NN 2 NH H a) R 3 aCH 2

COR

3 b, AcOH, EtOH; b) H 3

PO

4 , toluene; c) H 2 , Pd/C, EtOH [00203] Scheme 13 75

(R

3 )p- (R3)p- (R)p-1-cN VRd H N H H PG PG Rv ORv OR H2R RVe fV RR SN 1 ,, N II H 0 2N 0N~N H H 2 N H a) NaBH 3 CN; b) When PG= SO 2 Ph: PhSO 2 CI, Et 3 N, DMAP, CH 2

CL

2 ; When PG= Ac: AcCl, NaHCO 3 , CH 2 Cl 2 ; c) When RV= RCO: (RCO) 2 0, AiCl 3 , CH 2 C1 2 ; When RV=Br: Br 2 , AcOH; d) HBr or HCl; e) KNO 3 , H 2

SO

4 ; f) MnO 2 , CH 2

CL

2 or DDQ, 1,4-dioxane; g) H 2 , Raney Ni, EtOH. [002041 Scheme 14 0 b G- - RD I a b _ _ I U- N

(R

3 )p 1 H (R3)p-1 H

(R

3

)-

1

SO

2 R RD RD RD K-J N -N N - N

(R

3 )p- 1

SO

2 R (R 3 )p-1 H H h RD 02 -0NN N 0N I H HH (R3)p-1 (R 3 )p- 1 a) NaBH 3 CN; b) RSO 2 C, DMAP, Et 3 N, CH 2 C1 2 ; c) RDC(O)C1, AiCl 3 , CH 2

CL

2 ; d) NaBH 4 , THF; e) HBr; f) KNO 3 , H 2

SO

2 ; g) MnO 2 ; g) Raney Ni, H 2 , EtOH [00205] Scheme 15 76 (R3)p)-1 - (R3)p-1 - R3 (R 3 )p- 1 R3 I b

O

2 N a 2NN H2N N HNH H N H

(R

3 )p 1 CN (R 3 )p 1 CN I ~ bI 0 2 N N H2N N H HNH a) R 3 X (X=Br, I), zinc triflate, TBAI, DIEA, toluene; b) H 2 , Raney Ni, EtOH or H 2 , Pd/C, EtOH or SnC1 2 .2H 2 0, EtOH; c) CISO 2 NCO, DMF, CH 3 CN [002061 Scheme 16 R3 RR3 R R 3 02a I 2R3 b O2N R3 N2- R 3

-

02NF I N N~ H \R'3

R'

3 a) when X=Cl, Br, I, or OTs: R' 3 X, K 2 C0 3 , DMF or CH 3 CN; b) H 2 , Pd/C, EtOH or SnC1 2 .2H 2 0, EtOH or SnCl 2 .2H 2 0, DIEA, EtOH. [002071 Scheme 17 2 Na 0 2 N Br 0 2 N- Br O a b 0C I NH 2 a

NH

2 N-KR

(R

3 )p- 1

(R

3 )p- 1

(R

3

)P-

1 H (R3)p..1 ( )p (R3)p..1HR3) I

O

2 N R d 0 2 N e H 2 N N R t- N H H H a) Br 2 , AcOH; b) RC(O)C, Et 3 N, CH 2 C1 2 ; c) HC CR 3 a, Pd(PPh 3 ) 2 C1 2 , Cul, Et 3 N; d) TBAF, THF or tBuOK, DMF or Pd(PPh 3 ) 2 Cl 2 , CuI, DMF; e) H 2 , Pd/C, EtOH or SnC1 2 , MeOH or

HCO

2

NH

4 , Pd/C, EtOH [002081 Scheme 18 77 0 2 N NH0 2 N a Br 0 2 N a Ib IC FD l NH 2 F I NH 2 F) NH 2 R3 R3 R3 2 N RRd 0 2 N R e H 2 N R F2 NR F) NF H H H f0 2 N R3

H

2 N R3 I R3 eI R3 RD 0 ) N R N, H ROH a) Br 2 , AcOH, CHC 3 ; b) R 3 aC=CH, CuI, Et 3 N, Pd(PPh 3 ) 2 C1 2 ; c) RCOC, Et 3 N, CH 2 C1 2 ; d) TBAF, DMF; e) Raney Ni, H 2 , MeOH; f) ROK, DMF [002091 Scheme 19 0 2 N 0 2 N _" Br (3P R 3 :, Ia b 0 2 N 02N NH 2

NH

2 b NH 2

(R

3 )p-1 (R3)p-1

(R

3 )fr-j C 0 2 N _R3 d H 2 N R3 - NN H H a) Br 2 , AcOH; b) HC=CR 3 a, Pd(PPh 3 ) 2

C

2 , CuI, Et 3 N; c) Pd(PPh) 2

C

2 , CuI, DMF; d) H2, Pd/C, EtOH or SnC1 2 , MeOH or HCO 2

NH

4 , Pd/C, EtOH [00210] Scheme 20 78 0 2 N a 0 2 N b 2 N X c F NH NH (3)p-1 (R3)p-1 R'3 (R3)p-1 R'3 (R3)p-,lR 3 02N R3 d 0 2 N R3

H

2 N R3 NHNN I R' 3

R'

3 a) H 2

NR'

3 ; b) X=Br: Br 2 , HOAc; X=I: NIS; c) HC=CR 3 , Pd(PPh 3

)

2 Cl 2 , CuI, Et 3 N; d) CuI, DMF or TBAF, THF; e) H2, Pd/C, EtOH or SnC1 2 , MeOH or HCO 2 NH4, Pd/C, EtOH [002111 Scheme 21 0 2 N (R 3 )p- 1 0 2 N (R 3 )p- 1 0 2 N Br a '3 b 3 C F a NHR 3 NHR's (R3)p-1 TMs 0 2 N T d O 2 N '3H 2 NR - NHR' 3 ' N N a) R' 3

NH

2 , DMSO; b) Br 2 , AcOH; c) TMS-C=CH, CuI, TEA, Pd(PPh 3 ) 2 C1 2 ; d) CuI, DMSO; e) Raney Ni, H2, MeOH [00212] Scheme 22 R3 0 2 N Br O N a 0 2 /. b

NHR'

3

NHR'

3 (R3)p-1 (R3)p-1 0 2 N R3 c

H

2 N R, C" I N

(R

3 )p- 1 R'3 (R3)p-1 R'3 a) R 3 aC=CH, CuI, TEA, Pd(PPh 3 ) 2 C1 2 ; b) TBAF, THF; c) Raney Ni, MeOH [002131 Scheme 23 79

R

3 Br r ~Br ~ I NO 2 8NH 2 b 0KRW (R., (R3pI(R 1 - H (R 3 )PA H *dII

R

3 e

H

2 N R3 c -~ N Ni )-, N H IR 3 N N (3p H(3p- I H R3p- H a) NaBH 4 , NiCL 2 , MeOH; b) RC(O)CI; c) Pd(PPh 3 )C1 2 , HC=-C-R 3 , Cul, Et 3 N; d) tBuOK, DMF; e) KNO 3 , H 2 S0 4 ; f) NaBH 4 , NiCL 2 , MeOH [002141 Scheme 24 0 2 N a H 2 N * N -~ N

(R

3 )p- 1 R'93

(R

3 )p- 1

RP

3 a) SnCL 2 , EtOH or Pd/C, HCO 2

NH

4 or H 2 , Pd/C, EtOH or Raney Ni, H 2 , EtOH [002151 Scheme 25 PPh 3 Br 0 OH a ~ - PPh 3 Br b 0 0 N H 2 11:~. ' N - 1 ~Et /R p 1 I - NH 2

(R

3

),

1 H N CO 2 Et N C 2 Et N C 2 Et

(R

3 )p- 1

H(R

3 )p-l BO(R)1 o f ,RR 0 2 N R R -~ N CO 2 Et N CO 2 Et (3p1H (3p1H 0 2 N' R H 2 N R h: R i R N O H N OH (3p1H

(R

3 ) P 1 H a) PPh 3 , HBr; b) CL(O)CCH 2

CO

2 Et; c) tBuOK; d) (Boc) 20, DMAP; e) KH-MDS, R-X; KHMDS, R-X; f) TFA; g) NaNO3, H 2 S0 4 ; h) LiAIH 4 , THF; i) SnC1 2 , EtOH 80 [00216] Scheme 26 0 2 N Ra a 0 2 N Ra b 0 2 N NyRa Rb - ' Rb r Rb N C O 2 E t b NC 2 H 1O NQ NN R y R z

(R

3 )( H (R 3 )R3p H (R3)p1l H H 2 0 2 N Ra O b H2 -"R Rb NRyRz K N Ny

(R

3

))

1 H H ( a) LiOH; b) EDC, HOBt, Et 3 N, HNRyRz; c) BH 3 -THF; d) if RzCH3, RC(O)C (ZRC(O)-) or RS0 2 CI (Z=RSO 2 -) or RO(CO)CI (Z=RO(CO)-) or (RO(CO)) 20 (Z ZRO(CO)-), Et 3 N,

CH

2

CL

2 [002171 Scheme 27 0 2 N R0 2 N b H 2 N R3 N -N KN

(R

3 )p- 1

(R

3 )p - R'3 (R 3 )p- R' 3 a) R' 3 -X (X=Br, I, or OTs), base (K 2 C0 3 or CS 2 CO DMF or CH 3 CN; b) H 2 , P/C, EtOH or Pd/C, HCO 2

NH

4 [002181 Scheme 28

R

3

R

3 0 2 N a 2N R b H2N T;/: N - NN (R3)p- H 1 (R3)p-1 H ' (R3)p- 1 H' a) R 3 aX (XC, Br, I), Ai 3 , CH 2 C1 2 ; b) Raney Ni, H 2 , MeOH [00219] Scheme 29 Boc 0 2 N N H 2 N N H 2 N N (3P1H

(R

3 )p-I H

(R

3 41 1 H a) HC1/MeOH; PtO 2 , H 2 ; b) (BOC) 20, Et 3 N, TLIF [002201 Scheme 30 81

R

3

R

3

R

3

R

3 0 2 N a 2 N b O 2 N c O2N / NN N NC R' 3

HO

2 C R 3

RO

2 C R' 3 R'3 OH 3d

O

2 N 9N O R's NRyRz Ie

O

2 N r '3 NRyRz a) NaOH or LiOH; b) ROH, HCI; c) NaBH 4 or LiAIH 4 or DIBAL-H, THF; d) HNRyRz, HATU, Et 3 N, EtOH or DMF; e) LiA1H 4 , THF or BH 3 -THF; f) H 2 0 2 , H 2 0 (Ry=Rz=H); g) H 2 , Pd/C [002211 Scheme 31 O O 00 Ra RbOR R RbOH a 1ub c\1 d Ra Rb CI CI Rb RbOH e RbOR f Ra OR g 0 2 N Br 0 2 N o0 I NH2 / NH 2

R

3 2

R

3 Ra Rb OR' 0 0 0 ORO 02N O ' 02N OR H2N NRa Rb

R

3 R R 3 H

R

3 a) Ra-X, NaH; Rb-X, NaH; b) PCi 5 , CH 2

CI

2 ; c) NaOH; d) NaNH 2 , DMSO; e) CH 2

N

2 ; f) Pd(PPh 3 )4, CuT, Et 3 N; g) RC(O)C1, pyr, CH 2 Cl 2 ; h) Pd(CH 3 CN) 2 C1 2 , CH 3 CN; i) Raney Ni,

H

2 , MeOH [002221 Scheme 32 82

(R

2 )n A R 3

(R

2 )n A R 3 0_ a N(OR a0R N OH 0' Ri H R 1 H b

(R

2 )n R1 N N-R6 Rc a) LiOH, THF/H 2 0; b) HNRyRz, HATU, TEA, DMF/CH 2 Cl 2 [00223] Scheme 33 A R 0 OH o0 (R2)n A O3 0 R 1 N OR A b

(R

2 )n Ra 0R N OH a) LiBH 4 , THF/H 2 0 or LiAlH 4 , THF; b) Ra-Li, THF [00224] Scheme 34 A A NO

(R

2 )n (R 2 )O N-Ia a \ N-0. L- 0Nl/ 0 R~ N R3 R3 A

NH

2

(R

2 )A X. N-I -0 RJ X

R

3 a) NaNO 2 , AcOH/H 2 0; b) Zn; AcOH [00225] Scheme 35 83 A A

(R

2 )A

(R

2 )n b N-Ia N- Iz:

R

3

R

3 A A ( R 2 )

-

( R 2 ) R I N _~

CH

2

R

6

CH

2

R

6 a) NaBH 3 CN; b) R 6 CHO, NaHB(OAc) 3 , TFA, DCE; c) chloranil or CDCl 3 , light or DDQ [00226] Scheme 36 A A

(R

2 )n R2)

R

3 a) NaH, DMF-THF; R 3 -X (X=C%, Br I, or OTs) [002271 Scheme 37 A ~A B

(R

2 )a

(R

2 ) r

R

3 R

(R

2 )n r N 0 R'~ N R3 R a) NBS; b) Ar-B(OR) 2 , Pd-FibreCat 1007, K 2

CO

3 , EtOH [00228] Scheme 38 84

(R

2 )n A

SO

2 R X~ 0IC R3

(R

2 )n 3 I-I

(R

2 )n AR2 H 0 H

R

3

(R

2 )n d IN

R

3 A 0 H

(R

2 )bn A N

(R

2 )An I i , 0 R N/ a) RSO 2 C1, NaH, THF-DMF; b) R 3 -X (X=Br, I, or OTs), NaH, THF-DMF; c) ethylene dioxide, InCla; d) POC1 3 , DMF; e) H 2 N-OH, CH 2 Cl 2 ; Ac 2 O [00229] Scheme 39 85 A A

(R

2 )An

(R

2 )An ~- 0 AR 1 > 1-- H 0

R

3 R A A

(R

2 )An

(R

2 )6n N-I OH . 0 N, OH . 0 R 3 \ - O R 3 \ - N R y R z a) NaH, THF-DMF; epichiorohydrin; b) ROH; c) HNRYRZ [002301 Scheme 40

(R

2 An

(R

2 An a Rf NH R/ OH R3OH R - OTs bg (R)n(R 2 ) AR) OH AI R, N- I H RA) OH

R

3 CNR3N3R3ANNH N< A 3 h

(R

2 )

(R

2 )&nA N N OH \ICON OH ' NHRI A N R3N \-C 0HR 3 \ NR a) TsCI, Et 3 N, CH 2

CI

2 ; b) NaCN, DMF; c) NaOH, MeOH; d) NaN 3 , NI{ 4 CI; e) NaN 3 , DMF; f) Pd/C, H 2 , MeOH (R=H); h) RxC(O)C1 (Z=RxC(O)-) or RXSO 2 CI (Z=R'SO 2 -) or RxO(CO)CI (Z=RxO(CO)-) or (RXO(CO)) 2 0 ( Z=RxO(CO)-), Et 3 N, CH 2

CI

2 [002311 Scheme 41 86 A A A

(R

2 )n (R 2 )n

(R

2 )n R3 R3 ()R 3 A A

(R

2 )n Ad (R 2 )n R3 R3

NH

2 NHZ a) ClCH 2 CHO, NaHB(OAc) 3 , CH 2 Cl 2 ; CDC1 3 , light; b) NaN 3 , NaI, DMF; c) H 2 , Pd/C, MeOH, AcOH; d) RC(O)Cl (Z=RC(O)-) or RSO 2 CI (Z=RSO 2 -) or RO(CO)Cl (Z=RO(CO)-) or (RO(CO))2O (Z= RO(CO)-), EtN, CH1 2 C1 2 [00232] In the schemes above, the radical R employed therein is a substituent, e.g., RW as defined hereinabove. One of skill in the art will readily appreciate that synthetic routes suitable for various substituents of the present invention are such that the reaction conditions and steps employed do not modify the intended substituents. [002331 V. FORMULATIONS, ADMINISTRATIONS, AND USES [002341 Accordingly, in another aspect of the present invention, pharmaceuticals acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further cornprise one or more additional therapeutic agents. [00235] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceuticals acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. [00236] As used herein, the term "pharmaceutically acceptable salt" refers 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, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any salt or salt of an ester of a compound of this invention that, upon 87 administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. [002371 Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived 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 hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric 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, bydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include .alkali metal, alkaline earth metal, ammonium and N+(C 4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. 1002381 As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, 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, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.

88 W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, 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 derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower 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; buffering agents such as magnesium hydroxide and aluminum hydroxide;- alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00239] In yet another aspect, the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity. In certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of ABC transporter activity, the method comprising administering a composition comprising a compound of formulae (I, Ic, Id, II, Ila, Ilb, IIc, and Ild) to a subject, preferably a mammal, in need thereof. [002401 In certain preferred embodiments, the present invention provides a method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation Fibrinolysis deficiencies, such as Protein C deficiency, Type I hereditary angioedema, Lipid 89 processing deficiencies, such as Familial hypercholesterolemia, Type I 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 DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sj6gren's Syndrome, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formulae (I, Ic, Id, II, Ila, Ilb, lIc, and lId), or a preferred embodiment thereof as set forth above. [002411 According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a ' composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formulae (I, Ic, Id, II, Ila, I1b, Ilc, and lId), or a preferred embodiment thereof as set forth above. [002421 According to the invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of 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 I chylomicronernia, 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, Myle.operoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, 90 Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sj6gren's Syndrome. [00243] 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 severity of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type I hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type I 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 DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neui-odegenerative 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, Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sj6gren's Syndrome. [00244] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity 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 physically discrete unit of agent appropriate 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 91 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 variety of factors including the disorder being treated and the severity 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. [002451 The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 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. [002461 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 solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame 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, flavoring, and perfuming agents. [002471 Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents: The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium 92 chloride solution. In addition, sterile, 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 diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00248] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00249] 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 material 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 matrices 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(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. 1002501 Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers 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. [002511 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 carrier 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, carboxymethylcellulose, 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 93 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) lubricants 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 comprise buffering agents. 1002521 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 enteric 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 polymeric 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. [00253] 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 enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. 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 polymeric substances and waxes. [002541 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 sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being 94 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 matrix or gel. [002551 As described 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 severity of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder. When 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 a "ABC transporter-mediated disease, condition or disorder". Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state. [002561 The activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods described generally in the art and in the Examples herein. [002571 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, prior 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 "appropriate for the disease, or condition, being treated". [002581 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 95 composition comprising that therapeutic agent as the only active agent. 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 comprising that agent as the only therapeutically active agent. [00259] The compounds of this invention or pharmaceutically 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 comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials 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 fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. [00260] 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 comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00261] Modulation of ABC transporter activity in a biological sample is useful for a variety 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 biological and pathological phenomena; and the comparative evaluation of new modulators of ABC transporters. [002621 In yet another embodiment, a method of modulating activity of an anion channel in vitro or in vivo, is provided comprising the step of contacting said channel with a compound of formulae (I, Ic, Id, II, Ila, I1b, IIc, and IId). In preferred embodiments, the anion channel is 96 a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel. [002631 According to an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formulae (I, Ic, Id, II, Ila, Ib, IIc, and IId). 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. [002641 According to another preferred embodiment, the activity of the ABC transporter is measured by measuring the transmembrane voltage potential. Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods. [002651 The optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439). [002661 These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC 2 (3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. 1002671 In another aspect the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formulae (I, Ic, Id, II, Ila, IMb, IIc, and Ild) or any of the above embodiments; and (ii) instructions for a.) contacting the 97 composition with the biological sample and b.) measuring activity of said ABC transporter or a fragment thereof. In one embodiment, the kit further comprises instructions for a.) contacting an additional composition with the biological sample; b.) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c.) comparing 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 formulae (I, Ic, Id, II, Ila, lIb, 1Ic, and Ild). In preferred embodiments, the kit is used to measure the density of CFTR. 100268] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. [002691 VI. PREPARATIONS AND EXAMPLES [00270] General Procedure I: Carboxylic Acid Building Block A (RXX)x Hal Hal (RXX)x 50% NaOH (aq) / OH Hal = Cl, Br, I [00271] Benzyltriethylammonium chloride (0.025 equivalents) and the appropriate dihalo compound (2.5 equivalents) were added to a substituted phenyl acetonitrile. The mixture was heated at 70 *C and then 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 nitrile to the carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted with dichloromethane three times to remove side products. The basic aqueous solution was acidified with concentrated hydrochloric acid to pH less than one and the precipitate which began to form at pH 4 was filtered and washed with I M hydrochloric acid two times. The solid material was dissolved in dichloromethane and extracted two times with I M hydrochloric acid and one time with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give the cycloalkylcarboxylic acid. Yields and purities were typically greater than 90%. [00272] Example 1: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid 98 C1 Br O I: zzN 01D, O H 0 I 50% NaOH (aq) O [002731 A mixture of 2-(benzo[d][1,3]dioxol-5-yl)acetonitrile (5.10 g 31.7 mmol), 1 bromo-2-chloro-ethane (9.00 mL 109 mmol), and benzyltriethylammonium chloride (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 24 hours and then heated at 130 "C for 48 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 hydrochloric acid to pH less than one and the precipitate filtered and washed with 1 M hydrochloric acid. The solid material was dissolved in dichloromethane (400 mL) and extracted twice with equal volumes of 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried 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. 206.1, found 207.1 (M+1)l. Retention time 2.37 minutes. 'H NMR (400 MHz, DMSO d 6 ) 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, I H). [002741 General Procedure II: Carboxylic Acid Building Block A n(R2) Hal Hal n(R2) N n(R2) -~ NaOH .- NaOH OH Hal = CI, Br, 1, all other variables are as defined in the text. [002751 Sodium hydroxide (50 % aqueous solution, 7.4 equivalents) was slowly added to a mixture of the appropriate phenyl acetonitrile, benzyltriethylammonium chloride (1.1 equivalents), and the appropriate 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 dried over sodium sulfate and evaporated to dryness to give the crude cyclopropanecarbonitrile, which was used directly in the next step. [002761 The crude cyclopropanecarbonitrile was refluxed in 10% aqueous sodium hydroxide (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was washed with 99 ether (100 mL) and the aqueous phase was acidified to pH 2 With 2M hydrochloric acid. The precipitated solid was filtered to give the cyclopropanecarboxylic acid as a white solid. [002771 General Procedure III: Carboxylic Acid Building Block Br Pd(PPh 3

)

4

CO

2 Me LiAIH 4 OH n(R2) CO/CH 3 OH n(R2)~ n(R2)~I S O C 1 2 C 1 N aC N ' n(RC N n(R2FF - n(R2)

CICH

2

CH

2 Br CN NaOH

CO

2 H NaOH n(R2) n(R2)I [002781 Example 2: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid Br Pd(PPh F 0) CO SOC1 2 F 0 ) N 2 M LAIH 4 F> : C,--r 0 F - CQC 3 0H F O -C F F 0 Cl NaCN F , CN CICH 2

CH

2 Br F O CN NaOH F 0 NaOH F o F O CO 2 H F o F> O Br Pd(PPh 3

)

4 F O CO 2 Me F 0:]a CO/CH 3 OH F 0 [002791 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester [002801 A solution of 5-bromo-2,2-difluoro-benzo(1,3]dioxole (11.8 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh 3

)

4 , 5.78 g, 5.00 mmol] in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (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 purified 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.

100 F CO2Me LiAJH4 F OH [002811 (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-methanol [002821 Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was slowly added to a suspension of lithium aluminum hydride (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 dryness and the residue was purified by silica gel column chromatography to give (2,2-difluoro-benzo[1,3]dioxol-5-yl) methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil. F OH SOl 2 F C OH CI [00283] 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole [00284] Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromethane (200 mL) at 0 "C. The resulting mixture was stirred overnight at room temperature and then 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 dried over sodium sulfate, filtrated, and evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) which was used directly in the next step. F - CN F CN [00285] (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile [00286] A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]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 and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was used directly in the next step.

101 FN CN CICH 2

CH

2 Br F F_____ CN F__I CN NaOH F 1002871 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile [002881 Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70 *C. [002891 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 dried over sodium sulfate and evaporated to dryness to give crude 1-(2,2-difluoro benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile, which was used directly in the next step. NaOH F y& CN N F CO 2 H [002901 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yI)-cyclopropanecarboxylic acid [00291] 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (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 hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)*; 'H NMR (CDC 3 ) 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). [002921 Example 3: 2-(2,2-Dimethylbenzo[d][1,3]dioxo-5-yl)acetonitrile NC 0 BBr 3 , DeMY NC OH 2,2-dimethoxy-propane NC 0 0-.N OH p-TsOH, toluene 0 BBra, DCM O C)~ OH [00293] (3,4-Dihydroxy-phenyl)-acetonitrile [00294] To a solution of benzo[1,3]dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH 2 C1 2 (15 mL) was added dropwise BBr 3 (0.78 g, 3.1 mmol) at -78 "C under N 2 . The mixture was slowly warmed to room temperature and stirred overnight. H 2 0 (10 mL) was added to quench the reaction and the CH 2 Cl 2 layer was separated. The aqueous phase was extracted with CH 2

CI

2 (2 x 7 mL). The combined organics were washed with brine, dried over Na 2

SO

4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give (3,4-dihydroxy-phenyl)-acetfonitrile (0.25 g, 54%) as a white solid. 'H NMR (DMSO-d 6

,

102 400 MHz) 8 9.07 (s, 1 H), 8.95 (s, i H), 6.68-6.70 (in, 2 H), 6.55 (dd, J= 8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H). N C OH 2,2-dimethoxy-propane N O.. OH p-TsOH, toluene K O [002951 2-(2,2-Dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile [002961 To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.20 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.0 10 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 NaHCO 3 solution, H 2 0, brine, and dried over Na 2

SO

4 . The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-(2,2 dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 'H NMR (CDCl 3 , 400 MHz) 8 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H). [00297] Example 4: 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid N OBn BrCH 2 CH2C NC H2 N HH H HOO OBn OBn -f OH OH NC OBn BrCH 2

CH

2 CI_1 NC O~n - Bn [002981 1-(3,4-Bis-benzyloxy-phenyl)-cyclopropanecarbonitrile [00299] To a mixture of (n-C 4

H

9

)

4 NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis benzyloxy-phenyl)-acetonitrile (14 g, 42 mmol) in NaOH (50 g) and H 2 0 (50 mL) was added BrCH 2

CH

2 C1 (30 g, 0.21 mol). The reaction mixture was stirred at 50 *C for 5 h before being cooled to room temperature. Toluene (30 mL) was added and the organic layer was separated and washed with H 2 0, brine, dried over anhydrous MgSO 4 , and concentrated. The residue was purified by column on silica gel (petroleum ether/ethyl acetate 10:1) to give 1-(3,4-bis benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 66%). 'H NMR (DMSO 300 MHz) 8 7.46-7.30 (m, 10 H), 7.03 (d, J= 8.4 Hz, 1 H), 6.94 (d, J= 2.4 Hz, I H), 6.89 (dd, J= 2.4, 8.4 Hz, 1 H), 5.12 (d, J= 7.5 Hz, 4H), 1.66-1.62 (in, 2 H), 1.42-1.37 (in, 2 H). NC Bn H 2 NC [0000Pd/C cOH [003001 1-(3,4-Dihydroxy-phenyl)-CyClopropaflecarboflitrile 103 [003011 To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 28 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 4 h. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give 1 (3,4-dihydroxy-phenyl)-cyclopropanecarbonitrile (4.5 g, 92%). 'H NMR (DMSO 400 MHz) 8 9.06 (br s, 2 H), 6.67-6.71 (m, 2 H), 6.54 (dd, J= 2.4, 8.4 Hz, I H), 1.60-1.57 (m, 2 H), 1.30-1.27 (m, 2 H). NC NaOH HOOC_ Oa H OH [003021 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid [003031 To a solution of NaOH (20 g, 0.50 mol) in H 2 0 (20 mL) was added 1-(3,4 dihydroxy-phenyl)-cyclopropanecarbonitrile (4.4 g, 25 mmol). The mixture was heated at reflux for 3 h before being cooled to room temperature. The mixture was neutralized with HCI (0.5 N) to pH 3-4 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water, brine, dried over anhydrous MgSO 4 , and concentrated under vacuum to obtain 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic acid (4.5 g crude). From 900 mg crude, 500 mg pure 1-(3,4-dihydroxy-pheny)-cyclopropanecarboxylic acid was obtained by preparatory HPLC. 'IH NMR (DMSO, 300 MHz) 8 12.09 (br s, 1 H), 8.75 (br s, 2 H), 6.50-6.67 (m, 3 H), 1.35-1.31 (m, 2 H), 1.01-0.97 (m, 2 H). [003041 Example 5: 1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane carboxylic acid. HO MeOH MeO HNO 3 /Ac 2 O MOo NO2 BBr 3 0OMe OMe H MeO 2NO Ni/H 2 MeO [ NH 2 triphosgene MeO N OH ~ OH 0 I-~ LIOH HO HO MeOH MeOO e W~e ~OMe [003051 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [003061 To a solution of 1-(4-rnethoxy-pheny)-cyclopropanecarboxylic acid (50 g, 0.26 104 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. NaHCO 3 (100 mL) and brine, dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53 g, 99%). 'H NMR (CDCl 3 , 400 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 (q, J= 3.6 Hz, 2 H), 1.15 (q, J= 3.6 Hz, 2 H). Oe HNO3Ac 2 O MeO NOOW 2 0 ~0Me OMe e [00307] 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester [003081 To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac 2 O (300 mL) was added a solution of HNO 3 (14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0 *C. The reaction mixture was stirred at 0 ~ 5 *C for 3 h before aq. HCI (20%) was added dropwise at 0 *C. The resulting mixture was extracted with EtOAc (200 mL x 3). The organic layer was washed with sat. aq. NaHCO 3 then brine, dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenyl) cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 'H NMR (CDCl 3 , 300 MHz) 6 7.84 (d, J= 2.1 Hz, 1 H), 7.54 (dd, J= 2.1, 8.7 Hz, 1 H), 7.05 (d, J= 8.7 Hz, 1 H), 3.97 (s, 3 H), 3.65 (s, 3 H), 1.68-1.64 (m, 2 H), 1.22-1.18 (m, 2 H). MeO , NO 2 BBr 3 MeO

NO

2 0 OMe OH 1003091 1-(4-Hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester [00310J To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH 2 C1 2 (100 mL) was added BBr 3 (12.0 g, 47.8 mmol) at -70 *C. The mixture was stirred at -70 "C for 1 hour, then allowed to warm to -30 *C and stirred at this temperature for 3 hours. Water (50 mL) was added dropwise at -20 'C, and the resulting mixture was allowed to warm room temperature before it was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 15:1) to afford 1-(4-hydroxy-3 nitro-phenyl)-cyc'lopropanecarboxylic acid methyl ester (8.3 g, 78%). 'H NMR (CDC 3 ,400 MHz) 8 10.5 (s, 1 H), 8.05 (d, J= 2.4 Hz, 1 H), 7.59 (dd, J= 2.0, 8.8 Hz, I H), 7.11 (d, J= 8.4 Hz, 1 H), 3.64 (s, 3 H), 1.68-1.64 (m, 2 H), 1.20-1.15 (m, 2 H).

105 MeO

NO

2 Ni/H 2 MeO 0OH 0 OH [00311] 1-(3-Amino4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester [003121 To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in MeOH (100 mL) was added Raney Nickel (0.8 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at 35 'C for 8 hours. The catalyst was filtered off through a Celite pad and the filtrate was evaporated under vacuum to give crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give 1-(3 -amino-4-hydroxy-phenyl) cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 'H NMR (CDC1 3 , 400 MHz) S 6.77 (s, 1 H), 6.64 (d, J= 2.0 Hz, 2 H), 3.64 (s, 3 H), 1.55-1.52 (m, 2 H), 1.15-1.12 (m, 2 H). MeO_, NH 2 triphosgene MeO N 0 OH VW 0 [00313] 1-(2-Oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester [003141 To a solution of 1-(3-amino-4-hydroxy-pheny)-cyclopropanecarboxylic acid methyl ester (2.0 g, 9.6 mmol) in THF (40 mL) was added triphosgene (4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0 0 C. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 91%), which was directly used in the next step. 'H NMR (CDCl 3 , 300 MI-Iz) S 8.66 (s, I H), 7.13-7.12 (m, 2 H), 7.07 (s, 1 H), 3.66 (s, 3 H), 1.68-1.65 (m, 2 H), 1.24-1.20 (m, 2 H). M H UOH H H 0 N >= y" N = 0e 0 [00315] 1-(2-Oxo-2,3-dihydrobenzold oxazol-5-yl)cyclopropanecarboxyic acid [003161 To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H 2 0 (1.7 g, 41 mmol) in portions at room temperature. The reaction mixture was stirred for 20 hours at 50 'C. MeOH was removed by evaporation under vacuum before water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was separated, acidified with HCl (3 mol/L) and extracted with EtOAc (100 mL x 3). The combined organic layers 106 were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(2-oxo-2,3 dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 'H NMR (DMSO, 400 MHz) 5 12.32 (brs, 1 H), 11.59 (brs, 1 H), 7.16 (d, J= 8.4 Hz, 1 H), 7.00 (d, J= 8.0 Hz, I H), 1.44-1.41 (m, 2 H), 1.13-1.10 (m, 2 H). MS (ESI) m/e (M+H+) 218.1. [003171 Example 6: 1-(6-Fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid O 0 0 OOH 0~ 3 H ~ OBr3 BrCH 2 CI/DMF H NaBH4 HO F -O o F OHF SOC1 2 C1 0 NaCN NC BrCH2CH2CI NC F FxI1II F~ 10% NaOH HOOC 1 0 F 'O0 0 0 H BBr 3 H aOH F a oF OH [003181 2-Fluoro-4,5-dihydroxy-benzaldehyde [00319] To a stirred suspension of 2-fluoro-4,5-dimethoxy-benzaldehyde (3.00 g, 16.3 mmol) in dichloromethane (100 mL) was added BBr 3 (12.2 mL, 130 mmol) dropwise at -78 *C under nitrogen atmosphere. After addition, the mixture was warmed to -30 *C and stirred at this temperature for 5 h. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with dichloromethane to afford 2 fluoro-4,5-dihydroxy-benzaldehyde (8.0 g), which was used directly in the next step. 0 0 H H BrCH 2 CI/DMF H 0 FaOH F [00320] 6-Fluoro-benzo[1,3]dioxole-5-carbaldehyde To a stirred solution of 2-fluoro 4,5-dihydroxy-benzaldehyde (8.0 g) and BrCICH 2 (24.8 g, 190 mmol) in dry DMF (50 mL) was added Cs 2

CO

3 (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60 *C overnight and then poured into water. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO4, and evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-benzo[1,3]dioxole-5- 107 carbaldehyde (700 mg, two steps yield: 24%). 'H-NMR (400 MHz, CDCl 3 ) 5 10.19 (s, 1 H), 7.23 (d, J= 5.6, 1 H), 6.63 (d, J= 9.6, 1 H), 6.08 (s, 2 H). 0 H 'NO NaBHa HO- 0 F o 0> [003211 (6-Fluoro-benzo[1,3]dioxol-5-y)-methanoI [003221 To a stirred solution of 6-fluoro-beizo(1,3]dioxole-5-carbaldehyde (700 mg, 4.2 mmol) in MeOH (50 mL) was added NaBH 4 (320 mg, 8.4 mmol) in portions at 0 *C. The mixture was stirred at this temperature for 30 min and was then concentrated in vacuo to give a residue. The residue was dissolved in EtOAc and the organic layer was washed with water, dried over Na 2

SO

4 , and concentrated in vacuo to afford (6-fluoro-benzo[ 1,3]dioxol-5-yl) methanol (650 mg, 92%), which was directly used in the next step. HO 0 SOC 2 C0 F ~OF 0> [00323] 5-Chloromethyl-6-fluoro-benzo[1,3]dioxole [003241 (6-Fluoro-benzo(1,3]dioxol-5-yl)-methanol (650 mg, 3.8 mmol) was added to SOCl 2 (20 mL) in portions at 0 'C. The mixture was warmed to room temperature for 1 h and then heated at reflux for 1 h. The excess SOC1 2 was evaporated under reduced pressure to give the .crude product, which was basified. with sat. NaHCO 3 solution to pH ~ 7. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na 2 SO4 and evaporated under reduced pressure to give 5-chloromethyl-6-fluoro benzo[1,3]dioxole (640 mg, 90%), which was directly used in the next step. CI NaCN NC ' [003251 (6-Fluoro-benzo[l,3]dioxol-5-yI)-acetonitrile [00326] A mixture of 5-chloromethyl-6-fluoro-benzo(1,3]dioxole (640 mg, 3.4 mmol) and NaCN (340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30 IC for 1 h and then poured into water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2

SO

4 , and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford (6-fluoro benzo[1,3]dioxol-5-yl)-acetonitrile (530 mg, 70%). 'H-NMR (300 MHz, CDC1 3 ) 6 6.82 (d, J = 4.8, 1 H), 6.62 (d, J= 5.4, 1 H), 5.99 (s, 2 H), 3.65 (s, 2 H).

108 NC__~,' 0 C CO NC BrCH 2

CH

2 Cl NC F 0 F 0 100327] 1-(6-Fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile [003281 A flask was charged with water (10 mL), followed by a rapid addition of NaOH (10 g, 0.25 mol) in three portions over a 5 min period. The mixture was allowed to cool to room temperature. Subsequently, the flask was charged with toluene (6 mL), tetrabutyl ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (600 mg, 3.4 mmol) and 1-bromo-2-chloroethane (1.7 g, 12 mmol). The mixture stirred vigorously at 50 'C overnight. The cooled flask was charged with additional toluene (20 mL). The organic layer was separated and washed with water (30 mL) and brine (30 mL). The organic layer was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to give 1-(6 fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (400 mg, 60%). 1 H NMR (300 MHz, CDCl 3 ) 5 6.73 (d, J= 3.0 Hz, 1 H), 6.61 (d, J= 9.3 Hz, 1 H), 5.98 (s, 2 H), 1.67-1.62 (m, 2 H), 1.31-1.27 (m, 2 H). NC 10% NaOH HOOC 0 F 0 F 0 [00329] 1-(6-Fluoro-benzo[1,3]-dioxol-5-yl)-cyclopropanecarboxylic acid [003301 A mixture of 1-(6-fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (400 mg, 0.196 mmol) and 10% NaOH (10 mL) was stirred at 100 *C overnight. After the reaction was cooled, 5% HC1 was added until the pH < 5 and then EtOAc (30 mL) was added to the reaction mixture. The layers were separated and combined organic layers were evaporated in vacuo to afford 1-(6-fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (330 mg, 76%). 'H NMR (400 MHz, DMSO) 8 12.2 (s, 1 H), 6.87-6.85 (m, 2 H), 6.00 (s, 1 H), 1.42-1.40 (m, 2 H), 1.14-1.07 (m, 2 H). [003311 Example 7: 1-(Benzofuran-5-yl)cyclopropanecarboxylic acid 109 Br OEt HO MeO aEt WO 0Y CEt 00 OH NaH, DMF OEt PPA, xylene HO 0 Br OEt H Me-OR 0 . Et 0 -- 0 0-' OH NaH, DMF OEt [00332] 1-[4-(2,2-Diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid [003331 To a stirred solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) at 0 *C. After hydrogen evolution ceased, 2-bromo-1,1-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) and was extracted with CH 2 C1 2 . The combined organics were dried over Na 2

SO

4 . The solvent was evaporated under vacuum to give 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g), which was used directly in the next step without purification. H PPA, xylene H OEt [003341 1-Benzofuran-5-yl-cyclopropanecarboxylic acid [003351 To a suspension of 1-[4-(2,2-diethoxy-ethoxy)-pheny1]-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 purified by preparative HPLC to provide 1 -(benzofuran 5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 'H NMR (400 MHz, DMSO-d 6 ) 8 12.25 (br s, 1 H), 7.95 (d, J= 2.8 Hz, 1 H), 7.56 (d, J= 2.0 Hz, 1 H), 7.47 (d, J= 11.6 Hz, 1 H), 7.25 (dd, J= 2.4, 11.2 Hz, 1 H), 6.89 (d, J= 1.6 Hz, 1 H), 1.47-1.44 (m, 2 H), 1.17-1.14 (m, 2 H). [003361 Example 8: 1-(2,3-Dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid 110 HO Pt0 2 , MeOH HO 0 [00337] To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL) was added PtO 2 (75 mg, 20%) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at 20 *C for 3 d. The reaction mixture was filtered and the solvent was evaporated in vacuo to afford the crude product, which was purified by prepared HPLC to give 1-(2,3-dihydrobenzofuran-6 yl)cyclopropanecarboxylic acid (155 mg, 42%). 'H NMR (300 MHz, MeOD) S 7.13 (d, J= 7.5 Hz, 1 H), 6.83 (d, J= 7.8 Hz, 1 H), 6.74 (s, 1 H), 4.55 (t, J= 8.7 Hz, 2 H), 3.18 (t, J= 8.7 Hz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H). [003381 Example 9: 1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5 yl)cyclopropanecarboxylic acid. MeO AICI 3 /EtSH MeO O NIS MeO 0 01O~e 0 l~a OH 0Y~ O MaO 1 CeoMeO Bu 3 SnH MeO LiOH HO AIBN 0 0 M el AC 3 /EtSH MeO OH 0 a~ [003391 1-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester 1003401 To a solution of methyl 1-(4-methoxypheny)cyclopropanecarboxylate (10.0 g, 48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mL) under ice-water bath. The mixture was stirred at 0 *C for 20 min before AIC1 3 (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 dichloromethane (50 mL x 3). The combined organic layers were washed with H 2 0, brine, dried over Na 2

SO

4 and evaporated under vacuum to give 1-(4hydroxy-phenyl) cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). 'H NMR (400 MHz, CDC1 3 ) 8 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, 2 H).

