CA2948104C - Modulators of atp-binding cassette transporters - Google Patents

Abstract

Compounds and pharmaceutically acceptable compositions thereof are disclosed, which may be used as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR").

Description

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-MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
100011 This is a divisional of Canadian patent application number 2742980, filed November 6, 2009.
TECHNICAL FIELD OF THE INVENTION
100021 The present disclosure 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 of this divisional relates to the compound:
V H
\
F irk, N i< __ OH
r 0 1114P F N
CiOH
OH
or a pharmaceutically acceptable salt thereof Also provided is a use of the compound V H
F\ righ A Nrn I< ________ OH

OH
for promoting chloride transport by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein encoded by the AF508 CFTR gene.

BACKGROUND OF TI LE INVENTION
{00031 ABC
transporters are a family of membrane transporter proteins that regulate the transport or a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that hind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR I -P
glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
la [0004] 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.
[0005] One member of the ABC transporter family commonly associated with disease is the cAMP/ATP-mediated anion channel, CFIR. 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 CFIR is critical for the maintenance of electrolyte transpoit throughout the body, including respiratory and digestive tissue. CFFR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of lb 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.
[0006] The gene encoding CFTR has been identified and sequenced (See Gregory, R. 1. 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.
[0007] 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.
[0008] 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 at (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.sicIddds.on.ca/cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CF IR amino acid sequence, and is commonly referred to as M508-CFTR. This mutation OMITS
in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
[0009] The deletion of residue 508 in AF508-CPTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic

2 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-CHR, 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.
[0010] 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, Na172C171C co-transporter, NatKtATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell.
[0011] 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 CFIR present on the apical membrane and the Na+-KtATPase 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 Cr channels, resulting in a vectorial transport. Arrangement of Na/2C171(+ co-transporter, Na+-K -ATPase pump and the basolateral membrane IC channels on the basolateral surface and CI-TR on the lumina]
side coordinate the secretion of chloride via CFTR on the lumina1 side.
Because water is probably never actively transported itself, its flow across epithelia depends on tiny transcpithclial osmotic gradients generated by the bulk flow of sodium and chloride.
[0012] 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 ChTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
[0013] COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and

3 bronchiolitis. Activators of mutant or wild-type CFIR offer a potential treatment of mucus hypersecretion and impaired mucociliaty clearance that is common in COPD.
Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD.
Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as Cystic Fibrosis and Sjogrens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dennatomyositis.
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.
[0014] As discussed above, it is believed that the deletion of residue 508 in 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, PIPS, 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-C FIR as discussed above), Hereditary emphysema (due to al -antitrypsin; non Piz variants), Hereditary

4 hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to Lysosomal processing enzymes), Sandhof/Tay-Sachs (due to P-Hexosaminidase), Crigler-Najjar type II
(due to UDP-glucuronyl-sialyc-transferase), Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus (due to Insulin receptor), Laron dwarfism (due to Growth hormone receptor), Myleoperoxidase deficiency, Primary hypoparathyroidism (due to Preproparathyroid hormone), Melanoma (due to Tyrosinase). The diseases associated with the latter class of ER
malfunction are Glycanosis CDG type 1, Hereditary emphysema (due to al-Antitrypsin (PiZ
variant), Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, H, W
procollagen), Hereditary hypofibrinogenernia (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 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 a-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect).
[0015] 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.
[0016] Although there are numerous causes of diarrhea, the major consequences of diarrheal diseases, resulting from excessive chloride transport are common to all, and include dehydration, acidosis, impaired growth and death.
[0017] Acute and chronic diarrheas represent a major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
[0018] Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD).

million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel.
[0019] Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals.
Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the rust few hours of the animal's life.
[0020] The most common diarrhea causing bacteria is enterotoxogenic E-coli (E l'EC) 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.
[0021] Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
[0022] Accordingly, there is a need for modulators of an ABC transporter activity, and compositions thereof, that can be used to modulate the activity of the ABC
transporter in the cell membrane of a mammal.
10023] There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.
[0024] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal.
[0025] There is a need for modulators of CFFR activity that can be used to modulate the activity of CFTR in the cell membrane of a mammal.
[0026] There is a need for methods of treating CFTR-mediated diseases using such modulators of CFI R activity.
[0027] There is a need for methods of modulating CF 1R activity in an ex vivo cell membrane of a mammal.

[00281 SUMMARY OF THE INVENTION
[0029] 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:

n(R2) or a pharmaceutically acceptable salt thereof, wherein R1, R2, ring A, ring B, and n are defined below.
It has also now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity. These compounds have the general formula II:

R
= 0 N

or a pharmaceutically acceptable salt thereof, wherein R, R, R2, R3, R4, and R5 are defined below.
[0030j 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 1-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, diabetes mellitus, lawn dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis COG 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 supranuelear 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.
[0031] DETAILED DESCRIPTION OF THE INVENTION
[0032] I. DEFINITIONS
[0033] As used herein, the following definitions shall apply unless otherwise indicated.
[0034] 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.
[0035] The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CM and G551D CFTR (see, e.g., http://www.genet.sickkids.on.cakftri, for CFTR
mutations).
[0036] 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 CFI
R 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.

[0037] 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 CFIR activities and alleviation of symptoms of diseases not directly caused by ABC
Transporter and/or CFIR anion channel activities. Examples of diseases whose symptoms may be affected by ABC Transporter and/or CFT.It 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, Nephrogenie DL Chamot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophie 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 eneephalopathies, such as Hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
[0038] 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.
[0039] As described herein, compounds of the invention may option-ally be substituted with one or more substiments, such as are illustrated generally above, or as exemplified by = particular classes, subclasses, and species of the invention.
[0040] As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
[0041] 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)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylarni no, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloallcylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylami no alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamina sulfonyl [e.g., aliphatic-8021, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoallcyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-S02-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
[0042] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 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, heteroalylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamind sulfonyl [e.g., alkyl-S02-, cycloaliphatic-S02-, or aryl-S024 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-S02-amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
[0043] 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, hetermupyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl I e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-S02-, aliphaticamino-S02-, or cycloaliphatic-S02-1, amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroarallcylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, a1kylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl I e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryDalkoxy.
[0044] 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(0)-RY or -C(0)-N(Rx)2, when used terminally, and -C(0)-N(Rx)- or -N(Rx)-C(0)- when used internally, wherein Rx and RY are defined below.
Examples of amido groups include alkylamido (such as allcylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloallcyl)alkylamido, arylamido, aralkylanaido, (cycloalkyl)alkylamido, or cycloalkylamido.
[0045] As used herein, an "amino" group refers to -NRxRY wherein each of Rx and RY 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.
[0046] 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 C4_8 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;
(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyll; sulfonyl [e.g., aliphatic-S02- or amino-S02-];
sulfinyl [e.g., aliphatic-S(0)- or cycloaliphatic-S(0)-]; sulfanyl [e.g., aliphatic-S-];
cyano; halo; hydroxy;
mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
Alternatively, an aryl can be unsubstituted.
[0047] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-dihaloary1), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyparyl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonypary11; (amido)aryl [e.g., (aminocarbonyparyl, (((alkylamino)alkyl)aminocarbonyDaryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyllary11; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl;
(alkoxy)aryl;
(sulfamoyl)aryl (arninosulfonyl)aryll; (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-nz-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.
[0048] As used herein, an "araliphatic' such as an "aralkyl" group refers to an aliphatic group (e.g., a C1-4 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.
[00491 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 earboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloallcyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, allcylcarbonylamino, cycIoalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[00501 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.
[0051] 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.

[0052] 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.
[0053] 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.
[0054] 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, arnido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylarnino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, a]koxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)cathonyll, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-S02- and aryl-S024 sulfinyl [e.g., alkyl-S(0)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or calbamoyl.
[0055] 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.
[0056] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, 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[2.2.2joctyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.
[0057] 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.
[0058] 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, amyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylarnino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamind 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], sulfmyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0059] 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 heteroatorn (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, 1H-indazolyl, fury!, 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.
[0060] Without limitation, monocyclic heteroaryls include ftnyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
[0061] 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.
[0062] 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)car'bonyl;
((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatie)carbonylk, sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyll;
sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea;
thiourea; sulfainoyl;
sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.
[0063] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroary1);
cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dia1kyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)hctcroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl;

(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroary1]; (hydroxyalkyl)heteroa_ryl; (alkoxyalkypheteroaryl;

(hydroxy)heteroaryl; ((carboxy)alkypheteroaryl;
(((dialkyl)amino)alkyllheteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl;
(((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl;
(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroary11;
(alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryll.
[0064] A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C14 alkyl group) that is substituted with a heteroaryl group.
"Aliphatic," "alkyl," and "heteroaryl" have been defined above.
[0065] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C14 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, cycloallcyl, (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, heteroarylearbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0066] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, hi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
[0067] 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, adarnantanyl, norbomanyl, bicyclo[3.2.1loctyl, 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[3.3.1.03'7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarallqloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocathonyl, alkylcarbonylamino, cycloalkylcarbonylanaino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, amlkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0068] As used herein, an "acyl" group refers to a fonnyl group or Rx-C(0)-(such as alkyl-C(0)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups.
[0069] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(0)-or a heteroaryl-C(0)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
[0070] As used herein, an "alkoxy" group refers to an alkyl-0- group where "alkyl" has been defined previously.
[0071] As used herein, a "cathamoyl" group refers to a group having the structure -0-CO-NRxRY or -NRx-00-0-Rz, wherein Rx and RY have been defined above and Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0072] As used herein, a "cattoxy" group refers to -COOH, -COORx, -0C(0)H, -0C(0)Rx, when used as a terminal group; or -0C(0)- or -C(0)0- when used as an internal group.
[0073] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF3.
[0074] As used herein, a "mercapto" group refers to -SH.
[0075] As used herein, a "sulfo" group refers to -S03H or -SO3Rx when used terminally or -S(0)3- when used internally.
[0076] As used herein, a "sulfamide" group refers to the structure -NRx-S(0)2-NRYRz when used terminally and -NRx-S(0)2-NRY- when used internally, wherein Rx, RY, and Rz have been defined above.

[0077] As used herein, a "sulfonamide" group refers to the structure -S(0)2-NRxRY or -NRx-S(0)2-Rz when used terminally; or -S(0)2-NRx- or -NRx -S(0)2- when used internally, wherein Rx, RY, and Rz are defined above.
[0078] 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.
[0079] As used herein a "sulfinyl" group refers to -S(0)-Rx when used terminally and -S(0)- when used internally, wherein Rx has been defined above. Exemplary sulfinyl groups include aliphatic-S(0)-, aryl-S(0)-, (cycloaliphatic(aliphatic))-S(0)-, cycloalkyl-S(0)-, heterocycloaliphatic-S(0)-, heteroaryl-S(0)-, or the like.
[0080] As used herein, a "sulfonyl" group refers to-S(0)2-Rx when used terminally and -S(0)2- when used internally, wherein Rx has been defined above. Exemplary sulfonyl groups include aliphatic-S(0)2-, aryl-S(0)2-, (cycloaliphatic(aliphatic))-S(0)2-, cycloaliphatic-S(0)2-, heterocycloaliphatic-S(0)2-, heteroaryl-S(0)2-, (cycloaliphatic(arnido(aliphatic)))-S(0)2-or the like.
[0081] As used herein, a "sulfoxy" group refers to -0-S0-Rx or -SO-O-Rx, when used terminally and -0-S(0)- or -S(0)-0- when used internally, where Rx has been defined above.
[0082] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.
[0083] 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-0-C(0)-.
[0084] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-0-alkyl-, wherein alkyl has been defined above.
[00851 As used herein, a "carbonyl" refer to -C(0)-.
[0086] As used herein, an "oxo" refers to =O.
[0087] As used herein, the term "phospho" refers to phosphinates and phosphonates.
Examples of phosphinates and phosphonates include -P(0)(RP)2, wherein RP is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
[0088] As used herein, an "aminoalkyl" refers to the structure (Rx)2N-allcy1-.
[0089] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

100901 As used herein, a "urea" group refers to the structure -NRx-CO-NRYRz and a "thiourea" group refers to the structure -1\112x-CS-1\TRYRz when used terminally and -NRx-CO-NR'- or -NRx-CS-NRY- when used internally, wherein Rx, RY, and Rz have been defined above.
[0091] As used herein, a "guanidine" group refers to the structure -N=c(N(RxRy))N(Rx,rs.Y, ) or NRx x _c(_NRx)NRx¨Y
wherein Rx and RY have been defined above.
[0092] As used herein, the term "amidino" group refers to the structure -C=(NRx)N(RxRY) wherein Rx and RY have been defined above.
[0093] 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.
[0094] 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.
[0095] 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., Rx0(0)C-a1ky1 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(0)0- or alkyl-OC(0)-) and alkylcarboxyaryl (e.g., alkyl-C(0)0-aryl- or alkyl-0(C0)-aryl-) are examples of cathoxy groups used internally.
[0096] As used herein, an "aliphatic chain" refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure -[CH2]-, 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 -[CQQ1v- where each Q is independently a hydrogen or an aliphatic group;
however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
[0097] The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described herein, compounds of the invention can in optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R1, R2, and R3, 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 R1, R2, 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 hound.
[0098] 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.
[0099] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 C
or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

WU, .L11.11U/11:14 136 PCT/1JS2009/063475 [00100] 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.
[00101] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiorneric, 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 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.
[00102] Compounds of the present invention are useful modulators of ABC
transporters and are useful in the treatment of ABC transporter mediated diseases.
[00103] II. COMPOUNDS
[00104] A. Generic Compounds [00105] The present invention relates to compounds of formula I useful as modulators of ABC transporter activity:

1:111 I /
n(R2) 1") or a pharmaceutically acceptable salt thereof.
[00106] R1 is -ZAR4, 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-, -0O2-, -000-, -NRACO2-, -0-, -NRACONRA-, -OCONRA-, -AA NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, -NRAS02-, or -NRASO2NRA-. Each R4 is independently RA, halo, -OH, -NH2, -NO2. -CN, or -0CF,i. 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.
[00107] R, is -ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C1_5 aliphatic chain wherein up to two carbon units of Z13 are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -000-, -NRBCO2-, -0-, -NRBCONRB-, -000NRB_, 1BB -NRBCO-, -S-, -SO-, -SO2-, NRB,-SO2NRB-, -NRBS02-, or -NRBSO2NRB-. Each R5 is independently RB, halo, -OH, -NH2, -NO2, -CN, -CF3, or -0CF3. Each R13 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 R2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
[00108] Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, 0, and S.
[00109] Ring B is a group having formula Ia:

I ii p Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-3 and each R3 and R'3 is independently -ZcR6, where each Zc is independently a bond or an optionally substituted branched or straight Cl_6 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRc-, -CONRcNRc-, -0O2-, -000-, -NRcCO2-, -0-, -NRcCONRc-, _ocoNRc_, _NRcNRc_, _NRcco_, _s_, -SO-, -SO2-, NRc,-SO2NRc-, -NRcS02-, or -NRcSO2NRc-. Each 12., is independently Rc, halo, -OH, -NH2, -NO2, -CN, or -0CF3. Each Rc is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted hetenocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively, any two adjacent R3 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle. Furthermore, R3 and an adjacent R3 group, together with the atoms to which they are attached, form an optionally substituted heterocycle.
[00110] n is 1-3.
[00111] However, in several embodiments, when ring A is unsubstituted cyclopentyl, n is 1, R2 is 4-chloro, and R1 is hydrogen, then ring B is not 2-(tertbutyl)indo1-5-yl, or (2,6-dichlorophenyl(carbony1))-3-methy1-1H-indo1-5-y1; and when ring A is unsubstituted cyclopentyl, n is 0, and R1 is hydrogen, then ring B is not Nz \ Ho 0 N 111 N
N
, or = OH
_ N
=
[00112] B. Specific Compounds [00113] 1.1A.1 Group [00114] RI is -ZAR4, wherein each e is independently a bond or an optionally substituted branched or straight C1..6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -0O2-, -000-, -NRACO2-, -0-, -NRACONRA-, -000NTRA-,-NTRANRA-, -NRACO-, -S-, -SO-, -NRA-, -NRAS02-, or -NRASO2NRA-. Each R4 is independently RA, halo, -OH, -NH?, -NO2, -CN, or -0CF3. 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.
[00115] In several embodiments, R1 is -ZAR4, wherein each ZA is independently a bond or an optionally substituted branched or straight C1.6 aliphatic chain and each R4 is hydrogen.
[00116] In other embodiments, R1 is -ZAR4., wherein each ZA is a bond and each R4 is hydrogen.
[001171 2. R2 Group [00118] Each R2 is independently -ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight Ci_6 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONIeNTRB-, -CO2-, -000-, -NRBCO2-, -0-, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -NRB-, -SO2NRB-, -NRBS02-, or -NRBSO2NRB-. Each R5 is independently RB, halo, -OH, -NH2, -NO2, -CN, -CF3, or -0CF3. 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 R2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.
[00119] In several embodiments, R2 is an optionally substituted aliphatic. For example, R2 is an optionally substituted branched or straight Ci_6 aliphatic chain. In other examples, R, is an optionally substituted branched or straight Ci_6 alkyl chain, an optionally substituted branched or straight C2-6 alkenyl chain, or an optionally substituted branched or straight C2-6 alkynyl chain. In alternative embodiments, R2 is a branched or straight Ch6 aliphatic chain that is optionally substituted with 1-3 of halo, hydroxy, cyano, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. For example, R2 is a branched or straight Ci_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 optionally substituted with 1-3 of halo, hydroxy, cyano, aryl, heteroaryl, cycloaliphatic, or heterocycloaliphatic. In still other examples, R2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each of which is unsubstituted.
[00120] In several other embodiments, R2 is an optionally substituted branched or straight Ci_5 alkoxy. For example, R, is a Ci_5 alkoxy that is optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or combinations thereof. In other examples, R2 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.
[00121] In other embodiments, R2 is hydroxy, halo, or cyano.
[00122] In several embodiments, R2 is -Z5R5, and ZB is independently a bond or an optionally substituted branched or straight Ci_4 aliphatic chain wherein up to two carbon units of Z13 are optionally and independently replaced by -C(0)-, -0-, -S-, -S(0)2-, or -NH-, and R5 is RB, halo, -OH, -NH2, -NO2, -CN, -CF3, or -0CF3, and RB is hydrogen or aryl.
[00123] In several embodiments, two adjacent R2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle. For example, two adjacent R2 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 lb:
Zi ssizi-Z5 lb [00124] Each of Z1, Z7, Z3, Z4, and Z5 is independently a bond, -CR7R'7-, -NR7-, or -0-;
each R7 is independently -ZDR8, wherein each ZD is independently an optionally substituted branched or straight C1_6 aliphatic chain wherein up to two carbon units of ZD
are optionally and independently replaced by -CO-, -CS-, -CONRD-, -0O2-, -000-, -NRDCO2-, -0-, -NRDCONRD-, -000NRD-. -NRDNRD-, -NRDCO-, -S-, -SO-, -SO2-, -SO2NTRD-, -NRDS02-, or -NRDSO2NRD-. Each Rs is independently RD, halo, -OH, -NH2, -NO2, -CN, -CF3, or -0CF3. Each RD is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. Each R'7 is independently hydrogen, optionally substituted C1-6 aliphatic, hydroxy, halo, cyano, nitro, or combinations thereof.
Alternatively, any two adjacent R7 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 R7 and R'7 groups together with the atom or atoms to which they are attached form an optionally substituted 3-7 membered cathocyclic ring Or a heterocarbocyclic ring.
[00125] In several other examples, two adjacent R2 groups form an optionally substituted carbocycle. For example, two adjacent R2 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 R2 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, groups form an unsubstituted 5-7 membered carbocycle.
[00126] In alternative examples, two adjacent 122 groups form an optionally substituted heterocycle. For instance, two adjacent R2 groups form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatoms independently selected front N, 0, and S. In several examples, two adjacent Rz groups form an optionally substituted 5-6 membered heterocycle having 1-2 oxygen atoms. In other examples, two adjacent R2 groups form an unsubstituted 5-7 membered heterocycle having 1-2 oxygen atoms. In other embodiments, two adjacent R2 groups form a heterocyclic ring selected from:
<
,N F2c, ( I N, , 0 css, CY-55- 'css, , -=10 o(0i-Cc N fl-C"
0, ts NI, I
\--kss5 =0.,`-t,i/._ õ....Ø...õ1-LC:
H
I
N I
-42-?"
.., ir,,:-(.. .,- -,X
s55 N I
, Me0 OH , , 0---,1_ Ni N----,-(1.
and U.
c.c.s .

[00127] In alternative examples, two adjacent R2 groups form an optionally substituted carbocycle or an optionally substituted heterocycle, and a third R2 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 R2 groups; a third R2 group; and the phenyl of formula I form a group having formula Ic:
-----Z R
Z2 1 2...µ,õ.....
/

\-7 /--,'\ss-CIN
4"-Z5 IC
[00128] Z1, Z2, Z3, Z4, and Z5 has been defined above in formula lb, and R2 has been defined above in formula I.
[00129] In several embodiments, each R2 group is independently selected from hydrogen, halo, -OCH3, -OH, -CII2OH, -CH3, and -0CF3, andior two adjacent R2 groups together with the atoms to which they are attached form N--......q...-N--......!-C
\
< I F2CI ><
I
c....I I NI, I
Nsss, , µN---cs: , , H
____________________________________ I <>< I ss= 0 I s. N'õ ____,I
,0 _________________ <0 N---..A
H

..--H
õ...Ø.,X
N--r`z-t". :õ..,0,.. 1 I
I Y5' c55 Me N I
0 OH , , \ H , 0--..."-i.: N--..õ=1/4:
and XA19 XA20 XA21 .
[00130] In other embodiments, R2 is at least one selected from hydrogen, halo, methoxy, phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy, and methyl.
[00131] In some embodiments, two adjacent R2 groups, together with the atoms to which they are attached, foiin 0%_-< 1 or F2c, 1 [00132] 3. Ring A
[00133] Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, 0, and S.
[00134] 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, Ci_5 aliphatic, or combinations thereof.
[00135] 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.
[00136] In still other examples, ring A is selected from õ...(Rog lR8) q \----/(R8)q , , XB1 ' XB2 X63 X64 XB5 H
,2..s .)..,3=N, (RB)q,(R8 ) HN __ (R8)q 1..,(3%), /\q H, 1\2Xr, HN

H
N (Rs) ,19(R8)q cj , ..,..?c, OZZ(R8)q rZ(Fis)q S (R8)q HN
( _________________________________________________ (Rai (R8),, HN
and ' , , [00137] Each Rs is independently -ZER,, wherein each ZE is independently a bond or an optionally substituted branched or straight C1.5 aliphatic chain wherein up to two carbon units , of ZE are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CO2-, -000-, -NRECO2-, -0-, -NRECONRE-, -OCONRE-, _NRENRE_, _NREc0 -S-, -SO-, -SO2-, -NRE-, -SO2NRE-, -NRES02-, or -NRESO2NRE-, each R9 is independently RE, -OH, -NH2, -NO2, -CN, -CF3, oxo, or -0CF3. Each RE is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, , . .
or an optionally substituted heteroaryl.
[00138] q is 0-5.
30 .
' . , [00139] In other embodiments. ring A is one selected from , and [00140] In several embodiments, ring A is [00141] 4. Ring B
[00142] Ring B is a group having formula Ia:
R' /
Ia or a pharmaceutically acceptable salt thereof, wherein p is 0-3.
[00143] Each R3 and R'3 is independently -ZcR6, 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-, CO2, _NRccoNRc_, _ocoNRc_, _NRcNRc_, _NRcc0_, _ -000-, -NRcCO2-, -0-, S-, -SO-, -SO2-, -NRc-, -SO2NRc-, -NRcS02-, or -NRcS02NRc-. Each R6 is independently Rc, halo, -OH, -NH2, -NO2, -CN, or -0CF3. 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 R3 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 R3, i.e., attached to the 2 position of the indole of formula Ia, together with the atoms to which they are attached form an optionally substituted heterocycle.
[00144] In several embodiments, ring B is R.3 R.3 NTh R.3 R'3 _____N.

= (R,), 1110,13)õ, (R3)p sr( (R3)p , Or [00145] wherein q is 0-3 and each R20 is -ZGR21, where each ZG is independently a bond or an optionally substituted branched or straight C1_, aliphatic chain wherein up to two carbon units of ZG are optionally and independently replaced by -CO-, -CS-, -CONRG-, -0O2-, -CO-, -NRGCO2-,-OCONRG-, -NRGNRG-, -NRGCO-, -S-, -SO-, -SO2-, -NRG-, -SO2NRG-, -NRGS02-, or -NRGSO2NRG-. Each R21 is independently RG, halo, -OH, -NH2, -NO2, -CN, or -0CF3. 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.
[00146] For example, ring B is N,Th I (R20)C1 N,Th (R3)p (R3), , Or [00147] In several embodiments, R'3 is hydrogen and R3 is attached to the 2, 3, 4, 6, or 7 position of the indole of formula Ia. In several other examples, R3 is attached to the 2 or 3 position of the indole of formula Ia, and R3 is independently an optionally substituted aliphatic. For instance, R3 is an optionally substituted acyl group. In several instances, R3 is an optionally substituted (alkoxy)carbonyl. In other instances, R3 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, R3 is an optionally substituted (aliphatic)carbonyl. For example, R3 is an optionally substituted (alkyl)carbonyl that is optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. In other examples, R3 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.
[00148] In several embodiments, R3 is an optionally substituted (cycloaliphatic)carbonyl or an optionally substituted (heterocycloaliphatic)carbonyl. In several examples, R3 is an optionally substituted (C3_7 cycloaliphatic)carbonyl. For example, R3 is a (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentypcarbonyl, (cyclohexyl)carbonyl, or (cyclohcptyl)carbonyl, each of which is optionally substituted with aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof In several alternative examples, R3 is an optionally substituted (heterocycloaliphatic)carbonyl. For example, R3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N, 0, and S. In other examples, R3 is an optionally substituted (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N and 0. In still other examples, R3 is an optionally substituted 4-7 membered monocyclic (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N and 0. Alternatively, R3 is (piperidine-1-yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, or (morpholine-4-yl)carbonyl, (piperazine-1-yl)carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, or aliphatic.
[00149] In still other instances, R3 is optionally substituted (aliphatic)amido such as (aliphatic(amino(carbony1)) that is attached to the 2 or 3 position on the indole ring of formula Ia. In some embodiments, R3 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, R3 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, R3 is (N,N-dimethyl(amino))carbonyl, (methyl(arnino))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.
[00150] In other embodiments, R3 is an optionally substituted (alkoxy)carbonyl. For example, R3 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 C1_6 aliphatic. For example, R3 is an optionally substituted straight or branched C1.6 alkyl. In other examples, R3 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 C3_6 cycloaliphatic. Exemplary embodiments include cyclopropyl, 1-methyl-cycloprop- 1-yl, etc. In other examples, p is 2 and the two R3 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 Ci_6 aliphatic or C3_6 cycloaliphatic); 7 F 2 ( (optionally substituted Cj_6 aliphatic or C3_6 cycloaliphatic)), 4F-2-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic); 7-CN-2-(optionally substituted Ci_6 aliphatic or C3_6 cycloaliphatic); 7-Me-2-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic) and 7-0Me-2-(optionally substituted C1õ6 aliphatic or C3_6 cycloaliphatic).
[00151] In several embodiments, R3 is hydrogen.
[00152] In several embodiments, R3 is one selected from:
-H, -CH3, -CH2OH, -CH2CH3, -CH2CH2OH, -CF[2CH2CH3, -NH2, halo, -OCH3, -CN, -CF3, -C(0)0C1I2C113, -S(0)2CH3, -C112N112, -C(0)NH2, OH

ALNIk.,=-=CN'OH

0 %'-)H

2, 410 g N
N 'N
= 0 N'Th N

OH
Oil )41A k 22(fC72CH3 401 WO 2010/054138 PC JUL S20(19/06.54 1 Af/
N I
0 \ \
2((¨ -q--NH '--µ-'. N7 NH
.1 \ \ )(N

-k-Y
CONH2 0 \ 0 \ OH 0 , A.,-...,,,..."-OH )2,_<
\ ¨ ¨ .A
OH \ __ NH NH2 , , )((----i H NH Ar( OEt .....µf ? <
OH
/OH

kr\l"
H
/ -1\l'''" ',-'-` -'''';N
I 1 A--(----- CN õ...( N)._ iliNJ
_____________________________________ \ N

..r. / ./µ"..'\,) A'ss-rk,',--/- / X H

NH N D
..-\----"---N.' --I' 0 S
> _____________________________________________ OH )d----,k--\/- I 'µOH 0 CO2H
, and [00153] In another embodiment, two adjacent R3 groups form =
[00154] In several embodiments, R'3 is independently -ZcR6, 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_, -CO2-, -000-, -NRcCO2-, -0-, -NRcCONRc-, -000NRc-, -NRcNRc_, NI2cCO-S-, -SO-, -SO2-, -NRc-, SO2NRc, NRcSO2, or -NRcSO2NRc-. Each R6 is independently Rc, halo, -OH, -NH2, -NO2, -CN, or -0CF3. 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, Ci.6 aliphatic, or C3_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 Ci_6 alkyl optionally substituted with up to 4 -OH
substituents.
[00155] For example, in many embodiments, Rr3 is is independently -ZcR6, 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 -C(0)-, -C(0)NRc-, -C(0)0-, -NRcC(0)0-, -0-, -NRcS(0)2-, or -NRc-. Each R6 is independently RC, -OH, or -NH2. 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, C1_6 aliphatic, or C3_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 C1_6 alkyl optionally substituted with up to 4 -OH
substituents.
[00156] In other embodiments, R'3 is hydrogen or :62 R32 OH , [00157] wherein R31 is H or a C1-2 aliphatic that is optionally substituted with 1-3 of halo, -OH, or combinations thereof. R32 is -L-R33, wherein L is a bond, -CH2-, -CH20-, -CH2NHS(0)2-, -CH2C(0)-, -CH2NHC(0)-, or -CH2NH-; and R33 is hydrogen, or C1_2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl., each of which is optionally subsitututed with 1 of -OH, -NH2, or -CN. For example, in one embodiment, R31 is hydrogen and R32 is Ci_9 aliphatic optionally substituted with -OH, -NH2, or -CN.
[00158] In several embodiments, R3 is independently selected from one of the following:

-H, -CH3, -CH2CH3, -C(0)CH3, -CH2CH2OH, -C(0)0CH3, .
-----K -4- r0H
(3, Z2OH
, OH
, ----'0 ..r., NHOOCH3 =:i4 C 0 H A-y-NHMe -µ-'µ`rOMe 2 OH , OH =
N
)02.0H ' , ,Ø
µ ,-----0 ,.......Ni\IH )22.--,.,.NH 2'.....2,,-....õ...õ..... -.'*..,,,--,..,..) 5 OH 1 --CCONHMe = =
r--- 0 -µ-r-OEt c02H NH2 OH
, , -----.'NH
;2ie,Th N H CO M e 0 )iCN
A..-..õ......õ-õ,õ.
CONMe2 OH A OH
H )(Y\O
A NHS 02Me 4 x--i=CO2H 1(N

2.--=,,, 0-7c , OH , 0 , OH , I , -VN`rNHSO2Me A---'"r"*NHCO2Me , NH
A==-..NHCO2Me OH , OH OH Nz---Nf OH
OH
N
r3---OH -rN,.-ThrN
"N"---.µON
0 ..., A--,,_NHCO2tBu OH OH , 0 HO , 4 s A.r0 Nr- r,S-'j O NAO ...-< OH HN)--,--3-.
\S"------V-NHS02Et Aerr ..õ.", =-.-NH
OH OH kz X \ ) 0 t--0 " -0 ---Yu OH N -"\N----S-)224MNIH , OH ' ' )'-'--7-, I
&. -NN , t A--)r,N,...
\
N-0 5 and 0 .
[00159] In several embodiments, ring B is one selected from:

N o 0 N/ 0 Ni I
* 1,>---(N7 isol , Nt0H
/
, , H H H

.

01 N/7 il ip. a, so , N----- /
H
= H

N

* I NO a HN----\_0 H
, 0 .

N
N N NH
N/
NH
= I N\7 N
* I H
. I zc * 1 \
/
. . , H +/OH

. i H
OH I
.N N
I

. i H N N
N
F N
I
* I * I I
*
/ NHz H
H H N
H N N
N
= I = I --0 111 I
. I
, 1 , = ,

6 , . .
i I, ) o HO H= OH OH HOH)H H
, , .
-n=-,,, ,tq,,, /

1 .
I
N N ---7(LN* d N
N
A H 1-1 \\
N
) OH
OH
HOAH
HO

HN ( _________________________________ HN . 10 RN 41 HN d =
--..õ
---__ . , ' µ,,d=
\ /
i * HN .
II 40 HN * HN 0 H N
H
, / ) = 41 01 ¨ HN
,,,ANN
H N--- H
\\
N
SLt90/600ZSII/13.1 8O7S0/0i0Z OM

0, I

OH ,OH \
H
\N
,Y--- \N \N
N F N
. . I . 1 = i . i , -7--N) 0 __ H
. NH N
111 N \ ft, NH

0 \----_, and .
[00160] 5. n term [00161] n is 1-3.
[00162] In several embodiments, n is 1. In other embodiments, n is 2. In still other embodiments, n is 3.
In one aspect, the present invention relates to compounds of formula II useful as modulators of ABC transporter activity:

V H

11101 0 R2N 0 \

II
or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form ¨OCH20- or ¨0CF20-;
121 is H or alkyl;
R2 is H or F;

12 is H or CN;
R4 is 11, -CH2OCH2CH(OH)CH2OH, -CH2CH2N(CH3)3, or -CH2CH2OH;
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form a five membered ring.
In one embodiment, the present invention provides compounds of formula H, wherein the compounds set forth below are excluded:
IF H
\
N IP

H , V H
N
FX 0 0N \ 1 0 \OH

H
OH , N
FX 401 \ ____________________ V H

F 0 F .1 N \
LA 1101 0 IS t\\;' OH H
, 0 N * 0 N 101 \
111011( 0 H
, , lir IPF H
N
F,x = 0 . Fx0 ill 0 401 , L.\
OH , OH, V H
V
N
Fx0 401 0 *\ F.,(0 H = * \

OH, OH , Y V H
N
Oil 0 * \ IS \

F 0 F N .-C) N
HH
, , V H
N V H
<0 110 0 =\ N
\

\---"\
OH, OH, V H
<0* 0 N V H * \
0 F N ,C) N
µ---rH 0 0 \

F
OH, H , V H
V H
N
(0 0 * \

F
FX = 1 \ I
LALOH 0 N \¨OH
F OH , H , V H
V H N
0 N \
<
\ FX 0 \---\ F 0 N
\----COH
OH , OH, .,0 * N *
\ N
(0 0 0 \

H H , , N
Fx 0 0 \ 0 /
\ 0 0 0 \

H H , , N
<0 = 0 * \ 7H
N

<0 0 0 ON \ \ 1 --OH
OH, H , 0 * NO

Ho* N
0 \
N 0 0 \
N
T H
(i) H

N N
* \

N.. = 0 N

\---t_OH \---....OH
OH, OH, V H

V
F;x0 H
1161 N\ OH
N

OH , V H

\

HO
L¨rs0H I011 OH , V H
<0 0 10 \

HO

HO N
,and OH
In one embodiment of the compounds, two R taken together form -0CF20-, R1 is H, and R2 is F. In another embodiment, two R taken together faun -0CF20-, R1 is H, R2 is F, and R3 is H. In another embodiment. two R taken together form -0CF20-, R1 is H, R2 is F, R3 is II, and R. is II. In another embodiment, two R taken together form -0CF20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R
taken together form -0CF20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, two R taken together form -0CF20-, R1 is H, R2 is F, R3 is H, and R4 and R5 taken together form a five membered ring.
In one embodiment of the compounds, two R taken together form -OCH20-. Rj is H, and R2 is F. In another embodiment, two R taken together form - OCH20-, R1 is H, R2 is F, and R3 is II. In another embodiment, two R taken together form -OCH20-, R1 is H, R, is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, R is OH, R1 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, at least one R is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R
is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, two R taken together form -CH2CH2CH2-, is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment, the compound is represented by formula Ha:

111, H
N
F

Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, Or R4 and R5 taken together form a five membered ring.
[00163] In one embodiment of the compounds, R4 IS -CH2OCH2CH(OH)CH2OH, -CH2CH2N4(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH20II. In another embodiment, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH21\r(CH3)3, or -CH2CH2OH; and R5 is OH, -CII2OCII2C11(OH)CH2OH, or -CH2OH.
[00164] C. Exemplary compounds of the present invention [00165] Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

WO 2010/054138 PCT/1iS2009/063475 Table 1: Exemplary compounds of the present invention.

H
F N
H SI /
i N
A
Op 4: 0 ,-, 1.1 IIP

r0 ,0 r 0 .d N
<' 0 mai 0 lir Ha;
N I V
H
=C' I 40 /
H H'N N
H
F /
F
F

7 8 9 ... 0 * e a N
/ < D.C3r1-Cr 0 -."- =P"' N F/0,0 i H
I

H ,>(00._ N H
AI hr e0 1õ 0 Ai ..t4 0 N
lir I 0 -,;:ix1I-N lir i tti 0H --[--, F).(0oxi N N H
AN q , 0 - N
H

8 PCT/US2009/063475 .0 \--S, F

eo 0 ir. N
<P * 0 N H A H

A. H

F l"

'N 7 0 IP- 0 At N /
N lillij' 1 \

*

N
'ia ti m F> 0 1LN ' 1111-IP

N 4111117 H ' *
F 0 *
/
A H N
H

_A-1 -4--H

0 0 õAzMS 0 . N (' 0 mikb ---0 2,14 A H

--/-c o_c,1,_ 2, _ 1 .c, e , 0 f -3__...,:,,,,, 0 `
N
() -=-. 0 4fits N 0'-' J'' 13 - 4ti Th , Q
cit---12,, .1, , u, l, 11 \-=' F>C0 nil 0 0 N
/
F 0 qr N
A ii 181,--cilnil H * * /
<:C2',. 0,N 0 N '0 0 N
/ 0 ,ach)i I A H 04 h 0 )7-9i 0 0-" N I ; / 1 0 H ..S-al--C
H
ofd S 0 110 A
.0 'if-di N
N
F_,0 rah, 0 N*
H
F)C0 4,- / I-I 0 N
o A. N
$
H

ni ri --t4 W , F c_N

:
I ,v0 N -- (0 * A0 H * /
if-. N
--H F>(0* NCZ 1 = H

c H 34 C
gr dal,.
<o U..., ti 0, .,-,,,,,,N, i / a 0IS
r0 * D * N/ õ1 I i ri 0 "mil,' N H/

ANA H H

Ho F
C> 1 %
x0 * 0 gib. tl, H
<0 tigt HN --'C 1 A ff ZS H 0 0 *
F A-CE
r 43 44 45 .
1-i a Ho 1.-,Z1 H
F ...,,,... N 0 HN a A 0 < *0 N
FF>(00 * *
n /
1 0 I-I * 44 N
AK
0 1411) '1 0 ff-r-F
46 47 48 .
H
(`' 0 a 0 --71-- r 0 N * Nj <S 0 la F FX00 I * P47 A I aN Pt AN

N
C

/ ,r311,-1_ Cf, o - L\ ii 0 \___ 1 it,õ . hr_ , 0 ,.._ fi H H
H

/ . , Cri / I
, N
", 1 H

H

F
V H H F-F
N N H
N
e0 0 OS /( ..
o A N

\ 0 F---i-F

H
N,N
3,1 )' co N 7,...r F
AIAI A -j---? I HO -- / MI Yaõ ''' 1 )<
-,, 0 F
li7 A H
o \-o , H
F N
v I, C H
O= 40 N4 A 0 0 0 N
0 . , <0 H
. N
A H

\¨o oH (.4;=NH
Sj 6 F ) V 4 H
ON iiki N NH
F Ci 0 12> '\
F)<0 0 . t*1 I
N
AN

N

H NH
O H

. 0* 41 \ ) A H CI N
AN
<0 * 0 * N
/

AN

H
v 0 H ) Os) V H
N H
/ 0 Th) At, * N/ <I) 0 o 0 /
Fp 0 F > illik 0 = N
/
F 0 Ilir 0 411r1 N
AN H
. 50 HO

e--.*
N --.
H
V 11 . F a a t a o I
o rith, o = 1 ,... \ I
<Po 'IP 0 ' -- fi A H

C)11-7).2-N I --.-04 I
H
_ --,0 m _ H
e 1 ===. 0 ii NI\ v N
d 41.47 1,1-A
H
...-) 0 la 1,{ . l * 0 * /
N
AN
= H
79 80 81 , NN ti CA 0* 8 0 N14 i LI,:...a..ylt I _Ord 0 -4'o d_ ek o 8 AN
82 83 84 .
H F

0;o 1.10: F
,-S- H14 H li F tiggi N 4 Ha ___Z Hig lir / IO= A a A A .
F
F, UV Jo rikk 0 H .,.(y)4/ 1 0 0 ti \-a \¨o H ^i H
0 p4 ari N

\N . I
: ...:,.. N lir i WI N All oo N
ii FE A H *N5 /
H

¨1¨ H
of 0 CI H ra N/

HO ..ii7 0 ID.. ,..-71.11 0 0 dairl N < I A
< 0 A H
o 4 --- * µ?

-')oH
H
0 0 oy 41,1j F
4') K' 0 O 0 14 0N 4 0 * i 0 <0 5 5 N
/
N
H H A, H A H

on N
\ t aN

H IV ¨Q-- ) P0 0 0 /

Ci H
A' 0 N 0 I. OH* IS I
X")iji), fa2-4" ,7- r e0 0 0N *
fl 44*.,-) ii ,0 '4 _¨___a , e iii 0 14; I -cOay ei _C;_,L) i 0,, 0 41P--. N
A H rah 0 N

D" WI
A, H

H
e1 ,30.,-V,If,t4 , OL\IN * 4 0 ..., 0 IN i\,, H

H

Ho 110,ki\I
F Alt N
/ H
0 Atm, 0 all. NI, 44 00 A t.1 10 1'1/ HN 1413- i 0*

A H
FO
F

Ho --Ic3H 4. o la H
N
/ ....0 H
<0 0 41131 N 4164P = NH H
H

P
Q
O H
<0 lb 0 /I- _li4i N
#i 0 IP #1"1",, FF)?0 1,1 A H
/ H
N
A H

H

v H

N iir 0 N
H H <o * I
H

r_.o \rj F N
F
H
N pc, ii. 0 ri-"'xl, 1 0.1 A o 140 A 4 *
N
t4 / ..w a --\ ¨0 F
F

O F Ho C f ',õa. . * 14 a N 0 it', a *2 = / N
H '''N
N H
H

H H
N\4 0 N

110 NI o.
F 0 utp e0A.,,J.,=it.
U
H

H I
(9' -,, tsis)-2( 0 NH 0 41 0 0I ' = N kk ="" - fli --, * CY,!) 1 <0 1 ,,,, 0 Lai., /,.
1 4, o H .,_cii N l 11 1 4'-F
? lb c¨< J.?
0 111-P N-"-/.4..1-- 0 F)(F9 0 ,C6 I õ I
A H Ci 4111 0aliV I A '4 H

H0 . A' 0 --0 H
? la tp,r0:1-4' fc' N

L_. 8 -- - 44 a D . / 11 Po . la i - k N
A H
H

, 0O . .
H

?

hi+ <0 * 0 * \

<700 H

no o H
<0 / eo* *

H H
N = A m ,\H
H

H
F N

H
H / ii }.10 ti Pt A . Ho A
F

c) H
0 N 0 hi / F
F> 0 14 F >0 0 N* /
AN

F

CI
H
'0 H
H N = 1 *N
<00 . 210,N 0 N

0 1 '-, .., i i A 11 if H u H

H H
(0 0 * t4/
0 ,... 0 0I," 0 ..-- N .-- <0C, ,2.t. * \
N N
H H

oro =
Ca H 0 ,FI Tr, 0 Tr--....-11-N _49 v * * N/ b.-1!;+.2e1 ),c,,--.1" `,.__, 0+_ N H
ti ..õ N
N
A H
0 .., I

on0 *A ii N
' '0 4 N*
S I . 0 10 i H N
A H 0 N' H

N
0 if _ H

H
F
HN H Ho _iss, =... 0 0 / 4 d (2,0 .7/ (` 1 a -- rsi o 0 AG H *
N I" H /
A H N

cr¨
F
H
H
SI ,,,---j-' '-= I
*1 I. N
if Nj = H V
N N
H
H' /

CI FA¨C1 F

H
µ)----- F N
F N

H 0 ' 1.1-4 0 4' * /
N A 0 -- ,,, 0 =

Y) ...,I --N

-.. 0 166 167 168 .
/
\r"j H

H N * /
--'0 F 0 FP * o 0 14 <0 0 * /
AN N

1_0 o-5; i H!,1 H
N ,-0 f . * N
i H 0 0 t4 AN

-F
Ft1,4 * /

a Ke: 1:10 2M F>(.0 qpr N
C
1.11 A H
N
* 0 I

Cf F F --P 4 o la N
/-0 N 0 4,,, Ni dal A N A N o ump, illr N

H

,..-0 U
NH

HO)) HN
(P All 0 Au, 4 WO / ik 0 Pi H

\ --0 aq <cll . 0 ill 14/ Ho MN
N N millrir N A 0 AM H
0*
..--0 H
F N 1-, H N / / I \ \ ___0 1-1?=1 H

N
= 00 1.1 * \
ti H ? dlik 0 Lir o N

F

r0 SI Q d v H H
N H
<0 ipi i-o-:;+_4? 0 .
. 0OH C 0 I I
ki H
N
H = . N
/
F

HN o ki o H
Ailt 0 ..,..-- 1 1 x"--j2 \...z Laz?,,õ 1 <, ( o nal 0 ,. N
11 0 - g 0- 0 MP' A H IV

H
o oK
H t ol, (93, ccj,/,,H 1 < 0 /
= 001 Ni 0 '- x -N ,'4.-0 , N 0 N
A. H AN

OH
H Ci 1* 0 di l',/ 13F1, - H
<
0 Ala 0 N NIP hi 0 11111" N
A H F>cp diz 0 Ur / = H

= H

HO
F
. 14/ "1,1 _ N -(() I

0* H
\-0 H C;

< I " Q
0 ..- = 'if 0 hl F. P fill 0 ifili-1 N 0 diti -N
/ H A kW / (C) 0 qv, /
F 0 41,11-1 0 N
A N , H

F tiai.
H

1.111 Ni 1-10--F)(3 I '; ,,, * / Ill HN

F_P I. dik 0 dil I, H

* A H

\--8 _ ti "s-------'z:-.--14 H

H'N Il CI HOT4Z) A o . 40 NI

0 FX N Fõ0 al 0 * II4 el I ii 0 Ur N
AM /
\--0 H

HIO--F
c) H
>l F AILN. 1,1 0 Sill /
* * f-i 1 N {
0 * a * N HN
A H / A ' AM
*

\-0 . _ r4 0 ti AM AM

--- H

o I
r ) ..zo ,-, N
1 H). H
, 1 uz. at) , , N_ 0 10 i /
N5,x 1,- N i A t-i A H

H
H N
\F 0 HO ---Z

-2,1,-axic 40 "
I I I
40 * I 0 qe. N
H F 0 t4 A.
A H

H
H Il (9 tl ¨N V VI *0 N
N =
/
0 31-N fj0 40 , i 0 '14 H
H
226 , 227 228 F
H H H
<00 40 Ai N
0 N*
11) N./ 0 AO
=I
AK AK AK

, hb 1 --/" H 0 0 N i fj:) AI 0,' 0 01 N / Ilk H
N
1101 0 . /
i'o-F ''' 0 VP N A ii n AN A ti H H H
N
e 40 r-s o A9 H 0 /
r4/ ,OH
til, N 411147 A H A H

O Ho H

N I '' SI /
H D ,- N
I CI * / H
N
H
238 239 240 , cf H MN H
i \ 0 . Ili H4 0 N
>CO a N a /
N
H A ti r.. p di 0 *
i< N
r 0 lir N / i AN

HO
, H
NH
4µ) 0 N F
0 N (

9- 410 0 0 \
u H
N <P dal a frIz;>$4 I

A H

H cp HH H
\N * 0 At N.. N
F, 2 ilk 0 * N lip , .0 N
* /C' *
X / N
A H A H

A K

=N_ 0 al H Cit N 1 1E.X>
9i/ O A H la 34 ti CA n a i H

r0 H N
(=_-- el H
(0 dak. o iii 14/
o 1414, 31 111P N 0 /
A H 4" FF>c * rj 0 / 0 N

AN

cs CI
H H
E
H0-6- xi( I C . 1 * 14/ <030)1 Gt2--0 ..,, 0 14, --' = -N * N/ H
H

IC I'Prif cif4 / VH H
0 iiii N
0 reti N P.-- N
N
F >1 rib 0 41111-p. < WI i N H <90 A li H

\ &) N- F
H 0* Ni (00-* 0 N/ C1J) HN
4* N-N
= H / e = 0 0 N i A 0 A H

\..._.0 f¨a o . i Ha e 0 * N V g 0 figa /
0 lir H N e. 0 0 0 N`

H

;>.._ H

N

O N , = 0 ..a,..
=N

= * N
H
H /
H

H
o ci o 1 o . 0 s N
\
QWwits.:;'1"- I N¨C=N /
Illti 9 1 : - -, , W N
H
F 0 UIPPI ).1-A li \c`
HN
\I
? 110 = 14\ I
, u e 0 iii N 0 i H
O Lillr N 4115-P
H

H

Ho õii 1.i 81 - ---'0 I-f /
OTh).
N
Fx. fith. 0 rib , Fõ,. ,0 AI 0 * N F X0 . N
F o Vil- N Lir F-.)0 RP / F 0 0 AI%
ANN Alk PI
A H

H

H ) H
Hy/ 0 F , P , . - - , 0 c = - . ti ,4 N
i 0 N/ A I / al * 0,)<F
A tg F 0 ....' N 0 0 F
'lir H
II

..,--H

H I.S0 .4 4).
N
F 0 rdivh (3 Ai i a dal ti F
F>4'0 4111j N likr F.õ..,, * 0 ".. N Fi i 'Vt, A ii A. i / F c ---*
N WI i F

N ..--H
AN

H

S,..N FC1 0 0,s_ H l'4,õ/
15,1-.10:t4 13,k-cs) N 0 113T-1") F

j) fik, 0 * N F>C0VI /
H A
FA i N
F 0 - lir 1,1 A H
AN

1-i H 0 0, i 11 tli H N
KO ) CI
F., P rilli 0 at N 0 FP N
00 NW hi taIPP / = * 0 * /
AN CI

N
AN

II

Ho H H

-,, N 0N F.,_/.0 F
0 .' I 0 / F''''0 * o . ' la Pr F
H H
0*

F

H
:. ..
.Iµ) 14 Fifr-t) N
F.),,13 alb 0 KO =fiZ.,1 A Ft NF AI 0 Ai i F>.õ.0 0 0 ri---.. I\ I

N 4111141 F 0 ...k ....--1/ I
A H N
H

Ho N.... H
N
HO N-....c (*) N H /
N

F> * 0 . N

N
AN
-'' I

F F

H
H HN
/
HO 1.i== HO .p? A il H

O. N -F . ..... 0 X i -W I F 0 .=-= N * OH
A H H

I

D J
*
fib, N F>? Ali 0 La), 11/ 1 s F x0 . ,, 0 WI
/ F 0 um N OH
H H A li H

t4 F
trr 0H
F ,,,(3 ilk 0 iiiki.
1,11 f F"0 qv-N F
SI 111 Ni AN
'0 N' H
A N

cl,,o H N
%

F>c * IN * 1 AN

C :
) -=14.õ, i M I40'r \
0 H !
) -017 Hm-' , -"H.,:k,'" I \-0 014 = N = ,, o.1;,,,...... 9 o f-F F ,).-...0 k. 0 r H H

µ! ."
N
H ) 1., ) õ..,L /.." \ F C) - -'¨',','. --X ' E4 = ,' ''.:. ----:, 1 tk1= =,¨..,i4., I F . 0' ,A ...,c , j r.,..
J. 11 :s.,...-o F
313 3.14 315 ir J- H

\.' i - \
N =;
- .¨

C II, L
r II -,--- --I
J., , ..
..F,,,, A , , ...õ I, F

H

H
ki -,-",õ,, --ii H i . IL) -;,.> I
rIN-=-,.:- -, c, ¨0 0H / 0 r. -r \
''' ,k A .,;;1=-, /7 F blrE\
..p.1 )1¨'):, I
,___,,-= .,-1,:., H 14 .. ..K": ' H
, r ) ,;-4`
,., ..."
F 0 ."-i ss...s3 = 319 320 0 fi f Si 1 0 A.

=
116 *

vd, =
FrO
Afs)--L0 I
0 j In another aspect, the present invention relates to a pharmaceutical composition comprising (i) a compound of the present invention; and (ii) a pharmaceutically acceptable carrier. In another embodiment., the composition further comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CF 1K corrector, or a nutritional agent. In another embodiment, the composition further comprises an additional agent selected from compounds disclosed in U.S. Patent Application Serial No. 11/165,818, published as U.S. Published Patent Application No. 2006/0074075, filed June 24, 2005.
In another embodiment, the composition further comprises N-(5-hydroxy-2,4-ditert-butyl-pheny1)-4-oxo-1H-quinotine-3-carbortamide. These compositions are useful for treating the diseases described below including cystic fibrosis. These compositions are also useful in the kits described below.
In another aspect, the present invention relates to 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 formula II:

V H
R N \

Rt wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form -CH7CH2CH2-, -OCH20- or -OCF20-;
R1 is H or alkyl;
16 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2C117N4(CH3)3, or -CH2CH7OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together fonu a five membered ring.
In one embodiment of this method, the ABC transporter is CFTR.
In one embodiment of this method, two R taken together form -0CF20-, R1 is H, and R2 is F. In another embodiment, two R taken together form -0CF20-, 121 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form -0CF20-, R1 is H. R2 is F, R3 is H, and R4 is H. In another embodiment, two R taken together form -0CF20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R taken together form -0CF20-, RI is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, two R taken together form -0CF20-, R1 is H, R2 is F, R3 is H, and R4 and R5 taken together form a five membered ring.
In one embodiment of this method, two R taken together form -OCH20-, R1 is H, and R2 is F. In another embodiment, two R taken together form -OCH20-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form -OCH20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, R is OH, 121 is ll, R2 is H, R3 is II, and R4 is -C1420C1-12CH(011)0120H.

In one embodiment of this method, at least one R is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R is OCH3, at least two R1 are methyl. R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, two R taken together form ¨CH2CH2CH2-, R1 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, the compound is represented by formula Ha:
v H
0 N \
Ex F

Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N (CH3)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form a five membered ring.
In one embodiment of this method, 124 is -CH2OCH2CH(OH)CH2OH, -CH2CH21s1 (0-13)3, or -CH2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -CH20042CII(OIDCII20II, -CII2C112N+(CH3)3, or -0120120R and R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this method, the compound is selected from Table I.
In another aspect, the present invention relates to a method of treating a condition, disease, or disorder in a patient implicated by ABC transporter activity, comprising the step of administering to said patient a compound having formula II:

R 0 \

RA

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, 0013 or two R taken together form ¨CH2CH2CH2-, ¨OCH20- or OCF90-;
R1 is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N*(CH3)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form a five membered ring.
In one embodiment of this method, two R taken together form ¨0CF20-, R1 is H, and R2 is F. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, R3 is H, and R4 is II. In another embodiment, two R taken together form ¨00'20-, R1 is H, R2 is F. R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R taken together form ¨00-'20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2OCH7CH(OH)CH2OH. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, R3 is H, and R4 and R5 taken together form a five membered ring.
In one embodiment of this method, two R taken together form ¨OCH20-, R1 is H, and R2 is F. In another embodiment, two R taken together form ¨OCH20-, 121 is H, R2 is F, and R3 is II. In another embodiment, two R taken together form ¨OCH20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, R is OH, Ri is H, Ri is H, R3 is H, and R4 is -CH2OCH2CH(OH)C1120H.
In one embodiment of this method, at least one R is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is -Cl2OCH2CH(OH)CH2OH.
In one embodiment of this method, two R taken together form ¨CH2CH2CH2-, R1 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, the compound is represented by formula Ha:

V H
0 N *
F.x 1101 Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N4(C143)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form a five membered ring.
In one embodiment of this method, R4 is -CH2OCH2CH(OH)CH2OH, -CH2C1-I2W(CH3)3, or -CII2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this method, the compound is selected from Table 1.
In one embodiment of this method, said condition, disease, or disorder is selected from 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 hypoparaihyroidism, 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 much 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.

In another aspect, the present invention relates to 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 first composition comprising a compound of formula II:

R

wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form ¨CH2CH/CH2-, or ¨
OCRO-;
R1 is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH7OH, -CH2OH, or R4 and R5 taken together form a five membered ring; and (ii) instructions for: a) contacting the 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 said first composition.
In one embodiment, the kit is used to measure the density of CFIR.
In one embodiment of this kit, two R taken together form ¨0CF20-, R1 is H, and R2 is F. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, R3 is H, and R4 is H. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2CH2Nf(CH3)3. In another embodiment, two R taken together form ¨

OCF20-, R1 is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, two R taken together form ¨0CF20-, R1 is H, R2 is F, R3 is H, and R4 and R5 taken together form a five membered ring.
In one embodiment of this kit, two R taken together form ¨OCH20-, R1 is H, and is F. In another embodiment, two R taken together f01111 ¨OCH20-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form ¨00-120-, R1 is II, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, R is OH, R1 is H, R2 is H, R3 is H, and R4 is -CIL2OCH2CH(OH)CH2OH. In another embodiment, at least one R is OCH3, at least two R1 are methyl, R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R is OCH3, at least two 121 are methyl, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)C1120II. In another embodiment, two R taken together form ¨
CH2CH2CH2-, R1 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this kit, the compound is represented by formula Ha:
V H
F
)<C) 0 I \ __________ Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CII(OH)CI-I2OH, -CH2CH2N+(CH3)3, or -CILCH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form a five membered ring.
In one embodiment of this kit, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2N4(CH3)3, or -CH2CH2OH. In another embodiment, R5 is 011, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In another embodiment, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -C1-12CH2OH; and R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CI-120H.
In one embodiment of this kit, the compound is selecte.d from Table 1.
[00166] III. SUB GENERIC COMPOUNDS OF THE PRESENT INVENTION
[00167] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Id:

111:11 4N, n(R2) Ic or a pharmaceutically acceptable salt thereof.
[00168] RI, R2, and ring A are defined above in formula I, and ring B, R3 and p are defined in formula Ia. Furthermore, when ring A is unsubstituted cyclopentyl, n is 1, R2 is 4-chloro, and RI is hydrogen, then ring B is not 2-(tertbutyl)indo1-5-yl, or (2,6-clichlorophenyl(carbony1))-3-methy1-1H-indo1-5-y1; and when ring A is unsubstituted cyclopentyl, n is 0, and R1 is hydrogen, then ring B is not 411i H
N

0 0 \
, Or = OH
N
/ X
[00169] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Id:

n(2) Id or a pharmaceutically acceptable salt thereof.
[00170] RI, R.7, and ring A are defined above in formula I, and ring B, R3 and p are defined in formula Ia.
[00171] However, when R1 is H, n is 0, ring A is an unsubstituted cyclopentyl, and ring B
is an indole-5-y1 substituted with 1-2 of R3, then each R3 is independently -ZGR12, where each ZG is independently a bond or an unsubstituted branched or straight C1.6 aliphatic chain wherein up to two carbon units of ZG are optionally and independently replaced by -CS-, -CONRGNRG-, -CO2-, -000-, -NRGCO2-, -0-, -NRGCONRG-, -OCONRG-, -NRGNRG-, -S-, -SO-, -SO2-, -NRG-, -SO2NRG-, -NRGS02-, or -NRGSO2NRc-, each R12 is independently RG, halo, -OH, -NH2, -NO2, -CN, or -0CF3, 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 R3 groups together with the atoms to which they are attached form an optionally substituted heterocycle.
Futhermore, when R1 is H, n is 1, R2 is 4-chloro, ring A is an unsubstituted cyclopentyl, and ring B is an indole-5-y1 substituted with 1-2 of R3, then each R3 is independently -ZuR22, where each ZH is independently a bond or an unsubstituted branched or straight C13 aliphatic chain wherein up to two carbon units of ZH are optionally and independently replaced by -CS-, -CONRHNRH, -CO2-, -000-, -NRHCONR11-, -OCONRH-, -NRITNRH-, -S-, -SO-, -SO2-, -NRH-, -SO2NRH-, -NRHS02-, or -NRHSO2NRH-, each R22 is independently RH, halo, -OH, -NI-12, -NO2, -CN, or -0CF3, and each RH is independently hydmgen, a substituted C4 alkyl, an optionally substitituted C2_6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C4 alkenyl, an optionally substituted C4 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 R3 groups together with the atoms to which they are attached form an optionally substituted heterocycle.
[00172] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula II:
z-rzi R'3 LIP
A, p(R3) II
or a pharmaceutically acceptable salt thereof.
[00173] R3, R2, and ring A are defined above in formula I; R3, R'3, and p are defined above in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00174] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula [Ia:

,Z2 N
, Ri p(R3) Ha or a pharmaceutically acceptable salt thereof.
[00175] RI, R2, and ring A are defined above in formula I; R3, R'3, and p are defined above in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00176] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula lib:

Z3 llb irt (R3), or a pharmaceutically acceptable salt thereof.
[00177] RI, R2, and ring A, are defined above in formula I; R3, R3, and p are defined above in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00178] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula He:
(92)n 0 '3 /R
A 7" /)-R, llc or a pharmaceutically acceptable salt thereof.
[00179] R1, R2 and n are defined above in formula I; and R3, R3, and p are defined in formula Ia.