111 Me NIS MeO 0--- OH 'OH [00341 1-(4-Hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl ester [003421 To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH 3 CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 1-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl ester (3.5 g, 18%). 'H NMR (400 MHz, CDC1 3 ) 8 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). M OH [00343] 1-[3,5-Diiodo-4-(2-methyl-alyloxy)-phenyl]-cyclopropanecarboxylic acid methyl ester [003441 A mixture of 1-(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), K 2 C0 3 (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 1-[3,5-diiodo-4 (2-methyl-allyloxy)-pheny1]-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 'H NMR (300 MHz, CDCl 3 ) 6 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). Meo I Bu 3 SnH MeO o lq -y AIBN 0 0 [00345] 1-(3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester 1003461 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 Bu 3 SnH (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated at reflux overnight. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-(3,3-dimethyl 2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 'H 112 NMR (400 MHz, CDC1 3 ) 8 7.10-7.07 (m, 2 H), 6.71 (d, J= 8 Hz, I H), 4.23 (s, 2 H), 3.62 (s, 3 H), 1.58-1.54 (in, 2 H), 1.34 (s, 6 H), 1.17-1.12 (m, 2 H). M LiOH HO 0 0 [003471 1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid [003481 To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) cyclopropanecarboxylic acid methyl ester (1.0 g, 4.0 mmol) in MeOH (10 mL) was added LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40 *C overnight. HO (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 brine and dried over Na 2

SO

4 . The solvent was removed under vaccum and the crude product was purified by preparative HPLC to give 1-(3,3 dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g, 41%). 'HNMR (400 MHz, CDC1 3 ) 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 (in, 2 H). [00349] Example 10: 2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile. 0 0 0 MeO OH Me 2

SO

4 MeO OH CH 2 BrC MeO O LiAIH 4 SOH Na 2

B

4

O

7 -~OH 0 - OH OMe OMe HO SOCl2 NaCN NC > 0 OMe OMe OMe 0 0 M OH Me2SO4 OH - OH U OH OH Na 2

B

4

O

7 Ome [00350] 3,4-Dihydroxy-5-methoxybenzoate [00351] To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na 2

B

4 07 (50 g) in water (1000 mL) was added Me 2

SO

4 (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 conc. H 2 S0 4 and then filtered. The filtrate was extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification.

113 0 0 M OH CH 2 BrCI M 0 -OH NaCN0 OMe OMe 1003521 Methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate [003531 To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.0780 mol) in acetone (500 mL) was added CH 2 BrCl (34.4 g, 0.270 mol) and K 2 C0 3 (75.0 g, 0.540 mol) at 80 *C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K 2 C0 3 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, dried over anhydrous Na 2

SO

4 , and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to afford methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (12.6 g, 80%). 'H NMR (400 MHz, CDC1 3 ) 8 7.32 (s, 1 H), 7.21 (s, 1 H), 6.05 (s, 2 H), 3.93 (s, 3 H), 3.88 (s, 3 H). M O LiAJH 4 HO OMe OMe [003541 (7-Methoxybenzo[d][1,3]dioxol-5-yl)methanol [003551 To a solution of methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (14 g, 0.040 mol) in THF (100 mL) was added LiAlH 4 (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][1,3]dioxol-5-yl)methanol (7.2 g, 52%). 'H NMR (400 MHz, CDCl 3 ) 8 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90 (s, 3 H). HO - - : SOCI 2 ci OMe OMe [00356] 6-(Chloromethyl)-4-methoxybenzo[d][1,3]dioxole [003571 To a solution of SOC1 2 (150 mL) was added (7-methoxybenzo[d][1,3]dioxol-5 yl)methanol (9.0 g, 54 mmol) in portions at 0 *C. The mixture was stirred for 0.5 h. The excess SOCl 2 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO 3 to pH ~ 7. The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO4 and evaporated to 114 give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used in the next step without further purification. 'H NMR (400 MHz, CDCl 3 ) 5 6.58 (s, I H), 6.57 (s, 1 H), 5.98 (s, 2 H), 4.51 (s, 2 H), 3.90 (s, 3 H). C l -( : ' NaCN NC -O 0> NC -0 OMe OMe [003581 2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile [00359] To a solution of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g, 40 mmol) in DMSO (100 mL) was added NaCN (2.4 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 dried over anhydrous Na 2

SO

4 and evaporated to give the crude product, which was washed -with ether to afford 2-(7 methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile (4.6 g, 45%). IH NMR (400 MHz, CDCl 3 ) 5 6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 1 3 C NMR (400 MHz, CDC1 3 ) 5 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1. [003601 Example 11: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile. 0 0 NC OBn O NC NC OB e OMe t-BuOK We [003611 To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) at -78 *C. The mixture was stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 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 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 dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-(benzyloxy)-4-methoxyphenyl)- acetonitrile (5.0 g, 48%). 'H NMR (300 MHz, CDC1 3 ) 8 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). 1 3 C NMR (75 MHz, CDCl 3 ) 5 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3. [00362] Example 12: 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile.

115 NC OMe BBr 3 NC K 3 NC OBn ci I ~ c~ 1(2003, CH 3 CNI~c NC OMe N OH Ci C [003631 (4-Chloro-3-hydroxy-phenyl)acetonitrile [003641 BBr 3 (17 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3 methoxyphenyl)acetonitrile (12 g, 66 mmol) in dichloromethane (120 mL) at -78 'C under

N

2 . 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 dichloromethane (40 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2

SO

4 , and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 'H NMR (300 MHz, CDCl 3 ) 8 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). Br NC OH NC OBn Cl- K 2

CO

3 , CH 3 CN / C 1003651 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile [003661 To a solution of (4-chloro-3-hydroxy-phenyl)acetonitrile (6.2 g, 37 mmol) in

CH

3 CN (80 mL) was added K 2 C0 3 (10 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 purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3-(benzyloxy)-4-chlorophenyl) acetonitrile (5.6 g, 60%). 'H NMR (400 MHz, CDCl 3 ) 5 7.48-7.32 (m, 6 H), 6.94 (d, J = 2 Hz, 2 H), 6.86 (dd, J = 2.0, 8.4 Hz, 1 H), 5.18 (s, 2 H), 3.71 (s, 2 H). [00367] Example 13: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile. 0 0 NC HBn / NCOBn OMe t-BuOK [00368] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THIF (100 mL) at -78 *C. The mixture was 116 stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 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 (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-(benzyloxy)-4-methoxyphenyl)acetonitril (5.0 g, 48%). 'H NMR (300 MHz, CDC1 3 ) 8 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). 1 3 C NMR (75 MHz, CDC1 3 ) 8 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3. [003691 Example 14: 2-(3-Chloro-4-methoxyphenyl)acetonitrile. 0 NC 0 /\ H C- 0 NC O-' t-BuOK OMe [003701 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 (1.7 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 heated 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 dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-chloro-4-methoxyphenyl)acetonitrile (1.5 g, 83%). 'H NMR (400 MHz, CDCl 3 ) S 7.33 (d, J= 2.4 Hz, 1 H), 7.20 (dd, J= 2.4, 8.4 Hz, 1 H), 6.92 (d, J= 8.4 Hz, 1 H), 3.91 (s, 3 H), 3.68 (s, 2 H). 13 C NMR (100 MHz, CDC1 3 ) 8 154.8, 129.8, 127.3, 123.0, 122.7; 117.60, 112.4, 56.2, 22.4. [00371] Example 15: 2-(3-Fluoro-4-methoxyphenyl)acetonitrile. o 0 NC H F-NC F OMe t-BuOK [00372] To a suspension of t-BuOK-(25.3 g, 0.207 mol) in THF (150 mL) was added a 117 solution of TosMIC (20.3 g, 0.104 mol) in THF (50 mL) at -78 'C. The mixture was stirred for 15 minutes, treated with a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at -78 IC. 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 dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-fluoro-4-methoxyphenyl)acetonitrile (5.0 g, 58%). 'H NMR (400 MHz, CDCl 3 ) 8 7.02-7.05 (m, 2 H), 6.94 (t, J= 8.4 Hz, I H), 3.88 (s, 3 H), 3.67 (s, 2 H). 3 C NMR (100 MHz, CDC1 3 ) 8 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6. [003731 Example 16: 2-(4-Chloro-3-methoxyphenyl)acetonitrile. N. OH Mel, K 2 C OMe NBS Br OMe NC Oe 0. i NaCN e

CH

3 C A]N%~NC ABN, CCI, ~ c ~c OH Mel, K 2

C

3 OMe

CH

3 CN c CI C [003741 Chloro-2-methoxy-4-methyl-benzene [003751 To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH 3 CN (700 mL) was added CH 3 I (110 g, 0.78 mol) and K 2 C0 3 (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%). 'H NMR (300 MHz, CDC1 3 ) 8 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). OMe NBS Br OMe Cl~ ~ AIBN, CC1 4 CI [003761 4-Bromomethyl-1-chloro-2-methoxy-benzene [00377] To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl 4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 'H NMR (400 MHz, CDCl 3 ) 8 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).

118 OMe OMe Br O~e NaCN NC CI C 2

H

5 O C1 [003781 2-(4-Chloro-3-methoxyphenyl)acetonitrile [003791 To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C 2

H

5 0H (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 *C overnight. Ethanol was evaporated and the residue was dissolved in H 2 0. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine, dried over Na 2

SO

4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 'H NMR (400 MHz, CDCl 3 ) 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). ' 3 C NMR (100 MHz, CDCl 3 ) 8 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. [003801 Example 17: 1-(3-(Hydroxymethyl)-4 methoxyphenyl)cyclopropanecarboxylic acid. HO MeOH MeO MOMCI MeO C Na 2 CO3 0OMe 0OMe TUCI 4

CS

2 - OMel MeO H TBSCI MeO OTBS LIOH 40 0 C HO OH 0OMe - O Me' MeQH/H 2 0 OMe H OSe MeOH MeO OMe OMe [003811 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [003821 To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50 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. NaHCO 3 (100 mL) and brine, dried over anhydrous Na 2 SO4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53 g, 99%). 'H NMR (CDCl 3 .400 MHz) 8 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).

119 Me MOMCI MeaOC M OMe TI 4 , CS 2 0 e [00383] 1-(3-Chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [003841 To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCI (29.1 g, 364 mmol) in CS 2 (300 mL) was added TiC 4 (8.30 g, 43.5 mmol) at 5 *C. The reaction mixture was heated at 30 *C for 1 d and poured into ice water. The mixture was extracted with CH 2 C1 2 (150 mL x 3). The combined organic extracts were evaporated under vacuum to give 1-(3-chloromethyl-4-methoxy-phenyl) cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification. MeO MC1 Na 2

CO

3 M 0 H 0 0 C OMe [003851 1-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00386] To a suspension of 1-(3-chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (20 g) in water (350 mL) was added Bu 4 NBr (4.0 g) and Na 2

CO

3 (90 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 brine, dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/ethyl acetate 15:1) to give 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 39%). 'H NMR (CDCl, 400 MHz) 6 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). MeO OH TBSCI M IOTB OMe e [003871 1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenylcyclopropane carboxylic acid methyl ester [003881 To a solution of 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH 2 C1 2 (100 mL) were added imidazole (5.8 g, 85 mmol) and TBSCI (7.6 g, 51 mmol) at room temperature. The mixture was stirred overnight 120 at room temperature. The mixture was washed with brine, dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/ethyl acetate 30:1) to give 1-[3-(tert-butyl-dimethyl-silanyloxyrnethyl)-4-methoxy phenyl]-cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). 'H NMR (CDC1 3 , 400 MHz) 5 7.44-7.45 (m, 1 H), 7.19 (dd, J= 2.0, 8.4 Hz, 1 H), 6.76 (d, J= 8.4 Hz, 1 H), 4.75 (s, 2 H), 3.81 (s, 3 H), 3.62 (s, 3 H), 1.57-1.60 (m, 2 H), 1.15- 1.18 (m, 2 H), 0.96 (s, 9 H), 0.11 (s, 6 H). OTBS LIOH 40 0 C H ' OH eOMe MeOH/H 2 O OMe [00389 1-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid [00390] To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl] cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a solution of LiOH.H 2 0 (1.5 g, 36 mmol) in water (10 mL) at 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 brine, dried over anhydrous Na 2

SO

4 and evaporated under vacuum to provide 1-(3 hydroxyrnethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g). [003911 Example 18: 2-(7-ChlorobenzoId][1,3]dioxol-5-yl)acetonitrile. 0 0 0 OMe BB H . OH BrCICH 2 O H NaBH 4 TrHF H 3V H H ' OH OH CI C1 . C1 0 OH SOC1z 02 ( CI NaCN NC 0 C1 C CI 0 0 H N.OMe BBr 3 N.OH H AmH OH OH CI CI 1003921 3-Chloro-4,5-dihydroxybenzaldehyde 100393] To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr 3 (26.7 g, 107 mmol) dropwise at -40 *C under

N

2 . After addition, the mixture was stirred at this temperature for 5 h and then was poured into ice water. The precipitated solid was filtered and washed with petroleum ether. The 121 filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly used in the next step. 0 0 H OH BrCICH 2 H CI CI 1003941 7-ChlorobenzodlI1,3Idioxole-5-carbaldehyde [003951 To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrCICH 2 (23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs 2

CO

3 (25 g, 190 mmol). The mixture was stirred at 60 *C overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over Na 2

SO

4 and concentrated under reduced pressure to afford 7 chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). 'H NMR (400 MHz, CDCl 3 ) 8 9.74 (s, 1 H), 7.42 (d, J= 0.4 Hz, 1 H), 7.26 (d, J= 3.6 Hz, 1 H), 6.15 (s, 2 H). 0 K H NaBH 4 THF O OH ci CI [003961 (7-Chlorobenzo[d][1,3]dioxol-5-yl)methanol 1003971 To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0..g, 33 mmol) in THF (50 mL) was added NaBH 4 (2.5 g, 64 mmol) ) in portions at 0 'C. The mixture was stirred at this temperature for 30 min and then poured into aqueous NH 4 CI solution. The organic layer was separated, and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined extracts were dried over Na 2

SO

4 and evaporated under reduced pressure to afford (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol, which was directly used in the next step. o OH SOC1 2 0 C1 Cl C1 [00398] 4-Chloro-6-(chloromethyl)benzo[d][1,3]dioxole [003991 A mixture of (7-chlorobenzo[d][1,3]-dioxol-5-yl)methanol (5.5 g, 30 mmol) and SOCl 2 (5.0 mL, 67 mmol) in dichloromethane (20 mL) was stirred at room temperature for I h and was then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined extracts were washed with water and aqueous NaHC0 3 solution, dried over Na 2

SO

4 and evaporated under reduced pressure to afford 4-chloro-6-(chloromethyl)benzo[d]1(,3]dioxole, which was directly used in the next step.

122 CI NaCN NC O CI C1 [004001 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile 1004011 A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 nmol) in DMSO (20 mL) was stirred at 40 *C for 1 h and was then poured into water. The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried-over Na 2

SO

4 and evaporated under reduced pressure to afford 2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%). 'H NMR S 6.81 (s, 1 H), 6.71 (s, 1 H), 6.07 (s, 2 H), 3.64 (s, 2 H). 13 C-NMR 8149.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3, 23.1. [004021 Example 19: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid. MeO N 2 trimethy MeO A HO OH 0 0-o MeO NH 2 trimethyl M oOH 0 [00403] 1-Benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester [004041 To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount ofp-tolueneslufonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-benzooxazol-5-yl cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 'H NMR (CDC3, 400 MHz) 5 8.09 (s, 1), 7.75 (d, J= 1.2 Hz, 1 H), 7.53-7.51 (m, 1 H), 7.42 7.40 (m, 1 H), 3.66 (s, 3 H), 1.69-1.67 (m, 2 H), 1.27-1.24 (m, 2 H). MeO N AC1 3 HN [004051 1-(Benzo[dloxazol-5-yl)cyclopropanecarboxylic acid 123 [00406] To a solution of I -benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added AlCl 3 (5.3 g, 40 mmol) in portions at 0 *C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0 *C. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, 11% over two steps). 'H NMR (DMSO, 400 MHz) 6 12.25 (brs, I H), 8.71 (s, 1 H), 7.70-7.64 (m, 2 H), 7.40 (dd, J= 1.6, 8.4 Hz, 1 H), 1.49-1.46 (m, 2 H), 1.21-1.18 (m, 2 H). MS (ESI) m/e (M+H ) 204.4. [00407] Example 20: 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile 0 0 H BBra H BrCH 2 CIIDMF H 0 NaBH 4 HO - 0 )1?OH OH lo 0 -0 F F F F

SOCI

2 Cl 'N NaCN F F 0 0 H 0-- BBr 3 H OH O0H F F [00408] 3-Fluoro-4,5-dihydroxy-benzaldehyde [00409] To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 mL) was added BBr 3 (1.5 mL, 16 mmol) dropwise at - 78 *C under N 2 . After addition, the mixture was warmed to - 30 *C and it was stirred at this temperature for 5 h. The reaction mixture was poured into ice water. The precipitated solid was collected by filtration and washed with dichloromethane to afford 3-fluoro-4,5 dihydroxy-benzaldehyde (1.1 g, 89%), which was directly used in the next step. 0 0 H OH BrCH 2 CI/DMF H 0 OH 0 F F [004101 7-Fluoro-benzo[1,3]dioxole-5-carbaldehyde [00411] To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrC1CH 2 (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs 2

CO

3 (12.6 g, 39 mmol). The 124 mixture was stirred at 60 *C overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2

SO

4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford 7-fluoro-benzo[l,3]dioxole-5-carbaldehyde (0.80 g, 49%). 'H NMR (300 MHz, CDCl 3 ) 8 9.78 (d, J= 0.9 Hz, I H), 7.26 (dd, J= 1.5, 9.3 Hz, IH), 7.19 (d, J= 1.2 Hz, 1 H), 6.16 (s, 2 H). 0 H 0 NaBH 4 HO F F [004121 (7-Fluoro-benzo1,3]dioxol-5-yl)-methanol [00413] To a solution of 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 4.7 mmol) in MeOH (50 mL) was added NaBH 4 (0.36 g, 9.4 mmol) in portions at 0 *C. The mixture was stirred at this temperature for 30 min and was then concentrated to dryness. The residue was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na 2

SO

4 and concentrated to dryness to afford (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 98%), which was directly used in the next step. HO 'O o SOCI 2 C 0 FF [004141 6-Chloromethyl-4-fluoro-benzo[1,3]dioxole [004151 To SOC1 2 (20 mL) was added (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 4.7 mmol) in portions at 0 'C. The mixture was warmed to room temperature over I h and then was heated at reflux for 1 h. The excess SOC1 2 was evaporated under reduced pressure to give the crude product, which was basified with saturated aqueous NaHCO 3 to pH - 7. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na 2

SO

4 and evaporated under reduced pressure to give 6-chloromethyl-4 fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next step. Cl NaCN NC 0 > >~ -~0 0 F F [004161 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile [004171 A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3 mmol) and 125 NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30 *C for 1 h and was then poured into water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2

SO

4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford 2-(7 fluorobenzo[d][1,3]dioxol-5-y)acetonitrile (530 mg, 70%). 'H NMR (300 MHz, CDC1 3 ) 8 6.68-6.64 (m, 2 H), 6.05 (s, 2 H), 3.65 (s, 2 H). 13 C-NMR 6151.1, 146.2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3. [004181 Example 21: 1-(1H-Indol-5-yl)cyclopropanecarboxylic acid HO TsOH 3 Me

KNO

3 Ranney Ni 0 CH 3 0H 0 H 2 SO4/CH 2

CI

2 O NO 2 eoN1S Me ,,, Br MSm me- sime, MeO N2NBS MeO SrH2 Eta 3 e ie 0NH 2 0NH 2 EtN NM Cul Me IOH H DMF N 0 H H HO TsOH MeO 0 -1 CH 3 0H [004191 Methyl 1-phenylcyclopropanecarboxylate [004201 To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH 3 0H (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give crude product, which was dissolved into EtOAc. The EtOAc layer was washed with aq. sat. NaHCO 3 . The organic layer was dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to give methyl 1 -phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 'H NMR (400 MHz, CDCl 3 ) 8 7.37-7.26 (m, 5 H), 3.63 (s, 3 H), 1.63-1.60 (m, 2 H), 1.22-1.19 (m, 2 H). MeO -O KNO 3 MeO O

H

2

SO

4

/CH

2 Cl 2 O

NO

2 {004211 Methyl 1-(4-nitrophenyl)cyclopropanecarboxylate 126 [004221 To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in

H

2

SO

4

/CH

2 Cl 2 (40 mL/40 mL) was added KNO 3 (12.8 g, 0.13 mol) in portion at 0 *C. The mixture was stirred for 0.5 hr at 0 *C. Ice water was added and the mixture was extracted with EtOAc (100 mL x 3). The organic layers were dried with anhydrous Na 2

SO

4 and evaporated to give methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (21 g, 68%), which was used directly in the next step. 'H NMR (300 MHz, CDC1 3 ) 5 8.18 (dd, J= 2.1, 6.9 Hz, 2 H), 7.51 (dd, J= 2.1, 6.9 Hz, 2 H), 3.64 (s, 3 H), 1.72-1.69 (in, 2 H), 1.25-1.22 (in, 2 H). MeO Ranney Ni M NH2 0 N2 NH 2 [00423] Methyl 1-(4-aminophenyl)cyclopropanecarboxylate [00424] To a solution of.methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20 g, 0.09 mol) in MeOH (400 mL) was added Ni (2 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a pad of Celite and the filtrate was evaporated under vacuum to give crude product, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate =10:1) to give methyl 1-(4-aminophenyl)cyclopropanecarboxylate (11.38 g, 66%). 'H NMR (300 MHz, CDC1 3 ) S 7.16 (d, J= 8.1 Hz, 2 H), 6.86 (d, J 7.8 Hz, 2 H), 4.31 (br, 2 H), 3.61 (s, 3 H), 1.55-1.50 (m, 2 H),1.30-1.12 (in, 2 H). M NBS MeO Br o NH 2

NH

2 [004251 Methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate [004261 To a solution of methyl 1-(4-aminophenyl)cyclopropanecarboxylate (10.38 g, 0.05 mol) in acetonitrile (200 mL) was added NBS (9.3 g, 0.05 mol) at room temperature. The mixture was stirred overnight. Water (200 mL) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc (80 mL x3). The organic layers were dried with anhydrous Na 2

SO

4 and evaporated to give methyl 1-(4-amino-3 bromophenyl)cyclopropanecarboxylate (10.6 g, 78%), which was used directly in the next step. 'H NMR (400 MHz, CDC 3 ) 6 7.38 (d, J= 2.0 Hz, 1 H), 7.08 (dd, J= 1.6, 8.4 Hz, 1 H), 6.70 (d, J= 8.4 Hz, 1 H), 3.62 (s, 3 H), 1.56-1.54 (in, 2 H), 1.14-1.11(m, 2 H). MeO Br2 ENt MeOSie me-,-a

SW~

3 me, sMe 3

NH

2 Et 3

NNH

127 [004271 Methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropane carboxylate [004281 To a degassed solution of methyl 1-(4-amino-3-bromophenyl)cyclopropane carboxylate (8 g, 0.03 mol) in Et 3 N (100 mL) was added ethynyl-trimethyl-silane (30 g, 0.3 mol), DMAP (5% mol) and Pd(PPh 3

)

2 Cl 2 (5% mol) under N 2 . The mixture was refluxed at 70 *C overnight. The insoluble solid was filtered off and washed with EtOAc (100 mL x 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate =20:1) to give methyl 1 (4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.8 g, 56%). 'H NMR (300 MHz, CDC1 3 ) 67.27 (s, 1 H), 7.10 (dd, J= 2.1, 8.4 Hz, 1 H), 6.64 (d, J= 8.4 Hz, 1 H), 3.60 (s, 3 H), 1.55-1.51 (m, 2 H), 1.12-1.09 (m, 2 H), 0.24 (s, 9 H). MeO SiMe a Cu M MeO

NH

2 DMF [004291 Methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate [00430] To a degassed solution of methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl) cyclopropanecarboxylate (4.69 g, 0.02 mol) in DMF (20 mL) was added CuI (1.5 g, 0.008 mol) under N 2 at room temperature. The mixture was stirred for 3 hr at room temperature. The insoluble-solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate =20:1) to give methyl 1-(1H-indol-5 yl)cyclopropanecarboxylate (2.2 g, 51%). 'H NMR (400 MHz, CDCl 3 ) 8 7.61 (s, 1 H), 7.33 (d, J= 8.4 Hz, 1 H), 7.23-7.18 (m, 2 H), 6.52-6.51 (m, 1 H) 3.62 (s, 3 H), 1.65-1.62 (m, 2 H), 1.29-1.23(m, 2 H). MeO -IOH HO O N CH 3 0H 0 N H 100431] 1-(1H-Indol-5-yl)cyclopropanecarboxylic acid [004321 To a solution of methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (1.74 g, 8 mmol) in CH 3 0H (50 m L) and water (20 mL) was added LiOH (1.7 g, 0.04 mol). The mixture was heated at 45 *C for 3 hr. Water was added and the mixture was acidified with concentrated HCl to pH -3 before being extracted with EtOAc (20 mL x 3). The organic layers were dried over anhydrous Na 2 SO4 and evaporated to give 1-(1H-indol-5 yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1 H NMR (300 MHz, DMSO-d 6 ) 7.43 (s, I H), 128 7.30-7.26(m,2 H), 7.04 (dd,J= 1.5, 8.4 Hz, 1 H), 6.35 (s, I H), 1.45-1.41 (m,2 H), 1.14 1.10 (m, 2 H). [004331 Example 22: 1-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid MeO 2 C OMeO 2 C O 20% HCI OH Na MeO 2 C O (COCI) 2 HOOC MeO 2 C o MeO 2 C O aO OH Na [00434] 1-[4-(2-tert-Butoxycarbonyl-ethoxy)-phenyl]-cyclopropanearboxylic methyl ester [004351 To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (7.0 g, 3.6 mmol) in acrylic tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. The mixture was heated at 110 'C for 1 h. After cooling to room temperature, the resulting mixture was quenched with water and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl] cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material (3.0 g). 'H NMR (300 MHz, CDCl 3 ) 8 7.24 (d, J= 8.7 Hz, 2 H), 6.84 (d, J= 8.7 Hz, 2 H), 4.20 (t, J= 6.6 Hz, 2 H), 3.62 (s, 3 H), 2.69 (t, J= 6.6 Hz, 2 H), 1.59-1.56 (m, 2 H), 1.47 (s, 9 H), 1.17 1.42 (m, 2 H). MeO 2 C 0 20% HCI MeO 2 C OH 0- OH [004361 1-14-(2-Carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester [004371 A solution of 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was heated at 110 'C for I h. After cooling to room temperature, the resulting mixture was filtered. The solid was washed with water and dried under vacuum to give 1-[4-(2-carboxy-ethoxy)-phenyl] cyclopropanecarboxylic methyl ester (5.0 g, 96%). 'H NMR (300 MHz, DMSO) 8 7.23-7.19 129 (m, 2 H), 6.85-6.81 (m, 2 H), 4.13 (t, J= 6.0 Hz, 2 H), 3.51 (s, 3 H), 2.66 (t, J= 6.0 Hz, 2 H), 1.43-1.39 (m, 2 H), 1.14-1.10 (m, 2 H). Me02C MeO 2 C 0 O (COCI) 2 HOOC [004381 1-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid [00439] To a solution of 1-[4-(2-carboxy-ethoxy)-pheny1]-cyclopropanecarboxylic methyl ester (5.0 g, 20 mmol) in CH 2 01 2 (50 mL) were added oxalyl chloride (4.8 g, 38 mmol) and two drops of DMF at 0 *C. The mixture was stirred at 0-5 0C for I h and then evaporated under vacuum. To the resulting mixture was added CH 2 Cl 2 (50 mL) at 0 0C and stirring was continued at 0-5 'C for 1 h. The reaction was slowly quenched with water and was extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1-2:1) to give 1-(4 oxochroman-6-yl)cyclopropanecarboxylic acid (830 mg, 19%) and methyl 1-(4-oxochroman 6-yl)cyclopropanecarboxylate (1.8 g, 38%). 1-(4-Oxochroman-6-yl)cyclopropane-carboxylic acid: 'H NMR (400 MHz, DMSO) S 12.33 (br s, 1 H), 7.62 (d, J= 2.0 Hz, I H), 7.50 (dd, J= 2.4, 8.4 Hz, 1 H), 6.95 (d, J= 8.4 Hz, 1 H), 4.50 (t, J= 6.4 Hz, 2 H), 2.75 (t, J= 6.4 Hz, 2 H), 1.44-1.38 (m, 2 H), 1.10-1.07 (m, 2H). MS (ESI) m/z (M+H*) 231.4. 1-(4-Oxochroman-6 yl)cyclopropanecarboxylate: 'H NMR (400 MHz, CDC1 3 ) 8 7.83 (d, J= 2.4 Hz, 1 H), 7.48 (dd, J= 2.4, 8.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.55-4.52 (m, 2 H), 3.62 (s, 3 H), 2.80 (t, J= 6.4 Hz, 2 H), 1.62-1.56 (m, 2 H), 1.18-1.15 (m, 2H). [00440] Example 23: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid UGH HOOMe MeO 2 C L HOOC M [00441 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid [004421 To a solution of methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate (1.0 g, 4.1 mmol) in MeOH (20 mL) and water (20 mL) was added LiOH-H 2 O (0.70 g, 16 mmol ) in portions at room temperature. The mixture was stirred overnight at room temperature before the MeOH was removed by evaporation under vacuum. Water and Et 2 O were added to the residue and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL x 3). The combined organic extracts dried over anhydrous Na 2 SO4 and evaporated 130 under vacuum to give 1-(4-hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (480 mg, 44%). 'H NMR (400 MHz, CDCl 3 ) 8 12.16 (s, I H), 7.73 (d, J= 2.0 Hz, 1 H), 7.47 (dd, J= 2.0, 8.4 Hz, 1 H), 6.93 (d, J= 8.8 Hz, I H), 3.83-3.80 (m, 2 H), 3.39 (s, 3 H), 3.28 3.25 (m, 2 H), 1.71-1.68 (m, 2 H), 1.25-1.22 (m, 2H). MS (ESI) m/z (M+H ) 263.1. [004431 Example 24: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid MeoOC NaBH 4 dTFA0 MeOOc LiOH 3 HOOC MeOOC " NaBH 4 jrFA MeOOC [004441 1-Chroman-6-yl-cyclopropanecarboxylic methyl ester [00445] To trifluoroacetic acid (20 mL) was added NaBH 4 (0.70 g, 130 mmol) in portions at 0 *C under N 2 atmosphere. After stirring for 5 min, a solution of 1-(4-oxo-chroman-6-yl) cyclopropanecarboxylic methyl ester (1.6 g, 6.5 mmol) was added at 15 "C. The reaction mixture was stirred for I h at room temperature before being slowly quenched with water. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-chroman-6-yl cyclopropanecarboxylic methyl ester.(1.4 g, 92%), which was used directly in the next step. 'H NMR (300 MHz, CDCl 3 ) 8 7.07-7.00 (m, 2 H), 6.73 (d, J= 8.4 Hz, 1 H), 4.17 (t, J= 5.1 Hz, 2 H), 3.62 (s, 3 H), 2.79-2.75 (m, 2 H), 2.05-1.96 (m, 2 H), 1.57-1.54 (m, 2 H), 1.16-1.13 (m, 2H). MeOOC LiOH I HOOC [00446] 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid [004471 To a solution of 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 60 mmol) in MeOH (20 mL) and water (20 mL) was added LiOH-H 2 0 (1.0 g, 240 mmol ) in portions at room temperature. The mixture was stirred overnight at room temperature before the MeOH was removed by evaporation under vacuum. Water and Et 2 O were added and the aqueous layer was separated, acidified with HC1 and extracted with EtOAc (50 mL x 3). The combined organic extracts dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (1.0 g, 76%). ' H NMR (400 MHz, DMSO) 5 12.10 (br s, 1 H), 6.95 (d, J= 2.4 Hz, 2 H), 6.61-6.59 (m, I H), 131 4.09-4.06 (m, 2 H), 2.70-2.67 (m, 2 H), 1.88-1.86 (m, 2 H), 1.37-1.35 (m, 2 H), 1.04-1.01 (in, 2H). MS (ESI) m/z (M+H*) 217.4. [004481 Example 25: 1-(3-Methylbenzo[dlisoxazol-5-yl)cyclopropanecarboxylic acid HOOC O e MeOH/TsOH MeOOC O' e AIC 3 /AcCI MeOOC

NH

2 OH OMe -D- "OMe OH N OH -OAc MeOOC Ac 2 O MeOOC Py/DMFp MeOOC LiOH HOOC N 0 MeOOC OMe AICI 3 /AcCI MeOOC [004491 1-(3-Acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester [004501 To a stirred suspension of AlC1 3 (58 g, 440 mmol) in CS 2 (500 mL) was added acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5 min, methyl 1-(4 methoxyphenyl)cyclopropanecarboxylate (15 g, 73 mmol) was added. The reaction mixture was heated at reflux for 2 h before ice water was added carefully to the mixture at room temperature. The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic extracts were dried over anhydrous Na 2 SO4 and evaporated under reduced pressure to give 1-(3 -acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (15 g, 81%), which was used in the next step without further purification. 'H NMR (CDCl 3 , 400 MHz) S 12.28 (s, I H), 7.67 (d, J= 2.0 Hz, I H), 7.47 (dd, J= 2.0, 8.4 Hz, I H), 6.94 (d, J= 8.4 Hz, 1 H), 3.64 (s, 3 H), 2.64 (s, 3 H), 1.65-1.62 (m, 2 H), 1.18-1.16(m, 2 H). 0 N rOH MeOOC

NH

2 OH-HCI MeOOC OH OH [00451] 1-[4-Hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester [004521 To a stirred solution of 1-(3-acety1-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (14.6 g, 58.8 mmol) in EtOH (500 mL) were added hydroxylamine 132 hydrochloride (9.00 g, 129 mmol) and sodium acetate (11.6 g, 141 mmol) at room temperature. The resulting mixture was heated at reflux overnight. After removal of EtOH under vacuum, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-[4 hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester (14.5 g, 98%), which was used in the next step without further purification. 'H NMR (CDC1 3 , 400 MHz) 6 11.09 (s, 1 H), 7.39 (d, J= 2.0 Hz, I H), 7.23 (d, J= 2.0 Hz, 1 H), 7.14 (s, 1 H), 6.91 (d, J= 8.4 Hz, I H), 3.63 (s, 3 H), 2.36 (s, 3 H), 1.62-1.59 (in, 2 H), 1.18-1.15 (in, 2 H). NOH N'OAC MeOOC Ac 2 O MeOOC [004531 (E)-Methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane carboxylate 1004541 The solution of 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl] cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac 2 O (250 mL) was heated at 45 *C for 4 h. The Ac 2 O was removed by evaporation under vacuum before water (100 mL) and EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give (E)-methyl 1-(3-(1 (acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%), which was used in the next step without further purification. NOAc MeOOC Py/DMF MeOOC N OH [004551 Methyl 1-(3-methylbenzo[dJisoxazol-5-yl)cyclopropanecarboxylate [004561 A solution of (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4 hydroxyphenyl)cyclopropane carboxylate (10.5 g, 39.6 mmol) and pyridine (31.3 g, 396 mmol) in DMF (150 mL) was heated at 125 *C for 10 h. The cooled reaction mixture was poured into water (250 mL) and was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give methyl 1-(3-methylbenzo[dlisoxazol-5 yl)cyclopropanecarboxylate (7.5 g, 82%). 'H NMR (CDCl 3 300 MHz) 5 7.58-7.54 (in, 2 H), 133 7.48 (dd, J= 1.5, 8.1 Hz, I H), 3.63 (s, 3 H), 2.58 (s, 3 H), 1.71-1.68 (m, 2 H), 1.27-1.23 (m, 21H). MeOOC N UOH HOOC N [004571 1-(3-Methylbenzo[dlisoxazol-5-yl)cyclopropanecarboxylic acid [004581 To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5 yl)cyclopropanecarboxyl ate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH-H 2 0 (0.80 g, 19 mmol ) in portions at room temperature. The reaction mixture was stirred at room temperature overnight before the MeOH was removed by evaporation under vacuum. Water and Et 2 O were added and the aqueous layer was separated, acidified with HCl and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 1-(3-methylbenzo[d]isoxazol 5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 'H NMR (400 MHz, DMSO) 8 12.40 (br s, 1 H), 7.76 (s, 1 H), 7.60-7.57 (m, 2 H), 2.63 (s, 3 H), 1.52-1.48 (m, 2 H), 1.23-1.19 (m, 2H). MS (ESI) m/z (M+H) 218.1. [00459] Example 26: 1-(Spiro[benzo[d] [1,31 dioxole-2,1 '-cyclobutane]-5 yl)cyclopropane carboxylic acid Hooc H MeOH MeOOC OH O C__ OH OH MeOOC O LiOH HOOc 0 ~- 0 HOOC OH MeOH U MeOOC H OH OH [00460] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester [00461] To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) in MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at 50 'C overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). IH NMR (DMSO 300 MHz) 6 8.81 (brs, 2 H), 6.66 (d, J= 2.1 Hz, 1 H), 134 6.61 (d, J= 8.1 Hz, 1 H), 6.53 (dd, J= 2.1, 8.1 Hz, 1 H), 3.51 (s, 3 H), 1.38-1.35 (m, 2 H), 1.07-1.03 (m, 2 H). MeOOC OO MeOOC [004621 Methyl 1-(spiro[benzold][1,3]dioxole-2,1'-cyclobutane-5-yl)cyclopropane carboxylate [004631 To a solution of 1-(3,4-dihydroxy-pheny)-cyclopropanecarboxylic methyl ester (1.0 g, 4.8 mmol) in toluene (30 mL) was added TsOH (0.10 g, 0.50 mmol) and cyclobutanone (0.70 g, 10 mmol). The reaction mixture was heated at reflux for 2 h before being concentrated under vacuum. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 15:1) to give methyl I -(spiro[benzo[d][1,3]dioxole-2,1' cyclobutane]-5-yl)cyclopropanecarboxylate (0.6 g, 50%). 'H NMR (CDC1 3 300 MHz) 6 6.78-6.65 (m, 3 H), 3.62 (s, 3 H), 2.64-2.58 (m, 4 H), 1.89-1.78 (m, 2 H), 1.56-1.54 (m, 2 H), 1.53-1.12(m, 2 H). MeOOC LiOH HOOC 1004641 1-(Spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)cyclopropane carboxylic acid [004651 To a mixture of methyl 1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)cyc1 opropanecarboxylate (0.60 g, 2.3 mmol) in THF/H 2 0 (4:1, 10 mL) was added LiOH (0.30 g, 6.9 mmol). The mixture was stirred at 60 'C for 24 h. HC1 (0.5 N) was added slowly to the mixture at 0 'C until pH 2-3. The mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO 4 , and washed with petroleum ether to give 1 -(spiro[benzo[d][1 ,3]-dioxole-2, 1'-cyclobutane]-5 yl)cyclopropane carboxylic acid (330 mg, 59%). 'HNMR'(400 MHz, CDC1 3 ) 8 6.78-6.65 (m, 3 H), 2.65-2.58 (m, 4 H), 1.86-1.78 (m, 2 H), 1.63-1.60 (m, 2 H), 1.26-1.19 (m, 2 H). [004661 Example 27: 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile HO : CO 2 Et BrH 2

CCHI

2 Br C2Et LAA-i OH SOC1 2 C1 NaCN CN 0 0 135 HO CO 2 Et BrH 2

CCH

2 Br CO 2 Et HO 0 [004671 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester [00468] To a suspension of Cs 2

CO

3 (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 brine (100 mL), dried over Na 2

SO

4 and concentrated to dryness. The residue was purified by column (petroleum ether/ethyl acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 'H NMR (300 MHz, CDCl 3 ) 8 7.53 (dd, J = 1.8, 7.2 Hz, 2 H), 6.84-6.87 (m, 1 H), 4.22-4.34 (m, 6 H), 1.35 (t, J = 7.2 Hz, 3 H). O CO 2 Et - L- OH [004691 (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol 1004701 To a suspension of LiAlH 4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 *C under N 2 . 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[1,4]dioxin-6-yl)-methanol (10.6 g). 'H NMR (300 MHz, DMSO-d 6 ) 6 6.73-6.78 (m, 3 H), 5.02 (t, J = 5.7 Hz, 1 H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17-4.20 (m, 4 H). 0 OH SOC12 0C [004711 6-Chloromethyl-2,3-dihydro-benzo[1,4]dioxine 1004721 A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOC 2 (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 NaHCO 3 (sat solution), water and brine, dried over Na 2

SO

4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step. C1 NaCN

CN

136 [004731 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile [004741 A mixture of 6-chloromethyl-2,3-dihydro-benzo(1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for I 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 brine (50 mL), dried over Na 2

SO

4 and concentrated to dryness. The residue was purified by column (petroleum ether/ethyl acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][1,4]dioxin-6 yl)acetonitrile as a yellow oil (10.2 g, 86%). 'H-NMR (300 MHz, CDC1 3 ) S 6.78-6.86 (m, 3 H), 4.25 (s, 4 H), 3.63 (s, 2 H). [004751 The following Table 2 contains a list of carboxylic acid building blocks that were commercially available, or prepared by one of the three methods described above: Table 2: Carboxylic acid building blocks. Name Structure 1-benzo[1,3]dioxol-5-ylcyclopropane-1- / carboxylic acid 1-(2,2-difluorobenzo[1 ,3]dioxol-5- H - F yl)cyclopropane-1 -carboxylic acid \ / OH OH 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic OH acid 1-(3-methoxyphenyl)cyclopropane- I -carboxylic acid H 1-(2-methoxyphenyl)cyclopropane-1 -carboxylic 0 acid 1- [4-(trifluoromethoxy)phenyl] cyclopropane- I - FO carboxylic acid FHO 1-(2,2-dimethylbenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxylic acid OH tetrahydro-4-(4-methoxyphenyl)-2H-pyran-4 carboxylic acid

OH

137 Name Structure OH I -phenylcyclopropane- 1 -carboxylic acid 1 -(4-methoxyphenyl)cyclopropafle-l1-carboxylic OH acid -,r 0 1 -(4-chlorophenyl)cyclopropafle- 1 -carboxylic OH acid Ic- O 1 -(3-hydroxyphenyl)cyclopropanecarboxylic acid o I -phenylcyclopentanecarboxylic acid OH OH O I -(2-oxo-2,3 -dihydrobenzo[dloxazol-5- Uri r yl)cyclopropanecarboxylic acid 4 (\- / 0 H 0 1 -(benzofuran-5-y1)cyclopropanecarboxylic acid \ / I -(4-methoxypheny)cyclohexalecarboxylic acid 0- OH 1-(4-chloropheny1)cyclohexanecarboxylic acid C / 1 -(2,3-dihydrobenzofuran-5-H yl)cyclopropanecarboxylic acid\/ 1 -(3,3-dimethyl-2,3-dihydrobenzofurafl-5- O yl)cyclopropanecarboxylic acid O 1 -(7-rnethoxybenzold] [1 ,3]dioxol-5-/\ yI)cyclopropanecarboxylic acidH 138 Name Structure OH OH 1 -(3-hydroxy-4 methoxyphenyl)cyclopropanecarboxylic acid\/ OH OH 1 -(4-chloro-3- hydroxyphenyl)cyclopropanecarboxylic acid \/C H 1 -(3-(benzyloxy)-4- i chlorophenyl)cyclopropanecarboxylic acid 1-(4-chlorophenyl)cyclopentanecarboxylic acidC / OH 1 -(3-(benzyloxy)-4 methoxyphenyl)cyclopropanecarboxylic acid OH OH CI 1 -(3 -chloro-4- C methoxyphenyl)cyclopropanecarboxylic acid\/ OH F 1 -(3 -fluoro-4 methoxyphenyl)cyclopropanecarboxylic acid \ / \ OH 1 -(4-methoxy-3-

-

6 methylphenyl)cyclopropanecarboxylic acid \/c -~l 1 -(4-(benzyloxy)-3-0X methoxyphenyl)cyclopropanecarboxylic acid HO OH 0 1 -(4-chloro-3 methoxyphenyl)cyclopropanecarboxylic acid /CI OH CI 1 -(3-chloro-4- O hydroxyphenyl)cyclopropanecarboxylic acid \/O OH OH 1 -(3-(hydroxymethyl)-4 methoxyphenyl)cyclopropanecarboxylic acid \ / 9,\ 139 Name Structure 1 -(4-methoxypheny)cycopetanecarboxylic,: I -tr acid O- OH I -phenylcyclohexanecarboxylic acid 0 O OH 0 1 -(3 ,4-dimethoxypheny)cyclopropalecaboxylic / C acid 1 -(7-chlorobenzo[d][ 1,3]dioxol-5- \C / yl)cyclopropanecarboxylic acid H 0 1 -(benzo[dloxazo-5-y)cyclopropalecaboxylic / acid 1 -(7-fluorobenzo[d] [1,3 ]dioxol-5- \ yl)cyclopropanecarboxylic acid F 1 -(3 ,4-difiuoropheny1)cyclopropalecaboxylic HF acid\/ H 0 1 -(1 H-indo1-5-y1)cyclopropaflecarboxylic acid H /W N I -(I H-benzo[dlimidazol-5- / N yl)cyclopropanecarboxylic acid N H 700N I -(2-methyl-I H-benzo[d]imidazol-5- \ N/ yl)cyclopropanecarboxylic acid H 0 7 1 -(1-methyl-i H-benzo[d]imidazol-5- N,/ yl)cyclopropanecarboxylic acid 1-(3-methylbenzo[d]isoxazol-5- H__N yl)cyclopropanecarboxylic acid* \ /0 140 Name Structure H 0 1 -(spiro[benzo[d] [1,3]dioxole-2, 1'-cyclobutane] 5-yl)cyclopropanecarboxylic acid 1-(1H-benzo[d][1,2,3]triazol-5- NH yl)cyclopropanecarboxylic acid H 0-6 1 -(1-methyl-IH-benzo[d][1,2,3]triazol-5- HO/ yl)cyclopropanecarboxylic acid H 0 1-(1,3-dihydroisobenzofuran-5 yl)cyclopropanecarboxylic acid T / 1-(6-fluorobenzo[d][1,3]dioxol-5- c / yl)cyclopropanecarboxylic acid F 1-(2,3-dihydrobenzofuran-6 yl)cyclopropanecarboxylic acid H 0 1-(chroman-6-yl)cyclopropanecarboxylic acid HO / -- , H 1-(4-hydroxy-4-methoxychroman-6- H yl)cyclopropanecarboxylic acid 1-(4-oxochroman-6-y1)cyclopropanecarboxylic HO H 0 C1 1-(3,4-dichlorophenyl)cyclopropanecarboxylic c acid H 0 1-(2,3-dihydrobenzo[b][1,4]dioxin-6 yl)cyclopropanecarboxylic acid HO 0 0 1-(benzofuran-6-yl)cyclopropanecarboxylic acid H O [004761 Specific Procedures: Synthesis of aminoindole building blocks 141 [004771 Example 28: 3-Methyl-1H-indol-6-amine ON N NaNO 2 /HCI NH2.HCI O2N N 0 2 N NH, SflCI 2 0 2 N H 0,N0 I N0 2 H 3 P O 4 I + 2NH 2 /Pd-C 0,i N

H

2 NC N 6 N 2 H H H NaNO 2 /HCI NH2.HCI 0 2 N NH 2 SnC 2 0 2 N N [004781 (3-Nitro-phenyl)-hydrazine hydrochloride salt [004791 3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in the mixture of H 2 0 (40 mL) and 37% HCI (40 mL). A solution of NaNO 2 (13.8 g, 0.2 mol) in H 2 0 (60 mL) was added to the mixture at 0 *C, and then a solution of SnC1 2

.H

2 0 (135.5 g, 0.6 mol) in 37% HCI (100 mL) was added at that temperature. After stirring at 0 'C for 0.5 h, the insoluble material was isolated by filtration and was washed with water to give (3 nitrophenyl)hydrazine hydrochloride (27.6 g, 73%). O 0 2 N NH HC 0 2 N H H H [004801 N-(3-Nitro-phenyl)-N-propylidene-hydrazine [004811 Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitrophenyl)hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain (E)-1-(3-nitrophenyl)-2-propylidenehydrazine, which was used directly in the next step.