[00180] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has fmmula Hd:

=(R3)0-2 lld or a pharmaceutically acceptable salt thereof.
[00181] Both R2 groups, together with the atoms to which they are attached form a group selected from:
H I
I F0,0¨_,- I \/0-........--C.
C 2µ I 1 , ( I N. I , 0Ass5- , 0--)s- , Ocss- , s-v- , N*----sss µN----'cs-', , H
0,411. 0,.."--C ,. ,0--,-C
H

H 0,LIC I I
--1\1--fl - C
N I
)s4 , 0 , Me0 OH , \ H
( I s ( I
and XA1 9 XA20 XA21 .
[00182] R'3 is independently selected from one of the following:

-H, -CH3, -CH2CH3, -C(0)CH3, -CH3CH2OH, -C(0)0CH3, `'= , A
OH -V1--CH2OH -'3OH
, , N H C OC H
NHMe -µ''rOMe 3 '-V---N
CO 2H 2 OH , OH , 0 ---"-OH'-µ, ---- ---õ, 0 ii\ j,...__N,NH ,,,v-,,,_,NH2 -,;..õ:_õõ,,..õ-- -,.,õ.õ,--,_,551 OH .2. ' C''''CONHMe r 0 OEt CO2H )2,-.....N'NH2 OH , NH
NHCOMe C .1..--y-CN j )224.CONMe2 (DH A OH

' , NHSO2Me A---..,,i-0O2H A.---,,,...õ--,õir..Nõ..,...01.1 Am,,,,,,c02H o OH,0 , OH 0----k ,, -1.----T--"NHS02Me -ry---'NHCO2Me ''izN'NH
A55^...,NH002Me OH , OH OH NN1 , , '' OH
OH
OH N
150H A"-....----yNH--"OH
A4M)Y -µ..r 0 ...,- A.--.._,NHCO2tBu OH OH , 0 HO , 2. , q ..:S"--- (3/
O ? -Vy'lll h OH N, ...
'N2'0 2C`
NHS02Et "le.--- /7. 1 7,---NH
OH

N

OH H I
--5.....õ,,,,- N)-----:7 N=-5, OH H

, and 0 ; and each R3 is independently selected from -H, -CH3, -CH2OH, -CH2CH3, -CH2CH2OH, -CH2CH2CH3, -NH2, halo, -OCH3, -CN, -CF3, -C(0)0CH2CH3, -S(0)2CH3. -CH2NH2, -C(0)NH2, OH
( oH
H

-..y.õ..^...õ ......---...,, 'µ.'NJ-z, N
N SI
N
H 5 r,i - H

, N.,.....?
kj1.---11H
H
OH L'N,./'' I
, , F
, .:&_n r 'k----....,-,2.-.= .3 OH 110 , NH N' NH
I
---V(-- -3/4-- 1/ \
CONH2 0 \ 0 \ OH OH 0 0 , Am H ) )µ ( y A 0 OH "---0 OH NH ___________ NH2 ..Y-cf-k="---N k'l NI ____ OS -V / N A.-\/ ( /
o0Et A-< OH
( ,k< OH
H H _________ \ 0 _____ '=1,1 NTh N ==

__________________________ CN

)r IOH

,arid [00183] IV. GENERIC SYNTHETIC SCHEMES
[00184] The compounds of formulae (I, lc, Id, 11, Ha, Ilb, He, and Rd) 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, IL, Ha, LT13, llc, and lid) are provided below in Schemes 1-22 below.
[00185] 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 I.
[00186] Scheme 1:
(R2)n X OH
(R2)h A
(10 ,O1 1a (R2)b 1 a I I o lb a) SOC12, DMF (cat.), DCM; b) R14 , PYL; c) RçN , HATTJ, YEA, DCM/DMF.

[00187] Referring to Scheme 1, the acid la may be converted to the corresponding acid chloride lb using thionyl chloride in the presence of a catalystic amount of H
dimethylformamide. Reaction of the acid chloride with the amine Ri¨N
provides compounds of the invention I. Alternatively, the acid la may be directly coupled to the amine using Imiown coupling reagents such as, for example, HATIJ in the presence of triethylamine.
[00188] Preparation of the acids la may be achieved as illustrated in Scheme 2.
Scheme 2:

CI Br 0 a b OH
(R2)n (R2), 2b 1a 2a a) NaOH, B l'EAC; b) NaOH, A
[00189] 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 la.
In some instances, isolation of the intermediate 2b is unnecessary.
[00190] The phenylacetonitriles 2a are commercially available or may be prepared as illustrated in Scheme 3.
Scheme 3 40 Br a CO2Me OH" _ (R2)n (R2)n (R2)n 3b 3c CN
(R2)n (R2)n 3d 22 a) Pd(PPh3)4, CO, Me0H; b) LiA1H4, TI-EF; c) SOCl2; d) NaCN
[00191] Referring to Scheme 3, reaction of an aryl bromide 3a with carbon monoxide in the presence of methanol and tetralds(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.
[00192] Other methods of producing the nitrile 2a are illustrated in schemes 4 and 5 below.
Scheme 4 a CN
I
(R2)n 4a (R2)n 2a b I d OH
C
CI
7 3C 1 7Ari (R2)n (R2)n --a) TosMIC; b) NaBH4, THF; c) SOC12; d) NaCN
Scheme 5 a Br NC
(R2)n (R2)n (R2)n 5a 5b 2a a) NBS, AIBN, CC14; b) NaCN, Et0H
[00193] Preparation of R1-11-0 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.
[00194] One method for preparing Ri-11 4!) is illustrated in Scheme 6.
Scheme 6 (R3)p-1 (R3)p-1 (R3)p-1 IR
N -a r\r 2 6a 6b 6c (R3)p-1 (R3)p-1 6d 6e (R3)p-1 H (R3)p-1 6f 69 a) NaNO2, HCI, SnC12; b) NaOH, R3CH2C(0)R3, Et0H; c) H3PO4, toluene; d) H2, Pd-C, Et0H
[00195] Referring to Scheme 6, a nitroaniline 6a is converted to the hydrazine 6b using nitrous acid in the presence of HC1 and stannous chloride. Reaction of 6b with an aldehyde or ketone CH3C(0)R3 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.
[00196] An alternative method is illustrated in scheme 7.
[00197] Scheme 7 a =-',---/ 0 b 71 NH2 __õ,,,, / ¨ N R3 (R3)p-i (R3)p-1 H (R3)p-1 H
7a 7b 7c (1713)p-3 c ic----. itik -(R3) p_1 H
7d 7e e (R3)p-1 (R3)13-1 . \ R3 i R3 02N N ¨
(R H2N 101 (R3)p-1 3)p-1 7i H 1\ h 7i NH\
(R3)p-i i .,, ___... 1110 9 , 110 02N72_,, N H2 02N =NN H2 - - 02N let\'',(R3 H H \
7f 7g 7h a) R3aC0C1, Et3N, CH2C12; b) n-Bull, THF; c) NaBH4, AcOH; d) KNO3, H2SO4; e) DDQ, 1,4-dioxane; f) NaNO2, HC1, SnC12.2H20, H20; g) MeCOR3, Et0H; h) PPA; i) Pd/C, Et0H
or H2, Raney Ni, Et0H or Me0H
[00198]
[00199] Scheme 8 =
a p(R3) p(R3) I "
N
I c ----'-- \
' H
p(R3) p (R3) a) HNO3, H2SO4; b) Me2NCH(OMe)2, DMF; c) H2, Raney Ni, Et0H
, [00200] Scheme 9 r a b p,,,Br Br ,,,, 0 c fry7`.NH2 NH2 02N NH2 p(R3) 0%) p(Fi3) TMS
=
1 - 1110 e \
02N? 2 NH 02N N R2N la N
H H
p(Rs) p(R3) p(R3) a) NBS, DMF; b) KNO3, 1-12SO4; c) HCC-TMS, Pd(PPh3)2C12, Cu', Et3N, toluene, H20; d) Cul, DMIF; e) H2, Raney Ni, Me0H
[00201] Scheme 10 _,..,....,,,,CO2H .,_ 0 a :... I + 1 b NO2 02NNO2 -''-.`,..õ.), 002H --..,...ACO2Et -k,õ,,CO2H b I + I separation 11\102 02N NO2 ----- '-iNO2 CO2Et N ..õ,...., CO2Et d -C-\-----µi I c 'I-NO2KNO2 1-12Nkl'-'--- hl R3 R3 CO2Et a) HNO3, 112SO4; b) SOC12; Et0H; c) DMA, DMF; d) Raney Ni, 1-12, Me0H

_ [00202] Scheme 11 (R3)p-1 I (R3)p-1 CO2Et CO2Et a (R3)p-1 EtO2C

TM
a) DMA, DMF; b) Raney Ni, H2, Me0H
[00203] Scheme 12 3 Rs . a N%(11.3 2N _ Rs R3 R3 .3 C

Ra a) R3õCH2COR3b, AcOH, Et0H; b) H3PO4, toluene; c) H2, Pd/C, Et0H
[00204] Scheme 14 (193)1 (R3) 1 (R4-1 a Pto b \JR d =
PG
(113)p-1 = (Ra)p-i (113)p-1 . (R3)p-1.
f _v , g _ Fly _____.. , 02N N H4,1 a) NaB113CN; b) When PG= SO2Ph: PhS02C1, Et3N, DMAP, CH2C12; When P0= Ac:
AcC1, NaHCO3, CH2C12; c) When le= RCO: (RCO)20, AlC13, CH2C12; When Rv=Br: Br2, AcOH;
d) }Mr or HC1; e) ICN03, %SO4; Mn02, CH2C12 or DDQ, 1,4-dioxane; g) H2, Raney Ni, Et0H.

=

[00205] Scheme 14 o a b _______________________________ ' 0 ________________ *
N c ._ RD N
V-,"-----N '-1,-."---N , \

(R3)p-1 H (R3)p-1 H (R3)F-1 \SO2R (R3 SO2R
FID----.1- RD"--yr--\\ -e 1=1* 0 d r --..k"------tsk H H
(R3)p-1 SO2R (R3)p-1 (R3)p-1 RD----''''' h RD 0 \
...r."-------,. Fil N

(R3)p-, (R3)p-1 a) NaBH3CN; b) RSO2C1, DMAP, Et3N, CH2C12; c) RDC(0)C1, AlC13, CH2C12; d) NaBH4, TI-IF; e) HBr; f) KNO3, H2S02; g) Mn02; g) Raney Ni, H2, Et0H
[00206] Scheme 15 (R3)131 - (R3)p-1= R3 (R3)p0 = R3 Ili \ a , \
02N N 02N 11101 \ b N H2N 0 N
H H H
CN (R3)P', = N
b \
nt,,i 401 N
H

H H
a) R3X (X=Br, I), zinc triflate, TBAI, DMA, toluene; b) H2, Raney Ni, Et0H or H2, NIX, Et0H or SnC12.2H20, Et0H; c) C1S02NCO, DMF, CH3CN
[00207] Scheme 16 R3 R3,õõ,,,,,,, i R
1\---s' a 02N-Tc7,õ_ R3 n N---11\ ------) __ R --0-6 - 02 0 \
* -2- ii _ 3 I-Nd \-----'5'N
\ N
\
R.3 a) when X=C1, Br, I, or OTs: R'3X, K2CO3, DMY or CH3CN; b) H2, Pd/C, Et0H or SnC12.2H20, Et0H or SnC12.2H20, D1EA, Et0H.

' _ [00208] Scheme 17 =
03N...QL 02NcE3r b 02Nlz.frrI.N3r a 0 c NR2 -NH2 ,..õ.1.. _,...
(R3)p-1 (R3)p-1 (R3)F.-1H Ft (R3). 1 R3a (R3)p-1 0 (R3)1,1 02N -3... d 0214.(jc.. R e H2N \

W N R
H H H
. a) Br2, AcOH; b) RC(0)C1, Et3N, CH2C12; c) HC=-CR3õ, Pd(PPh3) 202, CUL Et3N; d) TBAF, THF or tEu0K, DMF or Pd(PPh3) 2C12, CuI, DMF; e) H2, Pd/C, Et0H Or SnC12, Me0H
or 11CO2N114, Pd/C, Et0H
[00209] Scheme 18 = R3 02N.,.....,..,N, 02N,..",õ...,,.Br I 02N -..<:' , I a b c F-'====`.-rs-NH2 1/.."-NH2 411 NH2 . R3 R3 . R3 R3.õ.õ,..,R3 .

02N 7 e H2N
, I d `N.
F'''' ..1./:1 F F R3 N
H
=

. e 02N ....õ,... ,...
411 \

. . H RD '''' RD. ' H
a) Br2, AcOH, CHCb; b) R3..G_=_--CH, CuI, Et3N, Pd(PE13)202; c) RCOCI, Et3N, CH2C12; d) .
TM .
TBAF, DMF; e) Raney Ni, 112, Me011; 1) ROK, DMF
=

. =
=

100210] Scheme 19 ( R3) p-1 R3 02N 0 Br , I a _ b 02N

(R3)p-1 (R3)-1 (R3)1 (R3), d H2N
c I 2 ________________________ R3 ___________________ 0 \ R3 ---'-'N N
H H
a) Br2, AcOH; b) HCCR32, Pd(PPh3) 202, Cul, Et3N; c) Pd(PPh3)2C12, CuI, DMF;
d) H2, Pd/C, Et0H or SnCl2, Me0H or HCO2NH4, Pd/C, Et0H
[00211] Scheme 20 I a ________________ , I b c -----=--NH
I
I
0.13)p-I (R3),1 R'3 (R3);D-1 R'3 ( R3) R3 (R3)p-1 02N H2N (R3)1 d Oil \ R3 e \ R3 R'3R'3 a) H2NR'3; b) X=Br: Br2, HOAc; X=I: NIS; c) HCEECR3, Pd(PPh3)2C12, CuI, Et3N;
d) CuI, DMF or TBAF, THF; e) H2, Pd/C, Et0H or SnC12, Me0II or IICO2NI14, Pd/C, Et0II
[00212] Scheme 21 (R3)0 02N 0 02N 0 Br b c I a - -.--'F NH R'3 NH A3 p(R3) TM S
02 N.,......i., I d e 02N 40 H2N 0 - \ \
N N
\ 1 p(R3) p(R3) R3 2( R3) a) R'3N112, DMSO; b) Br2, AcOH; c) TMS-CaCH, CuI, YEA, Pd(PPh3)2C12; d) CuI, DMSO;
e) Raney Ni, H2, Me0H

1002131 Scheme 22 02NBr a 02N .
________________________ ). b NHR'3 (R3)p-i (R3)p-1 02N \ R3 õ...õ,. H2N 40 1 _________________________ C
, \ p ¨3 \ \
(R3)p-1 R3 (R3)p-1 R3 a) R3aC:----CH, CuI, PEA, Pd(PPh3)2C12; b) 1BAF, THF; c) Raney Ni, Me0H
[00214] Scheme 23 ..õ----Br Br a b , 410 ---I1,,,---NO2 __ - -Ii_,--NH2 N R N R
(R3)p-1 (R2)p-1 013)p-1 H (:13)2_iv Fl d ¨R3a 9 , 02N 401 \ R3 f H2N 401 R3 \
' 1 N N
(R3)p-1 (F13)p-i H (R3)2-1 H
a) NaBH4, NiC12, Me0H; b) RC(0)C1; c) Pd(PPh3)C12, HCa-C-R3, CuI, Et3N; d) tBuOK, DMF; e) KNO3, H2SO4; f) NaBH4, NiC12, Me0H
[00215] Scheme 24 02N...õ.....in a H2N 401 , \
N
(R3) (R) p 43 \
3p R,3 a) SnC12, Et0H or Pd/C, HCO2NH4 or 112, Pd/C, Et0H or Raney Ni, H. Et0H

[00216] Scheme 25 PPh3Br aOH a . '1 PPh3Br b ____________ 110 0 0 c NH2 -,/1,-,' ,. .NH2 -----"' ______ N,-L.,_,A0E1 -(R3)p-1 (R3)p-1 (R3),i H
R
C d 0\ e . \ R
-1...."-N CO2E1 N CO2Et N CO2Et (R3),,1 H (R3)p-1 µBoc \
(R3)p-1 Boc R 02N ilo R
f (n __ R 9 \ R
--/'---N CO2Et N CO2Et (R3)r.-1 H (R3)p-1 H
h 02Ni---,...õ, RL,R i H2N 0 R
\ R
''1.-7--;--- \--OH N OH
(R3)p-1 H (1:13)p-1 H
a) PPh3, HBr; b) CI(0)CCH2CO2Et; c) tBuOK; d) (Boc)20, DMAP; e) KHMDS, R-X;

10-11VIDS, R-X; f) TFA; g) NaNO3, H2SO4; h) LiA1H4, THF; i) SnC12, Et0H
[00217] Scheme 26 a 02N.,,,,,-x.
, -- \ 11 % Rb CO2Et b C32N RaRb r N GO2H V N NRyRz d 02N I Ra , Rb K N NRyRz I N NRyZ

a) Li0H; b) EDC, HOBt, Et3N, HNRyRz; c) BH3-TTIF; cl) if Rz=H, RC(0)C1 (Z=RC(0)-) or RSO2C1 (Z=R502-) or RO(C0)C1 (Z=R0(C0)-) or (R0(C0))20 (Z= Z=R0(C0)-), Et3N, [00218] Scheme 27 a b H2NI--) R3 H R3 h.3 R3 R3 WO 2010/054138 PCTiUS2009/063475 a) R'3-X (X=Br, I, or OTs), base (K2CO3 or Cs2CO3), DMF or CH3CN; b) Hz, Pd/C, Et0H
or Ed/C, HCO2NH4 [00219] Scheme 28 R3, R3a a 02N ,,, b 7,:/'----"N 7:-.7--- N 7,---------N

a) R3aX (X=C1, Br, I), AlC13, CH2C12; b) Raney Ni, H2, Me0H
[00220] Scheme 29 H loc 021\1.y.t.-..õ,___ ( ---\ ., ,,.1 .,,,-z. (., a 1 ---- '--( N b H2N N
LI.¨N;11=1, H----r% ¨ '1.-%---N/ L.,'' ¨ '-f-% ¨Ni a) HCUMe0H; Pt02, H2; b) (30c) 20, Et3N, THF
[00221] Scheme 30 R3 R3 R, R3 02N,.....µ a 02N)__.µ 6 02Nx c 02N,r>
_ I ---- 1 -- Ni 7- N '-'=
NC {3'3 HO2C R'3 RO2C k*3 1.3 OH
1 d ,<,,....,g .._..: N

rnyRz i e R, 02N>
NRyRz a) NaOH or Li0H; I)) ROH, HC1; c) NaBH4 or LiA1H4 or DEBAL-H, THF; d) HNRyRz, HATU, Et3N, Et0H or DMF; e) LiA1H4, THE or BH3=THE; f) H202, H20 (Ry=-Rz=H);
g) H2, Pd/C

[00222] Scheme 31 () % Ra __ / Rb OH
)OR ) b c ____________________ Ra/ ( dY ¨ % o 0 RbOR
0 -----.-Ra Rb Cl a Rb Ra Rb OH e Ra Rb OR f Ra -- ____________ ¨ 0 / ¨ 0 02N.,..a,,. Br D2N 0 OR
¨'- __________________________________________________ 9 Ra Rb ,-"
02N ..,., ,-'' 0 h 02N .,... OR i H2N ..., OR

/ N Ra Rb Rh R3 R3 f1 R
a) Ra-X, NaH; Rb-X, NaH; b) PC15, CH2C12; c) NaOH; d) NaNH2, DMSO; e) CH2N2;
f) Pd(PPh3)4, CuI, Et3N; g) RC(0)C1, PYr, CII2C12; h) Pd(CH3CN) 2C12, CH3CN; i) Raney Ni, H2, Me0H
[00223] Scheme 32 Rs (R2)n RsI, (R2)n 9 A '=-= r.-==1,----\

a 0 FC.---" -N OR I .."- 0 RI 1 OH
H H
b (R2)n R3 IP
____________________ > \ -..., ,`,/,,,,,.- p n LL __ IV
I ( I1 '''-,"-- ¨N ' Rz ,....- .... Ri H ' Ry a) Li0H, THF/H20; b) HNRyRz, HATU, FBA, DMF/CH2C12 [00224] Scheme 33 12.3 (R2), 1:..-- N OH
(R2)n 9 iR3 H
1 , 0 R, ,...., -N OR '-'\õ,, (R2) H R3 b n 1 ._. 0 R OH
N OH
H
a) LiBH4, THF/H20 or LiA1H4, THF; b) Ra-Li, THF
[00225] Scheme 34 (R2)n IIP (R2)n 9 NO
\ -=
rn---) a \
N __________________________________________ b I ..,-- 0 k L7z,'"---N I
H H

(R2)n 9 NH

I / 0 1111 .1-/--------N

a) NaNO2, AcOH/H20; b) Zn, AcOH
[00226] Scheme 35 (R2)n 9 (R2)n 9 a __ o- \I rn---- b ________________________________________________________ 11.
Iõ,., 0 141 1-7.----. N I 0 F41 Ikt=-="¨N
H

(R2)n 9 (R2)n 9 \, ,.... ...õ- c \,....
0 fr-'----N, . 1 0 IA, K--N,cH2R'3 CH2R.3 a) NaBH3CN; b) R'3CHO, NaHB(0Ac) 3, TFA, DCE; c) chloranil or CDC13, light or DDQ

[00227] Scheme 36 (R2)n 9 (R. 9 a \
0 0 R, a) NaH, DIvIlF-THF; R3-X (X=C1, Br, I, or OTs) [00228] Scheme 37 (R2)n (R2)n 9 Br a \I b 0 Ai N0 =¨ -H k (R2)n Ar 0 Ai 1-kr-N

a) NBS; b) Ar-B(OR)2, Pd-FibreCat 1007, K2CO3, Et0H
[00229] Scheme 38 (R2)11 9 ..., i , .õ, 0 RI i t "---7--- N
H

(R2)r 9 b 7 0 iii U--t-------N
(R2)n H

-------`--II '=,- , OH

Ri - C
R3 ''''' (R2)n 9 \, 0 RI 1 17).---N
H

,.,_.
,(7 (R2)n 9 \,..... 1 \
17. 0 R17z/--"N
H

I e ON
(R2)n 9 \,..._ e---..õ-, N¨ I
I7 0 111 "k7z,"---N
H

a) RSO2C1, NaH, THF-DMF; b) R3-X (X=Br, I, or OTs), Nail, TIIF-DMF; c) ethylene dioxide, InC13; d) POC13, DMF; e) H2N-OH, CH2C12; Ac20 [00230] Scheme 39 , .

(Ron 9 (R2)n 1, \
rl ¨2--,- .-n---I___. j i . .

b/ \tc (R2)n IIP (R2)n 0 \,.. ,n--- \I
0 ,, ,z/..-"N OH .õ. o k 7 N al R3 µ---(...... R3 L.c.__ OR NRyRz a) NaH, THF-DMF; epichlorohydrin; b) ROH; c) HNRyRz [00231] Scheme 40 ovn (1=1,)n 9 \, 1, 0 il,, T N OH --.*- I ,"' 0 14) -OH
OH OTs , (R2)n 9 (R )n9 (R2)n 9 \ -,..
I , 0 r4, 1",,f_il--NI OH I

ON R, -.--C. R3 N, NHR
ic ..i 1 h (R,)n 9 (R2)n 9 (FlOn 9 NL}DHI ' R, OH
N
V--e'NH R3 Lt GO,H
14=-N riiR

a) TsCl, Et3N, CH2C12; b) NaCN, DNIF; c) NaOH, Me0H; d) NaN3, NI-14CL e) NaN3, DMF;
f) Pd/C, H2, Me0H (R=H); h) RT(0)C1 (Z=RT(0)-) or R'S02C1 (Z=RKS02-) or Rx0(C0)C1 (Z=Rx0(C0)-) or (Rx0(C0)) 20 ( Z=Rx0(C0)-), Et3N, CH2C12 [00232] Scheme 41 dR,Th IIP (92)n 9 (R2)n 0 \_ cQ--.-a \ ,..,, r"-y>sõ b \
ll 0 F1,17 N
R3 R, () R3 () (R,In 11, (R2)n 9 -r?"---X-k> d \ .,......
ri)---N
0 iii N
R, ? R, ?
NH, NHZ
a) C1CH2CHO, NaH11(0Ac)3, CH2C12; CDC13, light; b) NaN3, NaI, DMF; c) H2, Pd/C, Me0H, AcOH; d) RC(0)C1 (Z=RC(0)-) or RSO2C1 (Z=RS02-) or R0(C0)C1 (Z=R0(C0)-) or (R0(C0))20 (Z= R0(C0)-), Et3N, CH2Cl2.
Scheme 42 0 0 0 0Rb OR
Rai( b 0 ____,C ._ Rb OH
__.7Ra ,0 a ).1x,it, OR
OR --"'" _______________________________________________ d Ra Rb CI CI
Pb Rb OH y Rb OR f Ra Rax e Ra R3 õ......., OR 9 ...---¨ 0 ¨/ 0 02N 40 0 02N 40 Br R2 NH2 \ OR
R2 N Ra Rb H
b) Ra-X, NaH; Rb-X, NaH; b) PC15, CH202; c) NaOH; d) NaNH2, DMSO; e) R-OH, DCC; 0 Pd(PPb3)2C12, CuI, Et3N; g) PdC12, CH3CN

, Scheme 43 02N 40 \CH2)n-CO2R
a) 02N 40 ,n,H,c,_.H2o, b) 02N \
so n(H2C)-CH2OP
__________________________________ ), R2 N Ra Rb 1:32 N Ra Rb H H R2 N Ra Rb H
C) 02N Is \n(H2C)-CH2ORc d) H2N 40 \n(H2C)-CH2ORc --a- --).-R2 N Ra Rb R4 R2 11 Ra R b ri= 0 or 1 a) DEBAL-H; b) P-LG; P= protecting group like IEDMS and LG= leaving group like Cl; c) R4-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate, Rc=H
or R4; d) reducing conditions like Pd/C, H2 or ammonium formate.
Scheme 43 o o 02N too ORRa Rb OR

\ a) 02N 0 N, Ra Rb \ b) __________________________________ 3.

R2 ...."' N Ra Rb R, c) H2N 401 \ OH
---).-R2 N Ra Rb R4-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate; b) LiAIH4; c) reducing conditions like Pd/C, H2 or ammonium formate.
[00233] 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.
[00234] V. FORMULATIONS, ADMINISTRATIONS, AND USES
[00235] Accordingly, in another aspect of the present invention, pharmaceutically 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 LAJO-.4--1 comprise one or more additional therapeutic agents.
[00236] 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 pharmaceutically acceptable derivative or a procirug 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.
[002371 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 undne toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A
"pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
[00238] 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. 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, hydrobronaic 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, henaisulfate, heptanoate, hexanoate, hydroiodide, 2-hydnoxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, rnalate, maleate, malonate, rnethanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persnlfate, 3-phenylpiopionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include aiksli metal, alkaline earth metal, ammonium and 1C+(C1_ztalky1)4 salts. 'Ms 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.
[00239] 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.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in foiumlating 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 fauuulator.
[00240] 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, Ha, lib, Ile, and lId) to a subject, preferably a mammal, in need thereof.
[00241] hi certain preferred embodiments, the present invention provides a method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 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, I-Aron 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 1, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and SjOgren's Syndrome, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formulae (I, Ic, Id, II, Ila, llb, Hc, and Ltd), or a preferred embodiment thereof as set forth above.

WO 2010/054138 PCTiUS2009/063475 [00242] 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, Ha, ITb, IIc, and 11d), or a preferred embodiment thereof as set forth above.
[00243] 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 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type IT, Polyenclocrinopathy/Hyperinstilemia, 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, Fabry disease, Straussler-Schein_ker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and SjOgren's Syndrome.
[00244] 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 hennochromatosis, 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), Ne,urophyse.al 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 Spongiforni 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 SjOgren's Syndrome.
[00245] 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 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.
[00246] 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.

WO 2010/054138 PCT[US2009/063475 [00247] 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.
[00248] 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 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.
[00249] 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.
[00250] 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.
[00251] 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.
[00252] 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, cuboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar¨agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) 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.
[00253] 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.
[00254] 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 fatutulating 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 pacifying 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.
[00255] 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 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.
[00256] 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.
[00257] 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.
[00258] 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".
[00259] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition 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.
[00260] 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.
[00261] 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; biopsial material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[00262] 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.
[00263] 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, Ha, ID, He, and Ild). In prefeited embodiments, the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.
[00264] 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, Ha, lib, He, and lid). 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.
[00265] 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.
[00266] 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 (VIM) (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).
[00267] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (V,,,) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPRI'm II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
[00268] 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, 11, Ha, Hb, Hc, and 11d) or any of the above embodiments; and (ii) instructions for a.) contacting the 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, H, Ha, lib, He, and lid). In preferred embodiments, the kit is used to measure the density of CF1R.

[00269] 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.
[00270] VI. PREPARATIONS AND EXAMPLES
[00271] General Procedure I: Carboxylic Acid Building Block \
(Rxx)x Hal Hal (RxX)x N
I/
50% NaOH (aq) OH
Hal = Cl, Br, I
[00272] 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 1 M hydrochloric acid two times. The solid material was dissolved in dichloromethane and extracted two times with 1 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%.
[00273] Example 1: 1-Benzo[1,3]dioxo1-5-yl-cyclopropanecarboxylic acid CIr¨\Br 11, I

o 0 N
0 50% NaOH (aq) 0 11111 OH
[00274] A mixture of 2-(benzold1[1,3]dioxol-5-y1)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 nil.) 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 tn/z calc. 206.1, found 207.1 (M+1)+. Retention time 2.37 minutes. III NMR (400 MHz, DMSO-d6) 5 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).
[00275] General Procedure II: Carboxylic Acid Building Block Hal (XRx)\ 9 (XRx)x Hal x (XRx)x 9 \
N
N
NaOH NaOH OH
Hal = Cl, Br, I, all other variables are as defined in the text.
[00276] 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.
[00277] The crude cyclopropanecarbonitrile was refluxed in 10% aqueous sodium hydroxide (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M
hydrochloric acid. The precipitated solid was filtered to give the cyclopropane,carboxylic acid as a white solid.
[00278] General Procedure III: Carboxylic Acid Building Block , Pd(PPh3)4 r-"*.--"zz.---002rvie LiAIH4 ir.------------'0H
-...,....7" CO/CH3OH R
SOCl2NaCN
'`(-'..---'---1 i;=;*---.---".----'ON

CICH2CH2Br R eN NaOH
; .
'. i 1 NaOH ...--- ..----[00279] Example 2: 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid F r Pd(PFh3)4 F 0 CO2Me LiAIH
X 1101 B _____________ = X 0 ---i FX 1101 OH 30C12 V
FX 0 a NaCN Fx 0 = CN CICH2CH2Br * FXo 0 CN NaOH
F 0 F 0 NaOH F 0 V

F , 0 Br Pd(PPh3)4 F = 0 CO2Me FX=).' X
CO/CH3OH F =
[00280] 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester [00281] A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol) and tetralds(triphenylphosphine)palladium (0) [Pd(PPh3)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.
FN /6 10 CC2Me LiAl H4 F = 0 OH

FXe.