NO

2 2

H

3

PO

4 3 +O2 I

:

2 N< )

+O

2 N " N H NH H [004821 3-Methyl-4-nitro-1H-indole 3 and 3-methyl-6-nitro-1H-indole [004831 A mixture of (E)-1-(3-nitrophenyl)-2-propylidenehydrazine dissolved in 85 %

H

3 PO4 (20 mL) and toluene (20 mL) was heated at 90-100 *C for 2 h. After cooling, toluene was removed under reduced pressure. The resultant oil was basified to pH 8 with 10 % NaOH. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried, filtered and concentrated under reduced pressure to afford the mixture of 3- 142 methyl-4-nitro-IH-indole and 3-methyl-6-nitro-1H-indole [1.5 g in total, 86 %, two steps from (3-nitrophenyl)hydrazine hydrochloride] which was used to the next step without further purification. + O2N

H

2 /Pd-C N 0 2 N aN

H

2 NC Hf H [004841 3-Methyl-1H-indol-6-amine [004851 The crude mixture from previous steps (3 g, 17 mmol) and 10% Pd-C (0.5 g) in ethanol (30 mL) was stirred overnight under H 2 (1 atm) at room temperature. Pd-C was filtered off and the filtrate was concentrated under reduced pressure. The solid residue was purified by column to give 3-methyl-IH-indol-6-anine (0.6 g, 24%). 'H NMR (CDC 3 ) 8 7.59 (br s. IH), 7.34 (d, J= 8.0 Hz, IH), 6.77 (s, 1H), 6.64 (s, IH), 6.57 (m, IH), 3.57 (brs, 2H), 2.28 (s, 3H); MS (ESI) m/e (M+H+) 147.2. [004861 Example 29: 3-tert-Butyl-1H-indol-5-amine 0 2 N Br 0 2 N Raney Ni/H 2

H

2 N N AICIWCH 2 C1 2 N N H H H 0 2 N Br C 2 N -N AJCI/CH 2

CI

2 ~N H H [004871 3-tert-Butyl-5-nitro-1H-indole [004881 To a mixture of 5-nitro-IH-indole (6.0 g, 37 mmol) and AlC1 3 (24 g, 0.18 mol) in

CH

2 Cl 2 (100 mL) at 0 'C was added 2-bromo-2-methyl-propane (8.1 g, 37 mmol) dropwise. After being stirred at 15 *C overnight, the mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with

CH

2

CI

2 (30 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2

SO

4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give 3-tert butyl-5-nitro-1 H-indole (2.5 g, 31%). 'H NMR (CDCl 3 , 400 MHz) 5 8.49 (d, J= 1.6 Hz, 1 H), 8.31 (brs, 1 H), 8.05 (dd, J= 2.0, 8.8 Hz, I H), 7.33 (d, J= 8.8 Hz, I H), 6.42 (d, J= 1.6 Hz, 1 H), 1.42 (s, 9 H).

143

O

2 N Raney Ni/H 2

H

2 N -~ N -~ N H H [004891 3-tert-Butyl-1H-indol-5-amine [00490] To a solution of 3-tert-butyl-5-nitro-IH-indole (2.5 g, 12 mmol) in MeOH (30 mL) was added Raney Nickel (0.2 g) under N 2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 15 *C for 1 h. The catalyst was filtered off and the filtrate was concentrated to dryness under vacuum. The residue was purified by preparative HLPC to afford 3-tert-butyl-1 H-indol-5-amine (0.43 g, 19%). 'H NMR (CDC1 3 , 400 MHz) 8 7.72 (br.s, I H), 7.11 (d, J= 8.4 Hz, 1 H), 6.86 (d, J= 2.0 Hz, 1 H), 6.59 (dd, J= 2.0, 8.4 Hz, 1 H), 6.09 (d, J= 1.6 Hz, 1 H), 1.37 (s, 9 H); MS (ESI) m/e (M+H+) 189.1. [004911 Example 30: 2-tert-Butyl-6-fluoro-1H-indol-5-amine and 6-tert-butoxy-2-tert butyl-1H-indol-5-amine 02N N 2 2 N Br022N O o O2N NH2 2N DMF F N F N H H H H 02NBr 2 0 2 N B F NH 2 F, NH 2 [004921 2-Bromo-5-fluoro-4-nitroaniline [004931 To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br 2 (2.15 mL, 42.2 mmol) at 0 OC. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10%) to pH ~ 8.0-9.0 under cooling and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (80 mL x 2) and brine (100 mL), dried over Na 2

SO

4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). 'H-NMR (400 MHz, DMSO-d6) 5 8.26 (d, J= 8.0, Hz, 'H), 7.07 (brs, 2H), 6.62 (d, J= 9.6 Hz, IH).

144 0 2 N Br 0 2 N F NH 2 F NH 2 [004941 2-(3,3-Dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline [004951 A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-dimethyl but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh 3

)

2 Cl 2 (3.4 g, 4.86 mmol) and Et 3 N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70 *C for 4 h. The aqueous layer was separated and the organic layer was washed with water (80 mL x 2) and brine (100 mL), dried over Na 2

SO

4 and concentrated under reduced pressure to dryness. The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4 nitroaniline (4.2 g, 46%). 'H-NMR (400 MHz, DMSO-d 6 ) 8 7.84 (d, J= 8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J= 14.4 Hz, 1H), 1.29 (s, 9H). 02N c O N F NH, F N)' H [004961 N-(2-(3,3-Dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide [004971 To a solution of 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 17.8 mmol) in dichloromethane (50 mL) and Et 3 N (10.3 mL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmol) at 0 oC. The mixture was stirred at room temperature for 1 h and then poured into water. The aqueous phase was separated and the organic layer was washed with water (50 mL x 2) and brine (100 mL), dried over Na 2

SO

4 and concentrated under reduced pressure to dryness. The residue was washed with ether to give N-(2-(3,3 dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was used in the next step without further purification. 0 2 N TBAF 0 2 N 0 F N H F N)' H [004981 2-tert-Butyl-6-fluoro-5-nitro-1H-indole [004991 A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.0 g, 9.8 mmol) and TBAF (4.5 g, 17.2 mmol) in DMF (25 mL) was heated at 100 oc overnight. The mixture was poured into water and then extracted with EtOAc (80 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na 2

SO

4 and concentrated under reduced pressure to dryness. The residue was purified by 145 column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give compound 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 65%). 'H-NMR (400 MHz, CDCl 3 ) 5 8.30 (d, J= 7.2 Hz, IH), 7.12 (d, J= 11.6 Hz, 1H), 6.35 (d, J= 1.2 Hz, 1H), 1.40 (s, 9H). OZN

H

2 N F N H- H [005001 2-tert-Butyl-6-fluoro-1H-indol-5-amine 1005011 A suspension of 2-tert-butyl-6-f1uoro-5-nitro-1H-indole (1.5 g, 6.36 mmol) and Ni (0.5 g) in MeOH (20 mL) was stirred under H 2 atmosphere (1 atm) at the room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized in ether to give 2-tert-butyl-6-fluoro-1 H-indol-5 amine (520 mg, 38%). 'H-NMR (300 MHz, DMSO-d 6 ) 5 10.46 (brs, IH), 6.90 (d, J= 8.7 Hz, I H), 6.75 (d, J = 9.0 Hz, IH), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H); MS (ESI) m/e 206.6. 0 2 N BuOK 0 2 N H [00502] 6-tert-Butoxy-2-tert-butyl-5-nitro-lH-indole [005031 A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (500 mg, 1.63 mmol) and t-BuOK (0.37 g, 3.26 mmol) in DMF (10 mL) was heated at 70 *C for 2 h. The mixture was poured into water and then extracted with EtOAc (50 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO4 and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl- 5 -nitro-1 H-indole (100 mg, 21%). 'H-NMR (300 MHz, DMSO-d 6 ) 5 11.35 (brs, 1H), 7.99 (s, IH), 7.08 (s, 1H), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H). Raney Ni HN 1005041 6-tert-Butoxy-2-tert-butyl-1H-indol-5-amine [00505] A suspension of 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 0.36 mmol) and Raney Ni (0.5 g) in MeOH (15 mL) was stirred under H 2 atmosphere (1 atm) at the room temperature for 2.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized in ether to give 6-tert-butoxy-2 tert-butyl-1H-indol-5-amine (30 mg, 32%). 'H-NMR (300 MHz, MeOD) 6.98 (s, 1H), 6.90 (s, .H), 5.94 (d, J= 0.6 Hz, IH), 1.42 (s, 9H), 1.36 (s, 9H); MS (ESI) m/e 205.0.

146 [005061 Example 31: 1-tert-Butyl-1H-indol-5-amine

O

2 N H 2 N 0 2 N 0Nr A 2 N B3 r P 2 N F..K

B

2 IcHN Pd(PPh 3 )ZC1 2 Cul, DMF 0 2 N Raney Nil H 2 NI \ Do. ~N 0 0 N 0 2 N

H

2 N O2N 0- NH F [005071 N-tert-Butyl-4-nitroaniline [005081 A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75 *C overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (7 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2

SO

4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 'H NMR (CDC 3 , 400 MHz) 5 8.03 8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, IH), 1.42 (s, 9H). 0 2 N 0 2 N Br Br 2 / AcOH NH 3 NH [005091 (2-Bromo-4-nitro-phenyl)-tert-butyl-amine [005101 To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH (5 mL) was added Br 2 (0.86 g, 54 mmol) dropwise at 15 OC. After addition, the mixture was stirred at 30 *C for 30 min and then filtered. The filter cake was basified to pH 8-9 with aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2

SO

4 and concentrated under vacuum to give (2-bromo-4-nitro-phenyl)-tert-butyl-amie (0.6 g, 43%). 'H-NMR (CDCl 3 , 400 MHz) S 8.37 (dd, J= 2.4 Hz, 1H), 8.07 (dd, J= 2.4, 9.2 Hz, 1H), 6.86 (d, J= 9.2 Hz, IH), 5.19 (brs, 1H), 1.48 (s, 9H).

147 2N BrH _Si- 0 2 N NH W ) NH Pd(PPh) 2

C

2 [00511] tert-Butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine [005121 To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2 mmol) in Et 3 N (10 mL) was added Pd(PPh 3

)

2 Cl 2 (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N 2 protection. The reaction mixture was heated at 70 oC overnight. The solvent was removed under vacuum and the residue was washed with EtOAc (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2

SO

4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to afford tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (100 mg, 16%). 1 H-NMR (CDC1 3 , 400 MHz) 5 8.20 (d, J= 2.4, Hz, 1H), 8.04 (dd, J= 2.4, 9.2 Hz, IH), 6.79 (d, J 9.6 Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H). 0 2 N 0 2 NIC Cul, DMF I:) , I NH -p [00513] 1-tert-Butyl-5-nitro-1H-indole [005141 To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 mmol) in DMF (2 mL), was added CuI (13 mg, 0.07 mmol) under N 2 protection. The reaction mixture was stirred at 100 OC overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na 2

SO

4 and concentrated under vacuum to obtain 1-tert-butyl-5-nitro-IH-indole (7 mg, 93%). 'H-NMR (CDCl 3 , 300 MHz) 5 8.57 (d, J= 2.1 Hz, 1H), 8.06 (dd, J= 2.4, 9.3 Hz, 1H), 7.65 (d, J= 9.3 Hz, 1H), 7.43 (d, J= 3.3 Hz, 1H), 6.63 (d, J= 3.3 Hz, 1H), 1.76 (s, 9H). 2N Raney Ni/H 2 H2N [00515] 1-tert-Butyl-1H-indol-5-amine [005161 To a solution of 1-tert-butyl-S-nitro-1H-indole (6.5 g, 0.030 mol) in MeOH (100 mL) was added Raney Nickel (0.65 g, 10%) under N 2 protection. The mixture was stirred 148 under hydrogen atmosphere (1 atm) at 30 0 C for 1 h. The catalyst was filtered off and the filtrate was concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc 1:2) to give 1-tert-butyl-1H-indol-5-amine (2.5 g, 45%). 'H-NMR (CDC1 3 , 400 MHz) 8 7.44 (d, J= 8.8 Hz, 1H), 7.19 (dd, J= 3.2 Hz, 1H), 6.96 (d, J= 2.0 Hz, 1H), 6.66 (d, J= 2.0, 8.8 Hz, IH), 6.26 (d, J= 3.2 Hz, IH), 1.67 (s, 9H). MS (ESI) m/e (M+H+) 189.2. [005171 Example 32: 2-tert-Butyl-1-methyl-1H-indol-5-amine

O

2 N Br2/HOAc 0 2 N Br H2N NH NHN .. NH TBAF 0 2 N Ni/H 2

H

2 N 0 2 N 0 0 2 N Br Br 2 /HOAc NH NH [005181 (2-Bromo-4-nitro-phenyl)-methyl-amline [005191 To a solution of methyl-(4-nitro-phenyl)-amine (15.2 g, 0.1 mol) in AcOH (150 mL) and CHC1 3 (50 mL) was added Br 2 (16.0 g, 0.1 mol) dropwise at 5 *C. The mixture was stirred at 10 *C for lh and then basified with sat. aq. NaHCO 3 . The resulting mixture was extracted with EtOAc (100 mL x 3), and the combined organics were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-amine (2 bromo-4-nitro-phenyl)-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 'H NMR (300 MHz, CDC1 3 ) 8 8.37 (d, J = 2.4 Hz, 1 H), 8.13 (dd, J = 2.4, 9.0 Hz, 1 H), 6.58 (d, J = 9.0 Hz, 1 H), 5.17 (brs, I H), 3.01 (d, J = 5.4 Hz, 3 H). 0 2 N Br 02N NH [005201 [2-(3,3-Dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine [005211 To a solution of (2-bromo-4-nitro-phenyl)-methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) were added Et 3 N (19.7 g, 195 mmol), Pd(PPh 3

)

2 Cl 2 (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g, 195 mmol) successively under N 2 protection. The mixture was heated at 70 *C for 3 hours and then 149 cooled down to room temperature. The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous Na 2 SO4 and evaporated under vacuum to give [2-(3,3-dimethyl-but- I -yny)-4-nitro-phenyl)-methyl-amine (20.1 g, 94%), which was used in the next step without further purification. 'H NMR (400 MHz, CDCl 3 ) 8 8.15 (d, J = 2.4 Hz, I H), 8.08 (dd, J = 2.8, 9.2 Hz, IH), 6.50 (d, J = 9.2 Hz, IH), 5.30 (brs, 1H), 3.00 (s, 3H), 1.35 (s, 9H).

O

2 N -~ TBAF o 2 N NH 1005221 2-tert-Butyl-1-methyl-5-nitro-1H-indole 1005231 A solution of [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl1]-methyl-amine (5.0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 mL) was heated at reflux overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over Na 2

SO

4 and evaporated under vacuum to give 2-tert-butyl-1-methyl-5-nitro-1H-indole (5.0 g, 99%), which was used in the next step without further purification. 'H NMR (CDCl 3 , 400 MHz) 8 8.47 (d, J = 2.4 Hz, IH), 8.07 (dd, J = 2.4, 9.2 Hz, IH), 7.26-7.28 (in, IH), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H). 0 2 N Raney Ni/H 2

H

2 N X N -~N [005241 2-tert-Butyl-1-methyl-1H-indol-5-amine 1005251 To a solution of 2-tert-buty1-1-methyl-5-nitro-H-indole (3.00 g, 13.7 mmol) in MeOH (30 mL) was added Raney Ni (0.3 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The mixture was filtered through a Celite pad and the filtrate was evaporated under vacuum. The crude residue was purified by column chromatography on silica gel (P.E/EtOAc 20:1) to give 2-tert-butyl 1-methyl-1H-indol-5-amfine (1.7 g, 66%). 'H NMR (300 MHz, CDCl 3 ) S 7.09 (d, J =8.4 Hz, IH), 6.89-6.9 (in, IH), 6.66 (dd, J = 2.4, 8.7 Hz, 1H), 6.14 (d, J = 0.6 Hz, I H), 3.83 (s, 3H), 3.40 (brs, 2H), 1.45 (s, 9H); MS (ESI) m/e (M+H*) 203.1. [005261 Example 33: 2-Cyclopropyl-1H-indol-5-amiine 150 02N Br2, HOAc O2N Br -- Br 02N butyryl chloride

NH

2 r.t. NH 2 Cul, Et 3 N NH 2 Pd(PPh 3 )C1 2 0 2 N NHz TBAF 0 2 N Raney Ni H 2 N N H H H 0 2 N ,. Br 2 , HOAc 0 2 N Br

NH

2 r.t.

NH

2 [005271 2-Bromo-4-nitroaniline [005281 To a solution of 4-nitro-aniline (25 g, 0.18 mol) in HOAc (150 mL) was added liquid Br 2 (30 g, 0.19 mol) dropwise at room temperature. The mixture was stirred for 2 hours. The solid was collected by filtration and poured into water (100 mL), which was basified with sat. aq. NaHCO 3 to pH 7 and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to give 2-bromo-4-nitroaniline (30 g, 80%), which was directly used in the next step. 02N Br -- N 02N

NH

2 Cul. Et 3 N NH 2 Pd(PPh 3 )Cl 2 [00529] 2-(Cyclopropylethynyl)-4-nitroaniline [005301 To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-cyclopropane (1 g, 15 mmol) and Cul (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh 3

)

2 Cl 2 (210 mg, 0.3 mmol) under N 2 . The mixture was heated at 70 'C and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/l) to give 2 (cyclopropylethynyl)-4-nitroaniline (470 mg, 23%). 'H NMR (300 MHz, CDCl 3 ) 5 8.14 (d, J= 2.7 Hz, 1H), 7.97 (dd, J= 2.7, 9.0 Hz, 1H), 6.63 (d, J= 9.0 Hz, lH), 4.81 (brs, 2H), 1.55 1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).

O

2 N N butyryl chloride 0 2 N _ I- 0

NH

2 N

H

151 [005311 N-(2-(Cyclopropylethynyl)phenyl)-4-nitrobutyramide [005321 To a solution of 2-(cyclopropylethynyl)-4-nitroaniline (3.2 g, 15.8 mmol) and pyridine (2.47 g, 31.7 mmol) in CH 2 C1 2 (60 mL) was added butyryl chloride (2.54 g, 23.8 mmol) at 0 'C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice-water. The organic layer was separated. The aqueous phase was extracted with CH 2 Cl 2 (30 m L x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give N-(2-(cyclopropylethynyl)phenyl)-4-nitrobutyramide (3.3 g, 76%). IH NMR (400 MHz, CDCl 3 ) 5 8.61 (d, J= 9.2 Hz, 1H), 8.22 (d, J= 2.8 Hz, IH), 8.18 (brs, 1H), 8.13 (dd, J = 2.4, 9.2 Hz, 1H), 2.46 (t, J= 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 1.59-1.53 (m, 1H), 1.06 (t, J= 7.2 Hz, 3H), 1.03-1.01 (m, 2H), 0.91-0.87 (m, 2H). 0 2 N NH TBAF 0 2 N 0 1W I N H H [005331 2-Cyclopropyl-5-nitro-1H-indole [005341 A mixture of N-(2-(cyclopropylethynyl)phenyl)-4-nitrobutyramide (3.3 g, 0.01 mol) and TBAF (9.5 g, 0.04 mol) in THF (100 mL) was heated at reflux for 24 hours. The mixture was cooled to the room temperature and poured into ice water. The mixture was extracted with CH 2 C1 2 (50 m L x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 2 cyclopropyl-5-nitro-1H-indole (1.3 g, 64%). 'H NMR (400 MHz, CDCl 3 ) 5 8.44 (d, J= 2.0 Hz, 1H), 8.40 (brs, 1H), 8.03 (dd, J= 2.0, 8.8 Hz, IH), 7.30 (d, J= 8.8 Hz, lH), 6.29 (d, J= 0.8 Hz, 1 H), 2.02-1.96 (m, IH) 1.07-1.02 (m, 2H), 0.85-0.81(m, 2H). 02N Raney NI H 2 N \ 0 2 N N -~N N H [00535] 2-Cyclopropyl-1H-indol-5-amine [005361 To a solution of 2-cyclopropyl-5-nitro- IH-indole (1.3 g, 6.4 mmol) in MeOH (30 mL) was added Raney Nickel (0.3 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered through a Celite pad and the filtrate was evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 152 5/1) to give 2-cyclopropyl-1H-indol-5-amine (510 mg, 56%). 'H NMR (400 MHz, CDC1 3 ) 5 5.89 (d,J=8.4Hz, IH),6.50(d,J= 1.6Hz, IH),6.33 (dd,J=2.0, 8.4Hz, 1H),5.76(s, IH), 4.33 (brs, 2H), 1.91-1.87 (m, IH), 0.90-0.85(m, 2H), 0.70-0.66 (m, 2H); MS (ESI) m/e (M+H*) 173.2. [005371 Example 34: 3-tert-Butyl-1H-indol-5-amine O2N Br 0N Raney Ni/H 2

H

2 N D" '-N AICL 3

/CH

2

CI

2 N N H H H

O

2 N Br O 2 N _N AICL 3

/CH

2

CI

2 N H H [005381 3-tert-Butyl-5-nitro-1H-indole [00539] To a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and AiC1 3 (24 g, 0.18 mol) in

CH

2

CI

2 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) dropwise at 0 *C. After being stirred at 15 OC overnight, the reaction mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with

CH

2

CI

2 (30 mL x 3). The combined organic layers were washed with water, brine, dried over Na 2 SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 3-tert-butyl 5 -nitro-IH-indole (2.5 g, 31%). 'HNMR(CDC13,400 MHz) 8 8.49 (d,J= 1.6 Hz, IH), 8.31 (brs, 1H), 8.05 (dd, J= 2.0, 8.8 Hz, IH), 7.33 (d, J= 8.8 Hz, 1H), 6.42 (d, J= 1.6 Hz, 1H), 1.42 (s, 9H). 0 2 N Raney Ni/H 2

H

2 N H H [005401 3-tert-Butyl-1H-indol-5-amine [005411 To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in MeOH (30 mL) was added Raney Nickel (0.2 g) under N2 protection. The mixture was stirred under hydrogen atmosphere (I atm) at 15 *C for 1 hr. The catalyst was filtered off and the filtrate was concentrated under vacuum to dryness. The residue was purified by preparative HLPC to afford 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%). 'H NMR (CDC13, 400 MHz) 8 7.72 (brs, 1H), 7.11 (d, J= 8.4 Hz, IH), 6.86 (d, J= 2.0 Hz, IH), 6.59 (dd, J= 2.0, 8.4 Hz, 1H), 6.09 (d, J= 1.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/e (M+H*) 189.1.

153 [005421 Example 35: 2-Phenyl-1H-indol-5-amine Ph OBr2 22N Br 0 2 N Ch 0

NH

2 AcOH NH 2 Et 3 N NH 2 NH2 NH2 Ph 0 2 N * 0 TBF 0 2 N

H

2 N 0 BFPh Raney N! Ph H HH 0 2 N Br 2 /HOAC 0 2 N Br

NH

2

NH

2 [00543] 2-Bromo-4-nitroaniline [005441 To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was added liquid Br 2 (60 g, 0.38 mol) dropwise at 5 'C. The mixture was stirred for 30 min at that temperature. The insoluble solid was collected by filtration and poured into EtOAc (200 mL). The mixture was basified with saturated aqueous NaHCO 3 to pH 7. The organic layer was separated. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give 2-bromo-4 nitroaniline (56 g, 72%), which was directly used in the next step. Ph 0 2 N Br 0 2 N P N H 2 Et 3 NNH [005451 4-Nitro-2-(phenylethynyl)aniline [005461 To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-benzene (1.53 g, 0.015 mol) and CuT (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh 3

)

2 C1 2 (210 mg, 0.2 mmol) under N 2 . The mixture was heated at 70 *C and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 4-nitro-2 (phenylethynyl)aniline (340 mg, 14%). 'H NMR (300 MHz, CDC1 3 ) 5 8.37-8.29 (m, 1H), 8.08-8.00 (in, IH), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95 (brs, 2H). Ph 0Ph 0 2 N C 2 0

NH

2 H [005471 N-(2-(Phenylethynyl)phenyl)-4-nitrobutyramide 154 [005481 To a solution of 4-nitro-2-(phenylethynyl)aniline (17 g, 0.07 mmol) and pyridine (11.1 g, 0.14 mol) in CH 2

CI

2 (100 mL) was added butyryl chloride (11.5 g, 0.1 mol) at 0 *C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice-water. The organic layer was separated. The aqueous phase was extracted with CH 2

CI

2 (30 m L x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give N-(2 (phenylethyny)pheny)-4-nitrobutyramide (12 g, 55%). 'H NMR (400 MHz, CDC1 3 ) 5 8.69 (d, J=9.2 Hz, 1H), 8.39 (d, J=2.8 Hz, IH), 8.25-8.20 (in, 2H), 7.58-7.55 (in, 2H), 7.45-7.42 (in, 3H), 2.49 (t, J=7.2 Hz, 2H), 1.85-1.79 (m, 2H), 1.06 (t, J= 7.2 Hz, 3H). Ph 0 2 N ON TBAF 2Ph SN N H H [005491 5-Nitro-2-phenyl-1H-indole [005501 A mixture of N-(2-(phenylethynyl)phenyl)-4-nitrobutyramide (5.0 g, 0.020 mol) and TBAF (12.7 g, 0.050 mol) in THF (30 mL) was heated at reflux for 24 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with

CH

2

CI

2 (50 m L x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate- 10/1) to give 5-nitro-2-phenyl-1H-indole (3.3 g, 69%). 'H NMR (400 MHz, CDCl 3 ) 5 8.67 (s, 1H), 8.06 (dd, J= 2.0, 8.8 Hz, 1H), 7.75 (d, J =7.6 Hz, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.36 (t, J= 7.6 Hz, 1H). 6.95 (s, IH).

-

2 N Ph Raney Ni H 2 N Ph [:N ::NPh H H [005511 2-Phenyl-1H-indol-5-amine 1005521 To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in MeOH (30 mL) was added Raney Ni (510 mg) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered through a Celite pad and the filtrate was evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give 2-phenyl-1H-indol-5-amine (1.6 g, 77%). 'H NMR (400 MHz, CDCl 3 ) 8 7.76 (d, J=7.6 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.24 (t, J= 7.6 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 155 6.64 (d, J= 1.6 Hz, 1H), 6.60 (d, J=1.2 Hz, IH), 6.48 (dd, J= 2.0, 8.4 Hz, 1H), 4.48 (brs, 2H); MS (ESI) m/e (M+H+) 209.0. [005531 Example 36: 2-tert-Butyl-4-fluoro-1H-indol-5-anine F F 0 F F Br NaBH 4 /NiC1 2 r Br Pd(PPh 3

)

2

C

2 O

NO

2 MeOH NH 2 CuI/Et 3 N NH F F F t-BuOK

KNO

3 0 2 N NaBH4/NiC1 H2N DMF ~ NH 2 S0 4 ~ N MeOH H H H F F Br NaBH 4 /NiCI2 cBr

NO

2 MeOH / NH 2 [00554] 2-Bromo-3-fluoroaniline [005551 To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH 3 0H (50 mL) was added NiC 2 (2.2 g 10 mmol) and NaBH 4 (0.50 g 14 mmol) at 0 *C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic layers were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 'H NMR (400 MHz, CDCl 3 ) 5 7.07-7.02 (m, 1 H), 6.55-6.49(m, 1 H), 4.22 (br s, 2 H). F F

NH

2 NHk [005561 N-(2-Bromo-3-fluorophenyl)butyramfide [00557] To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH 2

CI

2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0*C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH 2 Cl 2 (50 mL x 3). The organic layers were dried anhydrous over Na 2

SO

4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step. F F Br 0 Pd(PPh 3

)

2 CIg 0 o CuI/Et 3 N N [00558] N-(2-(3,3-Dimethylbut-1-ynyl)-3-fluorophenyl)butyranide 156 [005591 To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et 3 N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), Cul (70 mg, 3.8 mmol), and Pd(PPh 3

)

2 Cl 2 (500 mg) successively at room temperature under N 2 . The mixture was heated at 80"C overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL x 3). The organic layers were washed with sat. NaCl, dried over anhydrous Na 2 SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut 1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 'H NMR (400 MHz, CDCl 3 ) 5 8.20 (d, J= 7.6, 1 H), 7.95 (s, I H), 7.21 (m, 1 H), 6.77 (t, J= 7.6 Hz, 1 H), 2.39 (t, J= 7.6 Hz, 2 H), 1.82-1.75 (m, 2 H), 1.40 (s, 9 H), 1.12 (t, J 7.2 Hz, 3 H). F 0 1-ROK - , DMF ( N NH" H [00560] 2-tert-Butyl-4-fluoro-1H-indole [00561] To a solution of N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (6.0 g, 20 mmol) in DMF (100 mL) was added t-BuOK(5.0 g, 50 mmol) at room temperature. The mixture was heated at 90 'C overnight before it was poured into water and extracted with EtOAc (100 mL x 3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na 2 SO4, and evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%). 'H NMR (400 MHz, CDCl 3 ) S 8.17 (br s, 1 H), 7.11 (d, J=7.2 Hz, 1 H), 7.05 6.99 (m, 1 H), 6.76-6.71 (m, 1 H), 6.34 (m, I H), 1.41 (s, 9 H). F F

KNO

3 0 2 N

H

2 S0 4 N H H [00562] 2-tert-Butyl-4-fluoro-5-nitro-1H-indole [00563] To a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in H 2

SO

4 (30 mL) was added KNO 3 (1.3 g, 10 mmol) at 0"C. The mixture was stirred for 0.5 h at -10 'C. The mixture was poured into water and extracted with EtOAc (100 mL x 3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na 2 SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1 H-indole (900 mg, 73%). 'H NMR (400 MHz, CDCl 3 ) 5 8.50 (br s, I H), 7.86 (dd, J= 7.6, 8.8 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 6.52 (dd, J = 0.4, 2.0 Hz, I H), 1.40 (s, 9 H).

157 F F 0 2 N N O2N NaBH 4 /NiCl2, H 2 N N ~MeOHN H H [00564] 2-tert-Butyl-4-fluoro-1H-indol-5-amine [005651 To a solution of 2-tert-butyl-4-fluoro-5-nitro-lH-indole (2.1 g, 9.0 mmol) in methanol (50 mL) was added NiC1 2 (4.2 g, 18 mmol) and NaBH 4 (1.0 g, 27 mmol) at 0*C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the . mixture was extracted with EtOAc (30 mL x 3). The organic layers were washed with sat. NaC1 and water, dried over anhydrous Na 2

SO

4 , evaporated under vacuum to give 2-tert-butyl 4-fluoro-1H-indol-5-amine (900 mg, 50%). 'H NMR (300 MHz, CDC 3 ) S 7.80 (brs, 1 H), 6.91 (d, J= 8.4 Hz, I H), 6.64 (dd, J= 0.9, 2.4 Hz, 1 H), 6.23 (s, 1 H), 1.38 (s, 9 H). [00566] Example 37: 2,3,4,9-Tetrahydro-H-carbazol-6-amine 0 2 N SnCl 2

H

2 N

I--A

H H [005671 2,3,4,9-Tetrahydro-IH-carbazol-6-amine [005681 6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol. Tin(II) chloride dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture and the resulting suspension was heated at 70 *C for 16 h. The crude reaction mixture was then diluted with 15 mL of a saturated aqueous solution of sodium bicarbonate and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-carbazol-6-amine (82 mg, 95%) which was used without further purification. [005691 Example 38: 2-tert-Butyl-7-fluoro-1H-indol-5-amine 0

O

2 N B 1r 2 /HOAC 0 2 N Br 2

NH

2 cul,Pd(PPha)2c, EtaN NH 2 Py,CH 2 C1 2 F F F 0 2 N F t-BuOK, DMF 2 N Raney-NI/H 2 N 0 N ' N NHF H F

F

158 0 2 N Br 2 /HOAC 2 N Br I? NH 2 F NH 2 F F 1005701 2-Bromo-6-fluoro-4-nitro-phenylam-line [005711 To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL) was added Br 2 (3.9 mL, 77 mmol) dropwise at 0 *C. The mixture was stirred at 20 *C for 3 h. The reaction mixture was basified with sat. aq. NaHCO 3 , and extracted with EtOAc (100 mL x 3). The combined organics were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 'H NMR (400 MHz, CDCl 3 ) S 8.22 (m, 1 H), 7.90 (dd, J= 2.4, 10.8 Hz, 1 H), 4.88 (brs, 2 H). 0 2 N Br 02N

NH

2 Cul,Pd(PPh) 2

C

2 , Et 3 N NH 2 F F [005721 2-(3,3-Dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine [005731 To a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol) in dry Et 3 N (100 mL) was added Cul (445 mg, 5% mol), Pd(PPh 3

)

2 Cl 2 (550 mg, 5% mol) and 3,3 dimethyl-but-1-yne (9.6 g, 120 mmol) under N 2 protection. The mixture was stirred at 80 'C for 10 h. The reaction mixture was filtered, poured into ice (100 g), and extracted with EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3,3-dimethyl but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 36%). 'H NMR (400 MHz, CDC 3 ) 8 8.02 (d, J= 1.2 Hz, 1 H), 7.84 (dd, J= 2.4, 10.8 Hz, 1 H), 4.85 (brs, 2 H), 1.36 (s, 9 H). 0 2 N 0 02N 0 2 N

NH

2 Py,CH 2

CI

2 N F F H [005741 N-[2-(3,3-Dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide [005751 To a solution of 2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH 2 C1 2 (30 mL) was added and butyryl chloride (1.8 g, 17 mmol) dropwise at 0 *C. After stirring for 5 h at 0 *C, the reaction mixture was poured into ice (50 g) and extracted with CH 2 C1 2 (30 mL x 3). The combined organic extracts were dried over anhydrous Na 2 SO4 and evaporated under vacuum to give N- 159 [2-(3,3-dimethyl- but-I -ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 62%), which was used in the next step without further purification. 'H NMR (300 MHz, DMSO) 8 8.10 (dd, J = 1.5, 2.7 Hz, 1 H), 7.95 (dd, J= 2.4, 9.6 Hz, 1 H), 7.22 (brs, I H), 2.45 (t, J= 7.5 Hz, 2 H), 1.82 (m, 2 H), 1.36 (s, 9 H), 1.06 (t, J= 7.5 Hz, 3 H). 0 2 N t-BuOK, DMF 0 2 N 0 -- A N N H H F F [005761 2-tert-Butyl-7-fluoro-5-nitro-1H-indole [005771 To a solution of N-[2-(3,3-dimethyl-but-1-ynyl)- 6-fluoro-4-nitro-phenyl] butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol) at room temperature. The mixture was heated at 120 *C for 2 g before being cooled down to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with CH 2

CI

2 (30 mL x 3). The combined organic extracts were dried over anhydrous Na 2 SO4 and evaporated under vacuum to give 2-tert-butyl-7-fluoro- 5-nitro-1H indole (2.0 g, 81%), which was used in the next step without further purification. 'H NMR (300 MHz, CDC 3 ) 6 9.95 (brs, I H), 8.30 (d, J= 2.1 Hz, I H), 7.74 (dd, J= 1.8, 11.1 Hz, 1 H), 6.43 (dd, J= 2.4, 3.3 Hz, I H), 1.43 (s, 9 H). 0 2 N Raney Ni/H 2

H

2 N H H F F [005781 2-tert-Butyl-7-fluoro-1H-indol-5-amine [005791 To a solution of 2-tert-butyl-7-fluoro- 5-nitro-lH-indole (2.0 g, 8.5 mmol) in MeOH (20 mL) was added Ni (0.3 g) under nitrogen atmosphere. The reaction mixture was stirred under hydrogen atmosphere (I atm) at room temperature overnight. The catalyst was filtered off through the celite pad and the filtrate was evaporated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 100:1) to give 2-tert-butyl-7-fluoro-1H-indol-5-amine (550 mg, 24%). 'H NMR (300 MHz, CDC1 3 ) 8 7.87 (brs, I H), 6.64 (d, J= 1.5 Hz, 1 H), 6.37 (dd, J= 1.8, 12.3 Hz, 1 H), 6.11 (dd, J= 2.4, 3.6 Hz, I H), 1.39 (s, 9 H). MS (ESI) m/z (M+H*) 207. [005801 Example 39: 5-Amino-2-tert-butyl-1H-indole-7-carbonitrile 0 2 N Br 2, O2N BA N NiC /NaB H2N NTBAF CNNC 2 NaBH Cuf,Pd(PPh),C 2 , I . N -~ N NH, NH, H CNH CN CN C 160 ON Br 0 2 N NH2 CuIPd(PPhs) 2 Cl2, Et 3 NH2 CN [005811 2-Amino-3-(3,3-dimethylbut-1-ynyl)- 5-nitrobenzonitrile [005821 To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et 3 N (60 mL) was added Cul (380 mg, 5% mol) and Pd(PPh 3

)

2

C

2 (470 mg, 5% mol) at room temperature. 3,3-dimethyl-but-1-yne (2.1 g, 25 mmol) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at 80 *C for 10 h. The reaction mixture was filtered and the filtrate was poured into ice (60 g), extracted with ethyl acetate. The phases were separated and the organic phase was dried over Na 2 SO4. The solvent was removed under vacuum to obtain the crude product, which was purified by column chromatography (2-10% EtOAc in petroleum ether) to obtain 2-amino-3-( 3

,

3 dimethylbut-1-ynyl)- 5-nitrobenzonitrile (1.7 g, 71%). 'H NMR (300 MHz, CDCl 3 ) S 8.28 (d, J= 2.7 Hz, 1 H), 8.27 (d, J= 2.7 Hz, 1 H), 5.56 (br s, 2 H), 1.37 (s, 9 H). 0 2 N TBAF 0 2 N

NH

2 H CN CN [005831 2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile 1005841 To a solution of 2-amino-3-(3,3-dimethylbut-1-ynyl)- 5-nitrobenzonitrile (1.7 g, 7.0 mmol) in THF (35 mL) was added TBAF (9.5 g, 28 mmol) at room temperature. The mixture was heated at reflux overnight. The reaction mixture was cooled and the THF was removed under reduced pressure. Water (50ml) was added to the residue and the mixture was extracted with EtOAc. The organics were dried over Na 2

SO

4 and the solvent was evaporated under vacuum to obtain 0.87 g of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile which was used directly in the next step without purification. 0 2 N N2B H 2 N I NiC1 2 /NaBH 4 CN CN [005851 5-Amino-2-tert-butyl-1H-indol-7-carbonitrile [005861 To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in MeOH (10 mL) was added NiC1 2 .6H 2 0 (1.8 g, 7.2 mmol) at -5 'C. The reaction mixture was stirred for 30 min, then NaBH 4 (0.48g, 14.32 mmol) was added to the reaction mixture at 0 'C. After 5 min, the reaction mixture was quenched with water, filtered 161 and extracted with EtOAc. The combined organic layers were dried over Na 2 SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (5-20% EtOAc in petroleum ether) to obtain 5-amino-2-tert-buty-1 H-indol 7-carbonitrile (470 mg, 32% over two steps). 'H NMR (400 MHz, CDC1 3 ) 5 8.25 (s, 1 H), 7.06 (d, J=2.4 Hz, 1 H), 6.84 (d, J= 2.4 Hz, I H), 6.14 (d, J= 2.4 Hz, 1 H), 3.57 (br s, 2 H), 1.38 (s, 9 H). MS (ESI) m/z: 214 (M+H+). [005871 Example 40: Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate 0 2 N KOH, EtOH 2N MeOH _? H SOC 2 CNH OH

H

2 N 0 2 N Raney-NiH 2 N N H H 0 0 0 2 N , KOH, EtOH 2 N-( N N CH H CN 01OH [005881 2-tert-Butyl-5-nitro-1H-indole-7-carboxylic acid [005891 2-tert-Butyl-5-nitro-IH-indole-7-carbonitrile (4.6 g, 19 mmol) was added to a solution of KOH in EtOH (10%, 100 mL) and the mixture was heated at reflux overnight. The solution was evaporated to remove alcohol, a small amount of water was added, and then the mixture was acidified with dilute hydrochloric acid. Upon standing in the refrigerator, an orange-yellow solid precipitated, which was purified by chromatography on silica gel (15% EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 77%). 'H NMR (CDCl 3 , 300 MHz) 8 10.79 (brs, 1 H), 8.66 (s, 1 H), 8.45(s, 1 H), 6.57 (s, 1 H), 1.39 (s, 9 H). 0 2 N MeOH 0 2 N H SOCI 2

H

0 OH 0 oY [00590] Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate [005911 SOCl 2 (3.6 g, 30mol) was added dropwise to a solution of 2-tert-butyl-5-nitro-1H indole-7-carboxylic acid (4.0 g, 15 mol) and methanol (30 mL) at 0 C. The mixture was stirred at 80 'C for 12 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%). 'H NMR (CDCl 3 , 300 162 MHz) 6 9.99 (brs, 1 H), 8.70 (d, J= 2.1 Hz, 1 H), 8.65 (d, J= 2.1 Hz, 1 H), 6.50 (d, J 2.4 Hz, 1 H), 4.04 (s, 3H), 1.44(s, 9H). 0 2 N Raney-Ni/H 2

H

2 N H o~ [005921 Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate [005931 A solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney Nickel (200 mg) in CH 3 0H (50 mL) was stirred for 5 h at the room temperature under

H

2 atmosphere. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%) 'H NMR (CDC 3 , 400 MHz) 69.34 (brs, 1H), 7.24 (d,J= 1.6 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J= 1.6 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H). [005941 Example 41: (5-Amino-2-tert-butyl-1H-indol-7-yl)methanol O2N DIBAL-H 0 2 N Raney NVH 2 H2N N H H H 0 0- OH OH 0 2 N N, O2N DIBAL-H 0 2 N H H O 0- OH [005951 (2-tert-Butyl-5-nitro-1iH-indol-7-yl) methanol 1005961 To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30ml) was added DIBAL-H (1.0 M, 20 mL, 20 mmol) at 78 *C. The mixture was stirred for 1 h before water (10 mL) was added slowly. The resulting mixture was extracted with EtOAc (120 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum to give (2-tert-butyl-5-nitro-1 H-indol 7-yl)methanol (4.0 g, 73%), which was used in the next step directly.