[00282] (2,2-Difluoro-benzo[1,3]dioxol-5-y1)-methanol [00283] Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THE) was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THE (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 'V 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-y1)-methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil.
FNie OH SOCl2 /. CI
)1P- FA.
[00284] 5-Chloromethy1-2,2-difluoro-benzo[1,3]dioxole [00285] Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of (2,2-difluoro-benzo[1,3]dioxo1-5-y1)-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-chloromethy1-2,2-difluoro-benzo[1,3]dioxole (4.4 g) which was used directly in the next step.
FNi=
CN
FA. V' CN
[00286] (2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-acetonitrile [00287] A mixture of crude 5-chloromethy1-2,2-difluoro-benzo[1,3]dioxole (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 nil ) 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]dioxo1-5-y1)-acetonitrile (3.3 g) which was used directly in the next step.

aCH2CH2Br V
Rve ON NaOH x:P CN
F"'\µ=
F
[00288] 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarbonitrile [00289] Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a mixture of crude (2,2-difluoro-benzo[1,3]dioxo1-5-y1)-acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70 C.
[00290] 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[1,31dioxo1-5-y1)-cyclopropanecarbonitrile, which was used directly in the next step.
V NaOH V
FN/41) 4101 ON Fx. CO2H
FA= F =
[00291] 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid [00292] 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-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]clioxo1-5-y1)-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 (CDC13) 5 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).
[00293] Example 3: 2-(2,2-Dimethylbenzo[d][1,3]dioxo1-5-yflacetonitrile NC 4110 0> BBr,,, IDGM,w NC OH 2,2-dimethoxy-propane NC
40 ,>, 0 OH p-Ts0H, toluene 0 N 0) ..3,,cm OH
NC
OiH
[00294] (3,4-Dihydroxy-pheny1)-acetonitrile [00295] To a solution of benzo[1,3]dioxo1-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH2C12 (15 mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at ¨78 C under N2. The mixture was slowly warmed to room temperature and stirred overnight. HA) (10 mL) was added to quench the reaction and the C112C12 layer was separated. The aqueous phase was extracted with C112C12 (2 x 7 mL). The combined organics were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give (3,4-dihydroxy-phenyl)-acetonitrile (0.25 g, 54%) as a white solid. 111 NMR (DMSO-d6, 400 MHz) 8 9.07 (s, 1 H). 8.95 (s, 1 H), 6.68-6.70 (m, 211), 6.55 (dd, J =
8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H).
NC soOH 2.2-dimethoxy-propanex. NC ao ox OH p-Ts0H, toluene 0 [00296] 2-(2,2-Dimethylbenzo[d][1,3]dioxol-5-yDacetonitrile [00297] 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 Ts0H (0.010 g, 0.065 mmol). The mixture was heated at reflex overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCOi solution, H70, brine, and dried over Na2SO4. 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 242,2-dimethylbenzo[d][1,3]dioxo1-5-ybacetonitrile (40 mg, 20%). 1H NMR (CDC13, 400 MHz) 8 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).
[00298] Example 4: 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid V =
40 OE3r, BrCH2CH2C1). NC C)6nNC OH OH
NaOH HOD
OBn 013n OH OH
NC OBn BrCH2CH2C10 NC OBn OBn OBn [00299] 1-(3,4-Bis-benzyloxy-phenyI)-cyclopropanecarbonitrile [00300] To a mixture of (n-C41-19)4NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis-benzyloxy-pheny1)-acetonitrile (14 g, 42 mmol) in NaOH (50 g) and H20 (50 mL) was added BrCH2CH2C1 (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 1120, brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by column on silica gel (petroleum ether/ethyl acetate 10:1) to give 1-(3,4-bis-benzyloxy-pheny1)-cyclopropanecarbonitrile (10 g, 66%). 1H NMR (DMSO 300 MHz) 7.46-7.30 (m, 10 H),7.03 (d, J=8.4 Hz, 1 H), 6.94 (d, J=2.4 Hz, 1 H), 6.89 (dd, J = 2.4, 8.4 Hz, 1 H), 5.12 (d, J. 7.5 Hz, 411), 1.66-1.62 (m, 2 H), 1.42-1.37 (m, 2 H).
= V
NC Ali an H2 _______________________ NC * =H
oBn PcVC
OH
[00301] 1-(3,4-Dihydrory-phenyl)-cydopropanecarbonitrile [00302] To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 28 mmol) in Me0H (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 Celitemf pad and the filtrate was evaporated under vacuum to give 1-(3,4-dihydroxy-pheny1)-cyclopropanecarbonitrile (4.5 g, 92%). NMR (DMSO 400 MTh) 9.06 (br s, 211), 6.67-6.71 (m, 2 H), 6.54 (dd, J .2.4, 8.4 Hz, 1 H), 1.60-1.57 (m, 211), 1.30-1:27 (m, 211).
= =
*
OH
NC 401 .4 OH OH
[00303] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid [00304] To a solution of NaOH (20 g, 0.50 mol) in H20 (20 mL) was added 143,4-dihydroxy-pheny1)-cyclopropanecarbonitrile (4.4g, 25 mmol). The mixture was heated at reflux for 3 h before being cooled to room temperature. The mixture was neutralized with HC1 (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 MgSO4, and concentrated under vacuum to obtain 1-(3,4-dihydroxy-pheny1)-cyclopropanecarboxylic acid (4.5 g crude). From 900 mg crude, 500 mg pure I -(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic acid was obtained by preparatory HPLC. 111 MAR (DMSO, 300 MHz) 8 12.09 (bra. 1 11), 8.75 (br a, 2 II), 6.50-6.67 (m, 3 H), 1.35-1.31 (m, 2 H), 1.01-0.97 (m, 2 H).
[00305] Example 5: 1-(2-0xo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane-carboxylic acid.

V õ V V
HO tip Ve0H io HNO,JAc20), Me 0 E3Br, OMe OMe OMe V
Me0 0 Me0 0 V
.0 N Nt/H2 40 NH2 trtphosgenleõ Me 110 OH OH HN
DOH HO v 0 oC) He V
0 1101 Me0H
Me0 OMe OMe [00306] 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00307] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50 g, 0.26 mol) in Me0H (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. Me0H
was removed by evaporation under vacuum and Et0Ac (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53 g, 99%). 1H NMR (CDC13, 400 MHz) 8 7.25-7.27 (m, 2 H), 6.85 (d, ./ =
8.8 Hz, 2 H), 3.80 (s, 3 El), 3.62 (s, 3 14), 1.58 (q, J= 3.6 Hz, 2 H), 1.15 (q, J= 3.6 Hz, 2 H).
'V
NA- = HNo3IAc2o).- 110 NO2 OMe OMe [00308] 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester [00309] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) in Ac20 (300 mL) was added a solution of HNO3 (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. HC1 (20%) was added dropwise at 0 C. The resulting mixture was extracted with Et0Ac (200 mL x 3). The organic layer was washed with sat. aq. NaHCO3 then brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-phenye-cyclopropane,carboxylic acid methyl ester (36.0 g, 98%), which was directly used in the next step. 1H NMR (CDC13, 300 MHz) 8 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, 111), 3.97 (s, 31-I), 3.65 (s, 31-I), 1.68-1.64 (m, 2 H), 1.22-1.18 (m, 211).

= Mee =
ilk NO2 " = NO-2 BBr3

11, OMe OH
[00310] 1-(4-Hydroxy-3-nitro-phenyl)-cyc1opropanecarboxylic acid methyl ester [00311] To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic acid methyl ester (10.0 g, 39.8 mmol) in CH2C12 (100 nal.) was added BBr3 (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 Et0Ac (200 ITT x 3). The combined organic layers were dried over nhydrous Na2SO4 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-pheny1)-cyclopropanecarboxylic acid methyl ester (8.3 g, 78%). Ili NNIR
(CDC13. 400 MHz) 510.5 (s, 1H), 8.05 (d, J = 2.4 Hz, 111), 7.59 (dd, J = 2.0, 8.8 Hz, 1 H), 7.11 (d, J=
8.4 Hz, 1 H), 3.64 (s, 3 H), 1.68-1.64 (in, 2 H), 1.20-1.15 (m, 2 H).
V =
Me= Nim2 M-= N1-42 tg" OH DH
[00312] 1-(3-Amino-4-hydroxy-phenyl)-eyclopropanecarboxylic acid methyl ester [00313] To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in Me0H (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 TM
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-pheny1)-cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 111 NMR (CDC13,400 MHz) 5 6.77 (s, 1 I-1), 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, 211).
V V
Me0 NH2 triphasgarlit, rilfh 1\10 IW OH o [00314] 1-(2-0xo-2,3-dihydro-benzooxaml-5-y1)-cyclopropanecarboxylic acid methyl ester [00315] TO a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid =

methyl ester (2.0 g, 9.6 mmol) in THF (40 mi.) was added triphosgene (4.2 2, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0 C. The resulting mixture was extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-y1)-cyclopropanecarboxylic acid methyl ester (2.0 g, 91%), which was directly used in the next step. 1H NMR
(CDC13, 300 MHz) (58,66 (s, 1 H), 7.13-7.12 (m, 2 I1), 7.07 (s, 1 H), 3.66 (s, 3 H), 1.68-1.65 (m, 2 H), 1.24-1.20 (m, 2 H).
V H V
LiOH =
Me0 0 = o 0 [00316] 1-(2-0xo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid [00317] To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-y1)-cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in Me0H (20 ml) and water (2 mL) was added Li0H.H20 (1.7 g, 41 mmol) in portions at room temperature. The reaction mixture was stirred for 20 hours at 50 C. Me0H was removed by evaporation under vacuum before water (100 mL) and Et0Ac (50 mL) were added. The aqueous layer was separated, acidified with HC1 (3 mol/L) and extracted with Et0Ac (100 m1 x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 1H NMR
(DMSO, 400 MHz) 8 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, H), 1.44-1.41 (m, 2 H), 1.13-1.10 (m, 2 H). MS (EST) ink (M+H ) 218.1.
[00318] Example 6: 1-(6-Fluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid H B13 H OH 1110 BrCH,CVDII: H* NaBH4 I.. HO =OH

=
SOCI, ___ CI 1101 (2.µ' NaCN õ. NC 1110 (5 BrCH2C1-1,CI N
C) =
10% NaOH HOC
, Oi o OH
H 11101 BBr3 H
OH
[00319] 2-Fluoro-4,5-dihydroxy--benzaldehyde [00320] To a stirred suspension of 2-fluoro-4,5-dimethoxy-benzaldehyde (3.00 g, 16.3 mmol) in dichloromethane (100 mL) was added BBr3 (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.

OH
H BrCH2CVDMF H 0>
_______________________________ No-[00321] 6-Fluoro-benzo[1,3]dioxole-5-carbaldehyde To a stirred solution of 2-fluoro-4,5-dihydroxy-benzaldehyde (8.0 g) and BrC1CH2(24.8 g, 190 mmol) in dry DMF
(50 mL) was added Cs2CO3 (62.0 g, 190 mmol) in portions. The resulting mixture was stirred at 60 'V overnight and then poured into water. The mixture was extracted with Et0Ac (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, 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[1,3Jdioxole-5-carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDC13) ö 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).
H:
0 NaBH4 HO 40 o>
>
)10 [00322] (6-Fluoro-benzo[1,3]dioxo1-5-y1)-methanol [00323] To a stirred solution of 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, 4.2 mmol) in Me0H (50 mL) was added NaBH4 (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 Et0Ac and the organic layer was washed with water, dried over Na2SO4, and concentrated in vacua to afford (6-fluoro-benzo[1,3]dioxo1-5-y1)-methanol (650 mg, 92%), which was directly used in the next step.

=

HO 40 0> so.,2 >

[00324] 5-Chlorotnethy1-6-fluoro-benzo[1,3]dioxole [00325] (6-Fluoro-benzo[1,3]dioxo1-5-y1)-methanol (650 mg, 3.8 mmol) was added to SOC12 (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 SOC12 was evaporated under reduced pressure to give the crude product, which was basified with sat. NaHCO3 solution to pH ¨
7. The aqueous phase was extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na7SO4 and evaporated under reduced pressure to give 5-chloromethy1-6-fluoro-ben7n[1,3]dioxole (640 mg, 90%), which was directly used in the next step.
CI so 0>
NaCN
NC 0 o>

[00326] (6-Fluoro-benzo[1,3]dioxo1-5-y1)-acetonitrile [00327] A mixture of 5-chloromethy1-6-fluoro-ben7o[1,3]dioxole (640 mg, 3.4 mmol) and NaCN (340 mg, 6.8 mmol) in DMSO (20 mT ) was stirred at 30 'V for 1 h and then poured into water. The mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (540% ethyl acetate/petroleum ether) to afford (6-fluoro-benzo[1,3]dioxol-5-y1)-acetonitrile (530 mg, 70%). 11I-NM12 (300 MHz, CDC13) 6.82 (d, J
= 4.8, 1 H), 6.62 (d, J= 5.4, 1 H), 5.99 ks, 2 H), 3.65 (s, 2 H).
V
NC
40 > BrCH2CH2CI NC =>

[00328] 1-(6-Fluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarbonitrile [00329] 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 mm period. llhe mixture was allowed to cool to room temperature. Subsequently, the flask was charged with toluene (6 mL), tetrabutyl-ammonium bromide (50 mg, 0.12 trunol), (6-fluoro-benzo[1,3]dioxo1-5-y1)-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-benzol1,31dioxol-5-y1)-cyclopropanecarbonitrile (400 mg, 60%). 1H NMR
(300 MHz, CDC13) 6673 (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 II), 1.31-1.27 (m, 2 H).
V V
NC 110 (3> 0% NaOH HOOC o>

[00330] 1-(6-Fluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid [00331] A mixture of 1-(6-fluoro-benzo[1,3]dioxo1-5-y1)-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 pII < 5 and then Et0Ac (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[1,31dioxo1-5-y1)-cyclopropanecarboxylic acid (330 m2, 76%). 1H NMR (400 MHz, DMSO) 612.2 (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, 211).
[00332] Example 7: 1-(Benzofuran-5-yl)cyclopropanecarboxylic acid Br( ry V
V HO
MeO 0 10 OEt OH NaH, DMF OEt V
PPA, xylene HO tail Bry0Et V
H=
Me0 OH NaH, DMF pp- 0 (1101 t OEt [00333] 144-(2,2-Dietboxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid [00334] To a stirred solution of 1-(4-hydroxy-pheny1)-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 C112C12. The combined organics were dried over Na2SO4. The solvent was evaporated under vacuum to give 144-(2,2-diethoxy-ethoxy)-phenylj-cyclopropanecarboxylic acid (10 g), which was used directly in the next step without purification.
IIF
HO PPA, xylene H=
o 11110 0 III
OEt [00335] 1-Benzofuran-5-yl-cyclopropanecarboxylic acid [00336] To a suspension of 1-14-(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%). 11-I NMR (400 MHz, DMSO-d6) 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).
[00337] Example 8: 1-(2,3-Dihydrobenzofuran-6-yl)cycIopropanecarboxylic acid V V
HO 0 Pt02, Me0H HO

[00338] To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in Me0H (50 mL) was added Pt02 (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, Me0D) 8 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 Ilz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H).
[00339] Example 9: 1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid.

V
Me0 A1013/Et 0 Sf I meo NO Me0 I
0 -11.- =._ OMe 'IF' OH OH
4_ WO V ail I
Bu3SnH Me DOH HO V
0 gip AIBN

0 up o .= AJCI3/EtSH .6 0 1.1 -1 - 0 1101 OH
[00340] 1-(4-Hydroxy-pheny1)-cyclopropanecarboxylic acid methyl ester [00341] To a solution of methyl 1-(4-niethoxyphenypcyclopropanecarboxylate (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 AlC13 (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 H20, brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-pheny1)-cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). 111 NMR (400 MHz, CDC13) 6 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).
VV
Me0 - = Si I

OH OH
[00342] 1-(4-Hydroxy-3,5-diiodo-pheny1)-cyclopropanecarboxylic acid methyl ester [00343] To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH3CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture 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-pheny1)-cyclopropanecarboxylic acid methyl ester (3.5 g, 18%). 1H NMR (400 MHz, CDC13) 6 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3 II), 1.59-1.56 (m, 2 H), 1.15-1.12 (m, 2 H).

-= y I
me0 0 gpi 0 OH
[00344] 143,5-Diiodo-4-(2-methyl-allyloxy)-phenyl]-cyclopropanecarbovlic acid methyl ester [00345] A mixture of 1-(4-hydroxy-3,5-diiodo-pheny1)-cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), K2CO3 (1.2 g, 8.6 mmol), Nat (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 143,5-dtiodo-4-(2-methyl-allyloxy)-phenyli-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 1H
NN1R (300 MHz, CDC13) 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).
V
r di..4 V
11, Bu3Sn H
AI BN __________________________ IP =

[00346] 1-(3,3-Dimethy1-2,3-dihydro-benzofuran-5-y1)-cyclopropanecarboxylic acid methyl ester [00347] To a solution of 143,5-diiodo-4-(2-methyl-allyloxy)-pheny1]-cyclopropane-carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added Bu3SnH (2.4 g, 8.4 mmol) and AMN (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-dimethy1-2,3-dihydro-benzofuran-5-y1)-cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). 3 H
NMR (400 MHz, CDC13) 6 7.10-7.07 (m, 2 11), 6.71 (d, J= 8 Hz, 1 H), 4.23 (s, 211), 3.62 (s, 3 H), 1.58-1.54 (m, 2 H), 1.34 (s, 6 H), 1.17-1.12 (m, 2 H).
V V
-= =
LiOH
0 I* =
o 101 0 [00348] 1-(3,3-Dimethy1-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid [00349] To a solution of 1-(3,3-dimethy1-2,3-dihydro-benzofuran-5-y1)-cyclopropanecarboxylic acid methyl ester (1.0 g, 4.0 mmol) in Me0II (10 mL) was added LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40 C overnight. HC1 (10%) was added slowly to adjust the pII to 5. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The extracts were washed with brine and dried over Na2SO4. The solvent was removed under vaccum and the crude product was purified by preparative HPLC to give 143,3-dimethy1-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g, 41%).

(400 MHz, CDC13) 8 7.11-7.07 (m, 2 H), 6.71 (d, = 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).
[00350] Example 10: 2-(7-Methoxybenzo[d][1,3]clioxo1-5-yDacetonitrile.
meo 40 OH Me2SO4 Me0 a OH CH,EirCI meo 0) LiAIH4 OH Na2B407 OH 0 OH OMe OMe HO 1101SOCl2 c, 0 NaGN NC

o> 1110 05 OMe OMe OMe Me0 go OH Me2S0, Me0 OH
______________________________ 71, OH OH
OH N9,213407 Oh&
[00351] 3,4-Dihydroxy-5-methoxybenzoate [00352] To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na213407 (50 g) in water (1000 mL) was added Me2SO4(120 mL) and aqueous NaOH
solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0 'C. The mixture was acidified to pH - 2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with Et0Ac (500 mt. x 3).
The combined organic layers were dried over anhydrous Na2SO4 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.
meo OH OH2Bra OH NaCN 0 OMe OMe [00353] Methyl 7-methoxybenzo[d][1,3]dioxole-5-earboxylate [00354] To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.0780 mol) in acetone (500 mL) was added CH2BrC1 (34.4 g, 0.270 mol) and K2CO3 (75.0 g, 0.540 mol) at 80 7C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room te,mperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in Et0Ac (100 mL). The organic layer was washed with water, dried over anhydrous Na2SO4, 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[cl][1,3]dioxole-5-carboxylate (12.6 g, 80%). 1H NMR (400 MHz, CDC13) 5 7.32 (s, 1 H), 7.21 (s, 11-1), 6.05 (s, 2 11), 3.93 (s, 3 H), 3.88 (s, 3 H).

Me0 =

LiAl H4 0 Ci> ___________________________ ap >
OMe OMe [00355] (7-Methoxybenzo[d][1,3]dioxo1-5-yl)methanol [00356] To a solution of methyl 7-methoxybenzo1d][1,3]dioxole-5-carboxylate (14 g, 0.040 mol) in THF (100 mL) was added LiA1H4 (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 rnL) 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]dioxo1-5-y1)methanol (7.2 g, 52%).
ill NMR (400 MHz, CDC13) 8 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 211), 4.57 (s, 2 H), 3.90 (s, 3 H).
t43 I o> so02 a OMe OMe [00357] 6-(Chloromethyl)-4-methoxybenzo[d][1,3]clioxole [00358] To a solution of SOCb (150 mL) was added (7-methoxybenzo[d][1,31dioxo1-yl)methanol (9.0 g, 54 mmo1) in portions at 0 'C. The mixture was stirred for 0.5 h. The excess SOO2 was evaporated under reduced pressure to give the crude product, which was basified with sat. aq. NaHCO3to pH ¨ 7, The aqueous phase was extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) 6 6.58 (s, 1 H), 6.57 (s, 1 H), 5.98 (s, 2 1-1), 4.51 (s, 2 H), 3.90 (s, 3 H).

CI NaCN NC 0>

OMe OMe [00359] 2-(7-Methoxybenzo[d][1,3]dioxo1-5-yl)acetonitrile [00360] To a solution of 6-(chloromethy1)-4-methoxybenzo[d][1,3]dioxole (10 g, 40 mmol) in HMSO (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 Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2Sa4and evaporated to give the crude product, which was washed with ether to afford 2-(7-methoxybenzo[d][131dioxo1-5-yl)acetonitrile (4.6 g, 45%). 1H NMR (400 MHz, CDC13) 6 6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 13C NMR (400 MHz, CDC13) 6 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.
[00361] Example 11: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.

H NC =

OBn OBn Me t-BuOK OMe [00362] To a suspension of t-liu0K (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 naL) 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 Et0Ac (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-methoxypheny1)- acetonitrile (5.0 g, 48%). 11-1NMR (300 MHz, CDC13) 6 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). 13C NMR
(75 MHz, CDC13) 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.
[00363] Example 12: 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile.

OMe BE1rNC, N 40 OBn c:cN).--a 2 3, , No OMe OH
BBrg N 40 ci [00364] (4-Chloro-3-hydroxy-phenyeacetonitrile [00365] I3Br3 (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 N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H
NMR (300 MHz, CDC13) 6 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 (his, 1H), 3_72 (s, 2 H).
401 Br OH OBn NC
a K2 CO3, CH3CN
[00366] 2-(3-(Benzyloxy)-4-ehlorophenyl)acetonitrile [00367] To a solution of (4-chloro-3-hydroxy-phenyl)acetonitrile (6.2 g, 37 mmol) in CH3CN (80 mL) was added K2CO3 (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-chloropheny1)-acetonitrile (5.6 g, 60%). 1H NMR (400 MHz, CDC13) 8 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).
[00368] Example 13: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.

= H OBn 0 NC
I I
S¨ so OBn ti NC

OMe t-BuOK OMe [00369] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 mL) was added a solution of Tos1VIIC (16.1 2, 82.6 mmol) in TI-IF (100 mL) at -78 C. The mixture was stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaidehyde (10.0 g, 51.9 mmol) in THF (50 mL) dropwisc, and continued to stir for 1.5 hours at -78 C. To the cooled reaction mixture was added methanol (50 nit). 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 Et0Ac (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-methoxyphenyHacetonitril (5.0 g, 48%). 1H
NMR (300 MHz, CDC13) 6 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). 12C NMR (75 MHz, CDC13) 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.
[00370] Example 14: 2-(3-Chloro-4-methoxyphenyl)acetonitrile.

ci H 40 CI 0 NC si o t-BuOK OMe [00371] To a suspension of t-13u0K (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mi ) 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 Et0Ac (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%). 1H NMR (400 MHz, CDC13) 8 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). 13C NMR (100 MHz, CDC13) 6 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.
[00372] Example 15: 2-(3-Fluoro-4-methoxyphenyl)acetonitrile.

NC
OMe t-BuOK OMe [00373] To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 mL) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 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 rumol) in THF (50 mL) clropwise, and continued to stir for 1.5 hours at ¨78 C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with Et0Ac (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-methoxyphenypacetonitrile (5.0 g, 58%). 1H NMR (400 MHz, CDC13) 8 7.02-7.05 (m, 2 H), 6.94 (t, J = 8.4 Hz, 111), 3.88 (s, 3 H), 3.67 (s, 2 FI). /3C NMR
(100 MHz, CDC13) 8 152.3, 147.5, 123.7, 122.5, 117_7, 115.8, 113.8, 56.3, 22.6.
[00374] Example 16: 2-(4-Chloro-3-methoxyphenyl)acetonitrile.
OH Mel, K2CO3 CH3CN Al BN,CCI, OMe NBS 11, Br io 2 OMe NN
CI CH NC 40 OMe CI CI CI
Mel, K2CO3 OMe COHI a [00375] Chloro-2-methoxy-4-methyl-benzene [00376] To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN
(700 mL) was added CH31 (110 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25 "C overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-chloro-2-niethoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDC13) 8 7.22 (d, J -= 7.8 Hz, 1 H), 6.74-6.69 (in, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
1101 OMe NBS Br A1BN, CC4 1 OMe CI CI
[00377] 4-Bromotnethy1-1-chloro-2-methoxy-benzene [00378] To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CC14 (350 mL) was added NBS (57 g, 0.32 mol) and ALBN (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%). 1H NMR (400 MHz, CDC13) 6 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).
OMe Br OMe NC 1110 NlaCN
CI C2H5OH¨

CI
[00379] 2-(4-Chloro-3-methoxyphenyflacetonitrile [00380] To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C21150H (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 1170.
The mixture was extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenypacetonitrile (25 g, 48%). 1II NMR (400 MHz, CDC13) 6 7.36 (d, J = 8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDC13) 6 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
[00381] Example 17: 1-(3-(Hydroxymethyl)-4-methoxyphenyl)cyclopropanecarboxylic acid.
V V V
HO
401 MeO
OMe Me0H
0 MOMCI Me CI
_, 110 OMe TiC14, CS 2 0 OMe Na2CO3 AO
Me0 V
Me0 HO
1-1 TBSCI SI aim LiOH 40 C). 40 OH

41111P-rir OMe OMe Me0H/H20 OMe =
0 a Me0H 40 OMe OMe [00382] 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00383] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50 g, 0.26 mol) in Me0H (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. Me0H
was removed by evaporation under vacuum and Et0Ac (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-pheny1)-cyclopropanecarboxylic acid methyl ester (53 g, 99%). 1H NMR (CDC13, 400 MHz) 6 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 I-1), 1.58 (m, 2 H), 1.15 (m, 2 H).
Me0 MOMCI Me*
a o TICI4, CS2 0 OMe OMe [00384] 1-(3-Chloromethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00385] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMC1 (29.1 g, 364 mmol) in CS2 (300 ml) was added TiC14 (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 CH2C12 (150 mL x 3). The combined organic extracts were evaporated under vacuum to give 1-(3-chloromethyl4-methoxy-pheny1)-cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.
V
Me=
Me a Na2003 /101 OH

OMe OMe [09386] 1-(3-Hydroxymethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00387] To a suspension of 1-(3-chloromeihy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (20 g) in water (350 mL) was added Bu4NBr (4.0 g) and Na2CO3 (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 mon) and extracted with Et0Ac (200 nit x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/ethyl acetate 15:1) to give 1-(3-hydroxymethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 39%). 1H NMR (CDC13, 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).

11, Me0 sm¨ =

O

OMe OMe [00388] 143-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyllcyclopropane carboxylic acid methyl ester [00389] To a solution of 1-(3-hydroxyrnethy1-4-methoxy-pheny1)-cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH2C12 (100 inL) were added imidazole (5.8 g, 85 mmol) and TBSCI (7.6 g, 51 mmol) at room temperature. The mixture was stirred overnight at room temperature. The mixture was washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum LO give crude product, which was purified by column (petroleum ether/ethyl acetate 30:1) to give 143-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-pheny1]-cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). 111 NMR (CDC13, 400 MHz) 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, 211), 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, 911), 0.11 (s, 6 H).
-= H=
fik ores UOH 40 Cip OH

4111111-17 OMe Me0H(H20 OMe [00390] 1-(3-Hydroxymethy1-4-methoxy-pheny1)-cyclopropanecarboxylic acid [00391] To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in Me0H (75 mL) was added a solution of Li0H.H20 (1.5 g, 36 mmol) in water (10 mL) at 0 C. The reaction mixture was stirred overnight at 40 C. Me0H was removed by evaporation under vacuum. AcOH
(1 moUL, 40 mL) and Et0Ac (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide 1-(3-hydroxymethy1-4-methoxy-pheny1)-cyclopropanecarboxylic acid (5.3 g).
[00392] Example 18: 2-(7-Chlorobenzo[d][1,3]dioxo1-5-yl)acetonitrile.

H
ome BBr3 BrCICH2 o 401 H NaBH4/THF
H 40 <

OH OH
CI CI CI
= Ail CI NaCN NC
40 0õ,>
(c) =

OH SOC12 <
0 igr ome BBr3 H H is OH
OH OH
CI CI
[00393] 3-Chloro-4,5-dihydroxybenzaldehyde [00394] To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54 mmol) in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at ¨40 C under N. 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 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.

H
0H BrCICH2 =

_________________________________ )0. \
OH
CI CI
[00395] 7-Ch1orobenzold][1,3]dioxole-5-carbaldehyde [00396] To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrC1CH2 (23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs2CO3 (25 g, 190 rnmol).
The mixture was stirred at 60 C overnight and was then poured into water. The resulting mixture was extracted with Et0Ac (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). 1H NMR (400 MHz, CDC13) 8 9.74 (s, 1 H), 7.42 (d, J - 0.4 Ifz, 1 II), 7.26 (d, J = 3.6 Hz, 111), 6.15 (s, 2 H).

NaBH/TI-IP = OH
< so H <=
=

[00397] (7-Ch)orobenz,o[d][1,3]dioxo1-5-yl)methanol [00398] To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 33 mmol) in TI-IF (50 mL) was added NaBH4 (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 NI-140 solution. The organic layer was separated, and the aqueous phase was extracted with Et0Ac (50 mL x 3).
The combined extracts were dried over Na2SO4 and evaporated under reduced pressure to afford (7-chlorobenzo[d][1,31dioxo1-5-yl)methanol, which was directly used in the next step.
< OH S0C12 <o = a __Am, =
a [00399] 4-Chloro-6-(chloromethyl)benzo[d][1,3]dioxole [00400] A mixture of (7-chlorobenzo[d][1,3]-dioxo1-5-y1)methanol (5.5 g, 30 mmol) and SOC12 (5.0 mL, 67 nunol) in dichloromethane (20 mL) was stirred at room temperature for 1 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 NaHCO3 solution, dried over Na2SO4 and evaporated under reduced pressure to afford 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole, which was directly used in the next step.
(4) > CI NaCN NC 0 = 0 CI CI
[00401] 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)aeetonitrile [00402] A mixture of 4-chloro-6-(chloromethyl)benzord1r1,31dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in HMSO (20 mL) was stirred at 40 'V for 1 li and was then poured into water. The mixture was extracted with Et0Ac (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 2-(7-ehlorobenzo[d][1,3]dioxo1-5-yl)acetonitrile (3.4 g, 58%). 1H NMR 8 6.81 (s, 1 H), 6.71 (s, 1 11), 6.07 (s, 2 H), 3.64 (s, 2 H). 13 CI M49.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3,23.1.
[00403] Example 19: 1-(Benzo[d]oxazol-5-yl)cyclopropaneearlboxylic acid.

'V' trimethyi Me0N
di H m NH2 orthoforail: MGO N\>
HO
0 0 0 o Mr O o thmethyl Me0 IF NH2 orthoformate Mee [00404] 1-Benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester [00405] To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 Q, 14.5 mmol) in DIVIF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-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 Et0Ac (100 inL x 3). The combined organic layers were dried over anhydrous Na2SO4 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.
1H N1VLR (CDC13, 400 MHz) 8 8.09 (s, 1), 7.75 (d, J= 1.2 Hz, 1 H), 7.53-7.51 (in, 1 H), 7.42-7.40 (m, 1 H), 3.66 (s, 3 I-1), 1.69-1.67 (m, 2 H), 1.27-1.24 (m, 2 H).
- = NNO13 H=
0 "0-[00406] 1-(Benzo[d]oxazol-5-ypcyclopropanecarboxylic acid [00407] To a solution of 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 ml) was added AlC13 (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 Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 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). 1H NMR (DMS0,400 MHz) 8 12.25 (brs, 1 11), 8.71 (s, 1 II), 7.70-7.64 (m, 2 H), 7.40 (dd, J= 1.6, 8.4 1-12, 1 H), 1.49-1.46 (m, 2 H), 1.21-1.18 (m, 2 H). MS
(ESI) ink (M+11 ) 204.4.
[00408] Example 20: 2-(7-Fluorobenzo[d][1,3]dioxo1-5-ybacetonitrile HBBr' ___________ H

BrCF,Cl/DMF H 0 Nal3H, HO =OH OH 0 O
SOCl2 = NaCN NC 11110 Q>
________________________ IP 0 OH
H C3'" B8r3 H 110 OH OH
[00409] 3-Fluoro-4,5-dihydroxy-benzaldehyde [00410] To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 ml) was added BBr3 (1.5 ml, 16 mmol) dropwise at ¨78 C
under N2. 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-benza ldehyde (1.1 g, 89%), which was directly used in the next step.

OH
H BrCH2CVDMF H

[00411] 7-Fluoro-benzo[1,3]dioxole-5-carbaldehyde [00412] To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrC1CH2(4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39 mmol). The mixture was stirred at 60 C overnight and was then poured into water. The resulting mixture was extracted with Et0Ac (50 ml. x 3). The combined organic layers were washed with brine (100 m1), dried over Na2SO4 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[1,31dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR
(300 MHz, CDCl3) 8 9.78 (d, J = 0.9 Hz, 1 H), 7.26 (dd, J = 1.5, 9.3 Hz, 1H), 7.19 (d, J = 1.2 Hz, 1 H), 6.16 (s, 2 H).