O

2 N Raney Ni/H 2

H

2 N N~ N H H OH OH [005971 (5-Amino-2-tert-butyl-1 H-indol-7-yl)methanol [005981 A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 16 mmol) and Raney Nickel (400 mg) in CH 3 0H (100 mL) was stirred for 5 g at room temperature under

H

2 . The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give (5-amino-2-tert-butyl-1H-indol-7-yl)methanol (3.4g, 80%). 'H NMR 163 (CDC1 3 , 400 MHz) S 8.53 (br s, 1H), 6.80 (d, J= 2.0 Hz, 1 H), 6.38 (d, J= 1.6 Hz, 1 H), 4.89 (s, 2 H), 1.37 (s, 9H). [005991 Example 42: 2-(1-Methylcyclopropyl)-1H-indol-5-amine n-BuLi TBAF '7 Me 2

SO

4 '-?

O

2 N Br 2 /HOAC ON Br O 2 N

NH

2

NH

2 Pd(PPh) 2 C1 2

NH

2 butyryl chloride O2N 0 2 N Raney Nirt- H 2 N H H n-BuLi Me 2

SO

4 [00600] Trimethyl-(1-methyl-cyclopropylethynyl)-silane [006011 To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mnol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0 *C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at -10 *C. The resulting solution was stirred at 10 *C and then at 20 *C for 30 min each. The reaction was quenched by adding a mixture of sat. aq.

NH

4 Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3 x 50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO 3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO 4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1 -methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 'H NMR (400 MHz, CDC1 3 ) 8 1.25 (s, 3 H), 0.92-0.86 (m, 2 H), 0.58 0.56 (m, 2 H), 0.15 (s, 9 H). TBAF [006021 1-Ethynyl-1-methyl-cyclopropane [006031 To a solution of trimethyl-(1-methyl-cyclopropylethynyl)-silane (20 g, 0.13 mol) in THF (250 mL) was added TBAF (69 g, 0.26 mol). The mixture was stirred overnight at 20 *C. The mixture was poured into water and the organic layer was separated. The aqueous 164 phase was extracted with THF (50 mL). The combined organic layers were dried over anhydrous Na 2

SO

4 and distilled under atmospheric pressure to obtain 1-ethynyl--methyl cyclopropane (7.0 g, contained 1/2 THF, 34%). 'H NMR (400 MHz, CDCI 3 ) 8 1.82 (s, I H), 1.26 (s, 3 H), 0.90-0.88 (m, 2 H), 0.57-0.55 (m, 2 H). 0 2 N Br 2 iHOAC 0 2 N Br

NH

2

NH

2 [006041 2-Bromo-4-nitroaniline [006051 To a solution of 4-nitro-phenylamine (50 g, 0.36 mol) in AcOH (500 mL) was added Br 2 (60 g, 0.38 mol) dropwise at 5 *C. The mixture was stirred for 30 min at that temperature. The insoluble solid was collected by filtration and basified with saturated aqueous NaHCO 3 to pH 7. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to obtain compound 2-bromo-4-nitroaniline (56 g, 72%), which was directly used in the next step. 0 2 N Br

NH

2 Pd(PPh 3

)

2 Cl 2 NH 2 [006061 2-((1-Methylcyclopropyl)ethynyl)-4-nitroaniline [006071 To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1 ethynyl-1I-methyl-cyclopropane (630 mg;8.0 mmol) in triethylamine (20 mL) was added Cu (76 mg, 0.40 mmol) and Pd(PPh 3

)

2 Cl 2 (140 mg, 0.20 mmol) under N 2 . The mixture was heated at 70 *C and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 2-((1 methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). 'H NMR (300 MHz, CDC1 3 ) 5 8.15-8.14 (m, 1 H), 7.98-7.95 (m, 1 H), 6.63 (d, J= 6.9 Hz, 1 H), 4.80 (brs, 2 H), 1.38 (s, 3 H), 1.04-1.01 (m, 2 H), 0.76-0.73 (m, 2 H). O2N 0 2 N Nz

NH

2 butyryl chloride NH [006081 N-[2-(1-Methyl-cyclopropylethynyl)-4-nitro-phenyl]-butyramide [006091 To a solution of 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH 2 C1 2 (20 mL) was added butyryl chloride (140 165 mg, 1.3 mmol) at 0 *C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH 2 Cl 2 (30 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to obtain N-[2-(1-methyl cyclopropyl-ethynyl)-4-nitro-phenyl]-butyramide (230 mg, 82%), which was directly used in the next step. 0 2 N N 0 2 N H [00610] 2-(1-Methylcyclopropyl)-5-nitro-1H-indole [00611] A mixture of N-[2-(1-methyl-cyclopropylethynyl)-4-nitro-phenyl]-butyramide (1.3 g, 4.6 mmol) and TBAF (2.4 g, 9.2 mmol) in THF (20 mL) was heated at reflux for 24 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH 2

CI

2 (30 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford 2-(1 methylcyclopropyl)-5-nitro-1H-indole (0.70 g, 71%). 'H NMR (400 MHz, CDC1 3 ) 8 8.56 (brs, I H), 8.44 (d, J= 2.0 Hz, I H), 8.01 (dd, J= 2.4, 8.8 Hz, 1 H), 7.30 (d, J= 8.8 Hz, 1 H), 6.34 (d, J= 1.6 Hz, I H), 1.52 (s, 3 H), 1.03-0.97 (m, 2 H), 0.89-0.83 (m, 2 H).

O

2 N ~ Raney Ni/H 2

H

2 N H H [00612] 2-(1-Methyl-cyclopropyl)-1H-indol-5-ylamine [00613] To a solution of 2-(1-methylcyclopropyl)-5-nitro-1H-indole (0.70 g, 3.2 mmol) in EtOH (20 mL) was added Raney Nickel (100 mg) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5/1) to afford 2-(1-methyl-cyclopropyl)-IH -indol-5-ylamine (170 mg, 28%). H NMR (400 MHz, CDC1 3 ) 8 7.65 (brs, 1 H), 7.08 (d, J= 8.4 Hz, I H), 6.82 (s, I H), 6.57 (d, J= 8.4 Hz, 1 H), 6.14 (s, I H), 3.45 (brs, 2 H), 1.47 (s, 3 H), 0.82-0.78 (m, 2 H), 0.68-0.63 (m, 2 H). 100614] Example 43: Methyl 2-(5-amino-1H-indol-2-yl)-2-methylpropanoate 166 OMe 0M0 NH aq. NaOH "IMel, NaH

PCI

5

_________

AKAO eOMe CH 2

CI

2 C1 OH OH CH 2

N

2 0 0 DMVSO = 0 CI 0 < 0. 0 2 N

O

2 N 0 2 N 0 O00

NH

2 Pd(PPh 3

)

4 , Cul, Et 3 N

NH

2 butyryl chloride 0P h 0 Pd(CH 3

CN)

2

C

2 0 2 N O Raney Ni H 2 N -CO H H OMe Mel, NaH [006151 Methyl 2,2-dimethyl-3-oxobutanoate [006161 To a suspension of NaH (42 g, 1.1 mol, 60%) in THF (400 mL) was added dropwise a solution of methyl 3-oxobutanoate (116 g, 1.00 mol) in THF (100 mL) at 0 *C. The mixture was stirred for 0.5 h at that temperature before Mel (146 g, 1.1 mol) was added dropwise at 0 *C. The resultant mixture was warmed to room temperature and stirred for 1 h. NaH (42 g, 1.05 mol, 60%) was added in portions at 0 'C and the resulting mixture was continued to stir for 0.5 h at this temperature. Mel (146 g, 1.05 mol) was added dropwise at 0 *C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into ice water and the organic layer was separated. The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give methyl 2,2-dimethyl-3-oxobutanoate (85 g), which was used directly in the next step. OMe O 0

PCI

5 OMe

CH

2

CI

2 CI [006171 Methyl 3-chloro-2,2-dimethylbut-3-enoate [006181 To a suspention of PCI 5 (270 g, 1.3 mol) in CH 2 C1 2 (1000 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0 'C, following by addition of approximately 30 drops of dry DMF. The mixture was heated at reflux overnight. The reaction mixture was 167 cooled to ambient temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH 2

CI

2 (500 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO 3 and dried over anhydrous Na 2

SO

4 . The solvent was evaporated and the residue was distilled under reduced pressure to give methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%). 'H NMR (400 MHz, CDC 3 ) 5 5.33 (s, 1 H), 3.73 (s, 3 H), 1.44 (s, 6 H). OMe OH aq. NaOH o 0 C1 C1 [006191 3-Chloro-2,2-dimethylbut-3-enoic acid [006201 A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (33 g, 0.2 mol) and NaOH (9.6 g, 0.24 mol) in water (200 mL) was heated at reflux for 5 h. The mixture was cooled to ambient temperature and extracted with ether. The organic layer was discarded. The aqueous layer was acidified with cold 20% HC solution and extracted ether (200 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give 3 chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in the next step. 'H NMR (400 MHz, CDCl 3 ) 8 7.90 (brs, I H), 5.37 (dd, J= 2.4, 6.8 Hz, 2 H), 1.47 (s, 6 H). OH OH 4 H NaNH 2 O D MSO- a C [006211 2,2-Dimethyl-but-3-ynoic acid [00622] Liquid NH 3 was condensed in a 3-neck, 250 mL round bottom flask at -78 *C. Na (3.98 g, 0.173 mol) was added to the flask in portions. The mixture was stirred for 2 h at -78 'C before anhydrous DMSO (20 mL) was added dropwise at - 78 'C. The mixture was stirred at room temperature until no more NH 3 was given off. A solution of 3-chloro-2,2 dimethyl-but-3-enoic acid (6.5 g, 43 mmol) in DMSO (10 mL) was added dropwise at -40 *C. The mixture was warmed and stirred at 50 *C for 5 h, then stirred at room temperature overnight. The cloudy, olive green solution was poured into cold 20% HCI solution and then extracted three times with ether. The ether extracts were dried over anhydrous Na 2

SO

4 and concentrated to give crude 2,2-dimethyl-but-3-ynoic acid (2 g), which was used directly in the next step. 'H NMR (400 MHz, CDCl3) 8 2.30 (s, 1 H), 1.52 (s, 6 H). OH 0

CH

2

N

2 - 0 -- - 0 168 [006231 Methyl 2,2-dimethylbut-3-ynoate [006241 To a solution of diazomethane (-10 g) in ether (400 mL) was added dropwise 2,2 dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) at 0 *C. The mixture was warmed to room temperature and stirred overnight. The mixture was distilled under atmospheric pressure to give crude methyl 2,2-dimethylbut-3-ynoate (14 g), which was used directly in the next step. 'H NMR (400 MHz, CDC1 3 ) 6 3.76 (s, 3 H), 2.28 (s, I H), 1.50 (s, 6 H). 00 0 2 N Br 0 2 N O Pd(PPh 3

)

4 , Cul, Et 3 N [006251 Methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate [006261 To a deoxygenated solution of compound 2-bromo-4-nitroaniline (9.43 g, 43.7 mmol), methyl 2,2-dimethylbut-3-ynoate (5.00 g, 39.7 mmol), CuL (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) in toluene/H20 (100/30 mL) was added Pd(PPh 3

)

4 (6.17 g, 3.97 mmol) under N 2 . The mixture was heated at 70 *C and stirred for 24 h. After cooling, the solid was filtered off and washed with EtOAc (50 mL x 3). The organic layer was separated and the aqueous phase was washed with EtOAc (50 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to obtain methyl 4-(2-amino-5-nitrophenyl)- 2 ,2-dimethylbut-3-ynoate (900 mg, 9%). 'H NMR (400 MHz, CDC1 3 ) 8 8.17 (d, J= 2.8 Hz, I H), 8.01 (dd, J= 2.8, 9.2 Hz, I H), 6.65 (d, J= 9.2 Hz, 1 H), 5.10 (brs, 2 H), 3.80 (s, 3 H), 1.60 (s, 6 H). 0 2 N O

O

2 N 0 0 0

NH

2 butyryl chloride N 1006271 Methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate [006281 To a solution of methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH 2 C1 2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0 *C. The reaction mixture was warmed to room temperature and stirred for 3 h before the mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH 2

CI

2 (30 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO4 and evaporated under reduced pressure to obtain methyl 4-(2-butyramido-5-nitropheny)- 2

,

2 -dimethylbut-3 -ynoate (150 mg, 45%), 169 which was used directly in the next step. 'H NMR (400 MHz, CDCl 3 ) 8 8.79 (brs, 1 H), 8.71 (d, J= 9.2 Hz, 1 H), 8.24 (d, J= 2.8 Hz, I H), 8.17 (dd, J= 2.8, 9.2 Hz, 1 H), 3.82 (s, 3 H), 2.55 (t, J= 7.2 Hz, 2 H), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J= 6.8 Hz, 3 H). OzN O Pd(CH 3

CN)

2 C O 2 N O SN N H [006291 Methyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate [006301 To a deoxygenated solution of methyl 4-(2-butyramido-5-nitrophenyl)-2, 2 dimethylbut-3-ynoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) was added Pd(CH 3

CN)

2 Cl2 (0.42 g, 1.6= mmol) under N 2 . The mixture was heated at reflux for 24 h. After cooling the mixture to ambient temperature, the solid was filtered off and washed with EtOAc (50 mL x 3). The filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1) to give methyl 2-methyl-2-(5-nitro-1 H-indol-2-yl)propanoate (320 mg, 23%). 'H NMR (400 MHz, CDC1 3 ) 8 9.05 (brs, 1 H), 8.52 (d, J= 2.0 Hz, I H), 8.09 (dd, J= 2.0, 8.8 Hz, I H), 7.37 (d, J= 8.8 Hz, I H), 6.54 (d, J= 1.6 Hz, 1 H), 3.78 (d, J= 9.6 Hz, 3 H), 1.70 (s, 6 H). 0 2 N O Raney Ni H 2 N O 0 H N H H 1006311 Methyl 2-(5-amino-1H-indol-2-yl)-2-methylpropanoate [006321 A suspension of methyl 2-methyl-2-(5-nitro-IH-indol-2-yl)propanoate (60 mg, 0.23 mmol) and Raney Nickel (10 mg) in MeOH (5 mL) was hydrogenated under hydrogen (1 atm) at room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give methyl 2-(5-amino 1H-indol-2-yl)-2-methylpropanoate (20 mg, 38%). 'H NMR (400 MHz, CDCl 3 ) 8 8.37 (br s, I H), 7.13 (d, J= 8.4 Hz, I H), 6.87 (d, J= 2.0 Hz, I H), 6.63 (dd, J= 2.0, 8.4 Hz, 1 H), 6.20 (d, J= 1.2 Hz, I H), 3.72 (d, J = 7.6 Hz, 3 H), 3.43 (br s, I H), 1.65 (s, 6 H); MS (ESI) m/e (M+H*) 233.2. [00633] Example 44: 2-Isopropyl-1H-indol-5-amine O2N TBAF/OMF 2 N ' Raney Ni H 2 N N N H

H

170 0 2 N 0 TBAFIDMF 0 2 N NHH [006341 2-Isopropyl-5-nitro-1H-indole [006351 A mixture of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut- 3 -ynoate (0.50 g, 1.5 mmol) and TBAF (790 mg, 3.0 mmol) in DMF (20 mL) was heated at 70 *C for 24 h. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ether (30 mL x 3). The combined organic layers were dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give 2-isopropyl-5-nitro-1H-indole (100 mg, 33%). 'H NMR (400 MHz, CDC 3 ) 8 8.68 (s, 1 H), 8.25 (br s, 1 H), 8.21 (dd, J= 2.4, 10.0 Hz, 1 H), 7.32 (d, J= 8.8 Hz, I H), 6.41 (s, 1 H), 3.07-3.14 (m, 1 H), 1.39 (d, J= 6.8 Hz, 6 H). 02N Raney Ni H 2 N -~N -~N H H [006361 2-Isopropyl-1H-indol-5-amine [006371 A suspension of 2-isopropyl-5-nitro-1H-indole (100 mg, 0.49 mmol) and Raney Nickel (10 mg) in MeOH (10 mL) was hydrogenated under hydrogen (1 atm) at the room temperature overnight. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by column (petroleum ether/ethyl acetate = 5/1) to give 2-isopropyl-1H-indol-5-amine (35 mg, 41%). 'H NMR (400 MHz, CDCl 3 ) 5 7.69 (br s, I H), 7.10 (d, J= 8.4 Hz, 1 H), 6.86 (d, J= 2.4Hz, 1 H), 6.58 (dd, J= 2.4, 8.8 Hz, 1 H), 6.07 (t, J= 1.2 Hz, I H), 3.55 (br s, 2 H), 3.06-2.99 (m, 1 H), 1.33 (d, J = 7.2 Hz, 6 H); MS (ESI) m/e (M+H+) 175.4. [006381 Example 45: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2 yl)-1H-indol-5-yl)cyclopropanecarboxamide 171 O O PPh 3 Br OH PPh 3 HBr PPh 3 Br Cl OEt 0 0

H

2

NH

2 OEt KOt-Bu C MCO 2 Et KHMDS N ~ N C 2 Et Ml Bo CO 2 Et N O02Et BocBo TEA NaNq 3 'NN TFO conO. N CO 2 Et H~ C 2 Et H HH OH PPh 3 HBr PPh 3 Br ( [NH 2

~NH

2 [006391 Triphenyl(2-aminobenzyl)phosphonium bromide [006401 2-Aminobenzyl alcohol (60.0 g, 0.487 mol) was dissolved in acetonitrile (2.5 L) and brought to reflux. Triphenylphosphine hydrobromide (167 g, 0.487 mol) was added and the mixture was heated at reflux for 3 h. The reaction mixture was concentrated to approximately 500 mL and left at room temperature for 1 h. The precipitate was filtered and washed with cold acetonitrile followed by hexane. The solid was dried overnight at 40 C under vacuum to give triphenyl(2-aminoberizyl)phosphonium bromide (193 g, 88%). 0 0 PPh 3 Br f'"P PhBr CI ' OEt O t

'NH

2 C H IJEt [006411 Triphenyl((ethyl(2-carbamoyl)acetate)-2-benzyl)phosphonium bromide [006421 To a suspension of triphenyl(2-aminobenzyl)phosphonium bromide (190 g, 0.43 mol) in anhydrous dichloromethane (1 L) was added ethyl malonyl chloride (55 ml, 0.43 mol). The reaction was stirred for 3 h at room temperature. The mixture was evaporated to dryness before ethanol (400 mL) was added. The mixture was heated at reflux until a clear solution was obtained. The solution was left at room temperature for 3 h. The precipitate was filtered, washed with cold ethanol followed by hexane and dried. A second crop was obtained from the mother liquor in the same way. In order to remove residual ethanol both crops were combined and dissolved in dichloromethane (approximately 700 mL) under 172 heating and evaporated. The solid was dried overnight at 50 *C under vacuum to give triphenyl((ethy(2-carbamoyl)acetate)-2-benzyl)-phosphonium bromide (139 g, 58%). PPh 3 Br 0 0 KOt-Bu N OEt KC-NBCO 2 Et H H [006431 Ethyl 2-(1 H-indol-2-yl)acetate [006441 Triphenyl((ethy1(2-carbamoy1)acetate)-2-benzyl)phosphonium bromide (32.2 g, 57.3 mmol) was added to anhydrous toluene (150 mL) and the mixture was heated at reflux. Fresh potassium tert-butoxide (7.08 g, 63.1 mmol) was added in portions over 15 minutes. Reflux was continued for another 30 minutes. The mixture was filtered hot through a plug of celite and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane over 45 min) to give ethyl 2 (I H-indol-2-yl)acetate (9.12 g, 78%). N CO 2 Et

CO

2 Et H Boc [006451 tert-Butyl 2-((ethoxycarbonyl)methyl)-1H-indole-1-carboxylate 1006461 To a solution of ethyl 2-(IH-indol-2-yl)acetate (14.7 g, 72.2 mmol) in dichloromethane (150 mL) was added 4-dimethylaminopyridine (8.83 g, 72.2 mmol) and di tert-butyl carbonate (23.7 g, 108 mmol) in portions. After stirring for 2 h at room temperature, the mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and purified by silica gel chromatography (0 to 20% EtOAc in hexane) to give tert-butyl 2-((ethoxycarbonyl)methyl)-IH-indole-1-carboxylate (20.0 g, 91%). 0: \

KH-MDS

1

CO

2 Et Mel D:

CO

2 Et Boc Boc [006471 tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indote-1-carboxylate [006481 tert-Butyl 2-((ethoxycarbonyl)methyl)- 1 H-indole- I -carboxylate (16.7 g, 54.9 mmol) was added to anhydrous THF (100 mL) and cooled to -78 *C. A 0.5M solution of potassium hexamethyldisilazane (165 mL, 82 mmol) was added slowly such that the internal temperature stayed below -60 *C. Stirring was continued for 30 minutes at -78 "C. To this mixture, methyl iodide (5.64 mL, 91 mmol) was added. The mixture was stirred for 30 min at room temperature and then cooled to -78 *C. A 0.5M solution of 173 potassium hexamethyldisilazane (210 mL, 104 mmol) was added slowly and the mixture was stirred for another 30 minutes at -78 *C. More methyl iodide (8.6 mL, 137 mmol) was added and the mixture was stirred for 1.5 h at room temperature. The reaction was quenched with sat. aq. ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 20% ethylacetate in hexane) to give tert-butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-1-carboxylate (17.1 g, 94%). TFA { CO 2 Et C :N CO 2 Et Boc [00649] Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate 1006501 tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-IH-indole-1-carboxylate (22.9 g, 69.1 mmol) was dissolved in dichloromethane (200 mL) before TFA (70 mL) was added. The mixture was stirred for 5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with saturated sodium bicarbonate solution, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to give ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (12.5 g, 78%). NaNO 3 , O2N N CO 2 Et conc. H 2

SO

4 / N CO 2 Et H H [006511 Ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate [00652] Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (6 mL) and cooled to -10 *C (salt/ice-mixture). A solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 min. Stirring was continued for another 30 min at -10 "C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-methyl-2 (5-nitro-IH-indol-2-yl)propanoate (0.68 g, 57%). O2N LiAIH 4 0 2 N O I N CO 2 EtN OH H H [00653] 2-Methyl-2-(5-nitro-1H-indol-2-yl)propan-1-ol 174 [00654] To a cooled solution of LiA1H 4 (1.0 M in THF, 1.1 mL, 1.1 mmol) in THF (5 mL) at 0 0C was added a solution of ethyl 2-methyl-2-(5-nitro- 1 H-indol-2-yl)propanoate (0.20 g, 0.72 mmol) in THF (3.4 mL) dropwise. After addition, the mixture was allowed to warm up to room temperature and was stirred for 3 h. The mixture was cooled to 0 0C before water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at room temperature for 0.5 h and was filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 2-methyl-2-(5-nitro-1H indol-2-yl)propan-l -ol (0.098 g, 58%). 0 2 N OH SnC1 2 .2H 2 0 H 2 N N OH N OH H H [00655] 2-(5-Amino-1H-indol-2-yl)-2-methylpropan-1-ol [006561 To a solution of 2-methyl-2-(5-nitro-1H-indol-2-y1)propan-1-ol (0.094 g, 0.40 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.451 g, 2.0 mmol). The mixture was heated in the microwave at 120 "C for 1 h. The mixture was diluted with ethyl acetate and water before being quenched with saturated aqueous NaHCO 3 . The reaction mixture was filtered through a plug of celite using-ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na 2

SO

4 , filtered and evaporated under reduced pressure to give 2 (5-amino-iH-indol-2-yl)-2-methylpropan-1-ol (0.080 g, 98%). [00657] Example 46: 2-(Pyridin-2-yl)-1H-indol-5-amine 0 2 N I N

N

2 N N t-BuOK/DMF NH2 Pd(PPha)2Cl2/Cui

NH

2 0 2 N N- SnC 2

H

2 N

N

- N N H O2N N N N0 2 N

NH

2 Pd(PPh) 2

C

2 /CUI 0

NH

2 175 [00658) 4-Nitro-2-(pyridin-2-ylethynyl)aniline 1006591 To the solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF (60mL) and Et 3 N (60 mL) was added 2-ethynylpyridine (3.0 g, 45 mmol), Pd(PPh 3

)

2

C

2 (600 mg) and CuI (200 mg) under N 2 . The reaction mixture was stirred at 60 'C for 12 h. The mixture was diluted with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 60%). 'H NMR (300 MHz, CDC1 3 ) 8 8.60 (s, I H), 8.13 (d, J= 2.1 Hz, 1 H), 7.98 (d, J= 1.8, 6.9 Hz, 1 H), 7.87-7.80 (m, 2 H), 7.42-7.39 (m, 1 H), 7.05 (brs, 2 H), 6.80 (d, J= 6.9 Hz, 1 H). IN 0 2 N . 0 2 N N t-BuOK/DMF o2 H

NH

2 [00660] 5-Nitro-2-(pyridin-2-yl)-1H-indole [00661] To the solution of 4-nitro-2-(pyridin- 2-ylethynyl)aniline (1.5 g, 6.3 mmol) in DMF (50 mL) was added t-BuOK (1.5 g, 13 mmol). The reaction mixture was stirred at 90 *C for 2 h. The mixture was diluted with water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 5-nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 67%yield). 'H NMR (300 MHz, d-DMSO) 8 12.40 (s, 1H), 8.66 (d, J= 2.1 Hz, 1 H), 8.58 (d, J= 1.8 Hz, 1 H), 8.07-7.91 (m, 3 H), 7.59 (d, J= 6.6 Hz, 1 H), 7.42-7.37 (m, 2 H). 0 2 N SnC 2

H

2 N N HH [006621 2-(Pyridin-2-yl)-1H-indol-5-amine [006631 To a solution of 5-nitro-2-(pyridin-2-yl)-1H-indole (700 mg, 2.9 mmol) in EtOH (20 mL) was added SnC1 2 (2.6 g, 12 mmol). The mixture was heated at reflux for 10 h. Water was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 2-(pyridin-2-yl)-1H-indol-5-amine (120 mg, 20%). 'H NMR (400 MHz, CDC1 3 ) 8 9.33 (brs, 1 H), 8.55 (dd, J = 1.2, 3.6 Hz, 1 H), 7.76-7.67 (m, 2 176 H), 7.23 (d, J= 6.4 Hz, I H), 7.16-7.12 (in, I H), 6.94 (d, J= 2.0 Hz, I H), 6.84 (d, J= 2.4 Hz, I H), 6.71-6.69 (dd, J= 2.0, 8.4 Hz, I H). [00664] Example 47: 2-(Pyridin-2-y)-1H-indol-5-amine 0 0 02N I -OTBDMS 2 N(I 0 2 N HfX H -,_,OBMS,-,_OTBDMS H 0 0NO,N 0 2 N HN PdCI 2 /CH3CN N DIBAL-H Oz N H 2 /Raney:! i N OH OH OH OH OH 0 2 N I O OTBDMS 0 2 N I

NH

2 N- OTBDMS H [00665] [2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-amine [00666] To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added TFA (1.5 mL) at 0 *C. The reaction mixture was stirred at this temperature for 30 min before NaCNBH 3 (900 mg, 15 mmol) was added in portions. The mixture was stirred for 2 h and was then quenched with water. The resulting mixture was extracted with EtOAc (30 mL x 3), the combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum, and the residue was purified by chromatography on silica gel (5 % ethyl acetate/petroleum) to afford [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo- 4 -nitro phenyl)-amine (800 mg, 25 %). 'H NMR (300 MHz, CDC1 3 ) 5 8.57 (d, J= 2.7 Hz, 1 H), 8.12 (dd, J= 2.4 ,9.0 Hz, I H), 6.49 (d, J= 9.3 Hz, I H), 5.46 (br s, 1 H), 3.89 (t, J= 5.4 Hz, 2 H), 3.35 (q, J= 5.4 Hz, 2 H), 0.93 (s, 9 H), 0.10 (s, 6 H). 0 0 0 2 N I 02N 0-' ON N OTBDMS TBDMS H H [00667] 5-{2-[2-(tert-Buty1-dimethyl-silanyloxy)-ethylamino]-5-nitro-pheny1}-3,3 dimethyl-pent-4-ynoic acid ethyl ester [00668] To a solution of [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl) amine (800 mg, 1.9 mmol) in Et 3 N (20 mL) was added Pd(PPh) 2 Cl 2 (300 mg, 0.040 mmol), CuI (76 mg, 0.040 mmol) and 3,3-dimethyl-but-1-yne (880 mg, 5.7 mmol) successively 177 under N 2 protection. The reaction mixture was heated at 80 *C for 6 h and allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous Na 2 SO4 and evaporated under vacuum to give 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl}-3,3 dimethyl-pent-4- ynoic acid ethyl ester (700 mg, 82 %), which was used in the next step without further purification. 'H NMR (400 MHz, CDC1 3 ) S 8.09 (s, I H), 8.00 (d, J= 9.2 Hz, I H), 6.54 (d, J= 9.2 Hz, 1 H), 6.45 (brs, I H), 4.17-4.10 (m, 4 H), 3.82 (t, J= 5.6 Hz, 2 H), 3.43 (q, J= 5:6 Hz, 2 H), 2.49 (s, 2 H), 1.38 (s, 6 H), 1.28 (t, J= 7.2 Hz, 3 H), 0.84 (s, 9 H), 0.00 (s, 6 H). 0 O 0 2 N 0 2 N O N OTBDMS PdCl2/CH 3 CN N H ( OH [006691 3-[1-(2-Hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester [006701 A solution of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro phenyl}-3,3- dimethyl-pent-4- ynoic acid ethyl ester (600 mg, 1.34 mmol) and PdCI 2 (650 mg) in CH 3 CN (30 mL) was heated at reflux overnight. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous Na 2

SO

4 and evaporated under vacuum. The residue was dissolved in THF (20 mL) and TBAF (780 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 1 h, the solvent was removed under vaccum, and the residue was purified by chromatography on silica gel (10% ethyl acetate/petroleum) to afford 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3 methyl-butyric acid ethyl ester (270 mg, 60 %). 'H NMR (300 MHz, CDC1 3 ) 3 8.45 (d, J= 2.1 Hz, 1 H), 8.05 (dd, J= 2.1, 9.0 Hz, 1 H), 6.36 (d, J= 9.0 Hz, 1 H), 6.48 (s, I H), 4.46 (t, J 6.6 Hz, 2 H), 4.00-3.91 (m, 4 H), 2.76 (s, 2 H), 1.61 (s, 6 H), 0.99 (t, J= 7.2 Hz, 1 H), 0.85 (s, 9 H), 0.03 (s, 6 H). 0 0N0 2 N DIBAL-H O2 OH OH OH [006711 3-[1-(2-Hydroxy-ethyl)-5-nitro-1H-indol-2-yll-3-methyl-butan-1-ol 178 [006721 To a solution of 3-[1-(2-hydroxy-ethyl)-5 -nitro- 1 H-indol-2-y]-3 -methyl-butyric acid ethyl ester (700 mg, 2.1 mmol) in THF (25 mL) was added DIBAL-H (1.0 M, 4.2 mL, 4.2 mmol) at -78 "C. The mixture was stirred at room temperature for I h. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous Na 2 SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (15 % ethyl acetate/petroleum) to afford 3-[1 (2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan--ol (300 mg, 49%). 'H NMR (300 MHz, d-DMSO) 8 8.42 (d, J= 1.5 Hz, I H), 7.95 (dd, J= 1.2, 8.7 Hz, 1 H), 6.36 (d, J= 9.3 Hz, 1 H), 6.50 (s, 1 H), 5.25 (br s, 1 H), 4.46-4.42 (m, 4 H), 3.69-3.66 (m ,2 H), 3.24-3.21 (m, 2 H), 1.42 (s, 6 H). 0 2 N

H

2 N N H 2 /Raney-Ni/ OH OH OH OH [006731 3-[5-Amino-1-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-1-ol [006741 A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro- IH-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH 3 0H (30 mL) was stirred for 5 h at room temperature under a H 2 atmosphere. The catalyst was filtered through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by preparative TLC to afford 3-[5-amino-1-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-1-ol (70 mg, 26%). 'H NMR (300 MHz, CDC1 3 ) 8 7.07 (d, J= 8.7 Hz, 1 H), 6.83 (d, J= 2.1 Hz, 1 H), 6.62 (dd, J= 2.1, 8.4 Hz, 1 H), 6.15 (s, 1 H), 4.47 (t, J= 5.4 Hz, 2 H), 4.07 (t, J= 5.4 Hz, 2 H), 3.68 (t, J= 5.7 Hz, 2 H), 2.16 (t, J= 5.7 Hz, 2 H), 4.00-3.91 (m, 4 H), 2.76 (s, 2 H), 1.61 (s, 6 H), 1.42 (s, 6 H). [006751 Example 48: tert-Butyl 2-(5-amino-1H-indol-2-yl)piperidine-1-carboxylate 02N PtO2/H2 H2N H Boc20 H2N zozN PtO 2 2 /2 2 H H H 0 2 N N ~ N-. PtO 2 i/H 2

H

2 N Hr HN N~ N H H [006761 2-(Piperidin-2-yl)-1H-indol-5-amine 1006771 5-Nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 4.2 mmol) was added to HCI/MeOH (2 M, 50 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was 179 evaporated under vacuum. PtO 2 (200 mg) was added to a solution of the residue in MeOH (50 mL) and the reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 2 h. The catalyst was filtered through a celite pad and the solvent was evaporated under vacuum to afford 2-(piperidin-2-yl)-1H-indol-5-amine (1.0 g), which was directly used in the next step.

H

2 N Boc2O H 2 N 1) N Et 3 NN H H H [006781 tert-Butyl 2-(5-amino-1H-indol-2-yl)piperidine-1-carboxylate [006791 To a solution of 2-(piperidin-2-yl)-1H-indol-5-amine (1.0 g) in Et 3 N (25 mL) and THF (25mL) was added Boc 2 O (640 mg, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) followed by preparative HPLC to afford tert-butyl 2-(5-amino-1H-indol-2-yl)piperidine-1-carboxylate (15 mg, 1% over 2 steps). 'H NMR (400 MHz, CDC1 3 ) S 8.82 (s, 1 H), 7.58 (s, 1 H), 7.22 (d, J= 8.8 Hz, 1 H), 7.02 (d, J= 1.6, 8.0 Hz, 1 H), 6-42 (s,-1H), 6.25 (s, 1 H), 3.91-3.88 (m, 1 H), 3.12-3.10 (m, 1 H), 2.81-2.76 (m, 1 H), 2.06-1.97 (m, 4 H), 1.70-1.58 (m, 2H), 1.53 (s, 9 H). [006801 Example 49: 6-amino-1H-indole-2-carbonitrile NaNO2/HCI CO 2 Et IN CO 2 Et Sn 2

N

2 N NN 0 2 N NH 2 02 H PPA NaOH D1,SOCla _ 0 2 N N CO 2 Et O 2 N N CO 2 H 2, NH 3

.H

2 0 0 2 N N CONH 2 H HH (C F 3 O ) 2 0 I2C R a n e y N ! H 2 H NC 0 2 ]- N O N CN 10 H 2 N"C N'CN H H NaNO2/HCI Sn ON NNH 2 .HCI SnI 2 0 2 N< IN 0 2 N NH2 H [006811 (3-Nitrophenyl)hydrazine hydrochloride 180 [006821 3-Nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H20 (40 mL) and 37% HC1 (40 mL). A solution of NaNO 2 (14 g, 0.20 mol) in H 2 0 (60 mL) was added to the mixture at 0 "C, and then a solution of SnCl 2

.H

2 0 (140 g, 0.60 mol) in 37% HCl (100 mL) was added. After stirring at 0 *C for 0.5 h, the insoluble material was isolated by filtration and was washed with water to give (3-nitrophenyl)hydrazine hydrochloride (28 g, 73%). 0

CO

2 Et N CO 2 Et

NH

2 .HCI Vo 0 2 N 0 2 N N- H H 1006831 (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate [006841 (3-Nitrophenyl)hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h before the solvent was evaporated under reduced pressure to give (E)-ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate, which was used directly in the next step. N CO 2 Et PPA 0 2 N N C2Et 2 N N CO 2 Et H- H [006851 Ethyl 4-nitro-1H-indole-2-carboxylate and ethyl 6-nitro-1H-indole-2 carboxylate [006861 (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propano ate was dissolved in toluene (300 mL) and PPA (30 g) was added. The mixture was heated at reflux overnight and then was cooled to room temperature. The solvent was decanted and evaporated to obtain a crude mixture that was taken on to the next step without purification (15 g, 40%). NaOH LI IIA-1 0 2 N N CO 2 Et 0 2 N N CO 2 H H H [006871 4-Nitro-1H-indole-2-carboxylic acid and 6-nitro-1H-indole-2-carboxylic acid [006881 A mixture of ethyl 6-nitro-1H-indole-2-carboxylate (0.5 g) and 10 % NaOH (20 mL) was heated at reflux overnight and then was cooled to room temperature. The mixture was extracted with ether and the aqueous phase was acidified with HCl to pH 1-2. The insoluble solid was isolated by filtration to give a crude mixture that was taken on to the next step without purification (0.3 g, 68%). 1. SOC1 2 0 2 N N CO 2 H 2. NH 3

.H

2 0 0 2 N N CONH 2 H

H

181 [006891 4-Nitro-1H-indole-2-carboxamide and 6-nitro-1-indole-2-carboxamide [00690] A mixture of 6-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl 2 (50 mL, 64 mmol) in benzene (150 mL) was heated at reflux for 2 h. The benzene and excess SOC1 2 was removed under reduced pressure. The residue was dissolved in anhydrous CH 2

CI

2 (250 mL) and NH 3

.H

2 0 (22 g, 0.32 mol) was added dropwise at 0 'C. The mixture was stirred at room temperature for 1 h. The insoluble solid was isolated by filtration to obtain crude mixture (9.0 g, 68%), which was used directly in the next step.

(CF

3

CO)

2 0 O2N N CONH 2 0 2 N N CN 0NH H 1006911 4-Nitro-1H-indole-2-carbonitrile and 6-nitro-1H-indole-2-carbonitrile [006921 6-Nitro-1H-indole-2-carboxamide (5.0 g, 24 mmol) was dissolved in CH 2

CI

2 (200 mL). Et 3 N (24 g, 0.24 mol) and (CF 3

CO)

2 0 (51 g, 0.24 mol) were added dropwise to the mixture at room temperature. The mixture was continued to stir for 1 h and was then poured into water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated under reduced pressure to obtain crude product which was purified by column chromatography on silica gel to give a impure sample of 4-nitro-1 H-indole-2 carbonitrile (2.5 g, 55%). Raney NiIH 2 I 0 2 N N CN R

H

2 N N CN H H [006931 6-Amino-1H-indole-2-carbonitrile [00694] A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney Nickel (500 mg) in EtOH (50 mL) was stirred at room temperature under H 2 (1 atm) for 1 h. Raney Nickel was removed via filtration and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatograpy on silica get to give 6-amino 1H-indole-2-carbonitrile (1.0 g, 49 %). 'H NMR (DMSO-d 6 ) 8 12.75 (br s, 1 H), 7.82 (d, J= 8 Hz, 1 H), 7.57 (s, 1H), 7.42 (s, 1 H), 7.15 (d, J= 8 Hz, 1 H); MS (ESI) m/e (M+H ) 158.2. 1006951 Example 50: 6-Amino-1H-indole-3-carbonitrile

CISO

2 NCO CN H 2 /Pd-C CN 0 2 N N OZN N H 2 N H H H CN

CISO

2 NCO O2N NH 0 2 N N H H 182 1006961 6-Nitro-1H-indole-3-carbonitrile 1006971 To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 mL) and CH 3 CN (240 mL) was added dropwise a solution of ClSO 2 NCO (5.0 mL) in CH 3 CN (39 mL) at 0 *C. After addition, the reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was then poured into ice-water and basified with sat. NaHCO 3 solution to pH 7-8. The mixture was extracted with ethyl acetate. The organics were washed with brine, dried over Na 2

SO

4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%). CN H 2 /Pd-C N 0 2 N N H H [006981 6-Amino-1H-indole-3-carbonitrile 1006991 A suspention of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 25 mmol) and 10% Pd-C (0.46 g) in EtOH (50 mL) was stirred under H 2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1) to give 6-amino-1H indole-3-carbonitrile (1.0 g, 98%) as a pink solid. 'H NMR (DMSO-d 6 ) 5 11.51 (s, I H), 7.84 (d, J= 2.4 Hz, 1 H), 7.22 (d, J= 8.4 Hz, 1 H), 6.62 (s, 1H), 6.56 (d, J= 8.4 Hz, 1 H), 5.0 (s, 2H); MS (ESI) m/e (M+H*) 157.1. 1007001 Example 51: 2-tert-Butyl-1H-indol-6-amine 0

NH

2 N n-BuU NaBHSAcOH H H K N 0 3/ 2 S OO DOQ NN R a n e y N i/H 2 H H )W H N 0 NH2 N 1007011 N-o-Tolylpivalamide [00702] To a solution of o-tolylamine (21 g, 0.20 mol) and Et 3 N (22 g, 0.22 mol) in CH 2

CI

2 was added 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) at 10 0 C. After addition, the mixture was stirred overnight at room temperature. The mixture was washed with aq. HCl (5%, 80 mL), saturated aq. NaHCO 3 and brine. The organic layer was dried over Na 2

SO

4 and concentrated under vacuum to give N-o-tolylpivalamide (35 g, 91%). 'H NMR (300 MHz, 183 CDC1 3 ) 8 7.88 (d, J= 7.2 Hz, 1 H), 7.15-7.25 (in, 2 H), 7.05 (t, J= 7.2 Hz, 1 H), 2.26 (s, 3 H), 1.34 (s, 9 H). N n-BuU 0 CC N H [007031 2-tert-Butyl-1H-indole [007041 To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol ) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15 *C. After addition, the mixture was stirred overnight at 15 *C. The mixture was cooled in an ice-water bath and treated with saturated NH 4 Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give 2-tert-butyl-1H-indole (24 g, 88%). 'H NMR (300 MHz, CDCl 3 ) 6 7.99 (br. s, I H), 7.54 (d, J= 7.2 Hz, I H), 7.05 (d, J= 7.8 Hz, I H), 7.06 -7.13 (m, 2 H), 6.26 (s, I H), 1.39 (s, 9 H). NaBH 4 /AcOH N 10CN H H [007051 2-tert-Butylindoline 1007061 To a solution of 2-tert-butyl-IH-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH 4 at 10 *C. The mixture was stirred for 20 minutes at 10 *C before being treated dropwise with H 2 O under ice cooling. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated under vacuum to give 2-tert-butylindoline (9.8 g), which was used directly in the next step. KNO3/H 2

SO

4 O -C N'_ 0 2 N H H [007071 2-tert-butyl-6-nitroindoline and 2-tert-butyl-5-nitro-1H-indole [007081 To a solution of 2-tert-butylindoline (9.7 g) in H 2

SO

4 (98%, 80 mL) was slowly added KNO 3 (5.6 g, 56 mmol) at 0 "C. After addition, the reaction mixture was stirred at room temperature for I h. The mixture was carefully poured into cracked ice, basified with Na 2

CO

3 to pH 8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g, 31% over two steps). IH NMR (300 MHz, CDC1 3 ) 5 7.52 (dd, J= 1.8, 8.1 Hz, 1 H), 7.30 (s, 1 H), 7.08 (d, J 184 = 7.8 Hz, 1 H), 3.76 (t, J= 9.6 Hz, 1 H), 2.98 - 3.07 (m, 1 H), 2.82 - 2.91 (m, 1 H), 0.91 (s, 9 H). DDQ 2 0N H 0 2 NC N [007091 2-tert-Butyl-6-nitro-1H-indole [007101 To a solution of 2-tert-butyl-6-nitroindoline (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ (6.9 g, 30 mmol) at room temperature. The mixture was heated at reflux for 2.5 h before being filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-lH-indole (1.6 g, 80%). 'H NMR (300 MHz, CDC1 3 ) 8 8.30 (br. s, 1 H), 8.29 (s, I H), 8.00 (dd, J= 2.1, 8.7 Hz, 1 H), 7.53 (d, J= 9.3 Hz, 1 H), 6.38 (s, 1 H), 1.43 (s, 9 H). 02N Raney Ni/H 2

H

2 N H 2 H [007111 2-tert-Butyl-1H-indol-6-amine [00712] To a solution of 2-tert-butyl-6-nitro-lH-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6 amine (1.0 g, 89%). 'H NMR (300 MHz, DMSO-d 6 ) 5 10.19 (s, 1 H), 6.99 (d, J= 8.1 Hz, 1 H), 6.46 (s, 1 H), 6.25 (dd, J= 1.8, 8.1 Hz, 1 H), 5.79 (d, J= 1.8 Hz, 1 H), 4.52 (s, 2 H), 1.24 (s, 9 H); MS (ESI) m/e (M+H*) 189.1. [007131 Example 52: 3-tert-Butyl-1H-indol-6-amine O2NBr Raney Ni-H 2 H 0 2 N JC N zinc tniflate N N H TBAJ, DIEA, 0 2 N H HN H -)Br OzN N zinctriflate H TBA, DIEA 0 2 N C N H [007141 3-tert-Butyl-6-nitro-1H-indole [007151 To a mixture of 6-nitroindole (1.0 g, 6.2 mmol), zinc triflate (2.1 g, 5.7 mmol), and TBAI (1.7 g, 5.2 mmol) in anhydrous toluene (11 mL) was added DIEA (1.5 g, 11 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 min at 120 *C, 185 followed by the addition of t-butyl bromide (0.71 g, 5.2 mmol). The resulting mixture was stirred for 45 min at 120 *C. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give 3-tert-butyl-6-nitro-1H-indole (0.25 g, 19%) as a yellow solid. 1 H-NMR (CDC1 3 ) 5 8.32 (d, J= 2.1 Hz, 1H), 8.00 (dd, J= 2.1, 14.4 Hz, 1H), 7.85 (d, J 8.7 Hz, 1H), 7.25 (s, 1 H), 1.46 (s, 9H). Raney Ni-H 2 H N2H H [007161 3-tert-Butyl-1H-indol-6-amine [007171 A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney Nickel (0.5 g) was hydrogenated under H 2 (1 atm) at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel (petroleum ether/ethyl acetate = 4:1) to give 3-tert-butyl-1H-indol-6-armine (2.0 g, 77%) as a gray solid. 'HNMR (CDC1 3 ) 5 7.58 (m, 2H), 6.73 (d, J= 1.2 Hz, 1H), 6.66 (s, 1H), 6.57(dd, J= 0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H). [007181 Example 53: 5-(Trifluoromethyl)-H-indol-6-amine

F

3 ~ HN 3

F

3 C Ir ~ ~---.N ae iH FC>~r F3CH 2

S

4 2 N

NO

2 D 2 N

N

2

H

2 H

F

3 C _ HN 3

F

3 C

H

2

S

4 0 2 N

NO

2 [00719] 1-Methyl-2,4-dinitro-5-(trifluoromethyl)benzene [007201 To a mixture of HNO 3 (98%, 30 mL) and H 2

SO

4 (98%, 30 mL) was added dropwise 1-methyl-3-trifluoromethyl-benzene (10 g, 63 mmol) at 0 *C. After addition, the mixture was stirred at rt for 30 min and was then poured into ice-water. The precipitate was filtered and washed with water to give 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 13%).

F

3 C DMA F 3 C N 0 2 N NO 2 0 2 N NO 2 [00721] (E)-2-(2,4-Dinitro-5-(trifluoromethyl)phenyl)-NN-dimethylethenamine [007221 A mixture of 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g, 8.0 mmol) and DMA (1.0 g, 8.2 mmol) in DMF (20 nL) was stirred at 100 *C for 30 min. The mixture 186 was poured into ice-water and stirred for 1 h. The precipitate was filtered and washed with water to give (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-NN-dimethylethenamine (2.1 g, 86%).

F

3 C Raney Ni/H 2

F

3 C H2N N 0 2 N NO 2

H

2 N H [007231 5-(Trifluoromethyl)-H-indol-6-amine [007241 A suspension of (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-NN dimethylethenamine (2.1 g, 6.9 mmol) and Raney Nickel (1 g) in ethanol (80 mL) was stirred under H 2 (1 atm) at room temperature for 5 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give 5 (trifluoromethyl)-IH-indol-6-amine (200 mg, 14%). 'H NMR (DMSO-d 6 ) 5 10.79 (br s, 1 H), 7.55 (s, 1 H), 7.12 (s, I H), 6.78 (s, 1 H), 6.27(s, 1 H), 4.92 (s, 2 H); MS (ESI) m/e (M+H*): 200.8. [007251 Example 54: 5-Ethyl-1H-indol-6-amine 050 O N AC 3

/CH

2 Cl 2 NaBH/rTHF 48%HBr CON _____ IN N NP HE3N/DMAP/CH2Cl2 6 OL- TFA S--L 0 6

KNO,/H

2 50 MnO 2 \ Raney Ni 02NN 0 2 N N Z H 2 N H H HN H 0 N O a~ H EtN/DMAP/CH2Cl2 [007261 1-(Phenylsulfonyl)indoline [007271 To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 124 mmol) in CH 2

CI

2 (200 mL) was added dropwise Et 3 N (19.0 g, 186 mmol) at 0 *C. The mixture was stirred at room temperature overnight. The organic layer was washed with water (2x), dried over Na 2 SO4 and concentrated to dryness under reduced pressure to obtain I -(phenylsulfonyl)indoline (30.9 g, 96%).

187 0 N Ac 2

O/A

3

I/CH

2 c 2 C \/ N 60 6 [007281 1-(1-(PhenyIsulfonyl)indolin-5-yl)ethanone [007291 To a suspension of A1C1 3 (144 g, 1.08 mol) in CH 2

CI

2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes before a solution of 1 (phenylsulfonyl)indoline (46.9 g, 0.180 mol) in CH 2 C1 2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and was quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH 2 C1 2 . The combined organics were washed with saturated aqueous NaHCO 3 and brine, dried over Na 2

SO

4 , and concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (42.6 g). 0 NaBH4/THF NN o 0 [007301 5-Ethyl-1-(phenylsulfonyl)indoline [007311 To TFA (1600 mL) at 0 0 C was added sodium borohydride (64.0 g, 1.69 mol) over 1 h. To this mixture was added dropwise a solution of 1-(I-(phenylsulfonyl)indolin-5 yl)ethanone (40.0 g, 0.133 mol) in TFA (700 mL) over 1 h. The mixture was then stirred overnight at 25 0 C. After dilution with H 2 0 (1600 mL), the mixture was made basic by the addition of sodium hydroxide pellets at 0 *C. The organic layer was separated and the aqueous layer was extracted with CH 2 C1 2 . The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethyl-i -(phenylsulfonyl)indoline (16.2 g, 47% over two steps). N 48%HBr o o 0 tH [00732] 5-Ethylindoline 188 [007331 A mixture of 5-ethy1-l-(phenylsulfonyl)indoline (15 g, 0.050 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH to pH 9 and then it was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2

SO

4 ,-'nd concentrated under reduced pressure. The residue was purified by silica column to give 5-ethylindoline (2.5 g, 32%).

KNO

3

/H

2 SO4 N'WM H 0 2 N H [007341 5-Ethyl-6-nitroindoline [007351 To a solution of 5-ethylindoline (2.5 g, 17 mmol) in H 2

SO

4 (98%, 20 mL) was slowly added KNO 3 (1.7 g, 17 mmol) at 0 *C. The mixture was stirred at 0 - 10 *C for 10 minutes. The mixture was then carefully poured into ice, basified with NaOH solution to pH 9, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2

SO

4 and concentrated to dryness. The residue was purified by silica column to give 5-ethyl-6-nitroindoline (1.9 g, 58%). MnO 2 H W 0 2 N H [007361 5-Ethyl-6-nitro-1H-indole [007371 To a solution of 5-ethyl-6-nitroindoline (1.9 g, 9.9 mmol) in CH 2 C1 2 (30 mL) was added MnO 2 (4.0 g, 46 mmol). The mixture was stirred at ambient temperature for 8 h. The solid was filtered off and the filtrate was concentrated to dryness to give 5-ethyl-6-nitro-1H indole (1.9 g). Raney Ni/H 2 , 0 N _N H7 N 2H H 2 N H [007381 5-Ethyl-1H-indol-6-amine [00739] A suspension of 5-ethyl-6-nitro-lH-indole (1.9 g, 10 mmol) and Raney Nickel (1 g) was hydrogenated under H 2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by silica gel column to give 5-ethyl-i H-indol-6-amine (760 mg, 48% over two steps). 'H NMR (CDCl 3 ) 8 7.90 (br s, IH), 7.41 (s, 1H), 7.00 (s, IH), 6.78 (s, 2H), 6.39 (s, IH), 3.39 (br s, 2H), 2.63 (q, J = 7.2 Hz, 2H), 1.29 (t, J= 6.9 Hz, 3H); MS (ESI) m/e (M+H*) 161.1. [00740] Example 55: Ethyl 6-amino-1H-indole-4-carboxylate 189 0 2 N COOH 0 2 N CO 2 Et COOH HNO3 SOC12;

H

2

SO

4 EtOH NO NO 2

NO

2 /

CO

2 Et DMA/DMF N\ SnC 2 i 02

H

2 N N

CO

2 Et H O2N COOH COOH HN3 N

H

2 SO4

NO

2 [007411 2-Methyl-3,5-dinitrobenzoic acid [007421 To a mixture of HNO 3 (95%, 80 mL) and H 2 SO4 (98%, 80 mL) was slowly added 2-methylbenzic acid (50 g, 0.37 mol) at 0 *C. After addition, the reaction mixture was stirred below 30 *C for 1.5 h. The mixture then was poured into ice-water and stirred for 15 min. The precipitate was filtered and washed with water to give 2-methyl-3,5-dinitrobenzoic acid (70 g, 84%). 0 2 N COOH 0 2 N CO 2 Et I ~ SOCIlz EtOH

NO

2 NOz [007431 Ethyl 2-methyl-3,5-dinitrobenzoate [007441 A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in SOC1 2 (80 mL) was heated at reflux for 4 h and then was concentrated to dryness. The residue was dissolved in CH 2 Cl 2 (50 mL), to which EtOH (80 mL) was added and the mixture was stirred at room temperature for 1 h. The mixture was poured into ice-water and extracted with EtOAc (3 x 100 mL). The combined extracts were washed sat. Na 2

CO

3 (80 mL), water (2 x 100 mL) and brine (100 mL), dried over Na 2 SO4 and concentrated to dryness to give ethyl 2-methyl-3,5 dinitrobenzoate (50 g, 88%) 0 2 N CO 2 Et

NO

2 / DMAJDMF /N\ N02 02 \O /

NO

2

CO

2 Et [007451 (E)-Ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate [007461 A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 *C for 5 h. The mixture was poured into ice- 190 water and the precipitated solid was filtered and washed with water to give (E)-ethyl 2-(2 (dimethylamino)vinyl)-3,5-dinitrobenlzoate (II g, 48%)

NO

2 /

CO

2 Et

-

/ N S n C 2 0 2 N H 2 N N

CO

2 Et H [00747] Ethyl 6-amino-1H-indole-4-carboxylate [007481 A mixture of (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 0.037 mol) and SnC1 2 (83 g, 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified using sat. aq. Na 2

CO

3 to pH 8. The precipitated solid was filtered and the filtrate was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 x 100 mL) and brine (150 mL), dried over Na 2

SO

4 , and concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g, 40%). '-INMR (DMSO-d 6 ) 8 10.76 (br s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (in, 1 H), 6.67-6.68 (in, 1 H), 4.94 (br s, 2 H), 4.32-4.25 (q, J= 7.2 Hz, 2 H), 1.35-1.31 (t, J= 7.2, 3 H); MS (ESI) m/e (M+H*) 205.0. [007491 Example 56: 5-Fluoro-1H-indol-6-amine F

HNO

3

IH

2

SO

4 F N F'a ~ 0 2 N N2 F ~ . H 2 /Raney-Ni F I2 HNN N 0 2 N NO 2 H

HNO

3

IH

2

SO

4 F 0 2 N N0 2 [00750] 1-Fluoro-5-methyl-2,4-dinitrobenzene [007511 To a stirred solution of HNO 3 (60 mL) and H 2

SO

4 (80 mL) was added dropwise 1 fluoro-3-methylbenzene (28 g, 25 mmol) under ice-cooling at such a rate that the temperature did not rise above 35 *C. The mixture was allowed to stir for 30 min at rt and was then poured into ice water (500 mL). The resulting precipitate (a mixture of 1-fluoro-5-methyl 2,4-dinitrobenzene and 1-fluoro-3-methyl-2,4-dinitrobenzene, 32 g, ca. 7:3 ratio) was collected by filtration and purified by recrystallization from 50 mL isopropyl ether to give pure 1 -fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).

191 0 F/ - F N, 0 2 N NO 2 0 2 N NO 2 [007521 (E)-2-(5-Fluoro-2,4-dinitrophenyl)-NN-dimethylethenamine [007531 A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100 0C for 4h. The solution was cooled and poured into water. The precipitated red solid was collected, washed with water, and dried to give (E)-2-(5-fluoro-2,4-dinitrophenyl)-NN-dimethylethenamine (8.0 g, 63%). F H 2 /Raney-Ni

H

2 N N 0 2 N NO 2 H [007541 5-Fluoro-1HI-indol-6-amine [007551 A suspension of (E)-2-(5-fluoro-2,4-dinitrophenyl)-NN-dimethylethenamine (8.0 g, 31 mmol) and Raney Nickel (8 g) in EtOH (80 mL) was stirred under H 2 (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to give 5-fluoro 1H-indol-6-amine (1.0 g, 16%) as a brown solid. 'HNMR (DMSO-d 6 ) 8 10.56 (br s, 1 H), 7.07 (d, J= 12 Hz, 1 H), 7.02 (m, 1H), 6.71 (d, J= 8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s , 2H); MS (ESI) m/e (M+H*) 150.1. [00756] Example 57: 5-Chloro-1H-indol-6-amine

HNO

3

/H

2

SO

4 C1 - CI 0 2 N NO 2 C1 H 2 /Raney-Ni A

H

2 N)O N 0 2 N NO 2 H

HNO

3

/H

2

SO

4 C1 C 0 2 N 1007571 .1-Chloro-5-methyl-2,4-dinitrobenzene t00758] To a stirred solution of HNO 3 (55 mL) and H 2

SO

4 (79 mL) was added dropwise 1 chloro-3-methylbenzene (25.3 g, 200 mmol) under ice-cooling at such a rate that the temperature did not rise above 35 0C. The mixture was allowed to stir for 30 min at ambient temperature and was then poured into ice water (500 mL). The resulting precipitate was 192 collected by filtration and purified by recrystallization to give 1-chloro-5-methyl-2,4 dinitrobenzene (26 g, 60%). C0l C1 N

O

2 N NO 2

O

2 N NO 2 [00759] (E)-2-(5-Chloro-2,4-dinitrophenyl)-NN-dimethylethenamine [007601 A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50.0 mmol), DMA (11.9 g, 100 mmol) in DMF (50 mL) was heated at 100 *C for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected by filtration, washed with water, and dried to give (E)-2-(5-chloro-2,4-dinitrophenyl)-NN-dimethylethenamine (9.84 g, 72%). I C1 CI ~ N~ H 2 /Raney-Ni H 0 2 N NO 2 H [007611 5-Chloro-1H-indol-6-amine [007621 A suspension of (E)-2-(5-chloro-2,4-dinitrophenyl)-NN-dimethylethenamine (9.8 g, 36 mmol) and Raney Nickel (9.8 g) in EtOH (140 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether/ethyl acetate = 10:1) to give 5-chloro 1H-indol-6-amine (0.97 g, 16%) as a gray powder. 'HNMR (CDCl 3 ) S 7.85 (br s, 1 H), 7.52 (s, I H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, IH); MS (ESI) m/e (M+H*) 166.0. [007631 Example 58: Ethyl 6-amino-1H-indole-7-carboxylate

CO

2 H 1. HNO3/H 2

SO

4 N0 2 CO2H 1. SC2 I 2. EtOH 2. SOCI 2 /EtOH

NO

2

~CO

2 Et DMA~ /2-\/N\ NiI CO2E H 2 N -? N H

NO

2 EtO 2 C NO 2

CO

2 E z CO 2 H 1. HNO 3

/H

2

SO

4 N02 CO2H 2. SOCl 2 /EtOH NO2 [007641 3-Methyl-2,6-dinitrobenzoic acid [00765] To a mixture of HN0 3 (95%, 80 mL) and H2S04 (98%, 80 mL) was slowly added 3-methylbenzic acid (50 g, 0.37 mol) at 0 *C. After addition, the mixture was stirred below 193 30 *C for 1.5 hours. The mixture was then poured into ice-water and stirred for 15 min. The precipitate solid was filtered and washed with water to give a mixture of 3-methyl-2,6 dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a solution of this mixture (70 g, 0.31 mol) in EtOH (150 mL) was added dropwise SOC1 2 (54 g, 0.45 mol). The mixture was heated at reflux for 2 h before being concentrated to dryness under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aq. Na 2

CO

3 (10%, 120 mL). The organic layer was washed with brine (50 mL), dried over Na 2

SO

4 , and concentrated to dryness to obtain ethyl 5-methyl-2,4-dinitrobenzoate (20 g), which was placed aside. The aqueous layer was acidified by HCl to pH 2 ~ 3 and the precipitated solid was filtered, washed with water, and dried in air to give 3-methyl-2,6-dinitrobenzoic acid (39 g, 47%).

NO

2

NO

2

CO

2 H 1. SOC2 CO2E 2. EtOH

NO

2 NO 2 1007661 Ethyl 3-methyl-2,6-dinitrobenzoate 1007671 A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOCl 2 (80 mL) was heated at reflux 4 h. The excess SOC1 2 was evaporated off under reduced pressure and the residue was added dropwise to a solution of EtOH (100 mL) and Et 3 N (50 mL). The mixture was stirred at 20 'C for I h and then concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with Na 2

CO

3 (10 %, 40 mL x 2), water (50 mL x 2) and brine (50 mL), dried over Na 2

SO

4 and concentrated to give ethyl 3-methyl-2,6 dinitrobenzoate (20 g, 53%).

NO

2

CO

2 Et DMA O2N 0

NO

2 EtO 2 C NO 2 1007681 (E)-Ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate [007691 A mixture of ethyl 3-methyl-2,6-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 *C for 5 h. The mixture was poured into ice water. The precipitated solid was filtered and washed with water to give (E)-ethyl 3-(2 (dimethylamino)vinyl)-2,6-dinitrobenzoate (25 g, 58%). O2 / Raney NVH H 02NP IW H 2 NJC N H EtO 2 C NO 2

CO

2 Et [007701 Ethyl 6-amino-1H-indole-7-carboxylate 194 [007711 A mixture of (E)-ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate (30 g, 0.097 mol) and Raney Nickel (10 g) in EtOH (1000 mL) was hydrogenated at room temperature under 50 psi for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6 amino-1H-indole-7-carboxylate as an off-white solid (3.2 g, 16%). 'H NMR (DMSO-d 6 ) 5 10.38 (s, 1 H), 7.42 (d, J= 8.7 Hz, 1 H), 6.98 (t, J= 3.0 Hz, 1 H), 6.65 (s, 2 H), 6.48 (d, J= 8.7 Hz, I H), 6.27-6.26 (m, 1 H), 4.38 (q, J= 7.2 Hz, 2 H), 1.35 (t, J= 7.2 Hz, 3 H). [007721 Example 59: Ethyl 6-amino-1H-indole-5-carboxylate OzN CO2Et DMA Et Raney Ni F4 2 N) N 02N N 2 NH

CO

2 Et DMA 2 2 N NO 2 0 2 N

NO

2 EtO 2 N [007731 (E)-Ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate [007741 A mixture of ethyl 5-methyl-2,4-dinitrobenzoate (39 g, 0.15 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 0 C for 5 h. The mixture was poured into ice water and the precipitated solid was filtered and washed with water to afford (E)-ethyl 5-(2 (dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 28%). 0 2 N ~. NO 2 EtQ2C Et2N Raney Ni E EtO2C 0N H [007751 Ethyl 6-anino-1H-indole-5-carboxylate [007761 A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6 amino-1H-indole-5-carboxylate (3.0 g, 30%). 'H NMR (DMSO-d 6 ) 5 10.68 (s, 1 H), 7.99 (s, 1 H), 7.01-7.06 (m, 1 H), 6.62 (s, 1 H), 6.27-6.28 (m, 1 H), 6.16 (s, 2 H), 4.22 (q, J= 7.2 Hz, 2 H), 1.32-1.27 (t, J= 7.2 Hz, 3 H). [007771 Example 60: 5-tert-Butyl-1H-indol-6-aine 195 t-Bu (EO)PO)B/a U/N6 t-Bu. HNOJ/H2SO4 t-B()u~ a (t)PC I/NaH HOEtO-P-OEt 0 \0- SC1 [0078] -ter-Buyl--metylpeny dityl phosphate 0 2 N NO tNO2 O 2 0N SnI 2 -N t-Bu t~u (EtO) 2 P(O)CI/NaH EtO-P-OEt 0 [007781 2-tert-Butyl-4-methylphenyl diethyl phosphate [007791 To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THF (200 mL) was added dropwise a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol) in THF (100 mL) at 0 *C. The mixture was stirred at 0 *C for 15 min and then phosphorochloridic acid diethyl ester (37 g, 0.21 mol) was added dropwise at 0 'C. After addition, the mixture was stirred at ambient temperature for 30 min. The reaction was quenched with sat. NH 4 Cl (300 mL) and then extracted with Et 2 O (350 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 , and then evaporated under vacuum to give 2-tert butyl-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, -100%), which was used directly in.the next step. t-Bu Li/NH 3 t-Bu EtO-P-OEt 11 0 [007801 1-tert-Butyl-3-methylbenzene [00781] To NH 3 (liquid, 1000 mL) was added a solution of 2-tert-butyl-4-methylphenyl diethyl phosphate (60 g, crude from last step, about 0.2 mol) in Et 2 O (anhydrous, 500 mL) at -78 *C under N 2 atmosphere. Lithium metal was added to the solution in small pieces until the blue color persisted. The reaction mixture was stirred at -78 *C for 15 min and then was quenched with sat. NH 4 Cl until the mixture turned colorless. Liquid NH 3 was evaporated and the residue was dissolved in water. The mixture was extracted with Et 2 O (400 mL x 2). The combined organics were dried over Na 2

SO

4 and evaporated to give 1-tert-butyl-3 methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%), which was used directly in next step.

196

NO

2 t-Bu HNO 3

/H

2

SO

4 t-Bu t-Bu 0 2 N NO 2

NO

2 1007821 1-tert-Butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4 dinitro-benzene. 1007831 To HNO 3 (95%, 14 mL) was added H 2

SO

4 (98 %, 20 mL) at 0 *C and then 1-tert butyl-3-methylbenzene (7.4 g, -50 nmol, crude from last step) dropwise to the with the temperature being kept below 30 *C. The mixture was stirred at ambient temperature for 30 min, poured onto crushed ice (100 g), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, before being evaporated to give a brown oil, which was purified by column chromatography to give a mixture of 1 -tert-butyl-5 methyl-2,4-dinitrobenzene and 1 -tert-butyl-3-methyl-2,4-dinitrobenzene (2:1 by NMR) as a yellow oil (9.0 g, 61%). t-Bu t-Bu + / _ t-Bu ~ 0 2 N NO 2

NO

2 0 2 N NO 2 [007841 (E)-2-(5-tert-Butyl-2,4-dinitrophenyl)-NN-dimethylethenamine [007851 A mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl 2,4-dinitrobenzene (9.0 g, 38 mmol,.2:1 by NMR) and DMA (5.4 g, 45 mmol) in DMF (50 mL) was heated at reflux for 2 h before being cooled to room temperature. The reaction mixture was poured into water-ice and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, before being evaporated to give a brown oil, which was purified by column to give (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-NN dimethylethen-amine (5.0 g, 68%). t-Bu SnCl2 t-Bu

O

2 N NO 2

H

2 N H [007861 5-tert-Butyl-1H-indol-6-amine [007871 A solution of (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-NN-dimethylethen-amine (5.3 g, 18 mmol) and tin (II) chloride dihydrate (37 g, 0.18 mol) in ethanol (200 mL) was heated at reflux overnight. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residual slurry was diluted with water (500 mL) and was basifed with 10 % aq. Na 2

CO

3 to pH 8. The resulting suspension was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extract was washed with water and brine, dried over 197 Na 2

SO

4 , and concentrated. The residual solid was washed with CH 2 Cl 2 to afford a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6 amine (0.40 g, 12%). 'H NMR (DMSO.d 6 ) 8 10.34 (br s, 1 H), 7.23 (s, 1 H), 6.92 (s, 1 H), 6.65 (s, 1H), 6.14 (s, 1 H), 4.43 (br s, 2 H), 2.48 (s, 9 H); MS (ESI) m/e (M+H*) 189.1. 1007881 General Procedure IV: Synthesis of acylaminoindoles A RN A RN HATU (R 2 )n I OH2) I AUX Ar 1 n + HN OJB B EtN, DMF B - 0 DCM [00789] One equivalent of the appropriate carboxylic acid and one equivalent of the appropriate amine were dissolved in NN-dimethylformamide (DMF) containing triethylamine (3 equivalents). O-(7-Azabenzotriazol-1 -yl)-N,N,NN'-tetramethyluronium hexafluorophosphate (HATU) was added and the solution was allowed to stir. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product. [007901 Example 61: N-(2-tert-Butyl-1H-indol-5-yl)--(4-methoxyphenyl) cyclopropanecarboxamide DMF H HATU H /~~ I -I E 3 N 0 o N OOH H N EtH [00791] 2-tert-Butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1-(4-methoxyphenyl) cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.00 mL) containing triethylamine (28 ptL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found 363.3 (M+1)+; Retention time 3.48 minutes. [00792] General Procedure V: Synthesis of acylaminoindoles

(R

2 )n A NRN OH SOC 2

(R

2 ) Ci + HN pyridine (R 2 )n N 0 DMF IB, 0 1 BA - 0 . 0 [007931 One equivalent of the appropriate carboxylic acid was placed in an oven-dried flask under nitrogen. A minimum (3 equivalents) of thionyl chloride and a catalytic amount of and NN-dimethylformamide were added and the solution was allowed to stir for 20 minutes at 60 *C. The excess thionyl chloride was removed under vacuum and the resulting 198 solid was suspended in a minimum of anhydrous pyridine. This solution was slowly added to a stirred solution of one equivalent the appropriate amine dissolved in a minimum of anhydrous pyridine. 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 HC1. The organic layer was then dried over sodium sulfate, evaporated to dryness, and then purified by column chromatography. [007941 Example 62: Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) 1H-indole-2-carboxylate (Compd. 28) H o1)SOC 2 0 N 0 o OH 2) dichloromethane O N OEt Et 3 N H H

H

2 N 0Et [007951 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under N 2 . NN-dimethylformamide (0.3 mL) was added and the solution was allowed to stir for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting solid was dissolved in anhydrous dichloromethane (15 mL) containing triethylamine (2.8 mL, 20.0 mmol). Ethyl 5-amino-1H-indole-2 carboxylate (2.04 g, 10.0 mmol) in 15 mL of anhydrous dichloromethane was slowly added to the reaction. The resulting solution was allowed to stir for 1 hour. The reaction mixture was diluted to 50 mL with dichloromethane and washed three times with 50 mL of iN HCI, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and evaporated to dryness to yield ethyl 5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate as a gray solid (3.44 g, 88 %). ESI-MS m/z calc. 392.4; found 393.1 (M+1)* Retention time 3.17 minutes. 'IH NMR (400 MHz, DMSO-d6) 8 11.80 (s, 1H), 8.64 (s, IH), 7.83 (m, 1H), 7.33 7.26 (m, 2H), 7.07 (m, 1 H), 7.02 (m, IH), 6.96-6.89 (m, 2H), 6.02 (s, 2H), 4.33 (q, J= 7.1 Hz, 2H), 1.42-1.39 (m, 2H), 1.33 (t, J= 7.1 Hz, 3H), 1.06-1.03 (m, 2H). [007961 Example 63: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5 yl)cyclopropanecarboxamide OH H o SOC1 2 - H 2 N CH 2

C

2 - O /'NH DMF N Et 3 N OO oOO H 199 [007971 1 -Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 mL of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of NN dimethylformamide (DMF) was added and the reaction mixture was stirred for 30 minutes. The excess thionyl chloride was evaporated and the resulting residue was dissolved in 15 mL of dichloromethane. This solution was slowly added to a solution of 2-tert-butyl-1H-indol-5 amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mL, 12.1 mmol). The resulting solution was allowed to stir for 10 minutes. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a gradient of 5-50 % ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a pale pink powder (1.24 g 62%). ESI-MS m/z calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 'H NMR (400 MHz, DMSO) 5 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J= 1.4 Hz, 1 H), 7.15 (d, J= 8.6 Hz, 1 H), 7.05 - 6.87 (m, 4H), 6.03 (s, 3H), 1.44 - 1.37 (m, 2H), 1.33 (s, 9H), 1.05-1.00 (m, 2H). 1007981 Example 64: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1 methylcyclopropyl)-1H-indol-5-yl)cyclopropanecarboxamide HATU H OH +2N Et 3 N N 0 0H + N [007991 1-Methyl-=2-(1-methylcyclopropyl)-1 H-indol-5-amine(20.0 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in NN-dimethylformamide (1 mL) containing triethylamine (42.1 pL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,NN,N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 6 h at 80 'C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropyl)-1H-indol-5 yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)*. Retention time of 3.05 minutes. [008001 Example 65: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl--2,3-dihydro-1H -pyrrolo[1,2-alindol-7-yl)cyclopropanecarboxamiide HATU H OH H 2 N EtN N 00 OH + 200 [008011 1,1-Dimethyl-2,3-dihydro-1fH-pyrrolo[1,2-a]indol-7-amine (40.0 mg, 0.200 mmol) and 1-(benzo[d][1,3]dioxol-5-y)cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in NN-dimethylformamide (1 mL) containing triethylamine (84.2 pL, 0.600 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture and the resulting solution was allowed to stir for 5 minutes at room temperature. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-dihydro-1H pyrrolo[1,2-a]-indol-7-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)*. Retention time of 2.02 minutes. 'H NMR (400 MHz, DMSO-d6) 8 8.41 (s, 1H), 7.59 (d, J= 1.8 Hz, 1H), 7.15 (d, J= 8.6 Hz, 1H), 7.06 - 7.02 (in, 2H), 6.96 - 6.90 (in, 2H), 6.03 (s, 2H), 5.98 (d, J= 0.7 Hz, 1H), 4.06 (t, J= 6.8 Hz, 2H), 2.35 (t, J= 6.8 Hz, 2H), 1.42 1.38 (in, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H). [008021 Example 66: Methyl 5-(1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-2-tert-butyl-H-indole-7-carboxylate ci ,H 2 N EtsN H 00 Y 0 [00803] 1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.20 mmol) and methyl 5-amino-2-tert-butyl-IH-indole-7-carboxylate (49.3 mg, 0.200 mmol) were dissolved in NN-dimethylformamide (2 mL) containing a magnetic stir bar and triethylamine (0.084 mL, 0.60 mmol). The resulting solution was allowed to stir for 10 minutes at room temperature. The crude product was then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield methyl 5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarbox-amido)-2-tert-butyl-IH-indole-7-carboxylate. ESI-MS m/z calc. 434.2, found 435.5. (M+1). Retention time of 2.12 minutes. [00804] Example 67: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2 yl)-1H-indol-5-yl)cyclopropanecarboxamide H H2N OHBTU, Et3N 0 OH OH 0 ~ H 0 0 N OH H ] OH [008051 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol) and Et 3 N (152 pL, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for 201 10 minutes before a solution of 2-(5-amino-1H-indol-2-yl)-2-methylpropan-1-ol (0.074 g, 0.36 mmol) in acetonitrile (1.94 mL) was added. After addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with I N HCI (1 x 3 mL) and saturated aqueous NaHCO 3 (1 x 3 mL). The organic layer was dried over Na 2 SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 1 (benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2-yl)-IH-indol-5 yl)cyclopropanecarboxamide (0.11 g, 75%). 'H NMR (400 MHz, DMSO-d6) 5 10.64 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04-6.90 (m, 4H), 6.06 (s, 1H), 6.03 (s, 2H), 4.79 (t, J = 2.7 Hz, 1H), 3.46 (d, J = 0.0 Hz, 2H), 1.41-1.39 (m, 2H), 1.26 (s, 6H), 1.05-1.02 (m, 2H). [008061 Example 67: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol 6-yl)cyclopropanecarboxamide HATUH OH H2N O 0 ~0 0 o O H H [008071 2,3,4,9-Tetrahydro-H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,NN,N'-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mnol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 70 *C. The solvent was evaporated and the crude product was then purified on 40 g of silica gel utilizing a gradient of 5-50% ethyl acetate in hexanes to yield 1 -(benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol-6 yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS m/z calc. 374.2, found 375.3 (M+1)*. Retention time of 3.43 minutes. 'H NMR (400 MHz, DMSO-d6) 5 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J= 1.8 Hz, 1H), 7.10 - 6.89 (m, 5H), 6.03 (s, 2H), 2.68 - 2.65 (m, 2H), 2.56 - 2.54 (m, 2H), 1.82 - 1.77 (m, 4H), 1.41 - 1.34 (m, 2H), 1.04 - 0.97 (m, 2H). [008081 Example 69: tert-Butyl 4-(5-(1-(benzo[d] [1,3]dioxol-5-yl)cyclopropanecarbox amido)-1H-indol-2-yl)piperidine-1-carboxylate 202 H 2 N 0 O C 1 - N4 N Na H Et 3 NH [00809] 1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and tert-butyl 4-(5-amino-IH-indol-2-yl)piperidine-1-carboxylate (60 mg, 0.19 mmol) were dissolved in dichloromethane (1 mL) containing a magnetic stir bar and triethylamine (0.056 mL, 0.40 mmol). The resulting solution was allowed to stir for two days at room temperature. The crude product was then evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield tert-butyl 4-(5-(l (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-IH-indol-2-yl)piperidine-I carboxylate. ESI-MS m/z calc. 503.2, found 504.5. (M+1)*. Retention time of 1.99 minutes. 1008101 Example 70: Ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-H-indol-2-yl)propanoate c KHMDS TFA NNO, O0 2 NC C0 2 Et MtEt N CKHMDSCO 2 OEt Boc BOo SnC] 2 .2H 2 0 HNH ~ N CO~t~K ~. HBTU EtN( H 2 0 OH 0 - ) -N c0 2 Et H NN KHM DS r~ CO 2 Et Mel Boc Boc [008111 tert-Butyl 2-(1-ethoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate [008121 tert-Butyl 2-(2-ethoxy-2-oxoethyl)-IH-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 mL) and cooled to -78 "C. A 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal temperature stayed below -60 *C. Stirring was continued for I h at -78 *C. Methyl iodide (727 pL, 11.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes at room temperature. The mixture was quenched with sat. aq. ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na 2

SO

4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 203 (ethylacetate/hexane = 1/9) to give tert-butyl 2-(1 -ethoxy- I -oxopropan-2-yl)- I H-indole- 1 carboxylate (2.8 g, 88%). TFA b{ CO 2 Et C N CO 2 Et Boc H 1008131 Ethyl 2-(1H-indol-2-yl)propanoate 1008141 tert-Butyl 2-(1 -ethoxy- 1 -oxopropan-2-yl)- 1 H-indole- 1 -carboxylate (2.77 g, 8.74 mmol) was dissolved in dichloromethane (25 mL) before TFA (9.8 mL) was added. The mixture was stirred for 1.5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with sat. aq. sodium bicarbonate, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to give ethyl 2-(1H-indol-2-yl)propanoate (0.92 g, 50%). NaNO 3

,

2 N N CO 2 Et conc. H 2 SO4 N CO2Et H H COE 1008151 Ethyl 2-(5-nitro-1H-indol-2-yl)propanoate 1008161 Ethyl 2-(1H-indol-2-yl)propanoate (0.91 g, 4.2 mmol) was dissolved in concentrated sulfuric acid (3.9 mL) and cooled to -10 *C (salt/ice-mixture). A solution of sodium nitrate (0.36 g, 4.2 mmol) in concentrated sulfuric acid (7.8 mL) was added dropwise over 35 min. Stirring was continued for another 30 min at -10 *C. The mixture was poured into ice and the product was extracted with ethyl acetate. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-(5-nitro-1H indol-2-yl)propanoate (0.34 g, 31%). 02N CO 2 Et SnCN2.2H20 H2N CO 2 Et H H 1008171 Ethyl 2-(5-amino-1H-indol-2-yl)propanoate [008181 To a solution of ethyl 2-(5-nitro-IH-indol-2-yl)propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The mixture was heated in the microwave at 120 *C for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHC0 3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer. The organic layer was dried over Na 2

SO

4 , filtered and evaporated under reduced pressure to give ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.088 g, 99%).