H
NaBH4 HO
> ____________ so o>

[00413] (7-Fluoro-benzo[1,3]dioxo1-5-y1)-methanol [00414] To a solution of 7-fluoro-benzo{1,31clioxole-5-carbaldehyde (0.80 2, 4.7 mmol) in Me0H (50 mL) was added NaBH4(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 Et0Ac. The Et0Ac layer was washed with water, dried over Na2SO4 and concentrated to dryness to afford (7-fluoro-benzo[1,31dioxol-5-y1)-methanol (0.80 g, 98%), which was directly used in the next step.
>
s0ci2 0 HID 401 00>
CI 40, [00415] 6-Chloromethy1-4-fluoro-benzo[1,3]dioxole [00416] To SOCl2 (20 mL) was added (7-fluoro-benzol1,31dioxol-5-y1)-methanol (0.80 g, 4.7 mmol) in portions at 0 C. The mixture was warmed to room temperature over 1 h and then was heated at reflux for 1 h. The excess SOCl2was evaporated under reduced pressure to give the crude product, which was basified with saturated aqueous NaHCO3 to pH ¨ 7.
The aqueous phase was extracted with Et0Ac (50 mL x 3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 6-chloromethy1-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next step.
ci 0 II 0) NaCN=
NC 0>
[00417] 2-(7-Fluorobenzo[d][1,3]dioxo1-5-yl)acetonitrile [00418] A mixture of 6-chloromethy1-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3 mmol) and 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 Et0Ac (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na7SO4 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][1,31dioxo1-5-yl)acetonitrilc (530 mg, 70%). 1H NMR (300 MHz.
CDCI3) 5 6.68-6.64 (m, 2 H), 6.05 (s, 2 H), 3.65 (s, 2 H). 13 C-NMR 8151.1, 146_2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3.
[00419] Example 21: 1-(1H-Indo1-5-yl)cyclopropanecarboxylic acid HO -= 1 F" - = Ramey N
0 Ts0H
Xr _______________ Ii. ___________ lir 0 CH3OH 0 Fi2SO4/01-12a2 0 1110 V 1 -= V du, Br ______ -= V SlMe3 Me0 0 Si NBS
, SiMe, ____________________________________________________ lib- 0 1110 NH2 Et3N
V = V
Cu l -= LiOH
a H
H
V V
HO Me0 0 TsCH
Oa-Si [00420] Methyl 1-phenylcyclopropanecarboxylate [00421] To a solution of 1-phenylcyclopropane,carboxylic acid (25 g, 0.15 mol) in CH3011 (200 mL) was added Ts0H (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 Et0Ac. The Et0Ac layer was washed with aq. sat. NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDC13) 57.37-7.26 (m, 5 H), 3.63 (s, 3 H), 1.63-1.60 (m, 2 H), 1.22-1.19 (m, 2 H).
V V
Me= KNO3 M-=
0 1101 FA n ir.H r.ilw ..2s-4, -. .2-.2 0 10 [00422] Methyl 1-(4-nitrophenyl)cyclopropanecarboxylate [00423] To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in H2SO4/CH2C12 (40 mL/40 mL) was added KNO3(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 Et0Ac (100 niL x 3). The organic layers were dried with anhydrous Na2SO4 and evaporated to give methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (21 g, 68%), which was used directly in the next step. 1H NMR (300 MHz, CDC13) 6 8.18 (dd, J= 2.1, 6.9 Hz, 2 H), 7.51 (dd, J= 2.1, 6.9 Hz, 2 IT), 3.64 (s, 3 H), 1.72-1.69 (m, 2 H), 115-1.22 (m, 2 H).
VV
Ranney Ni MeO
Me0 NO
[00424] Methyl 1-(4-aminophenyl)cyclopropanecarboxylate [00425] To a solution of methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20 g, 0.09 mol) in Me0H (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%).
1H NMR (300 MHz, CDCI3) 57.16 (d, J = 8.1 Hz, 2 H), 6.86 (d, J = 7.8 Hz, 2 H), 4.31 (br, 2 1-1), 3.61 (s, 311), 1.55-1.50 (m, 2 H), 1.30-1.12 (m, 211).
V Me0 V
Br Me0 1.1 NBS

[00426] Methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate [00427] To a solution of methyl 1-(4-aminophenypcyclopropartecarboxylate (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 Et0Ac (80 mL x3). The organic layers were dried with anhydrous Na2SO4 and evaporated to give methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate (10.6 g, 78%), which was used directly in the next step. III NMR (400 MHz, CDC13) 57.38 (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(m, 2 H), 1.14-1.11(m, 2 H).
Me = V Me= StMe3 Er =-=-SiMes 0 __________________________ )10- 0 Si NH2 Et3N N.2 [00428] Methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropane carboxylate [00429] To a degassed solution of methyl 1-(4-amino-3-bromophenyl)cyclopropane carboxylate (8 g, 0.03 mol) in Et3N (100 mL) was added ethynyl-trimethyl-silane (30 g, 0.3 mol), DMAP (5% mol) and Pd(PPh3)2C12 (5% mol) under N2. The mixture was refluxed at 70 C overnight. The insoluble solid was filtered off and washed with Et0Ac (100 niL 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%). 1H NMR
(300 MHz, CDC1() 87.27 (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).
Me0 V SiMe3 Cul Me0 [00430] Methyl 1-(1H-indo1-5-yl)cyclopropanecarboxylate [004311 To a degassed solution of methyl 1-(4-amino-3-((trimethylsilypethynyl)phenyl) cyclopropane,carboxylate (4.69 g, 0.02 mol) in DMF (20 mL) was added Cul (1.5 g, 0.008 mol) under N2 at room temperature. The mixture was stirred for 3 hr at room temperature.
The insoluble solid was filtered off and washed with Et0Ac (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-indo1-5-yl)cyclopropanecarboxylate (2.2 g, 51%). 'II NMR (400 MHz, CDC13) (37.61 (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 11).
VV
Me0 LiOH

[00432] 1-(1H-Indo1-5-yl)cyclopropanecarboxylic acid [00433] To a solution of methyl 1-(1H-indo1-5-yl)cyclopropanecarboxylate (1.74 g, 8 mmol) in CI13011 (50 m L) and water (20 inL) 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 HC1 to pH -3 before being extracted with Et0Ac (20 mL x 3). The organic _ .

layers were dried over anhydrous Na2SO4 and evaporated to give 1-(1H-indo1-5-yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1H NNW (300 MHz, DMSO-d6) 7.43 (s. 1 H), 7.30-7.26 (m, 2 H), 7.04 (cid, J = 1.5, 8.4 Hz, 1 H), 6.35 (s, 1 H), 1.45-1.41 (m, 2 H), 1.14-1.10 (m, 2 H).
[00434] Example 22: 1-(4-0xochroman-6-yl)cyclopropanecarboxylic acid V
V
meO2o 20% Ha OH ___________________________________ 2 jck ____________ V
o ( ) V
1,4.02 HOOC
OH
=
=

Me02C Me0 C
2 j lir OH Na 0 [00435] 144-(2-tert-Butoxycarbonyl-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester [00436] 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 'V for 1 h. After cooling to room temperature, the resulting mixture was quenched with water and extracted with Et0Ac (100 mL
x 3). The combined organic extracts were dried over anhydrous Na2SO4 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 114-(2-tert-butoxycarbonyl-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material (3.0 g). 11-I
NTMR (300 MHz, CDC13) 6 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, 211), 1.59-1.56 (m, 211), 1.47 (s, 9 H), 1.17-1.42 (m, 2 H).
V V
Me02C 11 0 20% HCI Me02C 40 0 0, 0 OH
[00437] 144-(2-Carboxy-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester [00438] A solution of 144-(2-tert-butoxycarbonyl-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester (6.3 g, 20 mmol) in HC1 (20%, 200 mL) was heated at 110 C for 1 h. After cooling to room temperature, the resulting mixture was filtered. The solid was washed with water and dried under vacuum to give 144-(2-carboxy-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester (5.0 g, 96%). 1H NMR (300 MHz, DMSO) 8 7.23-7.19 (m, 211), 6.85-6.81 (m, 2 H), 4.13 (t, J= 6.0 IIz, 2 I-I), 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).
V V
meo,c 0 COGI)2 HOOC 1110 .41111)VP.- 0 OH 0 [00439] 1-(4-0xochroman-6-yl)cyclopropanecarboxylic acid [00440] To a solution of 144-(2-carboxy-ethoxy)-phenyThcyclopropanecarboxylic methyl ester (5.0 g, 20 mmol) in CH2C12 (50 mL) were added oxalyl chloride (4.8 g, 38 rnmol) and two drops of DMF at 0 C. The mixture was stirred at 0-5 C for 1 h and then evaporated under vacuum. To the resulting mixture was added CH2C12 (50 mL) at 0 'V and stirring was continued at 0-5 'V for 1 h. The reaction was slowly quenched with water and was extracted with Et0Ac (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 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-(4-0xochroman-6-yl)cyclopropane-carboxylic acid: 1H NMR (400 MHz, DMSO) 5 12.33 (br s, 1 H), 7.62 (d, J = 2.0 Hz, 1 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-(4-0xochroman-6-yl)cyclopropanecarboxylate: 1H NMR (400 MHz, CDC13) 5 7.83 (d, J= 2.4 Hz, 1 H), 7.48 (dd, J= 2.4, 8.4 Hz, 11-i), 6.93 (d, J = 8.4 Hz. 1 H), 4.55-4.52 (m, 2 H), 3.62 (s, 3 11), 2.80 (t, J= 6.4 Hz, 211), 1.62-1.56 (m, 211), 1.18-1.15 (m, 2H).
[00441] Example 23: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid V LiOH V HO ome meo,c 5 __________________________________ HOOC

0 =
[00442] 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid [00443] To a solution of methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate (1.0g. 4.1 mmol) in Me0H (20 mL) and water (20 mL) was added Li011.1-170 (0.70 g, 16 mmol ) in portions at room temperature. The mixture was stirred overnight at room temperature before the Me0H was removed by evaporation under vacuum. Water and Et20 were added to the residue and the aqueous layer was separated, acidified with IIC1 and extracted with Et0Ac (50 mL x 3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-4-methoxychroman-6-yflcyclopropanecarboxylic acid (480 tri, 44%). 1H NMR (400 MHz, CDC13) 6 12.16 (s, I H), 7.73 (d, ./ = 2.0 Hz, 1 H), 7.47 (dd, J = 2.0, 8.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 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, 211). MS (ESI) raiz (MAT') 263.1.
[00444] Example 24: 1-(4-Hydroxy-4-methoxychroman-6-31)cyclopropanecarboxylic acid Me00C = NaBH/TFA meo0cu0H
__________________ )1. HOOG
0 411" 0 41111P 0 NaBH/TFA

Me00C =Me00C =
0 =
[00445] 1-Chroman-6-yl-cyclopropanecarboxylic methyl ester [00446] To trifluoroacetic acid (20 mL) was added NaBH4 (0.70 g, 130 mmol) in portions at 0 "V under N2 atmosphere. After stirring for 5 min, a solution of 1-(4-oxo-chroman-6-y1)-cyclopropanecarboxylic methyl ester (1.6 g, 6.5 mmol) was added at 15 C. The reaction mixture was stirred for 1 h at room temperature before being slowly quenched with water.
The resulting mixture was extracted with Et0Ac (50 mL x 3). The combined organic extracts dried over anhydrous Na2S0.4 and evaporated under vacuum to give 1-chroman-6-yl-cyclopropane,carboxylic methyl ester (1.4 g, 92%), which was used directly in the next step.
NMIR (300 MHz, CDC13) 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 ft), 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).
V V
Me00C =
LiOH

[00447] 1-(4-Hydroxy-4-methoxy-chroman-6-yl)cydopropanecarboxylic acid [00448] To a solution of 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (L4 g, 60 mmol) in Me0II (20 mL) and water (20 mL) was added Li0H-1120 (LO g, 240 mmol ) in portions at room temperature. The mixture was stirred overnight at room temperature before the Me0H was removed by evaporation under vacuum. Water and Et20 were added and the aqueous layer was separated, acidified with I IC1 and extracted with Et0Ac (50 niL x 3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (1.0 g, 76%). 1H
NMR (400 MHz, DMSO) 8 12.10 (br s, 1 H), 6.95 (d, J = 2.4 Hz, 2 H), 6.61-6.59 (m, 1 H), 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 (m, 2H). MS (EST) miz (M+H+) 217.4.
[00449] Example 25: 1-(3-Methylbenzo[dlisoxazol-5-y0cyclopropanecarboxylic acid V V V
meopc HDOC 40 Me0H/Ts0H is _______________ = AlC13/AcCI Me00C

OMe OMe OH
N.OH ,OAc Me000 = OH __________________ Me00C io OH
Ac20 Py/DMF Me0OG ,N LiOH
0' HOOC to ,N
0' V V
Me000 401 AlC13/AcCI Me000 OMe OH
[00450] 1-(3-Acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester [00451] To a stirred suspension of AlC13 (58 g, 440 mmol) in CS2 (500 mL) was added acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5 mm, 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 Et0Ac (150 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 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. 1H NMR (CDC13, 400 MHz) 8 12.28 (s, 1 H), 7.67 (d, J= 2.0 Hz, 1 H), 7.47 (dd, J =2.0, 8.4 Hz, 1 H), 6.94 (I, 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).
Ti 0 V V
Me00C NH2OH=HCI Me000 OH OH
[00452] 144-Hydroxy-3-(1-hydroxyimino-ethyl)-phenyftcyclopropanecarboxylic methyl ester [00453] To a stirred solution of 1-(3-acety1-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (14.6 e, 58.8 mmol) in Et0II (500 mL) were added hydroxylamine 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 Et0H
under vacuum, water (200 mL) and Et0Ac (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 144-hydroxy-3-(1-hydroxyimino-ethyl)-phenyli-cyclopropanecarboxylic methyl ester (14.5 g, 98%), which was used in the next step without further purification. 1H NMR
(CDC12, 400 MHz) 11.09 (s, 1 H), 7.39(d, J=2.0 H_z, 1 H), 7.23 (d, := 2.0 Hz, 1 H), 7.14(s, 1 H), 6.91 (d, J= 8.4 Hz, 1 H), 3.63 (s, 3 H), 2.36 (s, 3 H), 1.62-1.59 (m, 2 H), 1.18-1.15 (m, 2 H).
.oH
N_OAc V V
Me00C Ac20 __ Me00C 110 11, OH OH
[00454] (E)-Methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenypcyclopropane carboxylate [00455] The solution of 1- [4-hydroxy-3-(1-hydroxyimino-ethyl)-pheny1]-cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac20 (250 mL) was heated at 45 'V for 4 h. The Ac20 was removed by evaporation under vacuum before water (100 mL) and Et0Ac (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et0Ac (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give (E)-methyl 1-(3-(1-(acetoxyimino)ethy1)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%), which was used in the next step without further purification.

N,OAc V V
Me00C = Py/DMF Me00C 01101 \ N
OH
[004561 Methyl 1-(3-methylbenzo[dlisoxazol-5-Acyclopropanecarboxylate [004571 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 niL) and was extracted with Et0Ac (100 inL x 3). The combined organic layers were dried over anhydrous Na2SO4 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[d]isoxazol-5-yl)cyclopropanecarboxylate (7.5 g, 82%). 1II NMR (CDC13 300 MHz) 6 7.58-7.54 (m, 2 H), 7.48 (dd, J= 1.5, 8.1 Hz, 1 H), 3.63 (s, 3 H), 2.58 (s, 3 H), 1.71-1.68 (m, 2 H), 1.27-1.23 (m, 2 1-1).
V V
Me00C .01 \N ____________ LiOH HOOC =
[00458] 1-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid [00459] To a solution of methyl 1-(3-methylbenzoklilsoxazol-5-ypcyclopropanecarboxylate (1.5 g, 6.5 mmol) in Me0H (20 mi ) and water (2 mL) was added LiOILII20 (0.80 g, 19 mmol ) in portions at room temperature. The reaction mixture was stirred at room temperature overnight before the Me0H was removed by evaporation under vacuum. Water and Et20 were added and the aqueous layer was separated, acidified with HC1 and extracted with Et0Ac (50 naL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 1H NMR (400 MHz, DMSO) 6 12.40 (hr s, 111), 7.76 (s, 1 H), 7.60-7.57 (m,2 H), 2.63 (s, 3 H), 1.52-1.48 (in, 211), 1.23-1.19 (m, 211). MS (ESI) raiz (M+11) 218.1.
[00460] Example 26: 1-(Spiro[benzo[d][1,3]dioxole-2,1.-cyclobutane]-5-yl)cydoproparie carboxylic acid WO 2010/054138 PCTrus2009/063475 V V Er0 OH
H000 40 , Me00C 40 0H
OH OH
V
MeOOC Ov\
=0/ \*/ LION
_____________________________________ I 100C Ov,õ\
IP \Z
V
OH
HOOC 0 Me0H Me00C OH
OH OH
[00461] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester [00462] To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) in Me0H (30 mL) was added Ts0H (0.25 g, 1.3 mmol). The stirring was continued at 50 'V
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-pheny1)-cyclopropanecarboxylic methyl ester (2.1 2). 1H NMR (DMSO 300 MHz) 8 8.81 (brs, 2 H), 6.66 (d, J =
2.1 Hz, 1 H), 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).
V V
Me00C =OH Er _______________________________ Me00C = 0/"\-/
OH
[00463] Methyl 1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)cyclopropane carboxylate [00464] To a solution of 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (1.0 g, 4.8 mmol) in toluene (30 naL) was added Ts0H (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 1-(spirolbenzo[dll1,3ldioxole-2,1'-cyclobutame]-5-y1)cyclopropane,carboxylate (0.6 g, 50%). 1H NMR (CDC13300 MHz) 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).

V V
M e00C q\x/\ LiOH
= HOOC 0\/\
70-=
\'/
[00465] 1-(Spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)cyclopropane carboxylic acid [00466] To a mixture of methyl 1-(sp I benzo[d][1,31dioxole-2,1'-cyclobutane]-5-yl)cycl-opropanecarboxylate (0.60 g, 2.3 mmol) in THF/H20 (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 'V until pH 2-3. The mixture was extracted with Et0Ac (10 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and washed with petroleum ether to give 1-(spiro[benzo[d][1,3]-dioxole-2,1'-cyclobutane]-yecyclopropane carboxylic acid (330 mg, 59%). 11INMR (400 MHz, CDC13) 5 6.78-6.65 (m, 3 H), 2.65-2.58 (m, 4 H), 1.86-1.78 (m, 2 H), 1.63-L60 (m, 2 H), 1.26-1.19 (m, 2 H).
[00467] Example 27: 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile He ilft 002 Et BrH2COH2Br c = Ali 002Et LAH r=
4111" OH
= = 111" =
SOG2 =
a NiaCL0.1 C
I CN
= =
Hip CO2Et BrH2CCH2Br (0 GO2Et HO =
[00468] 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester [00469] To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2¨dibromoethane (54.3 2, 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 Et0Ac (200 mL x 3). The combined organic layers were washed with water (200 mL x 3) and brine (100 mL), dried over Na2SO4 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]clioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDC13) 5 7.53 (dd, J = 1.8, 7.2 Hz, 211), 6.84-6.87 (m, 1 H), 4.22-4.34 (m, 6 H), 1.35 (t, J = 7.2 Hz, 3 H).

soCO2E1 LAH c= OH

[00470] (2,3-Dihydro-benzo[1,4]dioxin-6-y1)-methanol [00471] To a suspension of fiA11-14 (2.8 g, 74 mmol) in THF (20 ml) was added dropwise a solution of 2,3-dihydro-benzo[1,41clioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THY' (10 mL) at 0 C under N2. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling.
The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-clihydro-benzo[1,4]dioxin-6-y1)--methanol (10.6 g). 1H N-MR (300 MHz, DMSO-d6) 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 11).
= soci2 40, [00472] 6-Chloromethy1-2,3-dihydro-benzo[1,4]dioxine [00473] A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOC12 (10 inL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3).
The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-ehloromethy1-2,3-dihydro-benzo[1,41dioxine (12 g, 88% over two steps), which was used directly in next step.
= NaCN
ON
C:
=
[00474] 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile [00475] A mixture of 6-chloromethy1-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 rnmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 nil. x 4). The combined organic layers were washed with water (50 ml x 2) and brine (50 raL), dried over Na2SO4 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]clioxin-6-yeacetonitrile as a yellow oil (10.2 g, 86%). 1H-NMR (300 MHz, CDCI3) 6 6.78-6.86 (m, 3 1-1), 4.25 (s, 4 H), 3.63 (s, 2 H).

[00476] 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]dioxo1-5-ylcyclopropane-1- H. o carboxylic acid 141 111 1-(2,2-difluorobenzo[1,3]dioxo1-5- H= 0 F

yl)cyclopropane-l-carboxylic acid 411 \ /
1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic =,õ OH El acid = H
1-(3-methoxyphenyl)cyclopropane-1-carboxylic H = 0 ¨

acid 111 HO
1-(2-methox3phenyl)cyclopropane-1-carboxylic =
acid c) yr 144-(trifluorometboxy)phenyllcyclopropane-1-carboxylic acid J
NW HO
1-(2,2-dimethylbenzo[d][1.3]dioxo1-5- =
yl)cyclopropanecarboxylic acid = = OH
=
tetrahydro-4-(4-methoxypheny1)-2H-pyran-4-carboxylic acid OH
OH gib 1-phenylcyclopropane-1-carboxylic acid 1-(4-methoxyphenyl)cyclopropane-1-carboxylic OH
acid 0 0 =

Name Structure I-(4-chlorophenyl)cyclopropane-l-carboxylic acid ci 1-(3-hydroxyphenyl)cyclopropanecarboxylic He 0 OH
acid 11 =
1-phenylcyclopentanecarboxylic acid OH
1 -(2-oxo-2,3 -dihydrobenzo [d]oxazol-5- OH
yl)cyclopropanecarboxylic acid 1-(benzofuran-5-yl)cyclopropanecarboxylic acid 1-(4-methoxyphenypcyclohexane,carboxylic acid \= 411 = OH
1-(4-chlorophenyl)cyclohexanecarboxylic acid c = =
=
OH
1-(2,3-dihydrobenzofuran-5- H= 0 yl)cyclopropanecarboxylic acid 1-(3,3-dimethy1-2,3-dihydrobenzofuran-5- =
=
yl)cyclopropanecarboxylic acid OH
¨=
1-(7-methoxybenzo [di [1,3]dio xo1-5-= 41c5t yl)cyclopropanecarboxylic acid L= H
1-(3-hydroxy-4- = OH OH
methoxyphenyl)cyclopropanecarboxylic acid =

Name Structure 1-(4-chloro-3- ., H H
hydroxyphenyl)cyclopropanecarboxylic acid I lik _____________________________________________________ _ .
He 1- (3-(benzyloxy)-4-= 1411 I,chlorophenypcyclopropanecarboxylic acid 0 a 1-(4-chlorophenyl)cyclopentanecarboxylic acid c 0 =
11.--' OH
I
=
1- (3-(benzyloxy)-4-lel A
naethoxyphenypcyclopropanecarboxylic acid 0 e .¨

OH
1-(3-chloro-4- ....... pH a methoxyphenyl)cyclopropanecarboxylic acid 4 IP ck 1-(3-fluoro-4- (L.. pH F
methoxyphenyl)cyclopropanecarboxylic acid 1-(4-methoxy-3- ,,... OH
methylphenyl)cyclopropanecarboxylic acid 4 It R
cy' 1-(4-(benzyloxy)-3- = Si 0 ..-methoxyphenyl)cyclopropanecarboxylic acid H*
=
1-(4-chloro-3- =,_ H 0¨

methoxyphenyl)cyclopropanecarboxylic acid 1-(3-ch.loro-4- = 0H I
hydroxyphenyl)cyclopropanecarboxylic acid .4 \_ / OH
1-(3-(hydroxymethyl)-4- ..... OH
OH
methoxyphenyl)cyclopropanecarboxylic acid 4 lit R

Name Structure 1-(4-methox yphenyl)cyclopentanecarboxylic = =
acid = OH
1-phenylcyclohexanecarboxylic acid = =
= OH
1-(3,4-dimethoxyphenyl)cyclopropanecarboxylic =oH 0¨

acid 4 ck Ho 1-(7-chlorobenzo[d][1,3]dioxo1-5-o yl)cyclopropanecarboxylic acid 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic H0 acid 411 Ho 1-(7-fluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid 1-(3,4-difluorophenyl)cyclopropane,carboxylic H. F
acid F
..___ Ho 0 1-(1H-indol-5-yl)cyclopropanecarboxylic acid lip NH
1-(1H-benzo[d]imidazol-5- Ho-f 1N/
.11) NH
yl)cyclopropanecarboxylic acid 1-(2-methyl-1H-benzo[d]imidazol-5- Ho *yl)cyclopropanecarboxylic acid NH
1- (1-methy1-1H-benzo[d]imidazol-5- Ho 0 yl)cyclopropanecarboxylic acid 4 N\

Name Structure 1-(3-methylbenzo[d]isoxazol-5- Ho ----r%
yl)cyclopropanecarboxylic acid 1-(spiro[benzo[d][1,31dioxolc-2,1'-cyclobutane]- H.
5-yl)cyclopropanecarboxylic acid 1-(1H-benzo[d][1,2,3]triazol-5- Ho /
ir \
yl)cyclopropanecarboxylic acid NH
1-(1-methy1-1H-benzo[d][1,2,3]triazol-5- Ho 1\
yl)cyclopropanecarboxylic acid 1 li r' 1-(1,3-dihydroisobenzofuran-5- H= = 0 yl)cyclopropanecarboxylic acid 1 .
Ho 0 H
1-(6-fluorobenzo[d][1,3]dioxo1-5-=41 lik 6 yl)cyclopropanecarboxylic acid F
1-(2,3-dihydrobenzofuran-6- Ho il yl)cyclopropanecarboxylic acid I .
H. 0 1-(chroman-6-yl)cyclopropanecarboxylic acid 111, . =
-.. 01-i 1-(4-hydroxy-4-methoxychroman-6- 0 =
H=
yl)cyclopropanecarboxylic acid I . =

=
1-(4-oxochroman-6-yl)cyclopropanecarboxylic o \
=
acid I . .
1-(3,4-dichlorophenyl)cyclopropanecarboxylic Ho 0 I
acid 1 it CI

Name I Structure 1-(2,3-dihyclrobenzo[b][1,4]ciiox in-6- H = 0 =

yl)cyclopropanecarboxylic acid e 1-(benzofuran-6-yl)cyclopropanecarboxylic acid HO--1004771 Specific Procedures: Synthesis of aminoindole building blocks [00478] Example 28: 3-Methyl-111.-indo1-6-amine 41111 NaNO2/HCI
02N NH Sn C12 02N N-NH2 HU
0,N

PO diak ell '-12iPd-C I I
gp I + 02N 1-2N
NaNO2/Ha N, N H2_ Ha SnCl2 02N

[00479] (3-Nitro-phenyl)-hydrazine hydrochloride salt [00480] 3-Nitro-phenylamine (27.6 g, (12 mol) was dissolved in the mixture of H20 (40 mL) and 37% HQ (40 mL). A solution of NaNO2 (13.8 g, 0.2 mol) in H70 (60 mL) was added to the mixture at 0 C, and then a solution of SnC12.1120 (135.5g. 0.6 mol) in 37% IIC1 (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%).
1410 N, NH2 Ha 0."

[00481] N-(3-Nitro-phenyl)-A"-propylidene-hydrazine [00482] 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 inL) 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 morn 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-nitrophenyI)-2-propylidenehydrazine, which was used directly in the next step.

02N H3PO4401 I 4_ 4011 1 [00483] 3-Methyl-4-nitro-1H-indole 3 and 3-methyl-6-nitro-1H-indole [00484] A mixture of (E)-1-(3-nitropheny1)-2-propylidenehydrazine dissolved in 85 %
H31304 (20 inL) 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 Et0Ac (100 mL x 3). The combined organic layers were dried, filtered and concentrated under reduced pressure to afford the mixture of 3-methy1-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole [1.5 gin total, 86 %, two steps from (3-nitrophenyl)hydrazine hydrochloride] which was used to the next step without further purification.

HJPdC

SI I +Q2 N I

[00485] 3-Methyl-1H-indo1-6-amine [00486] 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 II, (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-1H-indo1-6-amine (0.6 g, 24%). 'H NMR
(CDCI3) 8 7.59 (hr s. 1H), 7.34 (d, J= 8.0 Hz, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.57 (m, 111), 3.57 (brs, 2H), 2.28 (s, 3H); MS (ESI) m/e (M+H+) 147.2.
[00487] Example 29: 3-tert-Butyl-1H-indo1-5-amine Raney Ni/R2 N Ala3/cH2a:' N
02N so 02N so \
N ao3/cR2a, [00488] 3-tert-Butyl-5-nitro-1H-indole [00489] To a mixture of 5-nitro-1H-inclole (6.0 g, 37 mmol) and AlC13 (24 g, 0.18 mol) in CH2C12 (100 mL) at 0 C was added 2-bromo-2-methy1-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 CH2C12 (30 mL x 3). The combined organic layers were washed with water, brine, dried over Na2SO4and 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-buty1-5-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDC13, 400 MHz) 8 8.49 (d, J =
1.6 Hz, 1 H), 8.31 (brs, 1 H), 8.05 (dd, = 2.0, 8.8 Hz, 1 H), 7.33 (d, J= 8.8 Hz, 1 H), 6.42 (d, J = 1.6 Hz, 1 H), 1.42 (s, 9 H).
0.2N
Raney Ni/H2 N
[00490] 3-tert-Buty1-1H-indo1-5-amine [004911 To a solution of 3-tert-buty1-5-nitro-1H-indole (2.5 g, 12 mmol) in Me0H (30 mL) was added Raney Nickel (0.2 g) under N2 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-1H-indo1-5-amine (0.43 g, 19%). 1H NMR (CDC13, 400 MHz) 7.72 (br.s, 1 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 II), 6.09 (d, J= 1.6 Hz, 1 H), 1.37 (s, 9 H); MS (ESI) role (M+11 ) 189.1.
[00492] Example 30: 2-tert-Butyl-6-fluoro-1H-indo1-5-amine and 6-tert-butoxy-2-ten-buty1-1H-indol-5-amine ---=
02N 0 E3'2 02N 0 Br , =---- flak -';--0,N ill 0 --iv, Nk2 NH F N 1.11. NH, H
0,N H2N so TBAF \
0 N NI \
DAAF N
H H
-11.-{- 7 BuOK 02N Ail \ Ni ----1.- -1,N
= S \
N C = IWP N H
H

0 Br Br 2 02N
--VP-[00493] 2-Bromo-5-fluoro-4-nitroaniline [00494] To a mixture of 3-fluoro-4-nitroasilline (6.5 g, 42.2 mmol) in AcOH
(80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0 'C. 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 Et0Ac (50 mL x 3). The combined organic layers were washed with water (80 mL x 2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroandine (9 g, 90%). 11-1-NMR (400 MHz, DMSO-d6) 8 8.26 (d, J' 8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J= 9.6 Hz. 1H).
o2N 0 Br [00495] 2-(3,3-Dimethylbut-1-yny1)-5-fluoro-4-nitroaniline [00496] A mixture of 2-brotno-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(PPh3)2C12 (3.4 g, 4.86 mmol) and Et3N (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 Na2SO4 and concentrated under reduced pressure to dryness.
The residue was recrystallized with ether to afford 2-(3,3-dirnethylbut-1-yny1)-5-fluoro-4-nitroaniline (4.2 g, 46%). 11-1-NMR (400 MHz, DMSO-d6) 6 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 op C)2N 0 [00497] N-(2-(3,3-Dimethylbut-1-yny1)-5-fluoro-4-nitrophenyl)butyramide [00498] To a solution of 2-(3,3-dimethylbut-1-yny1)-5-fluoro-4-nitroaniline (4.2 g, 17.8 mmol) in dichloromethane (50 mL) and Et3N (10.3 InL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmol) at 0 C. 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 Na2SO4 and concentrated under reduced pressure to dryness. The residue was washed with ether to give N-(2-(3,3-dimethylbut-l-yny1)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was used M the next step without further purification.