204 HNii HBTU, Et N NH H2NCO 2 Et 0 OH H , taNCO 2 Et [008191 Ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol 2-yl)propanoate [008201 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et 3 N (160 pL, 1.15 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 min before a solution of ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCI (1 x 3 mL) and then saturated aqueous NaHCO 3 (1 x 3 mL). The organic layer was dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2 yl)propanoate (0.081 g, 50%). 'H NMR (400 MHz, CDCl 3 ) 8 8.51 (s, IH), 7.67 (s, 1H), 7.23-7.19 (m, 2H), 7.04-7.01 (m, 3H), 6.89 (d, J = 0.0 Hz, 1H), 6.28 (s, IH), 6.06 (s, 2H), 4.25-4.17 (m, 2H), 3.91 (q, J = 7.2 Hz, 1H), 1.72-1.70 (m, 2H), 1.61 (s, 2H), 1.29 (t, J= 7.1 Hz, 4H), 1.13-1.11 (m, 2H). 100821] Example 71: tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbox amido)-1H-indol-2-yl)-2-methylpropylcarbamate

O

2 N I 2 LiOH 2N HEDCHOBt 0 2 N N -~N CO 2 Et -~N C0 2 H NEt 3 , NH 4 CI -~N NH 2 H H- H 0

BH

3 -THF02N BO2 0 2 N Pd/C H 2 N N~ - -N 2 N1 2 NEt 3 N NHBoc HCONH 4 H2N NHBoc H H H H EDC, HOBt, NEt 3 N 0 -O N NHBoc C ~ OH H LIOHI 2 N O 2 Et N CO 2 H H H 1008221 2-Methyl-2-(5-nitro-1H-indol-2-yl)propanoic acid 205 [008231 Ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (4.60 g, 16.7 mmol) was dissolved in THF/water (2:1, 30 mL). LiOH'H 2 0 (1.40 g, 33.3 mmol) was added and the mixture was stirred at 50 0C for 3 h. The mixture was made acidic by the careful addition of 3N HCl. The product was extracted with ethylacetate and the combined organic phases were washed with brine and dried over magnesium sulfate to give 2-methyl-2-(5-nitro-1H-indol-2 yl)propanoic acid (4.15 g, 99%). 0 2 N 1 EDC, HOBt 0 2 N

CO

2 H Et 3 N, NH 4 CI N NH 2 H-H [008241 2-Methyl-2-(5-nitro-1H-indol-2-yl)propanamide 1008251 2-Methyl-2-(5-nitro-1H-indol-2-yl)-propanoic acid (4.12 g, 16.6 mmol) was dissolved in acetonitrile (80 mL). EDC (3.80 g, 0.020 mmol), HOBt (2.70 g, 0.020 mmol), Et 3 N (6.9 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) were added and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Combined organic phases were washed with brine, dried over magnesium sulfate and dried to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propanamide (4.3 g, 99%). 02N

NH

2 BHT O2N I NH2

H

0 O H [008261 2-Methyl-2-(5-nitro-1H-indol-2-yl)propan-1-amine [00827] 2-Methyl-2-(5-nitro-1H-indol-2-yl)propanamide (200 mg, 0.81 mmol) was suspended in THF (5 ml) and cooled to 0 "C. Borane-THF complex solution (1.0 M, 2.4 mL, 2.4 mmol) was added slowly and the mixture was allowed to stir overnight at room temperature. The mixture was cooled to 0 "C and carefully acidified with 3 N HCl. THF was evaporated off, water was added and the mixture was washed with ethylacetate. The aqueous layer was made alkaline with 50% NaOH and the mixture was extracted with ethylacetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-methyl-2-(5-nitro-IH-indol-2-yl)propan-1-amine (82 mg, 43%). B o c 2 O H E C 02N H H 2 NEt 3 , THF HBoc H H [008281 tert-Butyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propylcarbamate [008291 2-Methyl-2-(5-nitro-1H-indo1-2-yl)propan--amine (137 mg, 0.587 mmol) was dissolved in THF (5 mL) and cooled to 0 'C. Et 3 N (82 pL, 0.59 mmol) and di-tert-butyl 206 dicarbonate (129 mg, 0.587 mmol) were added and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethylacetate. The residue was purified by silica gel chromatography (10-40% ethylacetate in hexane) to give tert-butyl 2-methyl-2-(5-nitro- I H-indol-2-yl)propylcarbamate (131 mg, 67%). O, .pwc' g H 2 N ON N NHBoc HCO 2

NH

4 HN N NHBoc H H [008301 tert-Butyl 2-(5-amino-1H-indol-2-yI)-2-methylpropylcarbamate [008311 To a solution of tert-butyl 2-methyl-2-(5-nitro- I H-indol-2-yl)propylcarbamate (80 mg, 0.24 mmol) in THF (9 mL) and water (2 mL) was added ammonium formate (60 mg, 0.96 mmol) followed by 10% Pd/C (50 mg). The mixture was stirred at room temperature for 45 minutes. Pd/C was filtered off and the organic solvent was removed by evaporation. The remaining aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to give tert-butyl 2-(5-amino-1H-indol-2 yl)-2-methylpropylcarbamate (58 mg, 80%). H

H

2 N N cEDC, HOBt, NEt 3 N D-W\ N NHBoc K - N NHBoc H OH H [008321 tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H indol-2-yI)-2-methylpropylIcarbamate [008331 tert-Butyl 2-(5-amino-1H-indol-2-yl)-2-methylpropylcarbamate (58 mg, 0.19 mmol), 1-(benzo[d][1,3]dioxol-6-yl)cyclopropanecarboxylic acid (47 mg, 0.23 mmol), EDC (45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et 3 N (80 piL, 0.57 mmol) were dissolved in DMF (4 mL) and stirred overnight at room temperature. The mixture was diluted with water and extracted with ethylacetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (10-30% ethylacetate in hexane) to give tert-butyl 2-(5-(l (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-IH-indol-2-yl)-2-methylpropyl carbamate (88 mg, 94%). 'H NMR (400 MHz, CDCl 3 ) 8 8.32 (s, IH), 7.62 (d, J = 1.5 Hz, 1H), 7.18 - 7.16 (m, 2H), 7.02 - 6.94 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 6.19 (d, J = 1.5 Hz, lH), 6.02 (s, 2H), 4.54 (m, 1H), 3.33 (d, J = 6.2 Hz, 2H), 1.68 (dd, J = 3.7, 6.8 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H), 1.09 (dd, J = 3.7, 6.8 Hz, 2H).

207 1008341 Example 72: (R)-N-(2-tert-Butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1 (2,2-difluoro benzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamlide OTs CSO2O NHCj H OH 00 2 H H 0 N, CsCO TNNFi 4 EtN 0 0N 01 N K OH HOH OTs 02 002 I D- \ H [008351 (R)-2-tert-Butyl-1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole [008361 To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4 methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas was added 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs 2

CO

3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80 'C under nitrogen gas. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was re-treated with Cs 2

CO

3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80 *C for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered and washed with ethyl acetate and hexane (1:1). The layers were separated and the organic layer was washed with water (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane /hexane = 1.5/1) to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4 yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 'H NMR (400 MHz, CDC1 3 ) 5 8.48 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 2.2, 9.1 Hz, IH), 7.49 (d, J = 9.1 Hz, IH), 6.00 (s, 1H), 4.52-4.45 (m, 3H), 4.12 (dd, J= 6.0, 8.6 Hz, 1H), 3.78 (dd, J = 6.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).

208 Pd/C

H

2 N 02N.

NH

4 2CH [008371 (R)-2-tert-Butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl-H-indol-5-amine [008381 To a stirred solution of (R)-2-tert-butyl-l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5 nitro-1H-indole (1.0 g, 3.0 mmol) in ethanol (20 mL) and water (5 mL) was added ammonium formate (0.76 g, 12 mmol) followed by slow addition of 10 % palladium on carbon (0.4 g). The mixture was stirred at room temperature for I h. The reaction mixture was filtered through a plug of celite and rinsed with ethyl acetate. The filtrate was evaporated under reduced pressure and the crude product was dissolved in ethyl acetate. The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL). The organic layer was dried over Na 2 S04, filtered and evaporated under reduced pressure to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4 yl)methyl-IH-indol-5-amine (0.89 g, 98%). 'H NMR (400 MHz, CDC1 3 ) 8 7.04 (d, J= 4 Hz, IH), 6.70 (d, J= 2.2 Hz, IH), 6.48 (dd, J= 2.2, 8.6 Hz, 1H), 6.05 (s, 1H,), 4.38-4.1 (m, 2H), 4.21 (dd, J = 7.5, 16.5 Hz, IH), 3.87 (dd, J = 6.0, 8.6 Hz, IH), 3.66 (dd, J = 6.0, 8.6 Hz, 1H), 3.33 (br s, 2H), 1.40 (s, 3H), 1.34 (s, 9H), 1.25 (s, 3H). H

H

2 Et 3 N I N Fi P 0 N Oct 0 00 ~SOC12 OH [008391 N-((R)-2-tert-Butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1 (2,2-difluorobenzo[dl[1,31dioxol-5-yl)cyclopropanecarboxamide [008401 To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.73 g, 3.0 mmol) was added thionyl chloride (660 pL, 9.0 mmol) and DMF (20 gL) at room temperature. The mixture was stirred for 30 minutes before the excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (6.0 mL) and Et 3 N (2.1 mL, 15 mmol) were added. A solution of (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl-IH-indol 5-amine (3.0 mmol) in dichloromethane (3.0 mL) was added to the cooled acid chloride solution. After addition, the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was 209 purified by column chromatography on silica gel (ethyl acetate/hexane = 3/7) to give N-((R)-2 tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.33 g, 84%). 'H NMR (400 MHz, CDC1 3 ) 5 7.48 (d, J = 2 Hz, 1H,), 7.31 (dd, J = 2, 8 Hz, IH), 7.27 (dd, J = 2, 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.14 (d, J = 8 Hz, IH), 7.02 (dd, J = 2, 8 Hz, IH), 6.92 (br s, IH), 6.22 (s, 1H), 4.38-4.05 (in, 3H), 3.91 (dd, J = 5, 8 Hz, 1H), 3.75 (dd, J = 5, 8 Hz, 1H), 2.33 (q, J = 8 Hz, 2H), 1.42 (s, 3H), 1.37 (s, 9H), 1.22 (s, 3H), 1.10 (q, J = 8 Hz, 2H). H r7H F PTSA [008411 N-((R)-2-tert-Butyl-1-((2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo [d] [1,3]dioxol-5-yl)cyclopropanecarboxaIide [008421 To a stirred solution of N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) 1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamnide (1.28 g, 2.43 mmol) in methanol (34 mL) and water (3.7 mL) was added para-toluenesulfonic acid-hydrate (1.87 g, 9.83 mmol). The reaction mixture was stirred and heated at 80 "C for 25 minutes. The solvent was evaporated under reduced pressure. The crude product was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3 (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane = 13/7) to give N-((R)-2-tert-butyl-1-((2,3-dihydroxypropyl)-IH-indol-5-yl)-1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.96 g, 81%). 'H NMR (400 MHz, CDCl 3 ) 5 7.50 (d, J = 2 Hz, IH), 7.31 (dd, J = 2, 8 Hz, IH), 7.27 (dd, J = 2, 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.14 (d, J= 8 Hz, 1H), 7.02 (br s, IH,), 6.96 (dd, J = 2, 8 Hz, IH), 6.23 (s, IH), 4.35 (dd, J = 8, 15 Hz, 1H), 4.26 (dd, J = 4, 15 Hz, 1H,), 4.02-3.95 (m, IH), 3.60 (dd, J= 4, 11 Hz, IH), 3.50 (dd, J = 5, 11 Hz, IH), 1.75 (q, J = 8 Hz, 3H), 1.43 (s, 9H), 1.14 (q, J = 8 Hz, 3H). [00843] Example 73: 3-(2-tert-Butyl-5-(-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-H-indol-1-y)- 2 -hydroxypropanoic acid 210 O Ac

OL

4 OACH D MBH 4 R TTF O OH OH FaH FO~ 0 F}{ OOH DMSO, RTO OH OH OH S _N, amdo-1-ndl--y)2-xoroaoi ai MeOHM50 RT r OHH - :OHH OHH [00845] To a solution of N-(2--tert-butyl-1I-(2,3-dihydroxypropyl)-1I H-indol-5-yl)- 1-(2,2 difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane-carboxamide (97 mg, 0.20 mmol) in DMSO (1 mL) was added Dess-Martin periodinane (130 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 h. The solid was filtered off and washed with EtOAc. The filtrate was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine and dried over MgSO 4 . After the removal of solvent, the residue was purified by preparative TLC to yield 3 -(2-tert-butyl 5-(1I-(2,2-difluorobenzold] [1 ,3]dioxol-5-y1)cyclopropanecarboxamido)-1IH-indol-1I-y1)-2 oxopropanoic acid that was used without further purification. H N F, N MeOH, RT F 0 [00846] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbox amido)-1H-indol-1-yl)-2-hydroxypropaoic acid [00847] To a solution of 3-(2-tert-butyl-5-(1-(2,2-difluorobenzold][1,3]dioxol-5 yil)cyclopropanecarboxamido)-1H-indol-1yl)- 2 -opropanoic acid (50 mg, 0.10 mmol) in MeOH (1 mL) was added NaBH 4 (19 mg, 0.50 mmol) at 0 C. The mixture was stirred at room temperature for 15 mi. The resulting mixture was partitioned between EtOAc and 211 water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine and dried over anhydrous MgSO 4 . After the removal of the solvent, the residue was taken up in DMSO and purified by preparative LC/MS to give 3-(2-tert butyl-5-(I-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl) 2-hydroxypropanoic acid. 1H NMR (400 MHz, CDC1 3 ) 8 7.36 (s), 7.27-7.23 (m, 2H), 7.15 7.11 (m, 2H), 6.94 (d, J = 8.5 Hz, 1H), 6.23 (s, IH), 4.71 (s, 3H), 4.59 (q, J = 10.3 Hz, 1H), 4.40-4.33 (m, 2H), 1.70 (d, J= 1.9 Hz, 2H), 1.15 (q, J= 4.0 Hz, 2H). ' 3 C NMR (400 MHz, CDCl 3 ) 8 173.6, 173.1, 150.7, 144.1, 143.6, 136.2, 135.4, 134.3, 131.7, 129.2, 129.0, 127.6, 126.7, 116.6, 114.2, 112.4, 110.4, 110.1, 99.7, 70.3, 48.5, 32.6, 30.9, 30.7, 16.8. MS (ESI) m/e (M+H*) 501.2. [00848] Example 74: (R)-N-(2-tert-Butyl--(2,3-dihydroxypropyl)-1H-indol-5-yl)-1 (2,2-dideuteriumbenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide HO . OH MeOH HO : O, CD 2 Br 2 D 0 NaOH HO O pTsO HO s 2 Cca, DMF, 0 0 O THF-H20, 80*C

H

2 N ' SN OK OH D o O N N-TO 0- O H e H- 2 , 8 0 OH H -, OH MeOH H Ho f 0 p-TsOH HO - 0 [008491 Methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate [008501 To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (190 mg, 1.0 mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonic acid (19 mg, 0.10 mmol). The mixture was heated at 80*C overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with sat. NaHCO 3 and brine and dried over MgSO 4 . After the removal of solvent, the residue was dried in vacuo to yield methyl 1-(3,4- 212 dihydroxyphenyl)cyclopropanecarboxylate (190 mg, 91%) that was used without further purification. 'H NMR (400 MHz, DMSO-d 6 ) 5 6.76-6.71 (m, 2H), 6.66 (d, J = 7.9 Hz, 1H), 3.56 (s, 3H), 1.50 (q, J = 3.6 Hz, 2H), 1.08 (q, J = 3.6 Hz, 2H). HO 0- O CD 2 Br 2 D O Os HO / 0 Cs 2

CO

3 , DMF, 120 0 C D O [008511 Methyl 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylate [008521 To a solution of methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate (21 mg, 0.10 mmol) and CD 2 Br 2 (35 mg, 0.20 mmol) in DMF (0.5 mL) was added Cs 2

CO

3 (19 mg, 0.10 mmol). The mixture was heated at 120*C for 30 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with IN NaOH and brine before being dried over MgSO 4 . After the removal of solvent, the residue was dried in vacuo to yield methyl 1 (2,2-dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylate (22 mg) that was used without further purification. 'H NMR (400 MHz, CDC1 3 ) 8 6.76-6.71 (m, 2H), 6.66 (d, J 7.9 Hz, IH), 3.56 (s, 3H), 1.50 (q, J = 3.6 Hz, 2H), 1.08 (q, J = 3.6 Hz, 2H). D O THF NaOH D 0 OH D 0 I ~ TF- 2 0, 80C D0 0 [008531 1-(2,2-Dideuteriumbenzo[d][1,3]dioxo-5-yl)cyclopropanecarboxylic acid [008541 To a solution of methyl 1.-(2,2-dideuteriumbenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxylate (22 mg, 0.10 mmol) in THF (0.5 mL) was added NaOH (IN, 0.25 mL, 0.25 mmol). The mixture was heated at 80*C for 2 h. The reaction mixture was partitioned between EtOAc and IN NaOH. The aqueous layer was extracted with EtOAc twice, neutralized with IN HCl and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was dried in vacuo to yield 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxylic acid (21 mg) that was used without further purification.

H

2 N N H OH D ON D'O: 0 00 - 0~ D 0 . HATU, NEt. DMF, RT [008551 (R)-N-(2-tert-Butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl) 1-(2,2-dideuteriumbenzo[d][1 ,3]dioxol-5-yl)cyclopropanecarboxaiide 213 [008561 To a solution of 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxylic acid (21 mg, 0.10 mmol), (R)-2-tert-butyl-1-((2,2-dimethyl-1, 3 dioxolan-4-yl)methyl)- 1 H-indol-5-amine (30 mg, 0.10 mmol), HATU (42 mg, 0.11 mol) in DMF (1 mL) was added triethylamine (0.030 mL, 0.22 mmol). The mixture was heated at room temperature for 5 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with IN NaOH, IN HCI, and brine before being dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-40% ethyl acetate/hexane) to yield (R)-N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H indol-5-yl)-1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide (24 mg, 49% from methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate). MS (ESI) m/e (M+H*) 493.5. D p-TsOH D D)O M!0eOH-H 2 0,80OC DO0 0 N Q KOH K< OH [008571 (R)-N-(2-tert-Butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2 dideuterium-benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamifide [008581 To a solution of (R)-N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) 1H-indol-5-yl)-1-(2,2-dideuterium-benzo[d}[1,3]dioxol-5-y)cyclopropanecarboxamide (24 mg, 0.050 mmol), in methanol (0.5 mL) and water (0.05 mL) was added 4 methylbenzenesulfonic acid (2.0 mg, 0.010 mmol). The mixture was heated at 80*C for 30 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with sat. NaHCO 3 and brine before being dried over MgSO 4 . After the removal of solvent, the residue was purified by preparative HPLC to yield (R)-N-(2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4 yl)methyl)-1H-indol-5-yl)- 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide (12 mg, 52%). 'H NMR (400 MHz, CDCl 3 ) 8 7.44 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 22.8, 14.0 Hz, 2H), 6.95-6.89 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.14 (s, 1IH), 4.28 (dd, J = 15.1, 8.3 Hz, 1H), 4.19 (dd, J = 15.1, 4.5 Hz, 1H), 4.05 (q, J = 7.1 Hz, 1H), 3.55 (dd, J = 11.3, 4.0 Hz, 1H), 3.45 (dd, J = 11.3, 5.4 Hz, 1H), 1.60 (q, J = 3.5 Hz, 2H), 1.35 (s, 9H), 1.02 (q, J = 3.5 Hz, 2H). ' 3 C NMR (400 MHz, CDCl 3 ) 8 171.4, 149.3, 147.1, 146.5, 134.8, 132.3, 129.2, 126.5, 123.6, 114.3, 111.4, 110.4, 109.0, 107.8, 98.5, 70.4, 63.1, 46.6, 31.6, 30.0, 29.8, 15.3. MS (ESI) m/e (M+H*) 453.5.

214 [008591 It is further noted that the mono-deuterated analogue for this compound can be synthesized by substitution the reagent CHDBR 2 for CD 2

BR

2 and following the procedures described in example 74. Furthermore, deuterated analogues of the compounds as described herein such as of formula I can be produced using known synthesitc methods as well as the methodology described herein. The deuterated analogues include both di and mono deuterated analogues of the compounds of the present invention. The di and mono deuterated analoges of the compounds exhibit measurable acitivity when tested using the assays described below. [00860] Example 75: 4-(5-(1-(Benzo[d][1,3]dioxoI-5-yl)cyclopropanecarboxamido)-1H indol-2-yl)-4-methylpentanoic acid H OH i) SOCI 2 ,DMF N CN CN H H 77H KOH OH H OH 0 OH i)SOCI,.DMF CN K - ii) - J9-QCN 0oi 2 0 H *CNH H [008611 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide [008621 To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.068 g, 0.33 mmol) was added thionyl chloride (72 ptL, 0.99 mmol) and DMF (20 JIL) at room temperature. The mixture was stirred for 30 minutes before the excess thionyl chloride was evaporated under reduced pressure. To the resulting acid chloride, dichloromethane (0.5 mL) and Et 3 N (230 ptL, 1.7 mmol) were added. A solution of 4-(5-amino-1H-indol-2-yl)-4-methylpentanenitrile (0.33 mmol) in dichloromethane (0.5 mL) was added to the acid chloride solution and the mixture was stirred at room temperature for 1.5 h. The resulting mixture was diluted with dichloromethane and washed with I N HCl (2 x 2 mL), saturated aqueous NaHCO 3 (2 x 2 mL) and brine (2 x 2 mL). The organic layer was dried over anhydrous Na 2 SO4 and evaporated under reduced pressure to give I -(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano- 2 methylbutan-2-yl)-IH-inaol-5-yl)cyclopropanecarboxamide.

215 H N\N CN KOH OH

K

0 N N M N ~ KII HH OH 0 [008631 4-(5-(1-(Benzold][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-4 methylpentanoic acid [008641 A mixture of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H indol-5-yl)cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5 mmol) in 50% EtOH/water (2 mL) was heated in the microwave at 100 *C for 1 h. The solvent was evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered, and purified by reverse phase preparative HPLC to give 4-(5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-4-methylpentanoic acid. 'H NMR (400 MHz, DMSO-d6) 8 11.98 (s, 1H), 10.79 (s, 1H), 8.44 (s, 1H), 7.56 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.03-6.90 (m, 4H), 6.05 (s, 1H), 6.02 (s, 2H), 1.97-1.87 (m, 4H), 1.41-1.38 (m, 2H), 1.30 (s, 6H), 1.04-1.02 (m, 2H). [00865] Example 76: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H indol-5-yl)cyclopropanecarboxamide 2 o LiAIH 4 02 SnCl 2 .2H 2 0 H H H NN OH OH HBTU, Et 3 N OH H 2 ~H H o c t UALH 4 02 -N C0 2 Et -N OH H H [008661 2-(5-Nitro-1H-indol-2-yl)propan-1-o0 [008671 To a cooled solution of LiAlH 4 (1.0 M in THF, 1.2 mL, 1.2 mmol) in THF (5.3 mL) at 0 *C was added a solution of ethyl 2-(5-nitro-1H-indol-2-yl)propanoate (0.20 g, 0.76 mmol) in THF (3.66 mL) dropwise. After addition, the mixture was allowed to warm up to room temperature and was stirred at room temperature for 3 h. The mixture was cooled to 0 *C. Water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at room temperature for 0.5 h and was then filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 2-(5 -nitro- 1 H-indol-2-yl)propan- 1 -ol (0.14 g, 81%).

216 O2N OH SnC 2 .2H 2 0 H 2 N OH N OH 0 N OH H H 1008681 2-(5-Amino-1H-indol-2-yl)propan-1-oI [008691 To a solution of 2-(5-nitro-IH-indol-2-yl)propan-1-ol (0.13 g, 0.60 mmol) in ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). The mixture was heated in the microwave at 120 0 C for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO 3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na 2

SO

4 , filtered and evaporated under reduced pressure to give 2-(5-amino-1H indol-2-yl)propan-1-ol (0.093 g, 82%).

H

2 N H I O HBTU, Et 3 N ONOH N 0011 OH OH I-I H [008701 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide 1008711 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) were added HBTU (0.185 g, 0.49 mmol) and Et 3 N (205 RL, 1.47 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 minutes before a slurry of 2-(5-amino-IH-indol-2-yl)propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was stirred at room temperature for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with I N HCl (I x 3 mL) and saturated aqueous NaHCO 3 (1 x 3 mL). The organic layer was dried over Na 2

SO

4 , filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl.acetate/hexane = 13/7) to give 1-(benzo[d][1,3]dioxol-5 yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.095 g, 51%). 'H NMR (400 MHz, DMSO-d6) S 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, I H), 7.14 (d, J = 8.6 Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s, IH), , 6.02 (s, 2H), 4.76 (t, J= 5.3 Hz, IH), 3.68-3.63 (m, IH), 3.50-3.44 (m, 1 H), 2.99-2.90 (m, IH), 1.41-1.38 (m, 2H), 1.26 (d, J = 7.0 Hz, 3H), 1.05-1.02 (m, 2H). 1008721 Example 77: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N methylcyclopropanecarboxamide HATU O EtN 217 [00873] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N methylcyclopropanecarboxamide [008741 2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL). containing triethylamine (42.1 pL, 0.300 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,NN,N'-tetramethylurofnium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 80 *C. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-IH-indol-5-yl)-N methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)*. Retention time of 3.41 minutes. [00875] Example 78: N-(2-tert-Butyl-1-methyl-1H-indol-5-yl)---(benzo[d][1,3]dioxol 6-yl)-N-methylcyclopropanecarboxamide O ~~TH FC/ DMF 1) NaH Oa 02)

CH

3 1 \ ~~0 [00876] Sodium hydride (0.028 g, 0.70 mmol, 60% by weight dispersion in oil) was slowly added to a stirred solution of N-(2-tert-butyl-IH-indol-5-yl)-1 -(benzo[d][1,3]dioxol-6 yl)cyclopropanecarboxamide (0.250 g, 0.664 mmol) in a mixture of 4.5 mL of anhydrous tetrahydrofuran (THF) and 0.5 mL of anhydrous NN-dimethylformamide (DMF). The resulting suspension was allowed to stir for 2 minutes and then iodomethane (0.062 mL, 1.0 mmol) was added to the reaction mixture. Two additional aliquots of sodium hydride and iodomethane were required to consume all of the starting material which was monitored by LC / MS. The crude reaction product was evaporated to dryness, redissolved in a minimum of DMF and purified by preparative LC / MS chromatography to yield the pure product (0.0343 g, 13%) ESI-MS m/z calc. 404.2, found 405.3 (M+1)*. Retention time of 3.65 minutes. [00877] Example 79: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl)-1H-indol-5 yl)cyclopropanecarboxamide H H o)2t N 0 LiBH 4 , THF/H 2 0 ON O K ( I / OEt 25 0 C,l6hrs 0:]V NH H H [00878] Ethyl 5-(1-(benzo[d]{1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2 carboxylate (1.18 g, 3.0 mmol) was added to a solution of LiBH 4 (132 mg, 6.0 mmol) in THF 218 (10 mL) and water (0.1 mL). The mixture was allowed to stir for 16h at 25 'C before it was quenched with water (10 mL) and slowly made acidic by addition of I N HCL. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na 2

SO

4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl) 1H-indol-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 350.4, found 351.3 (M+1)*; retention time 2.59 minutes. [00879] Example 80: 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N tert-butyl-1H-indole-2-carboxamiide H H H 2 N.r0 H o I N OEt H 2 0 1,4-dioxane OH HATU, Et 3 N, DMF N 0. H UH H0 H H o N / Et H 2 0 1 4-dioxane oO [008801 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole- 2 carboxylic acid [008811 .Ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2 carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in H 2 0 (5 mL) and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100 0 C for 24 hours before it was cooled to room temperature. The mixture was acidified with IN HC1 and it was extracted with three 20 mL portions of dichloromethane. The organic extracts were dried over Na 2

SO

4 and evaporated to yield 5-(1-(benzo[d][1,3]-dioxol-5 yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 364.1, found 365.1 (M+1)+; retention time 2.70 minutes. H H 2 N- H ONDOOH HATU, EtN, DMF O N [008821 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-1H indole-2-carboxamide [00883] 5-(I-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2 carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12 mmol) were dissolved in NN-dimethylformamide (1.0 mL) containing triethylamine (28 tL, 0.20 mmol). O-(7-Azabenzotriazol-1 -yl)-N,N,N',N'-tetrarnethyluronium hexafluorophosphate (46 mg, 0.12 219 mnimol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamnido)-N-tert-butyl-1H-indole-2 carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)*; retention time 3.12 minutes. [008841 Example 81: N-(3-Amino-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide H H o ~N NaNO 2 Kil AcOH/H/I 0: :) N /NH NO H zn O N AcOH NNH V H . NH 2 [008851 A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5 yl)cyclopropane carboxamide (50 mg, 0.13 mmol) was dissolved in AcOH (2 mL) and warmed to 45 *C. To the mixture was added a solution of NaNO 2 (9 mg) in H 2 0 (0.03 mL). The mixture was allowed to stir for 30 min at 45 *C before the precipitate was collected and washed with Et 2 O. This material was used in the next step without further purification. To the crude material, 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-nitroso-1H-indol-5 yl)cyclopropanecarboxamide, was added AcOH (2 mL) and Zn dust (5 mg). The mixture was allowed to stir for lh at ambient temperature. EtOAc and H 2 0 were added to the mixture. The layers were separated and the organic layer was washed with sat. aq. NaHCO 3 , dried over MgSO 4 , and concentrated in vacuo. The residue was taken up in DMF (1 mL) and was purified using prep-HPLC. LCMS: m/z 392.3; retention time of 2.18 min. [008861 Example 82: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methylsulfonyl) 1H-indol-5-yl)cyclopropanecarboxamide 17H )NaH H S0 2 Me 0N 2) Me5,OaC H H [008871 1-(Benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl-3-(methylsulfonyl)-1H-indol-5 yl)cyclopropanecarboxamide [008881 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-IH-indol-5 yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N 2 , the suspension was cooled down to -15 *C and a solution of methanesulfonyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 220 30 min at -15 *C then for 6 h at room temperature. Water (0.5 mL) was added at 0 *C, solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methylsulfonyl)-1H-indol-5 yl)cyclopropanecarboxamide. 'H NMR (400 MHz, DMSO) 8 11.6 (s, 1H), 8.7 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.33 (dd, JJ =1.9 Hz, J2 =8.7 Hz, 1H), 7.03 (d, J =1.7 Hz, IH), 6.95 (dd, JJ =1.7 Hz, J2 =8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, IH), 6.02 (s, 2H), 3.07 (s, 3H), 1.56-1.40 (m, 9H), 1.41 (dd, JJ =4.0 Hz, J2 =6.7 Hz, 2H), 1.03 (dd, JI =4.0 Hz, J2 =6.7 Hz, 2H). MS (ESI) m/e (M+H*) 455.5. [008891 Example 83: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-1H-indol-5 yl)cyclopropane carboxamide OH HH Br HOB.j V H H HH NBN (O NBS Hyr 0 :Y H H [008901 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-1H-indol-5 yl)cyclopropanecarboxamide [008911 Freshly recrystallized N-bromosuccinimde (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(1H-indol-5 yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in NN-dimethylformamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes. The resulting green solution was poured into 40 mL of water. The grey precipitate which formed was filtered and washed with water to -yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3 bromo-1H-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc. 398.0, found 399.3 (M+1)*. Retention time of 3.38 minutes. 'H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J= 1.8 Hz, 1H), 7.50 (d, J= 2.6 Hz, 1H), 7.29 (d, J= 8.8 Hz, IH), 7.22 (dd, J= 2.0, 8.8 Hz, 1H), 7.02 (d, J= 1.6 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.03 (s, 2H), 1.43 - 1.40 (m, 2H), 1.09 - 1.04 (m, 2H).

221 OH H Br FHr 01 H 100892]1 1-(Benzold] [1,3] dioxol-5-yl)-N-(3-phenyI-1H-in~doI-5 yl)cyclopropanecarboxamfide [008931 Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1 (benzo [d] [1,3 ]-dioxol-5-yl)-N-(3 -bromo-1IH-indol-5-y1)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130 *C in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1 (benzo[d][1,3]dioxol-5-y)-N-(3-phenyl-IH-indol-5-yl)cyclopropane carboxamide. ESI-MS m/z calc. 396.2, found 397.3 (M+1)*. Retention time of 3.52 minutes. 'H NMR (400 MHz, DMSO-d6) 8 11.27 (d, J= 1.9 Hz, IH), 8.66 (s, IH), 8.08 (d, J= 1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J= 8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J= 1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H). [008941 Example 84: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5 yl)cyclopropanecarboxamide - - H O H POcly DMF H2N-OH, DCM 0o N H .H 0 H H o . - Ac 2 O o- N o N C2 0 N H H4)t XYNHO-N

'

H o POCI, DMF 0H H H 0 [008951 1-(Benzo[dl[1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5 yl)cyclopropane-carboxamide [008961 POC13 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at -20 *C. After the addition was complete, the reaction mixture was allowed to warm to 0 *C and was stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-IH-indol-5 yl)cyclopropanec.arboxamide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25 222 'C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h. The mixture was then heated at 100 *C for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL of a saturated aq. NaHCO 3 . The organics were dried over Na 2

SO

4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3 formyl-1H-indol-5-y1)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc. 404.5, found 405.5 (M+1)*; retention time 3.30 minutes. 'H NMR (400 MHz, DMSO-d6) 8 11.48 (s, 1H), 10.39 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97 6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H). H H 0 IH/ 2 N-OH, DCM o0 0 N H- H 0 HO-N [008971 (Z)-1-(Benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl-3-((hydroxyimino)methyl)-1H indol-5-yl)cyclopropanecarboxamide [008981 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-IH-indol-5 yl)cyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate/hexanes) to yield (Z)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3 ((hydroxyimino)methyl)-1 H-indol-5-yl)cyclopropanecarboxamide (81 mg, 77%). ESI-MS m/z calc. 419.5, found 420.5 (M+1)*; retention time 3.42 minutes. 'H NMR (400 MHz, DMSO-d6) 5 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 1.43 (s, 9H), 1.40 1.38 (m, 2H), 1.04-1.01 (m, 2H). H IH o N Ac 2 O O 0 N

K

0 N::) H H/ HO-N [008991 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5 yl)cyclopropane-carboxamide [009001 (Z)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)-methy1)-1H indol-5-yl)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and the precipitate was collected and washed with water. The solid was further dried under high vacuum to yield 1-(benzo[d][1,3]dioxol-5-y1)-N-(2-tert-butyl-3-cyano-IH-indol-5- 223 yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.5, found 402.5 (M+1)*; retention time 3.70 minutes. 'H NMR (400 MHz, DMSO-d6) S 11.72 (s, IH), 8.79 (s, 1H), 7.79 (s, 1H), 7.32 (m, 2H), 7.03-7.02 (m, 1H), 6.95-6.89 (m, 2H), 6.03 (s, 2H), 1.47 (s, 9H), 1.43-1.41 (in, 2H), 1.06-1.04 (in, 2H). [009011 Example 85: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-methyl-1H-indol-5 yl)cyclopropanecarboxamfide H H N Mel, DMF N HH [009021 A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5 yl)cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 pLL, 2.0 mmol) in N,N-dimethylformamide (1 mL) was heated at 120 'C in a sealed tube for 24 h. The reaction was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 390.5, found 391.3 (M+1)*; retention time 2.04 minutes. 'H NMR (400 MHz, DMSO-d6) 8 10.30 (s, 1H), 8.39 (s, 1H), 7.51 (m, IH), 7.13-7.11 (in, 1H), 7.03-6.90 (in, 4H), 6.03 (s, 2H), 2.25 (s, 3H), 1.40 1.38 (m, 11H), 1.03-1.01 (m, 2H). [009031 Example 86: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(2-hydroxyethyl) 1H-indol-5-yl)cyclopropanecarboxamide H nH N 211 /j N o0'N InC 3 , DCM 0 N H H HO [00904] Approximately 100 ptL of ethylene dioxide was condensed in a reaction tube at -78 0 C. A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5 yl)cyclopropanecarboxamide (200 mg, 0.50 mmol) and indium trichloride (20 mg, 0.10 mmol) in dichloromethane (2 mL) was added and the reaction mixture was irradiated in the microwave for 20 min at 100 *C. The volatiles were removed and the residue was purified by column chromatography (0-100 % ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5 yl)-N-(2-tert-butyl-3-(2-hydroxyethyl)-IH-indol-5-yl)cyclopropanecarboxamide (5 mg, 3%). ESI-MS m/z calc. 420.5, found 421.3 (M+1)+; retention time 1.67 minutes. 'H NMR (400 MHz, CD 3 CN) 6 8.78 (s, IH), 7.40 (m, 1H), 7.33 (s, I H), 7.08 (in, 1H), 6.95 - 6.87 (in, 3H), 6.79 (m, 1H), 5.91 (s, 2H), 3.51 (dd, J = 5.9, 7.8 Hz, 2H), 2.92 - 2.88 (m, 2H), 2.64 (t, J = 5.8 Hz, 1H), 1.50 (m, 2H), 1.41 (s, 9H), 1.06 (n, 2H). 1009051 Example 87: 2-(5-(1-(Benzoldl[1,31dioxol-5-yl)cyclopropanecarboxamido)-IH indol-2-yl)acetic acid 224 1 7 L OH.

H

2 0 O o ; - N

THF/H

2 O I o LN CO 2 H 0 N C 2 Et H [009061 To a solution of ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-1H-indol-2-yl)acetate (0.010 g, 0.025 mmol) in THF (0.3 mL) were added LiOH.H 2 0 (0.002 g, 0.05 mmol) and water (0.15 mL) were added. The mixture was stirred at room temperature for 2 h. dichloromethane (3 mL) was added to the reaction mixture and the organic layer was washed with 1 N HCI (2 x 1.5 mL) and water (2 x 1.5 mL). The organic layer was dried over Na 2 SO4 and filtered. The filtrate was evaporated under reduced pressure to give 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H indol-2-yl)-acetic acid. 'H NMR (400 MHz, DMSO-d6) 8 12.53 (s, 1H), 10.90 (s, 1H), 8.42 (s, IH), 7.57 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.17 (s, 1H), 6.02 (s, 2H), 3.69 (s, 2H), 1.41-1.39 (m, 2H), 1.04-1.02 (m, 2H). [009071 Example 88: 5-(1-(Benzo[dl[1,3]dioxol-5-yl)cyclopropanecarboxanmido)-2-tert butyl-1H-indole-7-carboxylic acid H H 0 N LiOH N 0 N 0 N H H 0 00 OH [009081 Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl 1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2 mL) containing a magnetic star bar and lithium hydroxide (30 mg, 0.71 mmol). The resulting solution was stirred at 70 *C for 45 minutes. The crude product was then acidified with 2.6 M hydrochloric acid and extracted three times with an equivalent volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimum of NN-dimethylformamide and then purified by preparative HPLC using a gradient of 0 99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylic acid. ESI-MS m/z calc. 434.2, found 435.5. Retention time of 1.85 minutes. 'H NMR (400 MHz, DMSO-d6) 5 13.05 (s, IH), 9.96 (d, J== 1.6 Hz, I H), 7.89 (d, J= 1.9 Hz, IH), 7.74 (d, J= 2.0 Hz, IH), 7.02 (d, J= 1.6 Hz,- I H), 6.96-6.88 (m, 2H), 6.22 (d, J= 2.3 Hz, 1H), 6.02 (s, 2H), 1.43 - 1.40 (in, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H). [00909] Example 89: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3 dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide 225 H O H LOH OO 0 OOH OH H Na(OAC) 3 BHH H'- A >OH 0 OH [009101 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2 yl)indolin-5-yl)cyclopropanecarboxamide [009111 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in dichloroethane (0.20 mL) and 2,2-dimethyl-1,3-dioxan-5-one (0.20 mL). Trifluoroacetic acid was added (0.039 mL) and the resulting solution was allowed to stir for 20 minutes. Sodium triacetoxyborohydride was added (55 mg, 0.26 mmol) and the reaction mixture was stirred for 30 minutes. The crude reaction mixture was then evaporated to dryness, dissolved in NN-dimethylformamide and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid. Chloranil N OH OH [009121 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)-1H indol-5-yl)cyclopropanecarboxamide [009131 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)indolin 5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6 tetrachlorocyclohexa-2,5-diene- 1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100 *C in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in a 1 mL of N,N-dimethylformamide and purified by purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3 dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxanide. ESI-MS m/z calc. 450.2, found 451.5 (M+1)*. Retention time of 1.59 minutes.