02N io TBAF
01 \
[00499] 2-tert-Butyl-6-fluoro-5-nitro-1H-indole [00500] A solution of N-(2-(3,3-dimethylbut-1-yny1)-5-fluoro-4-niqophenyl)butyramide (3.0 g, 9.8 mmol) and TBAF (4.5 g, 17.2 mmol) in DMF (25 mL) was heated at 100 C
overnight. The mixture was poured into water and then extracted with Et0Ac (80 mL x 3).
The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give compound 2-tert-butyl-6-fluoro-5-nitro-114-indole (1.5 g, 65%). 1H-NMR (400 MHz, CDC13) b 8.30 (d, J= 7.2 Hz, 11-1), 7.12 (d, J= 11.6 Hz, H-I), 6.35 (d, J= 1.2 Hz, 1H), 1.40 (s, 9H).
02N ih H2N mai F F
[00501] 2-tert-Buty1-6-fluoro-111-indo1-5-amine [00502] A suspension of 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 6.36 mmol) and Ni (0.5 g) in Me0H (20 mL) was stirred under H2 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-buty1-6-fluoro-IH-indol-5-amine (520 mg, 38%). 111-NMR (300 MHz, DMSO-d6) 8 10.46 (brs, 1H), 6.90 (d, J
= 8.7 Hz, 1H), 6_75 (d, J= 9.0 Hz, 1H), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H);
MS (ESI) m/e 206.6.
BuOK 02N si F 411111" 0 [00503] 6-tert-Butoxy-2-tert-butyl-5-nitro-1H-indole [00504] A solution of N-(2-(3,3-dimethylbut-1-yny1)-5-fluoro-4-nitrophenyl)butyramide (500 mg, 1.63 mmol) and t-BuOK (0.37 g, 3.26 mmol) in DMF (10 naL) was heated at 70 C
for 2 h. The mixture was poured into water and then extracted with Et0Ac (50 naL x 3). The combined extracts were washed with water (50 ml) and brine (50 rnL), dried over Na2SO4 and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-buty1-5-nitro-1H-indole (100 mg ,21%). 11-1-NMR (300 Milz, DMSO-d6) 6 11.35 (brs, 1H), 7.99 (s, 111), 7.08 (s, 111), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
o2N
Raney Ni H2N alb )0 ______________________________ )0, 1'0 141"
[00505] 6-tert-Butoxy-2-tert-butyl-1H-indo1-5-amine [00506] A suspension of 6-tert-butoxy-2-tert-buty1-5-nitro-1H-indole (100 mg, 0.36 mmol) and Raney Ni (0.5 g) in Me0H (15 ml) was stirred under H2 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-buty1-1H-indo1-5-amine (30 mg, 32%). 1H-NMR (300 MiElz, Me0D) 6.98 (s, 1H), 6.90 (s, 1H), 5.94 (d, J= 0.6 Hz, 1H), 1.42 (s, 9H), 1.36 (s, 9H); MS (ESI) m/e 205Ø
[00507] Example 31: 1-tert-Butyl-1H-indo1-5-amine H2N--(--- 02N di Br2 AcOH
02N fit Br 02N ga \
1.1 411V NH __ 11111" NH
Pd(PPh3)2C12 11111" NH
02N H2N gith Cul, DNIF \ Raney Ni' H2 411, N
H2N¨("-- or' 02N *NH
[00508] N-tert-Butyl-4-nitroaniline [00509] A solution of 1-fluoro-4-nitro-benzene (1 Q, 7.1 mmol) and tert-butylaniine (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 Et0Ac (7 ml, x 3). The combined organic layers were washed with water, brine, dried over Na2SO4 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%). 111NMR (CDC13, 400 MHz) 5 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
02N 02N 40 Br Br2 / AcOH
NH
NH
[00510] (2-Bromo-4-nitro-phenyl)-tert-butyl-amine [00511] To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in Ac0II
(5 mL) was added Br2 (0.86 g, 54 mmol) dropwise at 15 'C. After addition, the mixture was stirre,d at 30 C for 30 mm and then filtered. The filter cake was basified to pH 8-9 with aqueous NaHCO3. The aqueous layer was extracted with Et0Ac (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na2SO4and concentrated under vacuum to give (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 43%). 1H-NMR (CDCI3, 400 MHz) 5 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, 1H), 5.19 (brs, 1H), 1.48 (s, 9H).

02N Br NH _______________________ S\I 02N , Pd(PPh.3)2Cl2 [00512] tert-Butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine [00513] To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2 mmol) in Et3N (10 mL) was added Pd(PPh3)2C12 (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N2 protection.
The reaction mixture was heated at 70 C overnight. The solvent was removed under vacuum and the residue was washed with Et0Ac (10 mL x 3). The combined organic layers were washed with water, brine, dried over Na7SO4 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%). 1H-NMR
(CDC13, 400 MHz) 6 8_20 (d, J = 14, Hz, 1H), 8.04 (dd, J= 2.4, 9.2 Hz, 1H), 6.79 (d, J= 9.6 Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H).
si 02N 02.N so Cut, DMF
NH
[00514] 1-tert-Butyl-5-nitro-1H-indole [00515] To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 ininol) in DMF (2 int), was added CuI (13 mg, 0.07 mmol) under N2 protection.
The reaction mixture was stirred at 100 C overnight. At this time, Et0Ac (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain 1-tert-buty1-5-nitro-111-indole (7 mg, 93%). 111-NMR (CDC13, 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).

\ Raney Ni/ H2 [00516] 1-tert-Butyl-1H-indo1-5-amine [00517] To a solution of 1-tert-butyl-5-nitro-1H-indo1e (6.5 g, 0.030 mol) in Me0H (100 mL) was added Raney Nickel (0.65 g, 10%) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 30 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 (PEIEt0Ac 1:2) to give 1-tert-butyl-1H-indo1-5-amine (2.5 g, 45%). 1H-NTMR (CDC13, 400 MHz) 5 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, 1H), 6.26 (d, J = 3.2 Hz, 1H), 1.67 (s, 9H).
MS (ESI) m/e (M-FIr) 189.2.
[00518] Example 32: 2-tert-Butyl-1-methyl-111-indol-5-amine 02N ON Br NH
Br2 NH

'my'. NH
02N H,N1 TBAF \
Ni/H, N
02N 02N 401 Br Br2/HOAc NH NH
[00519] (2-Bromo-4-nitro-pheny1)-methyl-amine [00520] To a solution of methyl-(4-nil-phenyl)-amine (15.2 g, 0.1 mol) in AcOH
(150 mL) and CHC13 (50 mL) was added Br2 (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. NaHCO3. The resulting mixture was extracted with Et0Ac (100 mi x 3), and the combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-bromo-4-niu-o-pheny1)-methyl-amine (2-bromo-4-nitro-phenyp-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 1H NMR (300 MHz, CDC13) 6 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, 1 H), 3.01 (d, 1 =
5.4 Hz, 3 H).
02N Br ON
4" NH
tiV NH
[00521] [2-(3,3-Dimethyl-but-1-yny1)-4-nitro-pheny1]-methyl-amine [00522] To a solution of (2-bromo-4-nitro-pheny1)-methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) were added Et3N (19.7 g, 195 mmol), Pd(PPh3)2C12 (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g, 195 nunol) successively under N2 protection. The mixture was heated at 70 CC for 3 hours and then cooled down to room temperature. The resulting mixture was extracted with EtOAc (100 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give [2-(3,3-dimethyl-but-1-yny1)-4-nitro-phenyl]-methyl-amine (20.1 g, 94%), which was used in the next step without further purification. 1H NMR
(400 MHz, CDC13) 8 8.15 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 2.8, 9.2 Hz, 1H), 6.50 (d, J
= 9.2 Hz, 1H), 5.30 (brs, 1H), 3.00 (s, 31-1), 1.35 (s, 9H).
0,N
TBAF
0,N =
NH
[00523] 2-tert-Butyl-1-methyl-5-nitro-1H-indole [00524] A solution of [2-(3,3-dimethyl-but-1-yny1)-4-nitro-phenyThmethyl-araine (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 Et0Ac (100 mL). The organic phase was separated, dried over Na2SO4 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. 1H NMR (CDC13, 400 MHz) 6 8.47 (d, J -= 2.4 11z, 1H), 8.07 (dd, J = 2.4, 9.2 Hz, 1H), 7.26-7.28 (m, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 1.50 (s, 9H).

Raney Ni/F12 H2N
_______________________________ Ir 1111 N\
[00525] 2-tert-Buty1-1-methy1-1H-indo1-5-amine [00526] To a solution of 2-tert-butyl-1-methyl-5-nitro-1H-indole (3.00 g, 13.7 mmol) in Me0H (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.EfEt0Ac 20:1) to give 2-tert-buty1-1-methy1-1H-indo1-5-amine (1.7 g, 66%). 11-1NMR (300 MHz, CDCI3) 37.09 (d, J =
8.4 Hz, 11-1), 6.89-6.9 (m, 1H), 6.66 (dd, J = 2.4, 8.7 Hz, 1H), 6.14 (d, J = 0.6 Hz, 1H), 3.83 (s, 3H), 3.40 (brs, 2H), 1.45 (s, 9H): MS (EST) rri/e (M+H+) 203.1.
[00527] Example 33: 2-Cyclopropy1-1H-indo1-5-amine 02N Br2, HOAc 02N Br 02N so butyryl chloride NH2 it. NH2 Cul, Et3N NH2 Pd(PPh3)Cl2 11 io 0,N so TBAF 02N 0 \ 4 Raney Ni H2N
02N 02N Br Br2, HOAc ______________________________ )0, NH2 r.t. NH2 [00528] 2-Bromo-4-nitroartiline [00529] To a solution of 4-nitro-aniline (25 g, 0.18 mol) in HOAc (150 mL) was added liquid Br2 (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 nil ), which was basified with sat. aq. NaHCO3 to pH 7 and extracted with Et0Ac (300 mL x 3).
The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 2-bromo-4-nitromiline (30 g, 80%), which was directly used in the next step.
02N 40 Br ________________________ < 02N
NH2 Cut, E13N NH2 Pd(PPh3)C12 [00530] 2-(CyclopropylethynyI)-4-nitroaniline [005311 To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-cyclopropane (1 g, 15 mmol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2C12 (210 mg, 0.3 mmol) under N2. The mixture was heated at 70 C and stirred for 24 hours. The solid was filtered off and washed with Et0Ac (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-(cyclopropylethyny1)-4-nitroaniline (470 m2, 23%). 1H NMR (300 MHz, CDC13) 8 8.14 (d, J= 2.7 Hz, 1H), 7.97 (dd, f= 2.7, 9.0 Hz, 1H), 6.63 (d, J= 9.0 Hz, 1H), 4.81 (brs, 2H), 1.55-1.46 (m, 11-1), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).
hi butyryl chloride 02N rik 0 [00532] N-(2-(Cyclopropylethynyl)phenyI)-4-nitrobutyramide [00533] To a solution of 2-(cyclopropylethyny1)-4-nitroarriline (3.2 g, 15.8 mmol) and pyridine (2.47 g, 31.7 mmol) in CH2C12 (60 mL) was added butyryl chloride (2.54 g, 23.8 mmol) at () 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 CH2C12 (30 m L x 3). The combined organic layers were dried over anhydrous Na2SO4 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)pheny1)-4-nitrobutyramide (3.3 g, 76%). 1H
NNW (400 MHz, CDC13) 8.61 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 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, 7.2 Hz, 3H), 1.03-1.01 (m, 2H), 0.91-0.87 (m, 2H).

I"
0 _____________________________ 3Iw 110 \

[00534] 2-Cyclopropy1-5-nitro-1H-indole [00535] A mixture of N-(2-(cyclopropylethynyl)pheny1)-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 CH2C12 (50 m L x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 2-cyclopropy1-5-nitro-11I-indole (1.3 g, 64%). 1H NMR (400 MHz, CDC13) 5 8.44 (d, J= 2.0 Hz, 1H), 8.40 (brs, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6,29 (d, J =
0.8 Hz, 1H), 2.02-1.96 (m, 1H) 1.07-1.02 (m, 2H), 0.85-0.81(m, 2H).

02N a Raney NI H2N
\ 4 [00536] 2-Cyclopropy1-1H-indo1-5-amine [00537] To a solution of 2-cyclopropy1-5-nitro-111-indole (1.3 g, 6.4 ramol) in Me0II (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 =
5/1) to give 2-cyclopropy1-1H-indo1-5-amine (510 mg, 56%). 1H NMR (400 MHz, CDC13) 6.89 (d, J= 8.4 Hz, 1H), 6.50 (d, J= 1.6 Hz, 1H), 6.33 (dd, J= 2.0, 8.4 Hz, 1H), 5.76 (s, 1H), 4.33 (brs, 2H), 1.91-1.87 (m, 1H), 0.90-0.85(m, 2H), 0.70-0.66 (m, 2H); MS
(ESI) m/e (M+H+) 173.2.
[00538] Example 34: 3-tert-Butyl-1H-indo1-5-amine 02N Raney Ni/H2 Ail \
_____________________________________ 11P

02N, Br [00539] 3-tert-Butyl-5-nitro-1H-indole [00540] To a mixture of 5-nitro-1H-indole (6 g, 36.8 nunol) and AlC13 (24 g, 0.18 mol) in CH2C12 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) dropwise at 0 C. After being stirred at 15 C overnight, the reaction mixture was poured into ice (100 mL).
The precipitated salts were removed by filtration and the aqueous layer was extracted with CH2C12 (30 ml x 3). The combined organic layers were washed with water, brine, dried over Na2SO4 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--nitro-1H-indole (2.5 g, 31%). 'H NMR (CDC13, 400 MHz) 8 8.49 (d, J= 1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J .= 2.0, 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 1.6 Hz, HI), 1.42 (s, 9H).

02N so Raney Ni/H2 H2N
YOr¨

[00541] 3-tert-Butyl-1H-indo1-5-amine [00542] To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in Me0H (30 ml) was added Raney Nickel (0.2 g) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 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-indo1-5-amine (0.43 g, 19%). 1H NMR (CDC13, 400 MHz) 5 7.72 (brs, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.86 (d. J = 2.0 Hz, 1H), 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+11) 189.1.
[00543] Example 35: 2-Phenyl-1H-indo1-5-amine Ph 0 02N so 02N Br = ______________________________ Ph 02N 40 CI
_________________ Ns¨

NH2 AcOH NH2 Et3N

Ph 02N H2N Ph 40 40 N\ ph Raney NI
02N 40 Br2(HOAC 02N so Br _______________________________ low [00544] 2-Bromo-4-nitroaniline [00545] To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was added liquid Br2 (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 Et0Ac (200 mL). The mixture was basified with saturated aqueous NaHCO3 to pH 7. The organic layer was separated. The aqueous phase was extracted with Et0Ac (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.

WO 2010/054138 rt, 1/U
S2t0JY/U6S4 /3 Ph 02N Br ___________________________ Ph NH2 Et3N

[00546] 4-Nitro-2-(phenylethynyflaniline [00547] To a deoxygenated solution of 2-bromo-4-nitroani1ine (2.17 g, 0.01 inutol), ethynyl-benzene (1.53 g, 0.015 mol) and Cul (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2C12 (210 mg, 0.2 ramol) under N2. The mixture was heated at 70 C and stirred for 24 hours. The solid was filtered off and washed with Et0Ac (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)andine (340 mg, 14%). 1H NMR (300 MHz, CDC13) 6 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95 (brs, 2H).
Ph Ph Ci 1110 [00548] N-(2-(Phenylethynyl)pheny1)-4-nitrobutyramide [00549] To a solution of 4-nitro-2-(phenylethynyl)andine (17 g, 0.07 mmol) and pyridine (11.1 g, 0.14 mol) in CH2C12 (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 CIT2C12 (30 m L x 3). The combined organic layers were dried over anhydrous Na2SO4 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-(phenylethynyl)pheny1)-4-nitrobutyramide (12 g, 55%). 1H NMR (400 MHz, CDC13) 6 8.69 (d, J =9.2 Hz, 1H), 8.39 (d, J =2.8 Hz, 111), 8.25-8.20 (m, 2H), 7.58-7.55 (m, 2H), 7.45-7.42 (m, 3H), 2.49(t, J =7 .2 Hz, 2H), 1.85-1.79 (m, 2H), 1.06(t, J= 7.2 Hz, 3H).
Ph 02N TBAF \ Ph [00550] 5-Nitro-2-pheny1-11-1-indole [00551] A mixture of N-(2-(phenylethynyl)pheny1)-4-nitrobutyramide (5.0 g, 0.020 mol) and TBAF (12.7 g, 0.050 mol) in TI-IF (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 CH2C12 (50 m L x 3). The combined organic layers were dried over anhydrous Na2SO4 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-pheny1-1H-indole (3.3 g, 69%). 1H NMR (400 MHz, CDC13) 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, HI). 6.95 (s, 1H).
o2N so \ H 2N
Ph Raney Ni so Ph [00552] 2-Phenyl-1H-indol-5-amine [00553] To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in Me0H
(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%). 1H NMR (400 MHz, CDC13) 5 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), 6.64 (d, J = 1.6 Hz, 1H), 6.60 (d, J=1.2 Hz, 1H), 6.48 (dd, J = 2.0, 8.4 Hz, 1H), 4.48 (brs, 2H); MS (ESI) mie (M+1-) 209Ø
[00554] Example 36: 2-tert-Butyl-4-cluoro-1H-indo1-5-amine 0F , AI Br NaBH4/NiC12,.. Br o ilk= Br pd(pPh3)202.
111"
NO Me0H
NH2 tir Cu VEt3N 41B"
t-BuOK .03 02N 40 NaBH4/NiGI2 H2N
_______________________ = _______________ =
DMF H2SO4 N Me0H N
Br NaBH4/NiC120 40 Br NO2 Me0H

[00555] 2-Bromo-3-fluoroaniline [00556] To a solution of 2-bromo-1-fluoro-3-nitrobenz,ene (1.0 g. 5.0 mmol) in CH3OH (50 mL) was added NiC12 (2.2 g 10 nunol) and NaBH4 (0.50 g 14 rnmol) at 0 C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with Et0Ac (20 mL x 3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 11 NMR
(400 MHz, CDC13) 67.07-7.02 (m, 1 H), 6.55-6.49(m, 1I-I), 4.22 (br s, 2 II).

00 Br CI-L" so Br 0 [00557] N-(2-Bromo-3-fluorophenyl)butyramide [00558] To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2C12 (50 mL) was added butyryl chloride (1.3g. 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 CH2C12 (50 mL x 3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step.
40 Br a Pd(PPh3)2Cli. 0 CuliFt3N
4.27 N1-13 [00559] N-(2-(3,3-Dimethylbut-1-yny1)-3-fluorophenyl)butyramide [00560] To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et,N
(100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)2C12 (500 mg) successively at room temperature under N2. The mixture was heated at 80 C overnight. The cooled mixture was filtered and the filtrate was extracted with Et0Ac (40 mL x 3). The organic layers were washed with sat. NaC1, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% Et0Ac in petroleum ether) to give N-(2-(3,3-dirnethylbut-1-yny1)-3-fluorophenyl)butyramide (1.1 g, 55%). IIINMR (400 MHz, CDC13) 68.20 (d, J
7.6, 1 H), 7.95 (s, 1 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
t-BuOK
DMF
.11-r- NH
[00561] 2-tert-Butyl-4-fluoro1H-indole [00562] To a solution of N-(2-(3,3-dimethylbut-1-yny1)-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 Et0Ac (100 mL x 3). The organic layers were washed with sat. NaC1 and water, dried over anhydrous Na2SO4, and evaporated under vacuum to give 2-tert-buty1-4-fluoro-111-indole (5.8 g, 97%). 1H NMR (400 MHz, CDC13) 68.17 (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, 1 H), 1.41 (s, 9 H).
KNO
3 02N, [00563] 2-tert-Butyl-4-fluoro-5-nitro-1H-indole [00564] To a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in H2804(30 mL) was added KNO3 (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 Et0Ac (100 mL x 3). The organic layers were washed with sat. NaC1 and water, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% Et0Ac in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1H-indole (900 mg, 73%). 1H NMR (400 Mliz, CDC13) 68.50 (hr s, 1 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, 1 H), 1.40 (s, 9 H).

NaBH4/NiCl2 ______________________________ )1. H2 \
Me0H N
[00565] 2-tert-Butyl-4-fluoro-1H-indo1-5-amine [00566] To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (2.1 g, 9.0 mmol) in methanol (50 mL) was added NiC12 (4.2g. 18 mmol) and NaBH4 (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 Et0Ac (30 mL x 3). The organic layers were washed with sat.

NaC1 and water, dried over anhydrous Na2SO4, evaporated under vacuum to give 2-tert-buty1-4-fluoro-1H-indo1-5-arnine (900 mg, 50%). 1H NMR (300 MHz, CDC13) 8 7.80 (brs, 1 H), 6.91 (d, J= 8.4 I lz, 1 H), 6.64 (dd, J= 0.9, 2.4 Hz, 1 H), 6.23 (s, 1 II), 1.38 (s, 9 H).
[00567] Example 37: 2,3,4,9-Tetrahydro-1H-carbazol-6-amine (:),N io = SnCl2 H2N
[00568] 2,3,4,9-Tetrahydro-1/1-carbazol-6-amine [00569] 6-Nitro-2,3,4,9-tetTahydro-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(H) 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.
[00570] Example 38: 2-tert-Butyl-7-fluoro-1H-indol-5-amine a o 02N dal Brz/HOAc 02N sit e, NH2 Cul,Pd(PPY3)2C12, Et3N1.22N io ir NH2 Raney-NVH, 1-1-2N
ozN 0 t-BuOK, OMF
).= IMP

Br2/1-10Ac 02N io .2 [00571] 2-Bromo-6-fluoro-4-nitro-phenylamine [00572] To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH
(50 mL) was added Br2 (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. NaHCO3, and extracted with Et0Ac (100 mL

x 3). The combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 1H NMR (400 MHz, CDCI3) 6 8.22 (m, 1 H), 7.90 (dd, J -= 2.4, 10.8 Hz, 1 1-1), 4.88 (brs, 2 H).
02N Ail Br ON it =<-.9.
________________________________ )11.
Nii2 Cul,Pd(PPh3)201,, Et:RN NH, [00573] 2-(3,3-Dimethyl-but-1-yny1)-6-fluoro-4-nitro-phenylamine [00574] To a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol) in dry Et3N (100 mL) was added CuI (445 mg, 5% mol), Pd(PPh3)2C12 (550 mg, 5% mol) and 3,3-dimethyl-but-1-yne (9.6 g, 120 mmol) under N2 protection. The mixture was stirred at 80 C
for 10 h. The reaction mixture was filtered, poured into ice (100 g), and extracted with Et0Ac (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 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-dirnethyl-but-1-yny1)-6-fluoro-4-nitro-phenylamine (4.0 g, 36%). 1H NMR (400 MHz, CDC13) 5 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).
02N, NH2 Py,CH2Cl2 [00575] N42-(3,3-Dimethyl-but-l-yny1)-6-fluoro-4-nitro-phenyl]-butyramide [00576] To a solution of 2-(3,3-dimethyl-but-1-yny1)-6-fluoro-4-nitro-phenylanaine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH2C12 (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 CH2C12 (30 mL x 3). .The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give N-[2-(3,3-dimethyl- but-1-yny1)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 62%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO) 6 8.10 (dd, J
= 1.5, 2.7 Hz, 1 H), 7.95 (dd, J = 2.4, 9.6 Hz, 1 II), 7.22 (brs, 1 H), 2.45 (t, 1 = 7.5 Hz, 2 H), 1.82 (m, 2 1-1), 1.36 (s, 9 H), 1.06 (t, J= 7.5 Hz, 3 H).

02N 1- BuOK, DMF 02N

[00577] 2-tert-Buty1.7-fluoro-5-nitro1H-indole [00578] 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 nil- ) was added t-BuOK (2.3 a, 21 mmol) at room temperature. The mixture was heated at 120 C for 2 g before being cooled down to room temperature. Water (50 inL) was added to the reaction mixture and the resulting mixture was extracted with CH2C12 (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 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. 1H NMR
(300 MHz, CDC13) 8 9.95 (brs, 1 II), 8.30 (d, J= 2.1 Hz, 1 H), 7.74 (dd, J =
1.8, 11.1 Hz, 1 H), 6.43 (dd, J= 2.4, 3.3 Hz, 1 H), 1.43 (s, 9 H).

Raney NVH2 _____________________________ 710-[00579] 2-tert-Butyl-7-fluoro-111-indo1-5-amine [00580] To a solution of 2-tert-butyl-7-fluoro- 5-nitro-lII-indole (2.0 g, 8.5 mmol) in Me0H (20 mL) was added Ni (0.3 g) under nitrogen atmosphere. The reaction mixture was stirred under hydrogen atmosphere (1 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-indo1-5-amine (550 mg, 24%). 1H NMR
(300 MHz, CDC13) 8 7.87 (brs, 1 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, 1 H), 1.39 (s, 9 H). MS (ESI) m/z (M+H+) 207.
[00581] Example 39: 5-Anfino-2-tert-butyl-1H-indole-7-carbonitrile 02N 40 Br 02N 0,N
\ I-12N
-------NIC121NaBH \
Cul ,Pcl(PPIV,C12, EPTBAF
NH2 NH, CN CN CN CN

02N io Sr 1)( 02N
Cu Pd(P'113)2C12, Et2N1' CN
[00582] 2-Amino-3-(3,3-dimethylbut-1-yityl)- 5-nitrobenzonitrile [00583] To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et3N (60 mL) was added Cur (380 mg, 5% mol) and Pd(PPh3)2C12 (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 Na2SO4. The solvent was removed under vacuum to obtain the crude product, which was purified by column chromatography (2-10% Et0Ac in petroleum ether) to obtain 2-amino-3-(3,3-dimethylbut-1-yny1)- 5-nitrobenzonitrile (1.7 g. 71%). 1I1 NMR (300 MHz, CDCl3) 5 8.28 (d, J= 2.7 Hz, 1 11), 8.27 (d, J= 2.7 Hz, 1 11), 5.56 (hr s, 211), 1.37 (s, 9 H).

CN CN
[00584] 2-tert-Butyl-5-nitro-1H-indole-7-earbonitrile [00585] To a solution of 2-amino-3-(3,3-dimethylbut-1-yny1)- 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 (50m1) was added to the residue and the mixture was extracted with Et0Ac. The organics were dried over Na2SO4 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.

NiC12/NaBH4 _____________________________ 00, CN CN
[00586] 5-Amino-2-tert-butyl-1H-indo1-7-carbonitrile WO 2010/054138 PC11 US-2009/(1634 /
[00587] To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g. 3.6 mmol) in Me0I-1 (10 mL) was added NiC12.61120 (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 and extracted with Et0Ac. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (5-20% Et0Ac in petroleum ether) to obtain 5-amino-2-tert-butyl-1H-indol-7-carbonitrile (470 mg, 32% over two steps). 1H NMR (400 MHz, CDC13) 8 8.25 (s, 1 H), 7.06 (d, J =2.4 Hz, 1 H), 6.84 (d, .1 = 2.4 Hz, 1 H), 6.14 (d, J = 2.4 Hz, 1 H), 3.57 (hr S. 2 H), 1.38 (s, 9 H). MS (ES1) m/z: 214 (M411').
[00588] Example 40: Methyl 5-amino-2-tert-butyl-111-indole-7-carboxylate KOH, Et0H 02N to Me0H
____________________________ to-SOCl2 GN =0H
Fi2N

Raney-Nu2 = 0 = 0 02N io KOH, Et0H 02N *\
______________________________ =
CN H ="" OH
[00589] 2-tert-Butyl-5-nitro-1H-indole-7-carboxylic acid [00590] 2-tert-Butyl-5-nitro-1H-indole-7-carbonitri].e (4.6 g, 19 mmol) was added to a solution of KOH in Et0H (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%
Et0Ac in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 77%). 1IINMR (CDC13, 300 MHz) 8 10.79 (brs, 1 H), 8.66 (s, 1 H), 8.45(s, 11-1), 6.57 (s, 1 H), 1.39 (s, 9 H).

Me0H 02N
1141' N
SOCl2 = 01-I
[00591] Methyl 2-tert-butyl-5-nitro-111-indole-7-carboxylate [00592] SOC12 (3.6 g, 30mol) was added dropwise to a solution of 2-tert-buty1-5-nitro-1H-indoIe-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% Et0Ac in petroleum ether) to afford methyl 2-tert-buty1-5-nitro-1H-indole-7-carboxy1ate (2.95 g, 70%). 1H NMR
(CDC13, 300 MIIz) 5 9.99 (brs, III), 8.70 (d, J= 2.1 Hz, 11-1), 8.65 (d, J= 2.1 Hz, 11-1), 6.50 (d, J= 2.4 Hz, 1 H), 4.04 (s, 1.44(s, 9H).

Raney-Ni/H2 H2N
= 0"
o' [00593] Methyl 5-amino-2-tert-buty1-111-indole-7-earboxylate [00594] A solution of 2-tert-butyl-5-nitro-11-1-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney Nickel (200 mg) in CH3OH (50 rtiL) was stirred for 5 h at the room temperature under H2 atmosphere. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give methyl 5-amino-2-tert-buty1-1H-indole-7-carboxylate (1.2 g, 68%) 1H NMR (CDC13, 400 MHz) (59.34 (brs, 11-1), 7.24 (d, J = 1.6 Hz, 1H), 7.10 (s, 1H), 6.12 (d, J = 1.6 Hz, HI), 3.88 (s. 311), 1.45 (s, 9H).
[00595] Example 41: (5-Amino-2-tert-butyl-1H-indo1-7-yl)methanol 0214 s N
DIBAL-H 02is Raney Ni/H2 N N N

N LID \
= 0- OH
[00596] (2-tert-Butyl-5-nitro-1H-indo1-7-y1) methanol [00597] To a solution of methyl 2-tert-buty1-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30m1) 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 Et0Ac (120 nil, x 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-tert-buty1-5-nitro-1H-indo1-7-yl)methanol (4.0 g, 73%), which was used in the next step directly.