226 [009141 Example 90: N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1 (benzo[di [1,31-dioxol-5-yl)cyclopropanecarboxamide H Pd(IC H oI N

H

2 a ~N 0 .X 0 N 0 D O N H H II NH 2 N [00915] N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide . [009161 . 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-yano-1H-indol-5 yl)cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of ethyl acetate. The solution was recirculated through a continuous flow hydrogenation reactor containing 10% palladium on carbon at 100 *C under 100 bar of hydrogen for 8 h. The crude product was then evaporated to dryness and purified on 12 g of silica gel utilizing a gradient of 0 100% ethyl acetate (containing 0.5% triethylamine) in hexanes to yield N-(7-(aminomethyl) 2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)-cyclopropanecarboxamide (121 mg, 32%). ESI-MS m/z calc. 405.2, found 406.5 (M+1)*. Retention time of 1.48 minutes. [00917] Example 91: 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert butyl-1H-indole-7-carboxamide H H o N H 2 0 2 O : N H H II0 NH 2 N [00918] 5-(1-(Benzo d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H indole-7-carboxamide [009191 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl) cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of methanol (1.8 mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium hydroxide (0.150 mL). The resulting suspension was stirred for 72 h at room temperature. The hydrogen peroxide was then quenched with sodium sulfite. The reaction mixture was diluted with 0.5 mL of NN-dimethylformamide, filtered, and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1 -(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-2-tert-butyl-1H-indole-7 carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)*. Retention time of 1.74 minutes. [009201 Example 92: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl- 7 (methylsulfonamido-methyl)-1H-indol-5-yl)cyclopropanecarboxamide 227 H CH 3

SO

2 CI H

K

0 i~ N Et 3 N N < -D~r0 -Or N 01 D 0 H H

NH

2 NH

-S

0 [009211 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-(methylsulfonamidomethyl)-1H indol-5-yl)cyclopropanecarboxamide [009221 N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 p.L, 0.147 mmol) and a magnetic stir bar. Methanesulfonyl chloride (4.2 p.L, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7 (methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 483.2, found 484.3 (M+1)*. Retention time of 1.84 minutes. [009231 Example 93: N-(7-(Acetamidomethyl)-2-tert-butyl-1H-indol-5-yl)-l (benzo[d] [1,3]-dioxol-5-yl)cyclopropanecarboxamide o H CHCOCI H 0 Et 0 0 Nq H H

NH

2 NH [009241 N-(7-(Aminomethyl)-2-tert-butyl-IH-indol-5-yl)-I-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 ptL, 0.147 mmol) and a magnetic stir bar. Acetyl chloride (4.2 ptL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(7-(acetamidomethyl)-2-tert-butyl- IH-indol-5-y1)-l -(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamide. ESI-MS m/z calc. 447.2, found 448.3 (M+1)+. Retention time of 1.76 minutes. [00925] Example 94: N-(1-Acetyl-2-tert-butyl-1H-indol-5-yI)-1-(benzold][1,3]dioxol-5 yl)-cyclopropanecarboxamide 228 H '7H 1) NaH N N ~DMF-THF I \+ 0 0) N 2) ACCI N H [009261 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl- IH-indol-5 yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N 2 , the suspension was cooled down to -15 *C and a solution of acetyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at 15 'C then for 6 h at room temperature. Water (0.5 mL) was added at 0 'C, solvent was removed, and the residue was diluted with MeOH, filtrated and purified by preparative HPLC to give N-(1 -acetyl-2-tert-butyl- 1 H-indol-5-yl)-1 -(benzo[d] [1,3]dioxol-5-yl)cyclo propanecarboxamide. 'H NMR (400 MHz, DMSO) S 8.9 (s, IH), 7.74 (d, J=2.1 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.28 (dd, JJ =2.1 Hz, J2 =9.0 Hz, 1H), 7.01 (d, J=1.5 Hz, IH), 6.93 (dd, JJ =1.7 Hz, J2 =8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, IH), 6.54 (bs, I H), 6.02 (s, 2H), 2.80 (s, 3H), 1.42-1.40 (m, 11H), 1.06-1.05 (m, 2H). MS (ESI) m/e (M+H*) 419.3. [009271 Example 95: N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol- 5 -yl)-1 (2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide H N TFA, CH 2

C

2 F ><: If ) N F F~- N 0 HN

NH

2 H

CH

3 COCI Et 3 N, DMF F HN~< DC7H H N-> 0 TFA, CH 2

CI

2

F

0 _/ N F0 0 N 0 [00928] N-(1-(2-Aminoethyl)-2-tert-butyl1-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo [d] [1,3]dioxol-5-yl)cyclopropanecarboxamide [009291 To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-yl)ethylcarbamate (620 mg, 1.08 mmol) 229 in CH 2 C1 2 (8 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1.5 h before being neutralized with solid NaHCO 3 . The solution was partitioned between

H

2 0 and CH 2 C1 2 . The organic layer was dried over MgSO 4 , filtered and concentrated to yield the product as a cream colored solid (365 mg, 71%). 'H NMR (400 MHz, DMSO-d6) 5 8.38 (s, 1H), 7.87 (br s, 3H, NH3+), 7.52 (s, 1H), 7.45-7.38 (m, 3H), 7.32 (dd, J = 8.3, 1.5 Hz, 1H), 6.21 (s, 1H), 4.46 (m, 2H), 3.02 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H), 1.14 (m, 2H). HPLC ret. time 1.66 min, 10-99 % CH 3 CN, 3 min run; ESI-MS 474.4 m/z (M+H). H HN 0 ,CH,,COCI NN> F NEN.M IF N

NH

2 HN [00930] N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol- 5 -yl)-l-( 2

,

2 difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00931] To a solution of N-(I-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2 difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et 3 N (28 pL, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 pL, 0.10 mmol). The mixture was stirred at room temperature for 1 h before being filtered and purified by reverse phase HPLC (10 - 99 % CH 3 CN/ H 2 0) to yield N-(1-(2-acetanidoethyl)-2-tert-butyl-6 fluoro-1 H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y)cyclopropanecarboxamide. 'H NMR (400 MHz, DMSO-d6)-&8:35 (s, 1H), 8.15 (t, J = 5.9 Hz, 1 H), 7.53 (s, 1H), 7.43 7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m, 2H), 1.41 (s, 9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99 % CH 3 CN, 3 min run; ESI-MS 516.4 m/z (M+H*). [009321 Example 96: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-hydroxy-3 methoxy-propyl)-1H-indol-5-yl)cyclopropenecarboxamide 1. NaH, DMF-THF H 0H K0C N N 0 2. MeOH CO H H 0 [00933] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1 H-indol-5 yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N 2 . NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction 230 mixture was cooled to -15 *C before a solution of epichlorohydrin (79 ptL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at -15 *C, then for 8 h at room temperature. MeOH (1 mL) was added and the mixture was heated for 10 min at 105 *C in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl-l-(2 hydroxy-3-methoxy-propyl)-1H-indol-5-yl)cyclopropanecarboxamide. 'H NMR (400 MHz, DMSO-d6) 5 8.44 (s, IH), 7.59 (d, J= 1.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, IH), 7.03 (dd, J= 8.7, 1.9 Hz, 2H), 6.95 (dd, J= 8.0, 1.7 Hz, 1H), 6.90 (d, J= 8.0 Hz, IH), 6.16 (s, 1H), 6.03 (s, 2H), 4.33 (dd, J= 15.0, 4.0 Hz, IH), 4.19 (dd, J= 15.0, 8.1 Hz, IH), 4.02 (ddd, J= 8.7, 4.8 Hz, 1H), 3.41-3.32 (m, 2H), 3.30 (s, 3H), 1.41 (s, 9H), 1.41-1.38 (m, 2H), 1.03 (dd, J= 6.7, 4.0 Hz, 2H). MS (ESI) m/e (M+H*) 465.0. [009341 Example 97: 1-(Benzo[d][1,3]dioxol-5-yI)-N-(2-tert-butyl-1-(2-hydroxy-3 (methyl-amino)propyl)-1H-indol-5-yl)cyclopropanecarboxamide 1. NaH, DMF-THF H 0 H ON 2. MeNH 2 H HO HN 1009351 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5 yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N 2 . NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction mixture was cooled to -15 *C before a solution of epichlorohydrin (79 piL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at -15 *C, then for 8 h at room temperature. MeNH 2 (2.0 M in MeOH, 1.0 mL) was added and the mixture was heated for 10 min at 105 *C in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzo[d][1,3]dioxol-5-y)-N-( 2 tert-butyl-1-(2-hydroxy-3-(methylamino)propyl)-1H-indol-5-yl)cyclopropanecarboxamide. 'H NMR (400 MHz, DMSO-d6) 8 8.50 (s, IH), 7.60-7.59 (m, 1H), 7.35 (dd, J = 14.3, 8.9 Hz, 1H), 7.10 (d, J = 8.8 Hz, IH), 1H), 6.94 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.20 (d, J = 2.3 Hz, IH), 6.03 (s, 2H), 2.82 (d, J = 4.7 Hz, IH), 2.72 (d, J = 4.7 Hz, 1H), 2.55 (dd, J = 5.2, 5.2 Hz, 1H), 2.50 (s, 3H), 1.43 (s, 9H), 1.39 (dd, J = 6.4, 3.7 Hz, 2H), 1.04 (dd, J 6.5, 3.9 Hz, 2H). MS (ESI) m/e (M+HF) 464.0.

231 [009361 Example 98: (S)-N-(1-(3-Amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl) 1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide HH F TsCI, TEA, DCM F NaN3 FF SN H NOH OH OH OTs H 17H F 0. Pd/C F X KCOH OH

N

3 NH 2 HH F> N TsCI, TEADCM X&II F 0 F~ 0 N~ KOH __ _ _ >11: Ni~KOH OH OTs [009371 (R)-3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarbox-amido)-1H-indol-1-yl)-2-hydroxypropyl-4 methylbenzenesulfonate [009381 To a stirred solution of (R)-N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-IH-indol-5 yl)-1-(2,2-difluoro-benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (3.0 g, 6.1 mmol) in dichloromethane (20 mL) was added triethylamine (2 mL) and para-toluenesulfonylchloride (1.3 g, 7.0 mmol). After 18 hours, the reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified using column chromatography on silica gel (0-60% ethyl acetate/hexane) providing (R)-3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropyl-4-methyl benzenesulfonate (3.21 g, 86%). LC/MS (M + 1) = 641.2. 'H NMR (400 MHz, CDCl 3 ) 5 7.77 (d, 2H, J= 16 Hz), 7.55 (d, 1H, J= 2 Hz), 7.35 (d, 2H, J = 16 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, IH, J = 2, 8 Hz), 6.22 (s, IH), 4.33 (m, 1H), 4.31 (dd, 1H, J= 6, 15 Hz), 4.28 (dd, IH, J= 11, 15 Hz), 4.18 (m, IH), 3.40 (dd, IH, J= 3, 6 Hz), 3.36 (dd, 1H, J= 3, 6 Hz), 2.46 (s, 3H), 2.40 (br s, 1 H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2 H). H 77H F O F NaN 3 > 0 N Fo 0~ N OH OH OTs

N

3 232 [009391 (R)-N-(1-(3-Azido-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2 difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide [009401 To a stirred solution (R)-3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)- I H-indol- I -yl)-2-hydroxypropyl-4-methylbenzenesulfonate (3.2 g, 5.0 mmol) in DMF (6 mL) was added sodium azide (2.0 g, 30 mmol). The reaction was heated at 80 *C for 2 h. The mixture was partitioned between 20 mL ethyl acetate and 20 mL water. The layers were separated and the organic layer was evaporated. The residue was purified using column chromatography (0-85% ethyl acetate/hexane) to give (R)-N-(1-(3 azido-2-hydroxypropyl)-2-tert-butyl-IH-indol-5-yl)-I-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)-cyclopropanecarboxamide (2.48 g). LC/MS (M + 1) = 512.5. 'H NMR (400 MHz, CDCl 3 ) 8 7.55 (d, 1H, J= 2 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, 1H, J= 2, 8 Hz), 6.22 (s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J= 6, 15 Hz), 4.28 (dd, 1H, J= 11, 15 Hz), 4.18 (m, 1H), 3.40 (dd, 1H, J= 3, 6 Hz), 3.36 (dd, 1H, J= 3,6 Hz), 2.40 (br s, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2 H). ~~ ~ Pd/C F \oH

N

3 N

H

2 1909411 (S)-N-(1-(3Amino-2-hydroxypropyl)-2-tert-buty-1H-indol5-yl)-1-( 2

,

2 difluoro-benzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamfide 1009421 To a stirred solution (R)-N-( 1-(3 -azido-2-hydroxypropyl)-2-tert-butyl- 1H-indol-5 yl)-1-(2,2-difluorobenzo [d][1,3]ldioxol-5-yl)cyclopropanecarboxamide (2.4 g, 4.0 mmnol) in MeOH (25 mL ) was added 5 % Pd/C (2.4 g) under a Hydrogen gas filled balloon. After 18 h, the reaction mixture was filtered through celite and rinsed with 300 mL ethyl acetate. The organic layer was washed with 1 N HC1 and evaporated to give (S)-N-(1.-(3-amino-2 hydroxypropyl)-2-tert-butyl-1IH-indol-5-yl)-1I-(2,2-difluoro-benzo[d] [1,3]-dioxol-5 yl)cyclopropane-carboxamide (1.37 g). MS (M + 1) = 486.5. 1009431 Example 99: (S)-Methyl 3-(2-tert-butyl-5-(1-(2,2-difluorobezold][(1,3]dioxol [:NfH DCMTE F- H' N NH

NH

2 t00411(S)N-l-(-Amno2-hdroyprpy)-2ter-btylIH-ndo-5yl)I-(,0 233 [009441 To a stirred solution (R)-N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5 yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.10 g, 0.20 mmol) in methanol (1 mL) was added 2 drops of triethylamine and methylchloroformyl chloride (0.020 mL, 0.25 mmol). After 30 min, the reaction mixture was filtered and purified using reverse phase HPLC providing (S)-methyl 3-(2-tert-butyl-5-(I-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclo-propanecarboxamido)-IH-indol-1-yl)-2-hydroxypropylcarbamate. The retention time on a three minute run is 1.40 min. LC/MS (M + 1) = 544.3. 'H NMR (400 MHz, CDCl 3 ) S 7.52 (d, IH, J= 2Hz), 7.30 (dd, 1H, J= 2, 8 Hz), 7.28(m, IH), 7.22 (d, 1H, J= 8 Hz), 7.14 (d, 1H, J= 8 Hz), 7.04 (br s, 1H), 6.97 (dd, lH, J= 2, 8 Hz), 6.24 (s, 1H), 5.19 (1H, br s), 4.31 (dd, IH, J= 6, 15 Hz), 4.28 (dd, IH, J= 11, 15 Hz), 4.18 (m, 1H), 3.70 (s, 3H), 3.40 (dd, 1 H, J= 3, 6 Hz), 3.36 (dd, I H, J= 3, 6 Hz), 3.26 (m, 1H), 1.74 (m, 2H), 1.40 (s, 9 H), 1.11 (m, 2 H). [009451 Example 100: 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2 tert-butyl-1H-indol-1-yl)butanoic acid 0 "N H OH OK N NaBH 3 CN, AcOH N 0:0:N /O ID N NaBH 3 CN, H H MeOH-AcOH H H N NaBH 3 CN, AcOH N H OH [009461 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropanecarboxamide [00947] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl- IH-indol-5-yl)cyclo propanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 mL) was added NaBH 3 CN (309 mg, 4.91 mmol) at 0 "C. The reaction mixture was stirred for 5 min at room temperature after which no starting material could be detected by LCMS. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (5 40% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropanecarboxamide (760 mg, 89%).

234 0 OH H N Nj CN Q 00 N NaBH 3 CN, 0 0 H MeOH-AcOH 0 OH [009481 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert butylindolin-1-yl)butanoic acid [009491 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, I eq) in anhydrous methanol (6.5 mL) and AcOH (65 pL) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 min of stirring, NaBH 3 CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0 "C and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(I-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 30%). H H N, ,- COO1 3 , light N <openlair K I N 0 o OH OH [00950] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H indol-1-yl)butanoic acid [00951] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin 1-yl)butanoic acid (130 mg, 0.28 mmol) was taken up in a mixture of acetonitrile-H 2 0-TFA. The solvent was removed under reduced pressure and the residue obtained was dissolved in CDC1 3 . After a brief exposition to daylight (5-10 min), the solution turned purple. The mixture was stirred open to the atmosphere at room temperature until complete disappearance of the starting material (8 h). Solvent was removed under reduced pressure and the residue was purified by reverse pharse HPLC to give 4-(5-(1-(benzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-2-tert-butyl- 1 H-indol-1-yl)butanoic acid. 'H NMR (400 MHz, CDCl 3 ) 6 7.52 (d, J = 1.9 Hz, 1H), 7.18 (d, J == 2.1 Hz, IH), 7.16 (s, IH), 7.03 (dd, J = 9.4, 1.9 Hz, 1H), 7.00-6.98 (m, 2H), 6.85 (d, J = 7.9 Hz, 1H), 6.16 (s, 1H), 6.02 (s, 2H), 4.29-4.24 (m, 235 2H), 2.48 (dd, J = 6.9, 6.9 Hz, 2H), 2.12-2.04 (m, 2H), 1.69 (dd, J = 6.8, 3.7 Hz, 2H), 1.43 (s, 9H), 1.09 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H*) 463.0. [00952] Example 101: 1-(Benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl-1-(4-(2 hydroxyethyl-amino)-4-oxobutyl)-lH-indol-5-yl)cyclopropanecarboxamide H H N N HBTU Et0N, -zDMF K i O N ethanolamine 0OH HNf/OH OH [00953] To a solution of 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2 tert-butyl-1H-indol-1-yl)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were successively added Et 3 N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring for 10 min at 60 *C, ethanolamine (1.3 p.L, 0.022 mmol) was added, and the mixture was stirred for another 4 h at 60 *C. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(4-(2 hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) m/e (M+H*) 506.0. [009541 Example 102: 1-(Benzo[d] [1,3]dioxol-5-yI)-N-(2-tert-butyl-1-(2 (dimethylamino)-2-oxoethyl)-1H-indol-5-yl)cyclopropanecarboxamlide 1. NaH, DMF-THF 0 < ;7 H C K" J. - H N NN H2CID Pd-C

N---

/ N [009551 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 mL) and THF (1 mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N 2 . After 30 min of stirring, the reaction mixture was cooled to 0 *C and 2-chloro-N,N dimethylacetamide (11 mL, 0.14 mmol,) was added. The reaction mixture was stirred for 5 min at 0 *C and then for 10 h at room temperature. The mixture was purified by preparative HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of Pd-C (10 mg). The mixture was stirred open to the atmosphere overnight at room temperature. The reaction mixture was filtrated and purified by preparative HPLC providing 1 (benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-indol-5 yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462.0.

236 [00956] Example 103: 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo propanecarboxamido)-1H-indol-1-yl)propanoic acid H 1. NaBH(OAc) 3 H MF FNt(:E>{ DGM Fy, .- EtNNCN,+DF. 'N 0F ' 0IiE0-O H KIci cl 1. 50%aq KOH H _ F F ~ I1,4-dioxane Fy NS F 0 ~~ 2. CDci3, light, air

Q$

1 .OH N OH ~7H 1. NaBH(OAc) 3 H H cN [009571 N-(2-tert-Butyl-1-(2-chloroethyl)indolin-5-yl)-1-(2,2 difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide [009581 To a solution of N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (71 mg, 0.17 mmol) in anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 piL, 0.41 mmol) at room temperature under N 2 . After 20 min of stirring, NaBH(OAc) 3 (90 mg, 0.42 mmol) was added in two- portions. The reaction-mixture was stirred overnight at room temperature. The product was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)-1 -(2,2-difluorobenzo[d][1,3]dioxol 5-yl)cyclopropanecarboxamide (51 mg, 63%). H H H NI NaCN, DMF,_:N+ N F K, EtOH-H 2 0 Fy I F 0 ~ NF~r Ozz- 0 D:> [009591 N-(2-tert-Butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2 difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide [009601 N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol 5-yl)cyclopropanecarboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and KI (cat) in EtOH (0.6 mL) and water (0.3 mL) were combined and heated at 110 "C for 30 min in the microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-.(2-tert- 237 butyl- 1-(2-cyanoethyl)indolin-5-yl)-I-(2,2-difluorobenzo[d] [1,3]dioxol-5 yl)cyclopropanecarboxamide (24 mg, 48%). H H F 1. 50%aq KOH F> F>KC 1,-ixn F C> 2. CDC 3 , light, air OH NZ0 [009611 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo propanecarbox-amido)-H-indol-1-yl)propanoic acid [009621 N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol 5-yl)cyclopropane-carboxamide (24 mg, 0.050 mmol) was taken up in 50% aq. KOH (0.5 mL) and 1,4-dioxane (1 mL). The mixture was heated at 125 0 C for 2 h. The solvent was removed and the residue was purified by preparative HPLC. The residue was dissolved in CDCl 3 (1 mL) then briefly exposed to daylight. The purple solution that formed was stirred until complete disappearance of the starting material (1 h). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC providing 3-(2-tert-butyl 5-(I-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1 H-indol-1 yl)propanoic acid. MS (ESI) m/e (M+H+) 485.0. [009631 Example 104: 1-(Benzo[d][1,3]dioxol-5-yi)-N-(2-tert-butyl-6-fluoro-1-(2 hydroxy-ethyl)-1H-indol-5-yl)cyclopropenecarboxamide 0 0 H 1.NH N:0 HH N 0 F NNaBH 3 CN KFI 01 H MeOH-AcOH 2. CDC3, light, air OH [009641 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5 yl)cyclopropanecarboxamide (340 mg, 0.86 mmol) in anhydrous MeOH (5.7 mL) containing 1% of acetic acid was added glyoxal 40% in water (0.60 mL, 5.2 mmol) at room temperature under N 2 . After 20 min of stirring, NaBH 3 CN (120 mg, 1.9 mmol) was added in one portion and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue obtained was purified by column chromatography on silica gel (10-40% ethyl acetate/hexanes) providing a pale yellow oil which was treated with 50/50 CH 3

CN-H

2 0 containing 0.05% TFA and CDCl 3 . Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20-35% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert butyl-6-fluoro-1-(2-hydroxyethyl)-1 H-indol-5-yl)cyclopropanecarboxamide. 'H NMR (400 238 MHz, CDC1 3 ) 5 8.02 (d, J = 7.7 Hz, IH), 7.30 (d, J = 2.1 Hz, IH), 6.93 (dd, J = 1.6, 7.9 Hz, IH), 6.90 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, IH), 6.78 (d, J = 7.9 Hz, 1H), 6.08 (s, 1H), 5.92 (s, 2H), 4.21 (dd, J = 6.9, 6.9 Hz, 2H), 3.68 (m, 2H), 2.28 (s, 1 H), 1.60 (dd, J = 3.7, 6.7 Hz, 2H), 1.35 - 1.32 (m, 9H), 1.04 (dd, J = 3.7, 6.8 Hz, 2H). MS (ESI) m/e (M+H*) 439.0. [009651 Example 105: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(3 hydroxy-propyl)-1H-indol-5-yl)cyclopropanecarboxamide H H N)CN NaBH(OAc) 3 , DCM N 0 0 F N 2. CDCI 3 ,lght, air K 0 F 3. Pd-C, H 2 , MeOH HO OH PCC, DCM 0 OBn OBn [009661 3-(Benzyloxy)propanal [00967] To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous dichloromethane (8 mL) at room temperature under N 2 was added a solution of 3-benzyloxy- 1 -propanol (310 mg, 1.88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred overnight at room temperature, filtrated through Celite, and concentrated. The residue was purified by column chromatography on silica gel (1-10% ethyl acetate/hexanes) to give 3 (benzyloxy)propanal (243 mg, 79%). O H 1 OBnH NNaBH(OAC) 3 , DCMV YN_ _ F N 2. CDC 3 , light, air H 3. Pd-C, H 2 , MeOH HO [009681 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxypropyl)-1H indol-5-yl)cyclopropanecarboxamide [009691 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5 yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After 10 min of stirring, NaBH(OAc) 3 (140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was taken-up in a mixture of 50/50 CH 3

CN-H

2 0 containing 0.05% TFA. The mixture was concentrated to dryness and the residue was dissolved in CDCl 3 (5 239 mL).and briefly exposed to daylight. The purple solution was stirred open to the atmosphere at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with Pd-C (10 mg) in MeOH (2 mL) under 1 atm of H 2 for 2 h. The catalyst was filtered through Celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC 30% ethyl acetate/hexanes to provide 1 (benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxypropyl)-IH-indol-5 yl)cyclopropanecarboxamide (18 mg, 8% from 1-(benzo[d][1,3]dioxol-5-y)-N-(2-tert-butyl 6-fluoroindolin-5-y)cyclopropane-carboxamfide). 'H NMR (400 MHz, CDCl 3 ) 8 8.11 (d, J= 7.8 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.94 (dd, J = 7.9, 1.7 Hz, 1H), 6.91 (d, J = 1.6 Hz, IH), 6.85 (d, J = 11.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, IH), 6.10 (s, IH), 5.94 (s, 2H), 4.25-4.21 (m, 2H), 3.70 (dd, J = 5.7, 5.7 Hz, 2H), 1.93-1.86 (m, 2H), 1.61 (dd, J = 6.8, 3.7 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453.0. [009701 Example 106: N-(1-(2-Acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1 (benzo[d] [1,3]-dioxol-5-yl)cyclopropanecarboxamide H A t 1 NaBH(O~c) 3 M-NC N <LN 0 2. Et 3 N, THF, H ACCH c2.D a,13 iigght,ht airN3H 3. NaN3. NalN DMIF 0 1. NaBH(OA) 3 N

-

OI Hx e2. CD 3 h lights n air N 3. NaN 3 . Nal, [009711 N-(1-(2-azidoethyl)-2-tert-butyl-1 H-indol-5-yl)-l-(benzoid][1,3ldioxol-5-yI) cyclopropanecarboxamide [00972] To a solution of 1-(benzo[d][1 ,3]dioxol-5-yl)-N-(2-tert-butylindolin-5 yl)cyclopropane-carboxamide (73 mg, 0.19 mmol) in anhydrous dichloromethane (1.2 mL) was added choroacetaldehyde (60 iL, 0.24 mmol) at room temperature. After 10 m of stirring, NaBH(OAc) 3 (52 mg, 0.24 mmol) was added in one portion and the reaction mixture was stirred for another 30 min at room temperature. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the indoline, which oxidized to the corresponding indole when taken-up in CDCI 3 . The resulting indole was treated with NaN 3 (58 mg, 0.89 mmol) and Nal (cat) in anhydrous DMF (0.8 mL) for 2 h at 85 'C. The reaction mixture was purified by preparative HPLC providing N-(l-(2- 240 azidoethyl)-2-tert-butyl- 1 H-indol-5-yl)- 1 -(benzo[d] [1,3]dioxol-5 yl)cyclopropanecarboxamide (15 mg, 18% from 1-(benzo[d][1,3]dioxol-5-y1)-N-(2-tert butylindolin-5-yl)cyclopropane-carboxamide). H + 1. Pd-CH H 2.E0 3 N, THF, N. 0 N N3 NH [00973] N-(1-(2-Acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5 yl)cyclopropanecarboxamide [009741 A solution of N-(1-(2-azidoethyl)-2-tert-butyl-IH-indol-5-yl)-1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH-AcOH (0.2 mL, 99:1) in the presence of Pd-C (2 mg) was stirred at room temperature under I atm of

H

2 for 2 h, filtered through Celite, and concentrated under reduced pressure. The crude product was treated with AcCi (0.05 mL) and Et 3 N (0.05 mL) in anhydrous THF (0.2 mL) at 0 "C for 30 min and then I h at room temperature. The mixture was purified by preparative HP LC providing N-(1-(2-acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H*) 462.0. [009751 Example 107: N-(2-tert-Butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1 (2,2-difluorobenzo [d] [1,3]dioxol-5-yl)cyclopropanecarboxamide H H O H F TsCI, B 3 TsEtNF F ,~~N _C I'& 2 K N NaCN_() F7><')_ HO HTC E tsN FZ F F ODCM FH HO TsO [009761 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbox am-ido)-lH-indol-1-yl)-2-hydroxypropyl-4-methylbenzenesulfonate [009771 To a solution of N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2 difluorobenzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide (172 mg, 0.35 mmol) in anhydrous dichloromethane (1.4 mL) at 0 "C in the presence of Et 3 N (56 VL, 0.40 mmol) was added TsC1 (71 mg, 0.37 mmol). The reaction mixture was stirred for 2 h at room 241 temperature before being cooled to 0 "C and another portion of TsCl (71 mg, 0.37 mmol) was added. After I h of stirring at room temperature, the mixture was purified by column chromatography on silica gel (10-30% ethyl acetate/hexanes) providing 3-(2-tert-butyl-5-(1 (2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2 hydroxypropyl-4-methylbenzene-sulfonate (146 mg, 64%). H H F NaCN,DMF N '0 N F o NO -HT HO N 1009781 N-(2-tert-Butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-l-( 2

,

2 difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide 1009791 N-(2-tert-Butyl-1-(3-cyano-2-hydroxypropyl)-IH-indol-5-yl)-1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamide (145 mg, 0.226 mmol) was treated with powdered NaCN (34 mg, 0.69 mmol) in anhydrous DMF (1.5 mL) at 85 *C for 2 h. The reaction mixture was cooled down to room temperature before it was diluted with dichloromethane (10 mL) and aq. sat. NaHCO 3 (10 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with brine, dried with sodium sulfate, filtered then concentrated. The residue was purified by column chromatography on silica gel (25-55% ethyl acetate/hexanes) providing N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-1 H-indol-5-yl)- 1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (89 mg, 79%). 'H NMR (400 MHz, CDCl 3 ) 8 7.43 (d, J = 1.9 Hz, lH), 7.20-7.16 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.94 (s, lH), 6.88 (dd, J = 8.7, 2.0 Hz, 1H), 6.16 (s, 1H), 4.32-4.19 (m, 3H), 2.83 (s, 1IH), 2.40 (dd, J = 5.2, 5.2 Hz, 2H), 1.62 (dd, J = 6.6, 3.6 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J = 6.9, 3.9 Hz, 2H). MS (ESI) m/e (M+H*) 496.0. [00980] Example 108: N-(2-tert-Butyl-1-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-1H indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide H H

N

N NN H [009811 To a solution of N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1 (2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054 mmol) in 242 anhydrous DMF (1.2 mL) were successively added NH 4 C1 (35 mg, 0.65 mmol) and NaN 3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h at 110 *C in the microwave, at which stage 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to provide N-(2-tert-butyl 1-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539.0. 1009821 Example 109: 4-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo propanecarboxamido)-H-indol-1-yl)-3-hydroxybutanoic acid N H N 1 MeOH, NaOH N H H H:< N 0 1009831 A solution of N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-IH-indol-5-yl)-1-(2,2 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (14 mg, 0.028 mmol) in methanol (0.8 mL) and 4 M NaOH (0.8 mL) was stirred at 60 *C for 4 h. The reaction mixture was neutralized with 4 M HCI and concentrated. The residue was purified by preparative HPLC to provide 4-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5 yl)cyclopropanecarboxamido)-IH-indol-1-yl)-3-hydroxybutanoic acid. MS (ESI) m/e (M+H+) 515.0. 100984] Example 110: N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-H-indol.-5-yl)-1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide NaCN,KI 0 1. NH 4 C4. NaN3,.7 H ~- ~ EItt0 -HQN0'\ DMF YOii Z~~t02CCIa,Iight, <0 N air N N NH I NaC. HJ H / ~. N EtOHI-H 2 0 - N 0 N'~r 0 Y CI \ N 1009851 1-(Benzold][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl) cyclopropanecarboxamide [009861 To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2 chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol (0.8 mL) 243 and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room temperature. The reaction mixture was stirred for 30 min at 110 "C in the microwave before being purified by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to provide 1 (benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1 -(2-cyano-ethyl)indolin-5 yl)cyclopropanecarboxamide (50 mg, 77%). H 1. NH 4 C, NaNs, H ONDMF .Oy N C N I NN 2. CDGl 3 , light, air N ,N N-NH [009871 N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1 (benzo[dl[1,3]dioxol-5-yl)cyclopropanecarboxamide [00988] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF (2.6 mL) was added NH 4 C1 (230 mg, 4.3 mmol) and NaN 3 (280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110 "C in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDCl 3 (3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to.give N-(1 -(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H*) 473.0. [009891 Example 111: 1-(Benzo[dl[1,31dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l ((tetrahydro-2H-pyran-3-yl)methyl)-1H-indol-5-yl)cyclopropanecarboxamiide H I.NaBH(OAc) 3 , F N DCM 0~ N 0 HOO 2. CDC1 3 [00990] To a solution of 1-(benzo[d][1,3]dioxol-5-y1)-N-(2-tert-butyl-6-fluoroindolin-5 yl)cyclopropane-carboxamide (150 mg, 0.38 mmol) in anhydrous dichloromethane (2.3 mL) at room temperature under N 2 was added tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol). After 20 min of stirring, NaBH(OAc) 3 (110 mg, 0.51 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 6 h at room temperature before being purified by column chromatography on silica gel (5-20% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-((tetrahydro-2H-pyran- 3

-

244 yl)methyl)indolin-5-yl)cyclopropanecarboxamide (95 mg, 50%). CDCl 3 was added to the indoline and the solution was allowed to stir overnight at ambient temperature. The solution was concentrated to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1 ((tetrahydro-2H-pyran-3-yl)methyl)- IH-indol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 493.0. 1009911 Example 112: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(2-hydroxypropan-2-yl)-1H indol-5-yl)cyclopropanecarboxamide H 17H o CHL, o N OH ob-0~ 0 0 -N0 H H [009921 Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2 carboxylate (100 mg, 0.255 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) under an argon atmosphere. The solution was cooled to 0 *C in an ice water bath before methyllithium (0.85 mL, 1.6 M in diethyl ether) was added by syringe. The mixture was allowed to warm to room temperature. The crude product was then partitioned between a saturated aqueous solution of sodium chloride (5 mL) and dichloromethane (5 mL). The organic layers were combined, dried over sodium sulfate, filtered, evaporated to dryness, and purified on 12 g of silica gel utilizing a gradient of 20-80% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(2-hydroxypropan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide (35 mg; 36%)-as a white solid. -ESI-MS m/z calc. 378.2, found 379.1 (M+1)*. Retention time of 2.18 minutes. 'H NMR (400 MHz, DMSO-d6) 8 10.78 (s, 1H), 8.39 (s, 1H), 7.57 (d, J= 1.7 Hz, IH), 7.17 (d, J= 8.6 Hz, 1 H), 7.03 - 6.90 (m, 4H), 6.12 (d, J= 1.5 Hz, 1H), 6.03 (s, 2H), 5.18 (s, 1H), 1.50 (s, 6H), 1.41 - 1.38 (m, 2H), 1.05-0.97 (m, 2H). [009931 Example 113: N-(2-(1-Amino-2-methylpropan-2-y)-1H-indol-5-yl)-1 (benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide \7H ONTFA K y ~ > NHBoc 0

N

2 H H [009941 Trifluoroacetic acid (0.75 mL) was added to a solution of tert-butyl 2-(5-(1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2 methylpropylcarbamate (77 mg, 0.16 nimol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give N-(2-(1 -amino-2-methylpropan-2-yl)- 1 H-indol-5- 245 yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (53 mg, 86%). 'H NMR (400 MHz, CDCl 3 ) 8 9.58 (s, IH), 7.60 (d, J= 1.6 Hz, 1H), 7.18 - 7.15 (m, 2H), 7.02 - 6.94 (m, 3H), 6.85 (d, J= 7.8 Hz, 1 H), 6.14 (d, J 1.2 Hz, 1H), 6.02 (s, 2H), 2.84 (s, 2H), 1.68 (dd, J = 3.6, 6.7 Hz, 2H), 1.32 (s, 6H), 1.08 (dd, J = 3.7, 6.8 Hz, 2H). [009951 Example 114: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-methyl propan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide 'K Mel " 0 2 0 O N-C N H K2O30 7 COK- kNM 2

H

2 KM2 H H [009961 To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-IH-indol-5-yl)-1 (benzo[d][1,3]dioxol-5-y)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 pL, 0.11 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate, evaporated, coevaporated with toluene (3x) and purified by silica gel chromatography (0-30% EtOAc in hexane) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-methylpropan-2-yl) 1H-indol-5-yl)cyclopropanecarboxamide (7 mg, 33%). 'H NMR (400 MHz, CDCl 3 ) 5 9.74 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.01 - 6.95 (m, 3H), 6.85 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s, 2H), 2.24 (s, 6H), 1.68 (dd, J = 3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J = 3.7, 6.8 -Hz, 2H). [009971 Example 115: N-(2-(1-Acetamido-2-methylpropan-2-yl)-1IH-indol-5-yl)-1 (benzo[d] [1,31-dioxol-5-yl)cyclopropanecarboxamide \7H H S 0NH 2 0NHAc H H [009981 To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1 (benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (21 mg, 0.054 mmol) in dichloromethane (I mL) was added pyridine (14 pL, 0.16 mmol) followed by acetic anhydride (6.0 jiL, 0.059 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane, evaporated, coevaporated with toluene (3x) and purified by silica gel chromatography (60-100% ethylacetate in hexane) to give N-(2-(1 acetamido-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5 yl)cyclopropanecarboxamide (17 mg, 73%). 'H NMR (400 MHz, DMSO) 5 10.79 (s, 1H), 8.39 (s, 1H), 7.66 (t, J = 6.2 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.02 - 246 6.89 (m, 4H), 6.08 (d, J= 1.5 Hz, 1H), 6.03 (s, 2H), 3.31 (d, J = 6.2 Hz, 2H), 1.80 (s, 3H), 1.41 - 1.38 (m, 2H), 1.26 (s, 6H), 1.04 - 1.01 (m, 2H). [00999] Example 116: 1-(Benzold][1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-tetrazol-5 yl)butan-2-y)-1H-indol-5-yl)cyclopropanecarboxam-ide H NH HN NN H N [0010001 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in NN-dimethylformamide (1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol), and a magnetic stir bar. The reaction mixture was heated at 110 'C for 40 minutes in a microwave reactor. The crude product was filtered and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-tetrazol-5-yl)butan-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide. ESI-MS m/z calc. 458.2, found 459.2 (M+1)*. Retention time of 1.53 minutes. I H NMR (400 MHz, CD 3 CN) 9.23 (s, 1H), 7.51 - 7.48 (m, 2H), 7.19 (d, J= 8.6 Hz, 1H), 7.06 - 7.03 (m, 2H), 6.95 - 6.89 (m, 2H), 6.17 (dd, J= 0.7, 2.2 Hz, 1H), 6.02 (s, 2H), 2.61 - 2.57 (m, 2H), 2.07 - 2.03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s, 6H), 1.12-1.09 (m, 2H). [0010011 Example 117: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5 yl)cyclopropanecarboxamide H H [0010021 tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H indol-2-yl)piperidine-I-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1 (benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 403.2, found 404.4 (M+1)+. Retention time of 0.95 minutes. [0010031 Example 118: 5-tert-Butyl-1H-indol-6-ylamine 247 HCCSiMe 3 NH NBS, DMF Br KNO 3 , H2SOL Br Pd(PPh 3

)

2 C 2 N H -NH 2 0N t4 NH 2 CuI, Et 3 N 2 Tol, H20 sil cu DMF

H

2 , Raney Ni N 0 2 N _:5 )N H N 02N NH 2 0NH 2 NH - NBS. DMF NH 2

NH

2 [0010041 2-Bromo-4-tert-butyl-phenylamine [0010051 To a solution of 4-tert-Butyl-phenylamine (447 g, 3.00 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3.00 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2

SO

4 and concentrated. The crude product was directly used in the next step without further purification. Br I I'l Br B KNO3. H2SOd.B

NH

2 0 2 N NH 2 [0010061 2-Bromo-4-tert-butyl-5-nitro-phenylamine [0010071 2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to

H

2

SO

4 (410 mL) at room temperature to -yield -a clear solution. This clear solution was then cooled down to -5 to -10 'C. A solution of KNO 3 (83 g, 0.82 mol) in H 2

SO

4 (410 mL) was added dropwise while the temperature was maintained between -5 to -10 'C. Upon completion, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na 2

CO

3 and brine, dried over Na 2

SO

4 and concentrated. The residue was purified by a column chromatography (ethyl acetate/petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%). HCCSiMe 3 Br Pd(PPh 3

)

2 Cl 2 Si

O

2 N a NH 2 Cul, Et 3 N To, H 2 0 0 2 N NH 2 [0010081 4-tert-Butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine [0010091 To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et 3 N (27.9 mL, 200 mmol), Pd(PPh 3

)

2 Cl 2 (2.11 g, 3.00 mmol), CuI (950 mg, 0.500 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 *C in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug 248 of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH 4 0H solution and water, dried over Na 2 SO4 and concentrated. The crude product was purified by column chromatography (0 - 10 % ethyl acetate/petroleum ether) to provide 4 tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous liquid (25 g, 81 Si( Cul, DMF

O

2 N NH 2 H [0010101 5-tert-Butyl-6-nitro-1H-indole [0010111 To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere. The mixture was heated at 135 'C in a sealed pressure flask overnight, cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na 2

SO

4 and concentrated. The crude product was purified by column chromatography (10 - 20 % ethyl aetate/hexane) to provide 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69 %). H2 , Raney Ni HZ5 n H- 2 NW H [001012] 5-tert-Butyl-1H-indol-6-ylamine [001013] Raney Nickel (3 g) was added to 5-tert-butyl-6-nitro-IH-indole (15 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30 *C for 3 h. The catalyst was filtered off. The filtrate was dried over Na 2

SO

4 and concentrated. The crude dark brown viscous oil was purified by column chromatography (10 - 20 % ethyl acetate/petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine as a gray solid (11 g, 87 %). 'H NMR (300 MHz, DMSO-d6) 5 10.3 (br s, IH), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, I H), 4.4 (br s, 2H), 1.3 (s, 9H). [001014] A person skilled in the chemical arts can use the examples and schemes along with known synthetic methodologies to synthesize compounds of the present. invention, including the compounds in Table 3, below.