02N Raney Ni11-12 142N
N
11111" N
OH OH
[00598] (5-Amino-2-tert-buty1-1H-indo1-7-yOmethanol [00599] A mixture of (2-tert-butyl-5-nitro-1H-indo1-7-yl)methanol (4.0 g, 16 mmol) and Raney Nickel (400 mg) in CH3OH (100 mL) was stirred for 5 g at room temperature under I+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-indo1-7-yl)methanol (3.4g, 80%). 1H
NMR
(CDC13, 400 MIIz) 6 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).
[00600] Example 42: 2-(1-Methylcyclopropy1)-1H-indo1-5-amine n-BuLi TBAF
\ ____________ < ______ )1' Me2SO4 02N Ci Br2/HOAC 02N
Br NH2 NH2 Pd(P1h3)202 NH2 ilitYrYI
chloride ir \ Raney Ni/H2 NH¨c_ n-BuLi 1\si ________________ < _________ Me2SO4 [00601] Trimethyl-(1-methyl-cyclopropylethyny1)-silane [00602] To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) 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 'V for 30 min each. The reaction was quenched by adding a mixture of sat. aq.
NH4C1 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 niL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethyny1)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDC13) 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
==71 [00603] 1-Ethyny1-1-methyl-cyclopropane [00604] To a solution of trimethyl-(1-methyl-cyclopropylethyny1)-silane (20 g, 0.13 mol) in TI-IF (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 phase was extracted with THF (50 nil). The combined organic layers were dried over anhydrous Na2SO4 and distilled under atmospheric pressure to obtain 1-ethyny1-1-methyl-cyclopropane (7.0 2, contained 1/2 TIIF, 34%). 11-INMR (400 MHz, CDC13) 5 1.82 (s, 1 H), 1.26 (s, 3 H). 0_90-0.88 (m, 2 H), 0.57-0.55 (m, 2 H).
02N io BriHOAC 02N Br [00605] 2-Bromo-4-nitroaniline [00606] To a solution of 4-nitro-phenylatnine (50 g, 0.36 mol) in AcOH (500 mL) was added Br2 (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 NaHCO3 to pH 7. The aqueous phase was extracted with Et0Ac (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.
02N 40 Br ____________________________ )1, ON io NI-12 Pd(PPh3)2C12 NH2 [00607] 2-((1-Methylcyclopropyl)ethyny1)-4-nitroaniline [00608] To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 nunol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 inL) was added CuI
(76 mg, 0.40 mmol) and Pd(PPh3)2C12 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70 C and stirred for 24 h. The solid was filtered off and washed with Et0Ac (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 24(1-methylcyclopropyl)ethyny1)-4-nitroaniline (340 mg, 79%). IH NMR (300 MHz, CDC',13) 6 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 II), 1.04-1.01 (m, 2 II). 0.76-0.73 (m, 2 H).
ir o2N
o2N
NH2 butyryl chloride NI I
[00609] N42-(1-Methyl-cyclopropylethyny1)-4-nitro-phenyl]-bntyramide [00610] To a solution of 2((l-methylcyclopropyl)ethyny1)-4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2CL (20 mL) was added butyryl chloride (140 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 CH2C12 (30 mL x 3). The combined organic layers were dried over anhydrous Na.2804 and evaporated under reduced pressure to obtain N42-(1-methyl-cyclopropyl-ethyny1)-4-nitro-phenyll-butyramide (230 mg, 82%), which was directly used in the next step.
02N 02N so 0 TBAF \
NI ________________ I
[00611] 2-(1-MethylcyclopropyI)-5-nitro-1H-indole [00612] A mixture of N-[2-(1-methyl-cyclopropylethyny1)-4-nitro-phenyll -but yrami de (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 CH2C12 (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford methylcyclopropy1)-5-nitro-1H-indole (0.70 g, 71%). IH NMR (400 MHz, CDC13) 8 8.56 (brs, 1 H), 8.44 (d, J= 2.0 Hz, 1 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 llz, 1 II), 1.52 (s, 3 H), 1.03-0.97 (m, 2 H), 0.89-0.83 (m, 2 II).
0,N1 SH2N
\ -44 Raney Ni/H2 _______________________________ I"- S\ 4 N N
H H
[00613] 2-(1-Methyl-cyclopropy1)-1H-indol-5-ylamine [00614] To a solution of 2-(1-methylcyclopropyI)-5-nitro-1H-indole (0.70 g, 3.2 mmol) in Et0H (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-cyclopropy1)-1H -indo1-5-ylamine (170 mg, 28%). 1H
NMR (400 MHz, CDC13) 6 7.65 (brs, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.57 (d, J = 8.4 Hz, 1 LI), 6.14 (s, 1 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).
[00615] Example 43: Methyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropanoate _.?/...i0Me OMe Nal-4), v 1AOMe __ Fa5 ).-- ______________________________________ 0 eq. NaOH
_____________________________________________________ Yll.
cH202 a OH
,,,./ , NaN H2 OHC H2N2 .....j /0--_________________ )11. ___________ Va.-0 DMSO ¨/ 0 _FP
a 0 L, V__ -401 a or 02N -'-% 02N

0 _______________ 00 ___________________ )...-WI
NH2 butyr0 chloride NI I

Pd(PPh3)4, Cut, Ei3N
\
0 o Pd(CH3CN)2C12 02N 0 Haney Ni H2N id& o \
N ir \
H N
H

Mel, NaHip_ OMe OMe [00616] Methyl 2,2-dimethy1-3-oxobutanoate [00617] 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 Et0Ac (500 int x 3). The combined organic layers were dried and evaporated under reduced pressure to give methyl 2,2-dimethy1-3-oxobutanoate (85 g), which was used directly in the next step.
/O
Me 0 Me ) 1XL'OMe 0 CH2Cl2 CI
[00618] Methyl 3-chloro-2,2-dimethylbut-3-enoate [00619] To a suspention of PC15 (270 g, 1.3 mol) in CH2Cl2 (1000 nth) was added dropwise methyl 2,2-dimethy1-3-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 cooled to ambient temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (500 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. 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%). III NMR (400 MHz, CDC13) 6 5.33 (s, 1 1-1), 3.73 (s, 3 1-1), 1.44 (s, 611).
OMe OH
( aq. NaOH
0 _____________________________________ 0 ci [00620] 3-Chloro-2,2-dimethylbut-3-enoic acid [00621] 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% HC1 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.
1H NNW (400 MHz, CDC13) 8 7.90 (brs, 1 H), 5.37 (dd, J = 2.4, 6.8 Hz, 211), 1.47 (s, 6 H).
OH
NaNH2 yi0H
____________________ 0 DMSO
CI
[00622] 2,2-Dimethyl-but-3-ynoic acid [00623] Liquid NH3 was condensed in a 3-neck, 250 mi. 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 NH3 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 Na2SO4 and concentrated to give crude 2,2-dimethyl-but-3-ynoic acid (2 g), which was used directly in the next step. 11-INMR (400 MHz, CDC13) 2.30 (s, 1 H), 1.52 (s, 6 H).
/ pH

[00624] Methyl 2,2-dimethylbut-3-ynoate [00625] 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.
III NMR (400 MHz, CDC13) 8 3.76 (s, 3 H), 2.2g (s, 1 H), 1.50 (s, 6 H).

02N Br 02N so NH, Pd(PPh3)4, Cul, Et3N NH2 [00626] Methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate [00627] 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), CuI (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) in toluene/1120 (100/30 mL) was added Pd(PPh3)4 (6.17 g, 3.97 rrtmol) under N). The mixture was heated at 70 'C and stirred for 24 h.
After cooling, the solid was filtered off and washed with Et0Ac (50 mL x 3). The organic layer was separated and the aqueous phase was washed with Et0Ac (50 InL 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-nitropheny0-2,2-dimethylbut-3-ynoate (900 mg, 9%).

(400 MHz, CDC13) (58.17 (d, J = 2.8 Hz, 1 H), 8.01 (dd, J = 2.8, 9.2 Hz, 1 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).

N

0N so 2 NH2 butyryl chloride [00628] Methyl 4-(2-butyramido-5-nitropheny1)-2,2-dimethylbut-3-ynoate [00629] To a solution of methyl 4-(2-amino-5-nitropheny1)-2,2-dimethylbut-3-ynoate (260 mg, 1.0 mmol) and pyridine (160 mg, 2.0 ruol) in CH2C12 (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 CH202 (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain methyl 4-(2-butyramido-5-nitropheny1)-2,2-dimethylbut-3-ynoate (150 mg, 45%), which was used directly in the next step. IH NMR (400 MHz, CDC13) 8 8.79 (brs, 1 H), 8.71 (d, J= 9.2 Hz, 1 H), 8.24 (d, J= 2.8 Hz, 1 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 II), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J= 6.8 Hz, 3 H).

pd(cH3.N2a2 02N a Nit [00630] Methyl 2-methy1-2-(5-nitro-1H-indo1-2-yl)propanoate [00631] To a deoxygenated solution of methyl 4-(2-butyramido-5-nitropheny1)-2,2-dimethylbut-3-ynoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) was added Pd(CH3CN)2C12 (0.42 g, 1.6= mmol) under N2. The mixture was heated at reflux for 24 h. After cooling the mixture to ambient temperature, the solid was filtered off and washed with Et0Ac (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-1H-indo1-2-y1)propanoate (320 mg, 23%). 1H NMR (400 MHz, CDC13) 6 9.05 (brs, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.09 (dd, J = 2.0, 8.8 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 6.54 (d, J= 1.6 Hz, 1 H), 3.78 (d, J= 9.6 Hz, 3 H), 1.70 (s, 6 H).

Raney Ni H2N

[00632] Methyl 2-(5-amino-111-indo1-2-y1)-2-rnethylpropanoate [00633] A suspension of methyl 2-methyl-2-(5-nitro-1H-indo1-2-y1)propanoate (60 mg, 0.23 ininol) and Raney Nickel (10 mg) in Me0H (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-indo1-2-y1)-2-methylpropanoate (20 mg, 38%). 111 NMR (400 MHz, CDC13) 8 8.37 (hr s, 1 H),7.13 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 2.0 Hz, 1 H), 6.63 (dd, J = 2.0, 8.4 Hz, 1 H), 6.20 (d, J= 1.2 Hz, 1 H), 3.72 (d, J = 7.6 Hz, 3 H), 3.43 (br s, 1 H), 1.65 (s, 6 H); MS (ESI) m/e (Mi-}1 ) 233.2.
[00634] Example 44: 2-lsopropy1-1H-indol-5-amine 0 1 0,N 2N at 13AF/DINF - Raney NI \

tigr ________________ [00635] 2-Isopropyl-5-nitro-1H-indole [00636] A mixture of methyl 4-(2-butyramido-5-nitropheny1)-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 m1 x 3). The combined organic layers were dried over anhydrous Na2SO4 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%). 1H NMR (400 MHz, CDC13) .3 8.68 (s, 1 H), 8.25 (br s, 11-1), 8.21 (dd, J = 2.4, 10.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, ill), 6.41 (s, 1 H), 3.07-3.14 (m, 1 H), 1.39 (d, J= 6.8 Hz, 6 H).

Raney Ni H2N
[00637] 2-Isopropyl-111-indol-5-amine [00638] A suspension of 2-isopropyl-5-nitro-1H-indole (100 mg, 0.49 mmol) and Raney Nickel (10 mg) in Me0H (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-indo1-5-amine (35 mg, 41%).
111 NMR (400 MHz, CDC13) 57.69 (br s, 1 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, 1 H), 3.55 (br s, 2 H), 3.06-2.99 (m, 1 H), 1.33 (d, J
= 7.2 Hz, 6 I-1); MS (ESI) rn/e (M-1-1-r) 175.4.
[00639] Example 45: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropaneearboxamide r'sy--''PPh2Br PPh3Br OEt j , flyi PPh3 HB!
-NH2 OEt (Boc)20 40 KHMDS \
KOt-By * \ DMAP 02Et Mel N = 2Et 02Et Boo Boc so TEA. /1101 NaNO3 02N
N CO2Ft conc. H2SO4 CO2Et OH PPh3 HBcp, PPh3Br H 2 141,1 H2 [00640] Tripheny1(2-aminobenzybphosphonium bromide [00641] 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 tripheny1(2-aminobenzyl)phosphonium bromide (193 g, 88%).
PPh3Br 110 'Ph,Br CI Ft u f4H2 OEt [00642] Triphenyl((ethy1(2-earbamoyi)acetate)-2-benzy1)phosphonium bromide [00643] To a suspension of tripheny1(2-aminobenzypphosphonium 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 heating and evaporated. The solid was dried overnight at 50 C under vacuum to give triphenyl((ethyl(2-carbamoypacetate)-2-benzy1)-phosphonium bromide (139 g, 58%).
PPh3Br OEt KOt-Bu /110 CO2Et [00644] Ethyl 2-(1H-indo1-2-yl)acetate [00645] Triphenyl((ethyl(2-carbamoyl)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 mm) to give ethyl 2-(1H-indo1-2-yl)acetatc (9.12 g, 78%).
(Boc)20, N CO2Et DMAP N CO2Et Boo [00646] tert-Butyl 2-((ethoxycarbonypmethyl)-1H-indole-1-carboxylate [00647] To a solution of ethyl 2-(1H-indo1-2-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% Et0Ac in hexane) to give tert-butyl 2-((ethoxycarbonyl)methyl)-1H-indole-l-carboxylate (20.0 g, 91%).
\ KHMDS 110 N CO2Et Mel Nt CO2Et Boc Boc [00648] tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-y1)4H-indole-1-carboxylate [00649] tert-Butyl 2-((ethoxyearbonypmethyl)-1H-indole-1-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 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-y1)-1H-indole-1-carboxylate (17.1 g, 94%).
TFA
CO2Et ICIX)-4¨0O2Et Boc [00650] Ethyl 2-(1H-indo1-2-y1)-2-methylpropanoate [00651] tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-y1)-1H-indole-1-carboxylate (22.9 g, 69.1 mmol) was dissolved in dichloromethane (200 ) before 11-A (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% Et0Ac in hexane) to give ethyl 2-(1H-indo1-2-y1)-2-methylpropanoate (12.5 g, 78%).
401, NaNO3 02N
).

conc. H24 N CO2Et N CO2Et [00652] Ethyl 2-methy1-2-(5-nitro-1H-indo1-2-yl)propanoate [00653] Ethyl 2-(1H-indo1-2-y1)-2-methylpropanoate (1.0g. 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% Et0Ac in hexane) to give ethyl 2-methy1-2-(5-nitro-1H-indo1-2-yl)propanoate (0.68 g, 57%).

LiA1H4 02N to N CO2Et OH
[00654] 2-Methyl-2-(5-nitro-1H-indo1-2-y1)propan-1-ol [00655] To a cooled solution of LiA1H4 (1.0 M in THF, 1.1 mL, 1.1 mmol) in THF
(5 mL) at 0 C was added a solution of ethyl 2-methyl-2-(5-nitro-1H-indo1-2-yl)propanoate (0.20 g, 0.72 mmol) in THF (3.4 mL) dropwise. After addition, the mixture was allowed to want-) up to room temperature and was stirred for 3 h. The mixture was cooled to 0 C
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. r[he organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 2-methy1-2-(5-nitro-1H-indo1-2-yl)propan-1-ol (0.098 g, 58%).
02N ao N io Sn012.2H20 H2 [00656] 2-(5-Amino-1H-indo1-2-y1)-2-methylpropan-1-ol [00657] To a solution of 2-methyl-2-(5-nitro-1H-indo1-2-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 NaHCO3. The reaction mixture was filtered through a plug of cclite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indo1-2-y1)-2-methylpropan-1-01 (0.080 g, 98%).
[00658] Example 46: 2-(Pyridin-2-y1)-1H-indo1-5-amine ./ 1.
02N 401 I ) Q = N
___________________________ 02N io t-BuOK/DMF>
NH2 Pd(PPh3)2C12/CLJI

Sna2 H2N
______________________________ VP-I
C __________________________ 02N io I
N
________________________________ 02N
NH2 Pd(PPh3)2012/Cul [00659] 4-Nitro-2-(pyridin-2-ylethynyl)aniline [00660] To the solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF
(60mL) and Et3N
(60 mL) was added 2-ethynylpyridine (3.0 g, 45 mmol), Pd(PPh3)2C12 (600 mg) and Cul (200 mg) under N2. The reaction mixture was stirred at 60 C for 12 h. The mixture was diluted with water and extracted with dichloromethane (3 x 100 nil). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 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%). 11-1 NMR (300 MHz, CDC13) 8 8.60 (s, 1 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, 211), 7.42-7.39 (m, 1 H), 7.05 (brs, 2 H), 6.80 (d, J = 6.9 Hz, 1 H).
o2N
02N N 1-BuOK/DMF <\71) [00661] 5-Nitro-2-(pyridin-2-yI)-1H-indole [00662] 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 Na2SO4 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-y1)-1H-indole. (1.0 g, 67%yield). 1H NMR (300 MHz, d-DMSO) 612.40 (s, HI), 8.66 (d, J = 2.1 Hz, 1 H), 8.58 (d, 1J= 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).
SnCl2 ) NE
[00663] 2-(Pyridin-2-y1)-1H-indol-5-amine [00664] To a solution of 5-nitro-2-(pyridin-2-y1)-1H-indole (700 mg, 2.9 mmol) in Et0H
(20 mL) was added SnC12 (2.6 g, 12 mmol). The mixture was heated at reflux for 10 h.
Water was added and the mixture was extracted with Et0Ac (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 2-(pyridin-2-y1)-1II-indo1-5-amine (120 mg, 20%). 1H
NMR (400 MHz, CDC13) 8 9.33 (brs, 1 H), 8.55 (dd, J= 1.2, 3.6 Hz, 1 H), 7.76-7.67 (m, 2 H), 7.23 (d, J= 6.4 Hz, 1 H), 7.16-7.12(m, 1 H), 6.94(d, J= 2.0 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 6.71-6.69 (dd, J = 2.0, 8.4 Hz, 1 H).
[00665] Example 47: 2-(Pyridin-2-y1)-111-indo1-5-amine 02N so I 0-,..õ---,OTBDMS 02N Arnih -NH2 r [s--,,,OTBDMS
tH.r.-",OTBDMS
02N io H2N so 02N so LABAL-H. HiRa^ey-1._ Pcia2/CH2CN N
c) PH
OH OH
0, NH2 m,..,,OTBDMS
[00666] [2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-amine [00667] To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-butyldirnethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added I'M (1.5 mL) at 0 C. The reaction mixture was stirred at this temperature for 30 min before NaCNBH3 (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 Et0Ac (30 mL
x 3), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum, and the residue was purified by chromatography on silica gel (5 %
ethyl acetate/petroleum) to afford j2-(tert-butyl-dimethyl-silanyloxy)-ethyll-(2-iodo-4-nitro-phenyl)-amine (800 mg, 25 %). 1H NMR (300 MHz, CDC13) 6 8.57 (d, J = 2.7 Hz, 1 H), 8.12 (dd, J -= 2.4 ,9.0 Hz, 1 H),6.49 (d, J = 9.3 Hz, 1 H), 5.46 (br s, 1 H), 3.89(t, J5.4Hz, 211), 3.35 (q, J = 5.4 Hz, 2 H), 0.93 (s, 9 H), 0.10 (s, 6 H).
o2N
o2N
N MS
[00668] 5-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl)--3,3-dimethyl-pent-4-ynoic acid ethyl ester [00669] To a solution of [2-(tert-butyl-climethyl-silanyloxy)-ethy11-(2-iodo-4-nitro-pheny1)-amine (800 nag, 1.9 mmol) in Et3N (20 mL) was added Pd(PPh3)2C12 (300 mg, 0.040 mmol), CuI (76 mg, 0.040 mmol) and 3,3-dimethyl-but-1-yne (880 mg, 5.7 mmol) successively under N2 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 Et0Ac (30 mL x 3).
The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 5- {242-(tert-butyl-dimethyl-silanyloxy)-ethylaminol-5-nitro-phenyl I -3,3-dimethyl-pent-4- ynoic acid ethyl ester (700 mg, 82 %), which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) 6 8.09 (s, 1 H), 8.00 (d, J = 9.2 Hz, 1 H), 6.54 (d, J= 9.2 Hz, 1 II), 6.45 (brs, 1 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 = 7.2 117, 3 H), 0.84 (s, 9 H), 0.00 (s, 6 H).

OTBDMS PdC12/CH3CN N
[00670] 341-(2-Hydroxy-ethyl)-5-nitro-1H-indo1-2-yl]-3-methyl-butyric acid ethyl ester [00671] A solution of 5-12- [2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl }-3,3- dimethyl-pent-4- ynoic acid ethyl ester (600 mg, L34 mmol) and PdC12(650 mg) in CH3CN (30 mL) was heated at reflux overnight. The resulting mixture was extracted with Et0Ac (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was dissolved in THF (20 nil- ) 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 341-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-methyl-butyric acid ethyl ester (270 mg, 60 %). 1H NMR (300 MHz, CDCI3) 8 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, 1 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 11), 0.03 (s, 6 H).
0,N 02N 0 isoDIBAL-H_ OH
OH
[00672] 341-(2-Hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-methyl-butan-1-ol [00673] To a solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y11-3-methyl-butyric acid ethyl ester (700 mg, 2.1 mmol) in TI-IF (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 1 h.
Water (2 mL) was added and the resulting mixture was extracted with Et0Ac (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum.
The residue was purified by chromatography on silica gel (15 % ethyl acetate/petroleum) to afford 311-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-mettyl-butan-1-ol (300 mg, 49%). 11-1 NMR (300 MHz, d-DMSO) 8 8.42 (d, J== 1.5 Hz, 1 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 On ,2 H), 3_24-3.21 (m, 2 H), 1.42 (s, 6 H).
02N = H2N
H2/Raney-Ni OH OH
OH OH
[00674] 315-Amino-1-(2-hydroxy-ethyl)-1H-indol-2-y1]-3-methyl-butan-1-ol WO 2(110/054138 PCT/US2009/063475 [00675] A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-methyl-butan-1-01 (300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH3OH (30 mL) was stirred for 5 h at room temperature under a H2 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 345-amino-1-(2-hydroxy-ethyl)-1H-indo1-2-y1]-3-methyl-butan-1-ol (70 mg, 26%). 1H NMR (300 MHz, CDC12).6 7.07 (d, .1= 8.7 Hz, 1 H), 6.83 (d, J = 2.1 Hz, 1 H), 6.62 (lid, J = 2.1, 8.4 Hz, 111), 6.15(s, 1 H), 4.47 (t, J = 5.4 Hz, 211), 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).
[00676] Example 48: tert-Butyl 2-(5-amino-1H-indo1-2-yl)piperidine-1-carboxylate 0.2N
H2N gi6 \ Boc20 H
411,11 N Et3N
02N \ \ ptayi-12 I N ____________ 10- I

[00677] 2-(Piperidin-2-y1)-1H-indo1-5-amine [00678] 5-Nitro-2-(pyridin-2-y1)-1H-indole (1.0 g, 4.2 mmol) was added to HO/Me0H (2 M, 50 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under vacuum. Pt02 (200 mg) was added to a solution of the residue in Me0H
(50 mL) and the reaction mixture was stirred under hydrogen atmosphere (1 attn) 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-y1)-1H-indo1-5-amine (1.0 g), which was directly used in the next step.

H2N \ Boc20 Et3N H2N \
N
[00679] tert-Butyl 2-(5-amino-111-indo1-2-yl)piperidine-1-earboxylate [00680] To a solution of 2-(piperidin-2-y1)-1H-indo1-5-amine (1.0 g) ii Et3N
(25 mL) and TF1F (25mL) was added Boc20 (640 mg, 2.9 mmol). The reaction mixture was stirred at mom 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 Na2SO4 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-indo1-2-yl)piperidine-1-carboxylate (15 mg, 1%
over 2 steps). 114 NMR (400 MHz, CDC13) 8 8.82 (s. 1 7.58 (s, 1 11), 7.22 (d, J = 8.8 Iiz, 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) [00681] Example 49: 6-amino-1H-indole-2-carbonihile NaNO2/HCI AE1 2141111"
,,.NH2 Ha ________________________ 002 0,N1 sna2 02 N

PPA
I I NaOH
0, I sou, el 02N N CO2Et = 002H 2, NH3 I VD 02 N CONH2 (CF30)20 el I Raney Ni/H2 el I

410 NaNO2./H0 S
02N _NH2 Ha 02N NH2 na2 [00682] (3-Nitrophenyl)hydrazine hydrochloride [00683] 3-Nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H20 (40 mL) and 37% NCI (40 mL). A solution of NaNO2 (14 g, 0.20 mol) in H20 (60 mL) was added to the mixture at 0 C, and then a solution of SnC12.H20 (140 g, 0.60 mol) in 37% 1-10 (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%).
(3.
-Aco,Et 410 N C 0 2 Et 02N Si N'NH2-HCI _________________________ y [00684] (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate [00685] (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-nitrophenyphydrazono)propanoate, which was used directly in the next step.
1110,CO2Et PPA 4101 I

02N N CO2Et [00686] Ethyl 4-nitro-1H-indole-2-carboxylate and ethyl 6-nitro-1H-indole-2-carboxylate [00687] (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate 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%).
1.1 I NaOH

02N N CO2Et 02N N CO2H
[00688] 4-Nitro-1H-indole-2-carboxylic acid and 6-nitro-1H-indole-2-carboxylic acid [00689] A mixture of ethyl 6-nitro-1H-indole-2-carboxylate (0.5 g) and 10 7o 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 HC1 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%).
410i I 1. soc42 el I
02N N CO2H 2. NH3 H20 02 N CON H2 [00690] 4-Nitro-1H-indole-2-carboxamide and 6-nitro-1H-indole-2-carboxarnide [00691] A mixture of 6-nitro-I H-indole-2-carboxylic acid (12 g, 58 mmol) and SOC12 (50 mL, 64 mmol) in benzene (150 mL) was heated at reflux for 2 h. The benzene and excess SOC12 was removed under reduced pressure. The residue was dissolved in anhydrous CH2C12 (250 mL) and N113.H20 (22 g, 0.32 inol) 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.
=i I ( C F 3 C 0) 2 0 =i I

[00692] 4-Nitro-1H-indole-2-carbonitrile and 6-nitro-1H-indole-2-carbonitrile [00693] 6-Nitro-1H-indole-2-carboxamide (5.0 g, 24 mmol) was dissolved in C117C12 (200 mL). Et3N (24 g, 0.24 mop and (CF3C0)20 (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 Et0Ac (100 mL x 3). The combined organic layers were dried over Na2SO4, 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-1H-indole-2-carbonitrile (2.5 g, 55%).
4101 I Raney Ni/H2 =I I

[00694] 6-Amino-1H-indole-2-carbonitrile [00695] A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney Nickel (500 mg) in Et0H (50 mL) was stirred at room temperature under 117 (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 %). 1H NMR (DMSO-d6) 6 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) na/e (M-4-H) 158.2.
[006%] Example 50: 6-Amino-1H-indole-3-carbonitrile CN
CN
40, , 112Pd- C I I
02 (:)1\1 H2 01 , ciso2N.0 el I CN

[00697] 6-Nitro-1H-indole-3-carbonitrile [00698] To a solution of 6-nitroindole (4.9 g 30 rarnol) in DMF (24 mL) and CH3CN (240 mL) was added dropwise a solution of C1S02NCO (5.0 mL) in CH3CN (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. NaHCO3 solution to pH
7-8. The mixture was extracted with ethyl acetate. The organics were washed with brine, dried over Na7SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

PCTiLTS2009/063475 CN ON
H2/Pd-C 01 I
el I
__________________________________ H

[00699] 6-Amino-1H-indole-3-earbonitrile [00700] A suspention of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 25 mmol) and 10% Pd-C
(0.46 g) in Et0H (50 mL) was stirred under 112(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. 111 NMR (DMSO-d6) 8 11.51 (s, 1 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 (ES1) m/e (m-Fir) 157.1.
[00701] Example 51: 2-tert-Butyl-1H-indo1-6-amine 40 NH, 0 n-Li Bu NaBH4/AcOH
,o0.

KNO-11-1-,S0 -IP- \
Raney NUN, N

SLa sic NH2 _____________________________ )P- 1101 N-11)<
[00702] N-o-Tolylpivalamide [00703] To a solution of o-tolylamine (21 g, 0.20 mol) and Et3N (22 g, 0.22 mop in CH2C12 was added 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) at 10 C. After addition, the mixture was stirred overnight at room temperature. The mixture was washed with aq. HC1 (5%, 80 mL), saturated aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give N-o-tolylpivalamide (35 g, 91%). 111 NMR
(300 MHz, CD03) 8 7.88 (d, J= 7.2 Hz, 1 H), 7.15-7.25 (in, 211), 7.05 (t, J= 7.2 Hz, 1 H), 2.26 (s, 3 H), 1.34 (s, 9 H).
soNy< n-BuLi myArk [00704] 2-tert-Butyl-1H-indole [00705] To a solution of N-o-tolylpivalamide (30.0 a, 159 mmol) in dry THE
(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 NI-14C1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, 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%). 1H NMR (300 MHz, CDC13) 6 7.99 (br.
s, 1 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.06 ¨7.13 (m, 2 H), 6.26 (s, 1 H), 1.39 (s, 9H).
110 NaBH4/AcOH
C ___________________________ )0 1101 [00706] 2-tert-Butylindoline [00707] To a solution of 2-tert-butyl-1H-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH4 at 10 C. The mixture was stirred for 20 minutes at 10 C before being treated dropwise with H70 under ice cooling. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-tert-butylindoline (9.8 g), which was used directly in the next step.
1101 N KNO3/H2S0, 02 [00708] 2-tert-butyl-6-nitroindoline and 2-tert-buty1-5-nitro-1H-indole [00709] To a solution of 2-tert-butylindoline (9.7 g) in H2SO4 (98%, 80 mL) was slowly added KNO3 (5.6 g, 56 mmol) at 0 C. After addition, the reaction mixture was stirred at room temperature for 1 h. The mixture was carefully poured into cracked ice, basified with Na2CO3 to pH 8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g, 31% over two steps). 1H NMR (300 MHz, CDC13) 67.52 (dd, J= 1.8, 8.1 Hz, 1 H),7.30 (s, 1 H), 7.08 (d, J
= 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 Fl).

DDQ

[00710] 2-tert-Butyl-6-nitro-1H-indole [00711] lo 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-buty1-6-nitro-1H-indole (1.6 g, 80%). 1H
NMR (300 MHz, CDC13) 8 8.30 (br. s, 1 H), 8.29 (s, 1 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).
Raney N1/H2 [00712] 2-tert-Butyl-1H-indo1-6-amine [00713] To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in Me0H (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-buty1-1H-indo1-6-amine (1.0 g, 89%). 1H NMR (300 MHz, DMSO-d6) 8 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, 211), 1.24 (s, 9 H); MS (ESI) mfe (M-t-1-1) 189.1.
[00714] Example 52: 3-tert-Butyl-1H-indo1-6-amine *Br Raney Ni-H2 02N N zinc triflate \ I \
TBAI, DIEA 02 ) ___________________________ Br 02 N zinc tnflate TBAI, DIEA, 02N
[00715] 3-tert-Butyl-6-nitro-1H-indole [00716] To a mixture of 6-nitroindole (1.0 g, 6.2 mmol), zinc inflate (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, ,E1_1/USIMU9/trth>4 /3 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. 1I1-NMR (CDC13) 6 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J 2.1, 14.4 Hz, 111), 7.85 (d, J
= 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).
Raney Ni-H2 [00717] 3-tert-Buty1-1H-indol-6-amine [00718] A suspension of 3-tert-butyl-6-nitro-11-1-indole (3.0 g, 14 mmol) and Raney Nickel (0.5 g) was hydrogenated under H2 (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-buty1-1H-indo1-6-amine (2.0 g, 77%) as a gray solid. IIINMR (CDC13) 8 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz, 1H), 6.66 (s, 1H), 6.57(dd, .1 = 0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
[00719] Example 53: 5-(Trif)uoromethyl)-1H-indol-6-amine HNO3 a DMA F3 ail Raney F3C
H2SO4 02N NO2 02N 11111" NO2 N2N

[00720] 1-Methyl-2,4-dinitro-5-(trifluoromethyl)benzene [00721] To a mixture of HNO3 (98%, 30 mL) and H2SO4 (98%, 30 nit) 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%).