249 Table 3: Physical data of exemplary compounds. Compound LC/MS LC[RT NMR Compound LC/MS LC/RT NMR No. M+1 Min No. M+1 Min 1 373.3 2.49 17 389.2 2.02 H NMR (400 2 469.4 3.99 MHz, DMSO) 3 381.3 3.69 8.41 (s, 1H), 4 448.3 1.75 7.59 (d, J= 1.8 5 389.3 3.3 Hz, 1H), 7.15 6 463 1.87 (d, J= 8.6 Hz, 7 363.3 3.7 1H), 7.06 - 7.02 8 405.5 3.87 (m, 2H), 6.96 9 487.3 2.12 H NMR (400 6.90 (m, 2H), MHz, DMSO- 6.03 (s, 2H), d6) 8.65 (s, 5.98 (d,J 0.7 1H), 7.55 (d, J Hz, IH), 4.06 = 1.7 Hz, 1H), (t,J 6.8 Hz, 7.49 (d, J = 1.4 2H), 2.35 (t, J Hz, 1H1), 7.38 6.8 Hz, 2H), (d, J18.3 1.42-1.38 (m, Hz,H), 7.30- 2H), 1.34 (s, 7.25 ( , 2H), 6H), 1.05-1.01 7.08 (dd, J (m, 2H) =8.8, 1.9 Hz, 18 395.3 3.6 H NMR (400 1H), 6.11 (s, MHz, DMSO) 1H), 4.31 (t,J 10.91 (s, 1H), 7.4 Hz, 2H), 7.99 (s, 1H), 3.64 (t, J= 7.3 7.67 (d, J= 7.7 Hz, 2H), 3.20 Hz, 1H), 7.08 (t, J= 7.6 Hz, 6.92 (m, 4H), 2H), 1.92 (t, J 6.09 - 6.03 (m, 7.6 Hz, 2H), 3H), 1.47 - 1.42 1.45 (m, 2H), (m, 2H), 1.31 1.39 (s, 6H), (d, J = 7.3 Hz, 1.10 (n, 2H) 9H), 1.09-1.05 10 388 3.34 (m, 2H) 11 452.3 2.51 19 457.2 1.97 H NMR (400 12 527 2.36 MHz, CD3CN) 13 498 1.85 7.50 (d, J = 1.9 13 495 1.185 Hz, 1H), 7.41 14 404.5 1.18 (,J . z 15 369.2 3.81(dJ=1.Hz 15 369.2 3.81 2H), 7.36 (dd, J 16 419.2 2.248.3 Hz, 1iH), 7.29 - 7.24 (m, 2H), 7.02 (dd, J = 2.1, 8.8 Hz, I H), 6.24 (s, 1H), 4.40 (t, J= 7.1 Hz, 2H), 3.80 (t, J = 7.1 Hz, 2H), 1.59 1.55 (m, 2H), 1.50 (s, 9H), 1.15-1.12 (m, 2H) 20 375.5 3.71 21 496 206 22 421.14 1.53 250 Compound LC/MS LC/RT NMR Compound LC/MS LCIRT NMR No. M+1 Min No. M+1 Min 23 363.3 3.62 41 397.3 3.41 H NMR (400 24 378.5 2.66 MHz, DMSO) 25 417.5 3.53 11.44 (s, 1H), 26 454.3 3.18 8.52 (s, 1H), 27 596.2 2.58 7.85 (d, J= 1.2 28 379.3 2.92 Hz, 2H), 7.71 29 481 1.69 (d, J= 1.7 Hz, 30 504.2 1.95 1H), 7.47 - 7.43 31 517 1.92 (m, 2H), 7.32 32 403.5 3.5 H NMR (400 7.26 (m, 2H), MHz, DMSO) 7.12 dd, J = 10.76 (s, 1H), 2.0, 8.7 Hz, 8.72 (s, 1H), IH), 7.04 (d, J 7.79 (d, J = 2.3 = 1.6 Hz, H), Hz, 1H), 7.62 6.97 - 6.90 (m, (dd, J = 2.4, 8.6 2H), 6.84 (d, H Hz, I H), 7.55 = 1.3 Hz, 2H), (d, J= 1.5 Hz, 6.03 s, 2H), 1H), 7.14 (d, J 1.43 - 1.40 m, = 8.6 Hz, 1H), 2H), 1.07-1.03 7.5 6.01 (, J' 42 505.3 2.23 H NMR (400 = 1.6 Hz, 1H), MHz, DMSO 4.54 (t, J = 6.4 d6) 8.33 (s, Hz, 2H), 2.79 1H), 7.52 (s, (t, J= 6.4 Hz, 1H), 7.42-7.39 2H), 1.44 (m, (m, 2H), 7.33 2H), 1.32 (s, 7.25 (m, 2H), 9H), 1.03 (m, 6.14 (s, IH), 2H) 4.99 (s,, 1H), 33 321.3 2.98 4.31-4.27 (m, 34 450.2 2.02 3H), 3.64 (t, J= 34 45.2 ,2.027.0 Hz, 2H), 35 395.1 3.59 3.0 (t, J=7. - 36 509 2.01 -32 t . 36 509.2 2.01 Hz, 2H), 1.91 (t, J = 7.6 Hz, 38 379.1 2.16 H NMR (400- 2H), 1.46 (m, MHz, DMSO) 2H), 1.39 (s, 10.78 (s, IH), 6H), 1.13 (m, 8.39 (s, 1IH), 2H) 7.57 (d, J= 1.7 43 505.4 1.97 Hz, 1H), 7.17 44 407.7 1.76 H NMR (400 (d, J = 8.6 Hz, MHz, DMSO) 1H), 7.03 - 6.90 10.31 (s, 1H), (m, 4H), 6.12 8.34 (s, IH), (d, J= 1.5 Hz, 7.53 (d, J = 1.8 1H), 6.03 (s, Hz, 1H), 7.03 2H), 5.18 (s, (d, J= 1.6 Hz, 1H), 1.50 (s, 1H), 6.97 - 6.90 6H), 1.41 - 1.38 (m, 3H), 6.05 (m, 2H), 1.05- 6.03 (m, 3H), 0.97 (m, 2H) 4.72 (s, 2H), 39 373.3 3.741.40 - 1.38 (m, 40 372.8 3.8 2H), 1.34 (s, 9H), 1.04 1.00(m, 2H) 45 497.2 2.26 46 391.3 3.41 1 251 Compound LCIMS LC/RT NMR Compound LC/MS LC/RT NMR No. M+1 Min No. M+1 Min 47 377.5 3.48 95 375.3 3.43 H NMR (400 48 427.5 4.09 MHz, DMSO) 49 402.2 3.06 10.52 (s, 1H), 50 421.1 1.81 8.39 (s, 1H), 51 407.5 3.34 7.46 (d, J= 1.8 52 464.3 2.87 Hz, 1H), 7.10 53 405.3 3.65 6.89 (m, 5H), 54 375 1.84 6.03 (s, 2H), 55 505.4 1.96 2.68 - 2.65 (m, 56 335.3 3.18 2H), 2.56 - 2.54 57 445.2 3.27 (m, 2H), 1.82 58 491 1.88 1.77 (m, 4H), 59 47 1.8 1.41 - 1.34 (m, 59 478.3 1.98 2H), 1.04 - 0.97 60 413.3 3.95(m2H - (in, 2H) 61 402.5 3.71 96 346.1 3.1 62 393.3 1.98 97 367.3 3.72 63 407.2 2.91 98 440.3 3.26 64 505.4 1.98 99 393.1 3.18 H NMR (400 65 377.5 3.53 MHz, DMSO 66 417.5 4.06 d6) 11.80 (s, 67 333.3 3.53 1H), 8.64 (s, 68 397.3 3.86 1H), 7.83 (m, 69 506 1.67 1H), 7.33-7.26 70 501 2.1 (m, 2H), 7.07 71 335.3 3.22 (m, 1H), 7.02 72 487 1.93 (m, 1H), 6.96 73 417.5 3.88 6.89 (m, 2H), 74 395 1.95 6.02 (s, 2H), 75 548 1.64 4.33 (q, J= 7.1 76 418.3 2.9 Hz, 2H), 1.42 77 377.3 3.87 1.39 (m, 2H), 78 363.3 3.48 1.33 (t, J = 7.1 79 476 1.8 Hz, 3H), 1.06 80 447.3 2.18 1.03 (i, 2H) 81 492.4 2 100 421.3 1.85 H NMR (400 82 564.3 1.35 MHz, DMSO) 83 467.3 1.72 13.05 (s, 1H), 84 445.2 3.08 9.96 (d, J= 1.6 85 389.5 3.86 Hz, 1H), 7.89 86 374.3 3.11 (d, J= 1.9 Hz, 687 435 3.87 1H), 7.74 (d, J 88 465 1.89 = 2.0 Hz, 1H), 88 7.02 (d, J = 1.6 89 411.3 3.89 Hz, 1H), 6.96 90 449.3 3.92 6.88 (m, 2H), 91 393.3 3.12 6.22 (d, J = 2.3 92 469.6 1.75 Hz, 1H), 6.02 93 476.5 2.88 (s, 2H), 1.43 94 377.5 3.41 ... . . . 1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H) 101 387.5 2.51 102 479 3.95 103 420.3 3.12 104 469.5 3.97 105 391.3 2.04 _______J 252 Compound LC/MS LC/RT NMR Compound LC/MS LC/RT NMR No. M+1 Min No. M+1 Min 106 375.2 2.82 128 393 3.26 107 349.3 3.33 129 420.2 2.16 108 503.3 1.88 130 406.3 2.88 109 451.5 1.59 131 473.3 4.22 110 361.5 3.7 132 417.3 3.8 111 391.3 3.65 133 465 1.74 112 335.3 3.03 134 464.3 2.91 113 496.5 1.68 135 347.3 3.42 114 381.5 3.72 136 511 2.35 115 390.3 3.22 137 455.5 3.29 116 397.3 3.52 H NMR (400 138 393.3 3.54 MHz, DMSO- 139 335.1 3.08 d6) 11.27 (d, J 140 434.5 2.74 = 1.9 Hz, 1H), 141 381.3 2.91 8.66 (s, IH), 142 431.5 3.97 8.08 (d, J= 1.6 143 539 1.89 Hz, 1H), 7.65- 144 515 1.89 7.61 (m, 3H), 145 407.5 3.6 7.46-7.40 (m, 146 379.5 1.51 2H), 7.31 (d, J 147 409.3 4 = 8.7 Hz, 1H), 148 392.2 1.22 7.25-7.17 (m, 149 375.3 3.37 2H), 7.03 (d, J 150 377.3 3.61 = 1.6 Hz, 1H), 151 377.22 3.96 6.98-6.87 (m, 152 504.5 1.99 2H), 6.02 (s, 2H), 1.43-1.39 153 393.1 3.47 (m, 2H), 1.06- 155 321.3 3.13 1.02 (m, 2H) 155 321.3 3.1 117 377.5 3.77 156 407.5 3.2 118 515.3 2.3 157 406.3 1.43 __119 381.3 3.8 158 379.3 1.89 120 464.2 2.1 159 451 3.34 121 465 1.74 160 375.3 3.82 122 395.2 3.74 161 355.1 3.32 123 383.3 3.52 162 475 2.06 124 388.5 3.56 163 437.2 2.35 125 411.3 3.85 164 379.2 2.76 126 459.2 1.53 H NMR (400 165 462 3.44 MHz, CD3CN) 166 465.2 2.15 9.23 (s, 1H), 167 455.2 2.45 7.51 - 7.48 (m, 168 451 1.65 2H), 7.19 (d, J 169 528 1.71 = 8.6 Hz, 1H), 170 374.3 3.4 7.06 - 7.03 (m, 171 449.5 1.95 2H), 6.95 - 6.89 172 381.3 3.8 (m, 2H), 6.17 173 346.3 2.93 (dd, J= 0.7, 2.2 174 483.1 2.25 Hz, 1H), 6.02 175 411.2 3.85 (s, 2H), 2.61 - 176 431.5 4.02 2.57 (m, 2H), 177 485.5 4.02 2.07 - 2.03 (m, 178 528.5 1.18 2H), 1.55-1.51 179 473 1.79 (m, 2H), 1.39 180 479 2.15 (s, 6H), 1.12- 181 387.5 2.56 1.09 (m, 2H) 182 365.3 3.13 127 408.5 2.48 - - 183 493 2.3 253 Compound LC/MS LC/RT NMR Compound LCI/MN LuLKi M No. M+1 Min No. M+1 Min 184 461.3 2.4 H NMR (400 201 462 3.22 MHz, DMSO- 202 351.3 2.59 d6) 10.89 (s, 203 495.2 2.71 1H), 8.29 (s, 204 435 3.94 1H), 7.52 (s, 205 397.3 3.69 1H), 7.42-7.37 206 493 2.26 (m, 2H), 7.32 207 487 1.87 (dd, J= 8.3, 1.4 208 391.3 2.94 Hz, 1H), 7.01 ~ 209 397.2 3.3 (d, J = 10.9 Hz, 210 487.2 1.85 H NMR (400 1H), 6.05 (d, J MHz, CD3CN) = 1.7 Hz, 1H), 7.50 (d, J = 2.0 4.29 (t, J= 5.0 Hz, 1H), 7.41 Hz, IH), 3.23 (d, J= 1.6 Hz, (m, 2H), 1.81 2H), 7.37-7.32 (t, J = 7.7 Hz, (m, 2H), 7.25 2H), 1.46 (m, (d, J= 8.3 Hz, 2H), 1.29 (s, 1H), 6.98 (dd, J 6H), 1.13 (m, = 2.1, 8.8 Hz, 2H) 1H), 6.27 (d, J 185 377.5 3.63 = 0.6 Hz, 1H), 186 464 1.46 4.40 - 4.28 (m, 187 339.1 3.2 2H), 4.12 - 4.06 188 435.5 1.64 (m, 1H), 3.59 189 392.3 2.18 3.51 (m, 2H), 190 435.5 3.67 H NMR (400 1.59 - 1.50 (m, MHz, DMSO) 2H), 1.47 (s, 11.83 (s, 1H), 9H), 1.15 - 1.12 10.76 (s, 1H), (m, 2H) 8.53 (s, 1H), 211 381.3 3.69 7.93 (d, J = 1.8 212 461 2.04 Hz, 1H), 7.60 213 469 1.72 (dd, J= 2.3, 8.5 214 363.3 3.48 Hz, 1H), 7.53 215 432.3 3.07 (d, J = 1.4 Hz, 216 403.5 3.94 1H), 7.14 (d, J 217 420.4 1.27 = 8.6 Hz, 1H), 218 475 2.2 7.02 - 6.97 (in, 219 484.3 1.84 2H), 6.02 (d, J 220 419.3 3.87 = 1.5 Hz, 1H), 221 486.3 0.91 3.71 (t, J= 6.2 222 391.3 3.01 Hz, 2H), 3.37 223 398.3 1.3 (t, J= 6.2 Hz, 224 349.2 2.54 211), 3.25 (s, 24 392 25 3H), 1.44 (, 225 375.5 3.74 2H), 1.32 (s, 226 377.5 3.47 H NMR (400 9H), 1.08 (s, MHz, DMSO 9H), d6) 10.76 (s, 191 421.3 3.32 1H), 8.39 (s, 192 404.4 0.95 -- 1H), 7.55 (s, 193 451 1.71 ---- m 1H), 7.15-7.13 194 465 1.69 ( in, 1(), 7.03 195 434.2 2.29 6.03 (m, 3H), 196 363.3 3.46.3(,31) 19 633|3.1. 1.41-1.38 (m, 197 501 1.91 19 50 19I.-. 2H), 1.32 (s, 198 411.2 3.14 9H), 1.32-1.0 199 439 1.89 911), 1.04-1.01 200 434.4 1.53.

254 Compound LC/MS LC/RT NMR Compound LC/MS LCIRT NiviR No. M+l Min No. M+1 Minj 227 393.3 2.03 263 391.1 3.67 H NMR (400 228 398.3 1.24 MHz, DMSO) 229 487.2 1.78 1.01-1.05 (dd, J 230 361.1 3.47 =4.0,6.7 Hz, 231 351.5 .12 2H), 1.41 - 1.39 231 435.5 2.12 (m, 1IH), 3.81 232 3.3 2.91 (s, 3H), 6.03 (s, 233 413.3 13.77 2H), 6.15 (s, 234 393.3 1.58 1H), 6.96 - 6.90 235 465 1.92 (m, 2H), 7.02 236 361.3 3.18 (d, J = 1.6 Hz, 237 421 1.8 1H), 7.09 (dd, J 238 405.5 3.79 = 2.0, 8.8 Hz, 239 544.3 1.4 1H), 7.25 (d, J 240 405.3 3.9 = 8.8 Hz, 1H), 241 462 1.74 7.60 (d, J = 1.9 242 550 1.68 Hz, 1H), 8.46 243 395.2 1.98 244 517.3 1.94 264 421.3 1.66 H NMR (400 245 372.2 3.59 MHz, CD3CN) 246 361.3 3.58 8.78 (s, 1H), 247 490 1.95 7.40 (m, 1H), 248 407.3 1.52 H NMR (400 7.33 (s, 1H), MHz, DMSO) 7.08 (m, 1H), 10.74 (d, J = 6.95 - 6.87 (m, 1.2 Hz, 1H), 3H), 6.79 (m, 8.40 (s, 1H), 1H), 5.91 (s, 7.54 (d, J= 1.8 2H), 3.51 (dd, J Hz, 1H), 7.15 = 5.9, 7.8 Hz, (d, J= 8.6 Hz, 2H), 2.92 - 2.88 1H), 7.03 - 6.90 (m, 2H), 2.64 (m, 411), 6.03- (t, J = 5.8 Hz, 6.00 (m, 3H), 1H), 1.50 (m, 3.26 - 3.22 (m, 2H), 1.41 (s, 2H), 1.85-1.80 9H), 1.06 (m, (m, 2H), 1.41 .. 2H) 1.38 (m, 2H), 265 475 2.15 1.31 (s, 6H), 266 347.3 3.32 1.05-1.01 (m, 267 420.5 1.81 2H) 268 416.2 1.76 249 393.3 3.32 1 269 485 2.06 250 406.2 2.08 270 395.3 3.89 251 511 2.39 271 492 1.59 252 379.3 3.3 272 405.5 3.96 253 383 3.46 273 547.2 1.65 254 401.2 3.26 274 631.6 1.91 255 398.3 1.38 275 590.4 2.02 256 512.5 1.96 276 465.7 1.79 257 389.2 3.05 277 411.3 2.14 258 321.3 3.02 ' 278 385.3 1.99 259 392.1 2.74 , 279 425.3 2.19 260 462 1.81 280 473.2 1.74 261 453 1.91 262 349.3 3.22 255 Compound LC/MS LC[RT NMR Compound LC/MS LC/RT NMR No. M+1 Min No. M+l1 Min 281 469.4 2.02 H NMR (400 290 499.5 1.81 H NMR(400 MHz, DMSO) MHz, DMSO) 8.82 (s, 1H), 8.82 (s, IH), 7.84 (d, J= 1.7 7.83 (d, J= 1.7 Hz, 1H), 7.55 - Hz, 1H), 7.55 7.51 (m, 2H), 7.50 (m, 2H), 7.40 - 7.35 (m, 7.39 - 7.28 (m, 2H), 7.29 (dd, J 3H), 7.03 (s, = 1.7, 8.3 Hz, 1H), 4.97 (d, J 1H), 7.04 (s, = 5.6 Hz, 1H), 1H), 4.98 (t, J = 4.83 (t, J = 5.6 5.6 Hz, 1H), Hz, 1H), 4.33 4.27 (t, J = 6.1 (dd, J= 3.4, Hz, 2H), 3.67 15.1 Hz, 1H), (q, J= 6.0 Hz, 4.09 (dd, J = 2H), 1.48 (dd, J 8.7, 15.1 Hz, = 4.0, 6.7 Hz, 1H), 3.80 - 3.78 2H), 1.13 (dd, J (m, 1H), 3.43 = 4.1, 6.8 Hz, 3.38 (m, 1H), 2H) 3.35 - 3.30 (m, 282 644.4 1.83 1H), 1.49 - 1.46 283 544.6 1.97 (m, 2H), 1.14 284 465.4 1.56 . ..

4 1.11 (m, 2H) 285 485.2 1.8 291 455.4 2.02 H NMR (400 286 475.2 1.87 MHz, DMSO) 287 564.2 1.95 8.62 (s, 1H), 288 512.5 1.89 HNMR(400 7.56 (s, 1H), MHz, DMSO) 7.50 (s, 1H), 8.77 (s, 111), 7.38 (d, J= 8.3 7.97 (s, 1H), Hz, 1H), 7.29 7.51 (s, 1H), (dd, J = 1.5, 8.3 7.43 - 7.40 (i, Hz, 1.H), 7.23 2H), 7.33 (d, d (, J= 8.7 Hz, = 8.2 Hz, 11), 1H), 7.06 (dd, J 6.36 (s, 1H), = 1.7, 8.7 Hz, 4.99 - 4.97 (i, 1H), 6.19 (s, 211), 4.52 (m, 1H), 4.86 (t, J= = 13.1 Hz, 11), 5.4 Hz, 1H), 4.21 (dd, JH= 4.03 (t, J= 6.1 9.2, 15.2 Hz, Hz, 2H), 3.73 H), 3.86 (, (qn, J= 8.5 Hz, 1H), 3.51 -3.36 1H), 3.57 (q, J (1, 2H), 1.51 - = 5.9 Hz, 2H), 1.48 (m , 211), 2.39 - 2.33 (m, 1.43 (s, 9H), 2H), 2.18 - 1.98 1. 17-1.15 ( m, 3H), 1.88 1.17 -1.152() 1.81 (m , 1H), 294)3-61.47 - 1.44 (m, 289 |437.3 1.6 2H), 1.11 - 1.09 (m, 2H) 292 578.4 1.99 _ 293 630.4 1.8 | 256 Compound LC/MS LC/RT NMR Compound LCIMS LCIRT NMR No. M+1 Min No. M+1 Min 294 443.4 1.98 H NMR (400 296 438.7 2.12 H NMR (400 MHz, DMSO) MHz, DMSO) 8.62 (s, 1H), 11.43 (s, 1H), 7.55 (d, J = 1.8 8.74 (s, 1H), Hz, 1H), 7.50 7.63 (s, 1H), (d, J = 1.5 Hz, 7.51 (s, 1H), 1H), 7.38 (d, J 7.45 - 7.40 (m, = 8.3 Hz, 1H), 2H), 7.33 (dd, J 7.30 - 7.24 (m, = 1.4, 8.3 Hz, 2H), 7.05 (dd, J 1H), 6.25 (d, J = 2.0, 8.8 Hz, = 1.5 Hz, IH), 1H), 6.13 (s, 1.51 - 1.48 (m, 1H), 4.88 (t, J 2H), 1.34 (s, 5.5 Hz, 1H), 9H), 1.17 - 1.14 4.14 (t, J = 6.1 (m, 2H) Hz, 2H), 3.61 297 449.3 .1.6 (n, 2H), 3.21 298 517.5 1.64 (septet, J =6.8 299 391.5 2.05 Hz, 1H), 1.47 - 300 449.3 1.59 1.44 (m, 2H), 301 501.2 1.93 1.26 (d, J= 6.8 302 503.5 1.63 Hz, 6H), 1.11 - 303 437.3 1.6 1.08 (m, 2H) 304 425.1 2.04 H NMR (400 295 482.3 2 H NMR (400 MHz, DMSO) MHz, DMSO) 12.16 (s, 1H), 8.78 (s, 1H), 8.80 (s, IH), 7.92 (s, 1H), 7.83 (s, 1H), 7.51 (s, IH), 7.51 (d, J= 1.4 7.45 (s, IH), Hz, 1H), 7.39 7.41 (d, J= 8.3 7.28 (m, 4H), Hz, 1H), 7.33 6.95 (s, IH), (d, J= 8.4 Hz, 1.48 (dd, J = 1H), 6.34 (s, 4.0, 6.6 Hz, IH), 5.01 (t, J= 2H), 1.13 (dd, J 5.7 Hz, IH), = 4.0, 6.7 Hz, 4.41 (t, J = 6.6 2H) Hz, 2H), 3.68 305 459.2 1.67 (m, 2H), 1.51 - 306 558.4 2.05 1.47 (m, 2H), 1.42 (s, 9H), 1.19 - 1.15 (m, 2H) 257 [001015] VII. ASSAYS FOR DETECTING AND MEASURING AF508-CFTR CORRECTION PROPERTIES OF COMPOUNDS [0010161 Membrane potential optical methods for assaying AF508-CFTR modulation properties of compounds [001017] The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439). [001018] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC 2 (3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. [0010191 Identification of Correction Compounds [001020] To identify small molecules that correct the trafficking defect associated with AF508-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" AF508-CFTR. The cells were subsequently rinsed 3X with 258 Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate AF508 CFTR, 10 piM forskolin and the CFTR potentiator, genistein (20 piM), were added along with Cl-free medium to each well. The addition of Cl--free medium promoted C1~ efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes. [0010211 Identification of Potentiator Compounds [0010231 To identify potentiators of AF508-CFTR, a double-addition HTS assay format was developed. During the first addition, a Cl~-free medium with or without test compound was added to each well. After 22 sec, a second addition of Cl-free medium containing 2 - 10 PM forskolin was added to activate AF508-CFTR. The extracellular Cl concentration following both additions was 28 mM, which promoted CF~ efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.SolutionsBath Solution #1: (in mM) NaCI 160, KCl 4.5, CaC1 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH. [0010261 Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts. [001027] CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at 20 0 C. [0010281 DiSBAC 2 (3): Prepared as a 10 mM stock in DMSO and stored at -20'C. [001029] Cell Culture [001030] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 "C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, p-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For all optical assays, the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 *C before culturing at 27 *C for 24 hrs. for the potentiator assay. For the correction assays, the cells are cultured at 27 'C or 37 'C with and without compounds for 16 - 24 hoursElectrophysiological Assays for assaying AF508 CFTR modulation properties of compoundsUssing Chamber Assavussing chamber experiments were performed on polarized epithelial cells expressing AF508-CFTR to further characterize the AF508-CFTR modulators identified in the optical assays. FRTAF508-CFTR 259 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 Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 K./ cm 2 or more. The solutions were maintained at 27 *C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. 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 MPIOOA-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA). [001034] Identification of Correction Compbunds [0010351 Typical protocol utilized a basolateral to apical membrane Cl~ concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical 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 experiments were performed with intact monolayers. To fully activate AF508-CFTR, forskolin (10 pM) and the PDE inhibitor, IBMX (100 pM), were applied followed by the addition of the CFTR potentiator, genistein (50 pM). [001036] 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 yM of the test compound for 24 hours at 37'C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated Isc in compound-treated cells was normalized to the 27'C and 37*C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated Isc compared to the 37*C controls. [001037] Identification of Potentiator Compounds [001038] Typical protocol utilized a basolateral to apical membrane Cl~ concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 pg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large C1~ concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 pM) and all test compounds were added to both sides of the 260 cell culture inserts. The etticacy 01 the putative At: U5-UFTR potentiators was compared to that of the known potentiator, genistein. [0010391 Solutions [0010401 Basolateral solution (in mM): NaCl (135), CaCl 2 (1.2), MgC1 2 (1.2), K 2

HPO

4 (2.4), KHPO 4 (0.6), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated to pH 7.4 with NaOH. 10010411 Apical solution (in mM): Same as basolateral solution with NaCl replaced with Na Gluconate (135). [0010421 Cell Culture [0010431 Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FRTAF 5 08-CETR) were used for Ussing chamber experiments for the putative AF508-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% CO 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 jg/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 'C for 16 - 48 hrs to correct for the AF508-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. [0010441 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. Briefly, voltage-clamp recordings of IAF508 were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low pass filtered at 1 kHz. Pipettes had a resistance of 5 - 6 M92 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 G and a series resistance < 15 MQ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath. contained < 250 pil of saline and was continuously perifused at a rate of 2 ml/min using a gravity-driven perfusion system. [0010451 Identification of Correction Compounds [0010461 To determine the activity of correction compounds for increasing the density of functional AF508-CFTR in the plasma membrane, we used the above-described perforated- 261 patch-recording techniques to measure the current density tollowing 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 10 pM forskolin and 20 pM 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 pM of the test compound for 24 hours at 37"C and the current density was compared to the 27*C and 37*C controls (% activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 pM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37*C controls. [0010471 Identification of Potentiator Compounds [0010481 The ability of AF508-CFTR potentiators to increase the macroscopic AF508-CFTR Cl~ current (IAF508) 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 IAF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated Eci (-28 mV). [001049] Solutions [001050] Intracellular solution (in mM): Cs-aspartate (90), CsC1 (50), MgCl 2 (1), HEPES (10), and 240 pg/ml amphotericin-B (pH adjusted to 7.35 with CsOH). [001051] Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-CI (150), MgCl2 (2), CaCl 2 (2), HEPES (10) (pH adjusted to 7.35 with HC1). [0010521 Cell Culture [0010531 NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for whole-cell recordings. The cells are maintained at 37 *C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, -ME, I X pen/strep, and 25 mM HEPES in 175 cm 2 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 OC before use to test the activity of potentiators; and incubated with or without the correction compound at 37 "C for measuring the activity of correctors.

262 10010541 The single-channel activities of temperature-corrected AF508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. Briefly, voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz. Patch pipettes were fabricated- from Coming Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MCI when filled with the extracellular solution. The AF508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1 - 2 sec. To maintain AF508-CFTR activity during the rapid perifusion, the nonspecific-phosphatase inhibitor F~ (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min). Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (Vp) was maintained at 80 mV. 10010551 Channel activity was analyzed from membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of AF508-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 (P 0 ) were determined from 120 sec of channel activity. The P 0 was determined using the Bio-Patch software or from the relationship P 0 = I/i(N), where I = mean current, i = single-channel current amplitude, and N = number of active channels in patch. [001056] Solutions [001057] Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl 2 (5), MgCI 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base). 10010581 Intracellular solution (in mM): NMDG-Cl (150), MgCl 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCI). 10010591 Cell Culture 263 [0010601 NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised membrane patch-clamp recordings. The cells are maintained at 37 *C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, p-ME, I X pen/strep, and 25 mM HEPES in 175 cm 2 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. [001061] Compounds of the invention are useful as modulators of ATP binding cassette transporters. Using the procedures described above, the activities, i.e., EC50s, of compounds of the present invention have been measured to be from about 3.8 nM to about 13.5 pM. Furthermore, using those methods described above, the efficacies of compounds of the present invention have been measured to be from about 35 % to about 110 %. [0010621 OTHER EMBODIMENTS 10010631 It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description 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.

Claims (39)

1. A compound of formula Id: N A R 1 Ic or a pharmaceutically acceptable salt thereof, wherein R, is -ZA R 4 , wherein each ZA is independently a bond or an optionally substituted branched or straight C 1 - 6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONR -, -CONRAANRA, -CO 2 -, -OCO-, NR CO 2 -, -0-, -NRACONRA, -OCONRA, -NRANRA-, -NR CO-, -S-, -SO-, -SO 2 -, -NRA, -SO 2 NR A, -NRASO 2 -, or -NRASO 2 NRA-, Each R4 is independently RA, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 , Each RA is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an. optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R 2 is independently -ZBR 5 , wherein each ZB is independently a bond or an optionally substituted branched or straight C 1 . 6 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONR NR8-, CO 2 -, -OCO-, -NR BCO 2 -, -0-, -NRBCONRB-, -OCONRB-, -NR BNRB-, -NRBCO-, -S-, -SO-, -SO 2 -, -NRB-, -SO 2 NRB_, -NRBSO 2 -, or -NRBSO 2 NRB_ Each Rs is independently RB, halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3 , Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle; Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, 0, and S; 265 King ts is a group naving formula ia: R 3 K N (R3)p Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-2, Each R 3 and R' 3 is independently -ZcR 6 , where each ZC is independently a bond or an optionally substituted branched or straight C 1 . 6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRC-, CONRCNRC-, -CO 2 -, -OCO-, -NRcCO 2 -, -O-, -NRCCONRC-, -OCONRC-, -NRcNRc-, -NRCCO-, -S-, -SO-, -SO 2 -, -NRC-, -SO 2 NRC-, -NRCSO 2 -, or -NRcSO 2 NRc Each R 6 is independently Rc, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 , Each RC is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and n is 1-3, Provided that When ring A is unsubstituted cyclopentyl, n is 1, R 2 is 4-chloro, and R, is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6-dichlorophenyl(carbonyl))-3-methyl- I H indol-5-yl; and when ring A is unsubstituted cyclopentyl, n is 0, and R, is hydrogen, then ring B is not 0 NN/ - N NON N ,0 Hor 0 \ / OH - N 0- 266

2. The compound ot claim 1, wherein KI is -L -K4, L- -is a ona, anca K4 is nyorogen.

3. The compound of any of claims I or 2, wherein R 2 is an optionally substituted branched or straight C 1 .- aliphatic.

4. The compound of any of claims 1-3, wherein R 2 is a branched or straight C 1 -6 aliphatic chain that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.

5. The compound of any of claims 1-2, wherein R 2 is an optionally substituted branched or straight C 1 .. 5 alkoxy.

6. The compound of any of claims 1-2, or 5, wherein R 2 is a C 1 . 5 alkoxy that is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof.

7. The compound of any of claims 1-2, wherein R 2 is hydroxy, halo, or cyano.

8. The compound of any of claims 1-2, wherein R 2 is -ZBRs; ZB is independently a bond or an optionally substituted branched or straight C 1 - 4 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -C(O)-, -0-, -S-, -S(O) 2 -, or -NH-; R 5 is RB, halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3 , and RB is hydrogen or aryl.

9. The compound of any of claims 1-2, wherein two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle or an optionally substituted heteroaryl, either of which is fused to the phenyl of formula I, wherein the carbocycle or heterocycle has formula Ib: ,Z 1 Z2 1 Z3NZ Ib Each of ZI, Z 2 , Z 3 , Z 4 , and Z 5 is independently a bond, -CR 7 R' 7 -, -C(O)-, -NR 7 -, or -0 each R 7 is independently -ZDRs, wherein each ZD is independently a bond or an optionally substituted branched or straight C 1 . 6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by -CO-, -CS-, -CONR 0 -- , -C0 2 -, -OCO-, -NRDCO 2 -, -0-, -NRDCONRD-, -OCONRD-, -NRDNRD-, -NRDCO-, -S-, -SO-, -S02-, -NRD-, -SO 2 NRE-, -NR DS02-, or -NRDSO 2 NRD_; 267 hacni K8 is inaepenaenty K-, nalo, -u-, -Inn2, -1NU2, -UIN, -Ur 3 , or -uur 3 ; Each RD is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and Each R' 7 is independently hydrogen, optionally substituted CI.. aliphatic, hydroxy, halo, cyano, nitro, or combinations thereof.

10. The compound of any of claims 1-2, or 9, wherein two adjacent R 2 groups together with the atoms to which they are attached form a 5-6 membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy, cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof.

11. The compound of any of claims 1-2, or 9, wherein two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatoms independently selected from N, 0, and S.

12. The compound of any of claims 1-2, or 9, wherein two adjacent R 2 groups together with the atoms to which they are attached form a heterocycle selected from: H XAI XA2 XA3 XA4 XA5 XA6 H XA7 XA8 XA9 XAIO XAII XA12 N\I N , 0 ,MeO H XA13 XA14 XAI5 XA16 XA17 XA18 268 H 0 N N ' N sN / and. XA19 XA20 XA21

13. The compound of any of claims 1-2, wherein each R 2 group is independently selected from hydrogen, halo, -OCH 3 , -OH, -CH 2 OH, -CH 3 , and -OCF 3 , or two adjacent two adjacent R 2 groups together with the atoms to which they are attached form < F2C A, or O

14. The compound of any of claims 1-13, wherein ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy, CI.s aliphatic, or combinations thereof.

15. The compound of any of claims 1-13, wherein ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic.

16. The compound of any of claims 1-13, wherein ring A is one selected from R ) h R ) q Rs) q R ) (Rs)g RH)()q H N (R9)q NA9qR (9 HNg H NA(R)q HN- (R9)q (R0)q (Rg)q .HN 269 (N9)q "9)q (Rg)q (R)q (R)q S HN >-r and wherein Each R 9 is independently -ZERio, wherein each ZE is independently a bond or an optionally substituted branched or straight CI, aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced by -CO-, -CS-, -CONRE-, -0 2 -, -OCO-, -NR ECO 2 -, -O-, -NRECONRE-, -OCONRE-, -NRENRE-, -NRECO-, -S-, -SO-, -SO 2 -, -NRE_, -SO 2 NRE-, -NRESO 2 -, or -NRESO 2 NR E; Each RIO is independently RE, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , oxo, or -OCF 3 , Each RE is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and q is 0-5.

17. The compound of any of claims 1-16, wherein ring B is SR 3 R 3 NN NN p 3R p r3P \~ //~) - -) ,or

18. The compound of any of claims 1-17, wherein ring B is HH H H \ (R3) / )P ()p ,r (R3)p / 9< or

19. The compound of any of claims 1-17, wherein one of R' 3 or R 3 is an optionally substituted acyl group.

20. The compound of any of claims 1-17, wherein one of R 3 or R' 3 is an (alkoxy)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. 270

21. The compound of any of claims 1-17, wherein one ot R 3 or R' 3 is an (aliphatic)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof.

22. The compound of any of claims 1-17, wherein one of R 3 or R' 3 is a (cycloaliphatic)carbonyl or a (heterocycloaliphatic)carbonyl, each is optionally substituted with 1-3 of aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof.

23. The compound of claim 22, wherein one of of R 3 or R' 3 is (piperidine-1-yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, (morpholine-4-yl)carbonyl, (piperazine-1-yl)carbonyl, (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, or combinations thereof.

24. The compound of any of claims 1-17, wherein R 3 is optionally substituted (aliphatic)amido that is attached to the 2 or 3 position on the indole ring of formula Ia.

25. The compound of any of claims 1-17 or 24, wherein R 3 is (N,N dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-y(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. R 3 1 R32

26. The compound of any of claims 1-17 wherein R' 3 is OH , wherein R 3 1 is H or a C 1 - 2 aliphatic that is optionally substituted with 1-3 of halo, -OH, or combinations thereof, R32 is -L-R 33 , wherein L is a bond, -CH 2 -, -CH 2 0-, -CH 2 NHS(O) 2 -, -CH 2 C(O)-, CH 2 NHC(O)-, or -CH2NH-, and R 3 3 is hydrogen, or C 1 - 2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally subsitututed with 1 of -OH, NH 2 , or -CN.

27. The compound of claim 26 , wherein R' 3 is independently selected from one of the following:-H, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 CH 2 OH, -C(O)OCH 3 , 271 - OH CH2OH OH OOH " O NCC3VrNHMe - OMe NHCOCH3 CO2H OH OH , A OH "\ N INH ~NH 2 OH N Hj NH2 < CONHMe O Et -\ NH N O O OH \-ICO 2 H OH , A NHCOMe ( rJCN NH -- '- CONMe 2 OH OH H NHSO2Me CO 2 H OH CO 2 H OH 0 OH NHSO 2 Me A NHCO 2 Me V NHC2Me NH OH OH OH NHCNt OH OH H N OA- *N -OH~ OH02~ OHOH 0 NHO 0 N - - , , a n -~OH NHOE ~OH H" OH 0 0 %% A NS 0 OH H --z OH H Z.,N NN N 0 and 0

28. The compound of any of claims 1-29, wherein R 3 is hydrogen.

29. The compound of any of claims 1-17, wherein R' 3 is independently -ZCR 6 , where each ZC is independently a bond or an optionally substituted branched or straight CI-6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by -Co-, -CS-, -CONRc-, -CONRcNRc-, -C0 2 -, -OCO-, -NRcCO 2 -, -- , -NRCCONRC-, 272 -OCONR'-, -NR''NR--, NR'CO-, -S-, -SO-, -SU2-, -N K-, -SU 2 NK~-, -NK TU2-, or -NRcSO 2 NRc-, wherein each R 6 is independently RC, halo, -OH, -NH 2 , -NO 2 , -CN, or OCF 3 ., and each Rc is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, or an optionally substituted heteroaryl.

30. A compound having the structure of compound numbers 1-306 as shown in Table 1.

31. A pharmaceutical composition comprising a compound as described in any of claims 1-30 and a pharmaceutically acceptable carrier.

32. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of the formula: n(RD A R 1 or a pharmaceutically acceptable salt thereof, wherein R, is -ZAR4, wherein each ZA is independently a bond or an optionally substituted branched or straight C 1 , aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONR -, -CONR NRA, -CO 2 -, -OCO-, -NRACO 2 -, -0-, -NR ACONRA-, -OCONR -, -NRANR^-, -NRACO-, -S-, -SO-, -SO 2 -, -NR -, -SO 2 NR -, -NR ASO 2 -, or -NRASO 2 NRA-, Each R4 is independently RA, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 , Each RA is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R 2 is independently -ZBR 5 , wherein each ZB is independently a bond or an optionally substituted branched or straight C,.6 aliphatic chain wherein up to two carbon units BB B_ of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONR NRB CO 2 -, -OCO-, -NRBCO 2 -, -O-, -NRBCONRB-, -OCONR -, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO 2 -, -NR -, -SO 2 NR -, -NR BSO 2 -, or -NRBSO 2 NR, Each R 5 is independently RB, halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3 , Each RB is independently hydrogen, an optionally substituted aliphatic, an 273 optionally substituted cycloalipnatic, an optionally suostitutea neterocycioaipnatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R 2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle; Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, 0, and S; Ring B is a group having formula Ia: R'3 SN, (R 3 )p Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-2, Each R 3 and R' 3 is independently -ZcR 6 , where each Zc is independently a bond or an optionally substituted branched or straight C. 6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by -CO-, -CS-, -CONRc_, CONRCNRc , -CO 2 -, -OCO-, -NRcCO 2 -, -O-, -NRCCONRC-, -OCONRC-, -NRcNRC-, -NRcCO-, -S-, -SO-, -SO 2 -, -NRc-, -SO 2 NRc-, -NRcSO 2 -, or -NRcSO 2 NRc , Each R6 is independently RC, halo, -OH, -NH 2 , -NO 2 , -CN, or -OCF 3 , Each Rc. is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R 3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and n is 1-3.

33. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound as shown in any of claims 1-30 or the pharmaceutical composition of claim 32.

34. The method of any of claims 32-33, wherein the ABC transporter is CFTR.

35. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, 274 coagulation-fibrinolysis deficiencies, such as protein U aeticiency, I ype 1 nereciitary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type I 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, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, -Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, said method comprising the step of administering to said patient an effective amount of a compound according to any of claims 1-30 or 32, or the pharmaceutical compositon of claim 31.

36. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound as shown in Table 1.

37. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising: (i) a composition comprising a compound according to any of claims 1-30 or 32; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuring activity of said ABC transporter or a fragment thereof.

38. The kit of claim 37, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound; and 275 c) comparing the activity 01 tfe ABU transporter in tne presence oi tne acoimonat compound with the density of the ABC transporter in the presence of a composition of formula (I).

39. The kit of claim 37or claim 38, wherein the kit is used to measure the density of CFTR.