DMA F3C is N

[00722] (E)-2-(2,4-Dinitro-5-(trifluoromethyl)pheny1)-N,N-dimethylethenamine [00723] 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 mL) was stirred at 100 C for 30 min. The mixture 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)pheny1)-N,N-dimethylethenamine (2.1 g, 86%).
F3 aN Raney Ni/H2 F3C 40 .2N NO2 H2N
[00724] 5-(Trifluoromethyl)-111-indol-6-amine [00725] A suspension of (E)-2-(2,4-dinitro-5-(trifluoromethyl)pheny1)-N,N-dimethylethenamine (2.1 g, 6.9 mmol) and Raney Nickel (1 g) in ethanol (80 mL) was stirred under 112 (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)-1H-indol-6-amine (200 mg, 14%). 1H NMR (DMSO-c/6) 5 10.79 (br s, 1 H), 7.55 (s, 1 H), 7.12 (s, 1 H), 6.78 (s, 1 H), 6.27(s, 1 H), 4.92 (s, 2 H);
MS (LSI) ink (M+W): 200.8.
[00726] Example 54: 5-Ethyl-1H-indo1-6-amine 0¨L0 =
N Ar,O/Ala,tCH2C1 NaBH/THF 489µHEr 40 N _____ 0s0 N
311.- _____ 311. _____________________ 311.-H El3N/DVAPICH20, 1FA
410 s, 4110 411t 410 N NIn02 \ Raney NI
02N *

Ola 40 N ___________________________ H Et,N,DNA4P/CH2C12 [00727] 1-(Phenylsulfonyl)indoline [00728] To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 124 mmol) in CH2C12 (200 mL) was added dropwise Et3N (19.0 g, 186 PCT/US201.19/00.54 in mmol) at 0 C. The mixture was stirred at room temperature overnight. The organic layer was washed with water (2x), dried over Na2SO4 and concentrated to dryness under reduced pressure to obtain 1-(phenylsulfonyl)indoline (30.9 g, 96%).
Q") Acp/A1C110-12C1, CLC), 411t 411t [00729] 1-(1-(Phenylsulfonyl)indolin-5-ypethanone [00730] To a suspension of A1C13 (144 g, 1.08 mol) in CH2C12 (1070 mL) was added acetic anhydride (54 nit). The mixture was stirred for 15 minutes before a solution of 1-(phenylsulfonyl)indoline (46.9 g, 0.180 mol) in CH2C12 (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 C112C12.
The combined organics were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (42.6 g).
NaBEIJI-HF
41, [00731] 5-Ethyl-1-(phenylsulfonyl)indoline [00732] To TFA (1600 mL) at 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-(1-(phenylsulfonyl)indolin-5-yDethanone (40.08, 0.133 mol) in TFA (700 mL) over 1 h. The mixture was then stirred overnight at 25 C. After dilution with 1120 (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 CH2C12. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethy1-1-(phenylsulfonyl)indoline (16.2 g, 47% over two steps).

48%HBr ______________________________ 70 Ozz-s.,0 N
=
[00733] 5-Ethylindoline [00734] A mixture of 5-ethyl-1-(phenylsulfonyl)indoline (15 g, 0.050 mop 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 Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethylindoline (2.5 g, 32%).
KNo3/H2s04 NN

[00735] 5-Ethyl-6-nitroindoline [00736] To a solution of 5-ethylindoline (2.5 g, 17 mmol) in H2SO4 (98%, 20 mL) was slowly added KNO3 (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 Na2SO4 and concentrated to dryness. The residue was purified by silica column to give 5-ethyl-6-nitroindoline (1.9 g, 58%).
mn02 02N 41 N _________________________ 02N 141 N
[00737] 5-Ethyl-6-nitro-111-indole [00738] To a solution of 5-ethyl-6-nitroindolinc (1.9 g, 9.9 mmol) in C112C12 (30 mL) was added Mn02 (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-ethy1-6-nitro-1H-indole (1.9 g).
Raney Ni/H2). \

Fi2N
[00739] 5-Ethyl-1H-indo1-6-amine [00740] A suspension of 5-ethyl-6-nitro-11-1-indole (1.9 g, 10 mmol) and Raney Nickel (1 g) was hydrogenated under H2 (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-1H-indo1-6-amine (760 mg, 48% over two steps). 'H NMR
(CDC13) 8 7.90 (hr s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (hr s, 2H), 2.63 (q, J
=---= 7.2 Hz, 2H), 1.29 (t, J= 6.9 Hz, 3H); MS (ESI) mie (M+11-') 161.1.
[00741] Example 55: Ethyl 6-amino4H-indole-4-carboxylate 02N 40 coo. 02N õI .02E, COOH HNO3 sca2;
H2s04 Et0H

c NO2 7 o2Ef DMWDMF
02 el Fi2N
cont COOH HNo., [00742] 2-Methyl-3,5-dinitrobenzoic acid [00743] To a mixture of HNO3 (95%, 80 mL) and 1-12SO4 (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%).
02N01 cool-q 02N co2Et soci2;
DOH

[00744] Ethyl 2-methyl-3,5-dinitrobenzoate [00745] A mixture of 2-methy1-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in SOC12 (80 mL) was heated at reflux for 4 h and then was concentrated to dryness. The residue was dissolved in CH7C12 (50 mL), to which Et0H (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 Et0Ac (3 x 100 inL). The combined extracts were washed sat. Na2CO3 (80 mL), water (2 x 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to dryness to give ethyl 2-methyl-3,5-dinitrobentoale (50 g, 88%) 02N 002Et NO2 /
DAANDMF / N
02 41, NC
C 2Et [00746] (E)-Ethyl 2-(2-(dimethylamino)vinyI)-3,5-dinitrobenzoate [00747] A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32g.
0.27 mol) in DMF (200 mL) was heated at 100 C for 5 h. The mixture was poured into ice-water and the precipitated solid was filtered and washed with water to give (E)-ethyl 2-(2-(dimethylarnino)viny1)-3,5-dinitrobenzoate (11 g, 48%) CO,Et = / Njx, sna2 CO2Et [00748] Ethyl 6-amino-1H-indole-4-carboxylate [00749] A mixture of (E)-ethyl 2-(2-(dinaethylamino)viny1)-3,5-dinitrobenzoate (11 g, 0.037 mol) and SnC12 (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.
Na2CO3 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 Na2SO4, 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%). 11INMR
(DMSO-d6) 6 10.76 (hr s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (m, I H), 6.67-6.68 (m, 1 H), 4.94 (his, 2 H), 4.32-4.25 (q, J= 7.2 Hz, 2 H), 1.35-1.31 (t, J= 7.2,3 H); MS
(ES1) rale (M+1-1) 205Ø
[00750] Example 56: 5-Fluoro-1H-indo1-6-amine arki r-ion HNO3r142SO4 F \N-________________________ 7/2 F 02N nro, F
RIP N H2/Raney-I'S F
H2 el I

=

HNO:,/H2SO4 ___________________________________ )0- F

[00751] 1-Fluoro-5-methyl-2,4-dinitrobenzene [00752] To a stirred solution of HNO3 (60 mL) and fl2SO4 (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 raL). The resulting precipitate (a mixture of 1-fluoro-5-methy1-2,4-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-methy1-2,4-dinitro-benzene as a white solid (18 g, 36%).
\N¨r F N

[00753] (E)-2-(5-Fluoro-2,4-dinitropheny1)-N,N-dimethylethenamine [00754] A mixture of 1-fluoro-5-methy1-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100 C 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-dinitropheny1)-N,N-dimethylethenamine (8.0 g, 63%).
141 N H2/Raney-Ni [00755] 5-Fluoro-111-indo1-6-amine [00756] A suspension of (E)-2-(5-fluoro-2,4-dinitrophenyI)-N,N-climethylethenamine (8.0 g, 31 mmol) and Raney Nickel (8 g) in Et0H (80 mL) was stirred under H2 (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-indo1-6-amine (1.0 g, 16%) as a brown solid. 3HNMR (DMSO-d6) 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.
[00757] Example 57: 5-Chloro-1H-indo1-6-amine = WO

\_10¨

HNO3/H2s04 a /'"

CI
a gam H2/Raney-Ni

14-PF4Ig I I
H

HNo3tH,so4 0 `-'2"m [00758] 1-Chloro-5-methyl-2,4-dinitrobenzene [00759] To a stirred solution of HNO3 (55 mT ) and H2SO4 (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 C. The mixture was allowed to stir for 30 min at ambient temperature and was then poured into ice water (500 nil). The resulting precipitate was collected by filtration and purified by recrystallization to give 1-chloro-5-methy1-2,4-dinitrobenzene (26 g, 60%).
\N-e-o_ a 4Il NO2 0.2 [00760] (E)-2-(5-Chloro-2,4-dinitrophenyI)-N,N-dimethylethenamine [00761] A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50.0 rnmol), DMA
(11.9 g. 100 mmol) in DAV (50 mT ) 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-dinitropheny1)-N,N-dimethylethenamine (9.84 g, 72%).
ci CI gar H2/Raney-Ni 41,1N 401 I

[00762] 5-Chloro-1H-indo1-6-amine [00763] A suspension of (E)-2-(5-chloro-2,4-dinitrophenyI)-N,N-dimethylethenamine (9.8 g, 36 mmol) and Raney Nickel (9.8 g) in Et0H (140 mi.) 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-indo1-6-amine (0.97 g, 16%) as a gray powder. IHNMR (CDC13) 5 7.85 (br s, 1 H), 7.52 (s, 1 H), 7.03 (s, 111), 6.79 (s, 111), 6.34 (s, 11I), 3.91 (hr s, 111); MS
(ES]) m/e (M+1.14) 166Ø
[00764] Example 58: Ethyl 6-amino-1H-indole-7-carboxylate so.2, 1. HN.3/H2. N Op4 002, 1. 300I2 2. S0Cl2/Et0H NO 2. Et0H
No2 so co,Et DMA 02 = N\ Ni ¨11*- H2 NO2 Et020 NO2 2E-t 401, .02. 1.
.02H
2. S0012./Et0F1 101 [00765] 3-Methyl-2,6-dinitrobenzoic acid [00766] To a mixture of HNO3 (95%, 80 mL) and H9SO4 (98%, 80 niL) was slowly added 3-methylbenzic acid (50 g, 0.37 mol) at 0 C. After addition, the mixture was stirred below 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-methy1-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a solution of this mixture (70 g, 0.31 ma]) in Et0H (150 mL) was added dropwise SOC12 (54g, 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 Et0Ac (100 mL) and aq. Na2CO3 (10%, 120 mL), The organic layer was washed with brine (50 mL), dried over Na ,SO4, 2- -4, an._ concentrated to dryness to obtain ethyl 5-methyl-2,4-dinitrobenzoate (20 g), which was placed aside. The aqueous layer was acidified by HC1 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, No, co2H . t SOC12 2. Et0H 002E1 [00767] Ethyl 3-methyl-2,6-dinitrobenzoate [00768] A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and SOC12(80 rut) was heated at reflux 4 la. The excess SOC12was evaporated off under reduced pressure and the residue was added dropwise to a solution of Et0H (100 nth) and Et3N (50 mL). The mixture was stirred at 20 'V for 1 h and then concentrated to dryness. The residue was dissolved in Et0Ac (100 tr?-1 ), washed with Na2CO3 (10 %, 40 mf, x 2), water (50 ml. x 2) and brine (50 mL), dried over Na2SO4 and concentrated to give ethyl 3-methy1-2,6-dinitrobenzoate (20 g, 53%).
No2 401 co2B DMA 02 N\
NO2 EtO2C NO2 [00769] (E)-Ethyl 3-(2-(dimethylamino)viny1)-2,6-dinitrobenzoate [00770] 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)viny1)-2,6-dinitrobenzoate (25 g, 58%).

0 N\ Raney Ni/H2 2 v, H2N 401 N
EtO2C NO2 CO2 Et [00771] Ethyl 6-amino-1H-indole-7-earlboxylate [00772] A mixture of (E)-ethyl 3-(2-(dimethylamino)viny1)-2,6-dinitrobenzoate (30 g, 0.097 mol) and Raney Nickel (10 g) in Et0H (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 (3.2g. 16%). 1H NMR (DMSO-c/6) 8 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, 1 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).
[00773] Example 59: Ethyl 6-amino-1H-indole-5-earboxylate 401 032a DMA 02 r402 IE/02C
I , Raney Ni NO eto2 vki,N) = 2 Eto2c [00774] (E)-Ethyl 5-(2-(dirnethylamino)viny1)-2,4-dinitrobenzoate [00775] 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 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 542-(dimethylamino)viny1)-2,4-dinitrobenzoate (15 g, 28%).

Raney Ni ________________________________ )11`

Et02 N H2N
[00776] Ethyl 6-amino-1H-indole-5-carboxylate [00777] A mixture of (E)-ethyl 5-(2-(dimethylamino)viny1)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in Et0F1 (500 mI,) 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%). 1H NMR (DMSO-d6) 8 10.68 (s, 1 H), 7.99 (s, 1 H), 7J31-7.06(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).
[00778] Example 60: 5-tert-Butyl-1H-indo1-6-amine t-au io t-Bu (Et0)2P(0)CVNaH Li/NH3 io HNO3/H2S0, ____________________ ), H= Et01- OEt t-B. t-Hu ,r1,-+ 2 t-Bu H2 iNg= NO2 NO2 02N NO2 t-Bu mai 1-Bu (Et0)2P(0)CVNal I

HO 411111111)P BO¨P¨OEI

[00779] 2-tert-Butyl-4-methylphenyl diethyl phosphate [00780] To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in TH_F
(200 inL) was added dropwise a solution of 2-tert-buty1-4-methylphenol (33 g, 0.20 mol) in THE (100 mL) at 0 C. The mixture was stirred at 0 C for 15 min and then phosphorochloridic acid diethyl ester (37 2, 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.
NI-1.4C1 (300 mL) and then extracted with Et20 (350 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na?SO4, and then evaporated under vacuum to give 2-tert-buty1-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, -100%), which was used directly in the next step.
t-Bu LiiNH3 t-Bu =
EtO¨P¨OEt [00781] 1-tert-Buty1-3-methylbenzene [00782] To NH3 (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 Et20 (anhydrous, 500 mL) at -78 C under N2 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. NI-14Cluntil the mixture turned colorless. Liquid NH3 was evaporated and the residue was dissolved in water. The mixture was extracted with Et20 (400 ml. x 2). The combined organics were dried over Na2SO4 and evaporated to give 1-tert-buty1-3-methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%), which was used directly in next step.

t-Bu 40 HNO3/H2SO4 t-Bu t-Bu ________________________ lib [00783] 1-tert-Butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyI-2,4-dinitro-benzene [00784] To HNO3 (95%, 14 mL) was added H2SO4 (98 To, 20 mL) at 0 C and then 1-tert-buty1-3-methylbenzene (7.4 g, -50 nunol, crude from last step) dropwise to the with the temperature being kept below 30 C. The mixture was stirred at ambient temperature for 30 mm, poured onto crushed ice (100 g), and extracted with Et0Ac (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-tent-butyl-5-methy1-2.4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-dinitrobenzenc (2:1 by NMR) as a yellow oil (9.0 g, 61%).
No2 , t-Bu t-Eu t-Bu [00785] (E)-2-(5-tert-Buty1-2,4-dinitropheny1)-N,N-dimethylethenamine [00786] A mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-buty1-3-methyl-2,4-dinitrobenzene (9.0 g, 38 nunol, 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 Et0Ac (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-buty1-2,4-clinitropheny1)-N,N-dimethylethen-amine (5.0 g, 68%).
t-Bu Sn012 t-Bu \

[00787] 5-tert-Butyl-1H-indo1-6-amine [00788] A solution of (E)-2-(5-tert-buty1-2,4-dinitropheny1)-N,N-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. Na2CO3 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 Na2SO4, and concentrated. The residual solid was washed with CH2C12to afford a yellow powder, which was purified by column chromatography to give 5-tert-buty1-1H-indo1-6-amine (0.40 g, 12%). 1H NMR (DMSO_d6) 6 10.34 (hr s, 1 H), 7.23 (s, 1 H), 6.92 (s, 1 II), 6.65 (s, I H), 6.14 (s, I H), 4.43 (hr s, 2 II), 2.48 (s, 9 H); MS (ESI) mie (M+1-1') 189.1.
[00789] General Procedure IV: Synthesis of acylaminoindoles (RxX)x OHHN RN
HATU (RxX)x Ar I ' B
I B Et3N, DMF 0 = = WO 2010/054138 [00790] One equivalent of the appropriate carboxylic acid and one equivalent of the appropriate amine were dissolved in N,N-dimethylforrnainide (DMF) containing triethylamine (3 equivalents). 0-(7-Azaberizotriazol-1-y1)-N,N,NcN'-tetramethylurollinM
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 =
[00791] Example 61: N-(2-to1-Buty1-1H-indol-5-y1)-1-(4-methoxypheny1)-cyclopropanecarboxamide DMF

/0 0 Et3Nso 0 411 N

H
[00792] 2-tert-Butyl-1H-indo1-5-amine (19 mg, 0.10 mmol) and 1-(4-methoxypheny1)-cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.00 mL) containing triethylamine (281.1.L, 0.20 mmol). 0-(7-Azabenzotriazol-1-y1)-N,NA',N'-tetramethyluronium hexafluorophosphate (42 fig, 0.11 nunol) 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 ITPLC. ESI-MS rn/z calc. 362.2, found 363.3 (M4-1)+; Retention time 3.48 minutes.
[00793] General Procedure V: Synthesis of acylaminoindoles RN RN
OH soci2 (RxX)x C HN I pyridine (RxX)x NI
\ \

[007941 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 N,N-diniethylforrnamide 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 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 1N HC1. The organic layer was then dried over sodium sulfate, evaporated to dryness, and then purified by column chromatography.

[00795] Example 62: Ethyl 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (Compd. 28) <0, 1) S0012 40 0 so N 0 DMF
0 OH 2) dichloromethane 0NI OEt A
Et,N H
N
I-12N 41113". On [00796] 1-Benzo[1,31dioxo1-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under N2. N,N-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-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 1N HO, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride_ The organic layer was dried over sodium sulfate and evaporated to dryness to yield ethyl (benzo[d][1,3]clioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate as a gray solid (3.44 g, 88 %). ESI-MS m/z calc. 392.4; found 393.1 (M4-1)' Retention time 3.17 minutes. 1H NMR (400 MHz, DMSO-d6) 6 11.80 (s, 1H), 8.64 (s, 1H), 7.83 (in, 111), 7.33-7.26 (m, 2H), 7.07 (m, 1H), 7.02 (m, 1H), 6.96-6.89 (in, 2H), 6.02 (s, 2H), 4.33 (q, J= 7.1 Hz, 2H), 1.42-1.39 (in, 2H), 1.33 (t, J= 7.1 Hz. 3H), 1.064.03 (m, 21-1).
[00797] Example 63: 1-(Benzo[d][1,3]dioxol-5-y1)-N-(2-tert-butyl-1H-indol-5-ypeyelopropanecarboxamide 11, OHCI 11 lif = 0 SOCl2 _______ 0 .H211 Ali \ CH2C12 =0 4111r NH
DMF N Et3N

[00798] 1-Benzo[1,3]dioxo1-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 m1 of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of N,N-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-buty1-111-indo1-5-amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mlõ

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 nilz calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 111 NMR (400 WIElz, DMSO) 810.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J= 1.4 Hz, 111), 7.15 (d, J= 8.6 Hz, 111,7.05 - 6.87 (m, 4H), 6.03 (s, 311), 1.44 - 1.37 (m, 214), 1.33 (s, 9H), 1.05-1.00 (m, 2H).
[00799] Example 64: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropy1)-1H-indol-5-yOuclopropanecarboxamide HATU
VH
0 =
V H2N tE 3N 0 <= OH < 0 \

[00800] 1-Methyl-2-(1-methylcyclopropy1)-1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1-(benz.o[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dirnethylformamide (1 ml) containing triethylamine (42.1 !IL, 0.300 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,N,NN'-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]dioxo1-5-y1)-N-(1-methy1-2-(1-methylcyclopropy1)-1H-indol-5-ypcyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+.
Retention time of 3.05 minutes.
[00801] Example 65: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(1,1-dimethy1-2,3-dihydro-pyrrolo[1,2-a]indol-7-yl)cyclopropanecarboxarnide V H
V H2N Et3N
K= <* 400 _______________________________________ \

11.9 [00802] 1,1-Dimethy1-2,3-dihydro-1H-pyrrolo[1,2-alindol-7-amine (40.0 mg, 0.200 mmol) and 1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (1 .mL) containing triethylamine (84.2 p.L, 0.600 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,/V,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]dioxo1-5-y1)-N-(1,1-dimethy1-2,3-dihydro-IH-pyrrolo[1,2-a]-indo1-7-yl)cyclopropanecarboxamide. ESI-MS tn/z calc. 388.2, found 389.2 (M+1)+. Retention time of 2.02 minutes. III NMR (400 MHz, DMSO-d6) 8.41 (s, 1H), 7.59 (d, J= 1.8 Hz, 1H), 7.15 (d, Jr 8.6 Hz, 1H), 7.06- 7.02 (m, 2H), 6.96-6.90 (m, 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 (m, 211), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
[00803] Example 66: Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-earboxylate H =
H2N Et3N
0 v CI + ao o qffli 0 0 III 0 [00804] 1 -(Benzo [d][1,3]dioxo1-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.20 mmol) and methyl 5-amino-2-tert-buty1-1H-indole-7-carboxylate (49.3 mg, 0.200 mmol) were dissolved in N,N-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]dioxo1-5-y1)cyclopropanecarbox-amido)-2-tert-butyl-1H-indole-7-carboxylate.
ESI-MS nilz calc. 434.2, found 435.5. (M+1) . Retention time of 2.12 minutes.
[00805] Example 67: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-yfleyclopropaneearboxamide kl Fi2N
(c3j OH 0LAI Et,N, = di 0 N =H 0 0 MP = H
[00806] To a solution of 1-(benzo[d][1,3]clioxo1-5-y1)cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol) and Et3N
(152 uL, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for minutes before a solution of 2-(5-amino-1H-indo1-2-y1)-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 1 N HCl PCT/[1S2009/063475 (1 x 3 mL) and saturated aqueous NaHCO3 (1 x 3 mL). The organic layer was dried over Na2SO4, 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-(benzotd][1,3]dioxol-5-y1)-N-(2-(1-hydroxy-2-methylpropan-2- y1)-1H-indo1-5-ypcyclopropanecarlxmamide (0.11 g, 75%). III NMR (400 MHz, DMSO-d6) 6 10.64 (s, 1H), 8.38 (s, 111), 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, 211), 1.41-1.39 (m, 2H), 1.26 (s, 6H), 1.05-1.02 (m, 2H).
[00807] Example 67: 1-(Benzo[d][1,3]dioxol-5-y1)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)eyclopropanecarboxataide HATU
V N H2N idu DIEA H

OH 1P) <o0 101 0 o 11103 [00808] 2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,31dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 nunol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-NANN'-tetramethyluronium hexafluorophosphate (183 mg, 0.482 minol) 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]dioxo1-5-y1)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS nilz calc. 374.2, found 375.3 (M+1)+. Retention time of 3.43 minutes. 1H 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, 211), 2.68 - 2.65 (m, 2H), 2.56 - 2.54 (m, 2H), 1.82 - 1.77 (m, 411), 1.41 - 1.34 (m, 211), 1.04 - 0.97 (m, 2H).
[00809] Example 69: tert-Butyl 4-(5-(1-(benzo[e/][1,3]dioxo1-5-ylleyelopropanecarbox-amido)-1H-indo1-2-yl)piperidine-1-carboxylate V a \
N40 ( = ____________________ (3+

[00810] 1-(Be.nzo[d][1,31dioxo1-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and tert-butyl 4-(5-amino-1H-indo1-2-yl)piperidine-1-carboxylate (60 mg, 0.19 mmol) were dissolved in dichlorornethane (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 NA-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-(1-(benzo[di[1,31dioxol-5-ypcyclopropanecarboxamido)-1H-indol-2-y1)piperidine-1-carboxylate. ESI-MS mtz calc. 503.2, found 504.5. (M+1)+. Retention time of 1.99 minutes.
[00811] Example 70: Ethyl 2-(5-(1-(benzo[d][1,31dioxol-5-yl)cyclopropaneearboxamido)-1H-indol-2-y1)propanoate N 002E1 Mel N aN 025 , co2E, cone.,,,d4 gr, N

Bee Boo SnCI 2E1,0, Nµ co2Et (C) H BTU , Ei3N. /0 Ali N
A OH \c) Mgr gr N GO2E1 KHMDS
CO2Et Mel CO2Et Boo Boc [00812] tert-Butyl 2-(1-ethoxy-1-oxopropan-2-y1)-1H-indole-1-earboxylate [00813] tert-Butyl 2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 niL) 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 1 h at ¨78 'C. Methyl iodide (727 1_1,, 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 Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate/hexane .----- 1/9) to give tert-butyl 2-(1-ethoxy-1-oxopropan-2-y1)-1H-indole-1-carboxylate (2.8 g, 88%).

TFA
¨3-Nt CO2 Et CC)¨(iC 02 Et Boc [00814] Ethyl 2-(1H-indo1-2-yl)propanoate [00815] tert-Butyl 2-(1-ethoxy-1-oxopropan-2-y1)-1H-indole-1-carboxylate (2.77 g, 8.74 mmol) was dissolved in dichloromethane (25 mL) before TFA (9.8 int) was added.
The mixture was stirred for 1.5 h at room temperature. 'The mixture was evaporated to dryness, taken up in dichlorornethane and washed with sat. aq. sodium bicarbonate, water, and brine.
The product was purified by column chromatography on silica gel (0-20% Et0Ac in hexane) to give ethyl 2-(1H-indo1-2-yl)propanoate (0.92 g, 50%).
NaNO3 C)2N
CCNI>4CO2Et conc. H2SO4 N CO2Et [00816] Ethyl 2-(5-nitro-1H-indo1-2-yl)propanoate [00817] Ethyl 2-(1H-indo1-2-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% Et0Ac in hexane) to give ethyl 2-(5-nitro-1H-indo1-2-yl)propanoate (0.34 g, 31%).

sn ci2.2H20 H2N
NJ CO2Et N CO2Et [00818] Ethyl 2-(5-amino-1H-indo1-2-yl)propanoate [00819] To a solution of ethyl 2-(5-nitro-1H-indo1-2-yl)propanoate (0.10 g, 0.38 mmol) in ethanol (4 inL) 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 NaHCO3 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 Na2SO4, filtered and evaporated under reduced pressure to give ethyl 2-(5-amino-1H-indo1-2-yl)propanoate (0.088 g, 99%).

<AO HETU, Et35 = l= 0 NCT.
N CO2E1 0 OH N CO2Ei [00820] Ethyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-yecyclopropaneearboxamido)-1H-indol-2-y1)propanoate [00821] To a solution of 1-(benzo[d][1,3]dioxol-5-yficyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mE) were added 11113TU (0.146 g, 0.384 mmol) and Et3N
(160 tit, 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-indo1-2-y1)propanoate (0.089 Q, 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 HC1 (1 x 3 InL) and then saturated aqueous NaHCO3 (1 x 3 mL). The organic layer was dried over Na.2SO4, 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]dioxo1-5-yl)cyclopropasiecarboxamido)-1H-indol-2-y1)propanoate (0.081 g, 50%). 111 NMR (400 MHz, CDC.13) 8 8.51 (s, 1H), 7.67 (s, 111), 7.23-7.19 (m, 2H), 7.04-7.01 (m, 3H), 6.89 (d, J =- 0.0 Hz, 111), 6.28 (s, 111), 6.06 (s, 2H), 4.25-4.17 (m, 2H), 3.91 (q, J = 7.2 Hz, 111), 1.72-1.70(m, 211), 1.61 (s, 211), 1.29 (t, J = 7.1 Hz, 4H), 1.13-1.11 (m, 211).
[00822] Example 71: tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarbox-amido)-1H-indol-2-y1)-2-methylpropylearbamate 02N di =

LiOH 02 EDC, HOBt C)2N
N CO2Et N CO2H NEt3, NH4CI N H2 BH2 THFC)2N Boc20 02N . Pd/C H2N
_ 400 =
H2 NEt, HBoc HOO2NH4 HBoc EDC, HOBt, NEt3' N
V _________ 00I N HBoc = 46 = gr 0 OH

0, boH 0, co,Et Co2H
[00823] 2-Methy1-2-(5-nitro-1H-indo1-2-y1)propanoic acid [00824] Ethyl 2-methyl-2-(5-nitro-1H-indo1-2-y1)propanoate (4.60 g, 16.7 mmol) was dissolved in THF/water (2:1, 30 mL). Li01-1=H70 (1.40 g, 33.3 mmol) was added and the mixture was stirred at 50 C for 3 h. The mixture was made acidic by the careful addition of 3N HCI. The product was extracted with ethylacetate and the combined organic phases were washed with brine and dried over magnesium sulfate to give 2-methy1-2-(5-nitro-1H-indol-2-yl)propanoic acid (4.15 g, 99%).

\ EDC, HOD. 1.1 \
00211 Et3N, NH4CI

H 0'/
[00825] 2-Methyl-2-(5-nitro-1H-indo1-2-yl)propanamide [00826] 2-Methy1-2-(5-nitro4H-indol-2-y1)-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), Et3N (6.9 nth, 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-methy1-2-(5-nitro-1H-indo1-2-y1)propanamide (4.3 g, 99%).

BH33HF o2 Si NH

[008271 2-Methy1-2-(5-nitro-1H-indo1-2-yl)propan-1-amine [00828] 2-Methyl-2-(5-nitro-1H-indo1-2-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
HCI. 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-1H-indo1-2-yl)propan-1-amine (82 mg, 43%).

Boc,0 0, H2 NE13, TH F H Ebc [00829] tert-Butyl 2-methyl-2-(5-nitro-111-indo1-2-y1)propylcarbamate [00830] 2-Methy1-2-(5-nitro-11I-indol-2-y1)propan-1-amine (137 mg, 0.587 mmol) was dissolved in THE (5 mL) and cooled to 0 C. Et3N (82 p.L, 0.59 mmol) and di-tert-butyl 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-1H-indo1-2-yl)propylcarbamate (131 mg, 67%).

" Pd/C

HBoc HCO2NH4 H2N
N HBoc [00831] tert-Butyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropylcarbamate [00832] To a solution of tert-butyl 2-methyl-2-(5-nitro-1H-indo1-2-y1)propylcarbarnate (80 mg, 0.24 mmol) in THE (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-indo1-2-y1)-2-methylpropylcarbamate (58 mg, 80%).
H

EDC, HOOt, NEt3 = V
<
NHBoc V =
NHBoc OH
=
= 0 [00833] tert-Butyl 2-(5-(1-(berao[d][1,31dioxol-5-3,1)cyclopropanecarboxarnido)-111-indol-2-y1)-2-methylpropylcarbamate [00834] tert-Butyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropylcarbamate (58 mg, 0.19 mmol), 1-(benzo[d][1,3]dioxo1-6-y])cyclopropanecarboxylic acid (47 mg , 0.23 mmol), EDC
(45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (80 uL, 0.57 mmol) were dissolved in DWIF (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-(1-233 =

(benzof dj [1,3J di oxo1-5 -yl)cyclopropanec arboxamido)- 11I-indol-2-y1)-2-methylpropyl-carbamate (88 mg, 94%). 111 NMR (400 MHz, CDC13) 8 8.32 (s, 1H), 7.62 (d, J
1.5 Hz, 114), 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, 1H), 6.02 (s, 2H). 4.54 (m, 1H), 3.33 (d, 1= 6.2 Hz, 21-1), 1.68 (dd, I = 3.7, 6.8 Hz, 2H), 1.36 (s, 914), 1.35 (s, 6H), 1.09 (dd, J = 3.7. 6.8 Hz, 2H).
[00835] Example 72: (R)-N-(2-tert-Buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-(2,2-difluorobenzo[d][1,3]dioxol-5-ypcyclopropaneearboxamide ars HA1 = N
0, Ail , FTC
-";"1-14/ Cs2CO3 N\
scc10><
,D ><
V
di F/ 0 =V H V H
Etpl = = 11 \C 11W " PISA = 0 N

c0-1 00><
07s ccOK
Oz õcos 40 ,0)<

[00836] (R)-2-tert-Buty1-14(2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-5-nitro-1H-indole [00837] To a stirred solution of (S)-(2,2-dimethy1-1,3-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 rnmol) followed by Cs2CO3 (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 Cs2CO3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethy1-1,3-dioxolan-4-yl)niethyl 4-methylbenzenesulfonate (1.58 g, 5.50 mrnol) 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 Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane /hexane = 1.511) to give (R)-2-tert-butyl-1-((2,2-di methy1-1,3-dioxolan-4-yl)methyl)-5-nitro-11-1-indole (1.0 g, 66%). 314 NMR (400 MHz, CDC13) 5 8.48 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 2.2, 9.1 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (in, 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).
02 pcpc IP 1Ni N NH4+C.02-c.00K
[00838] (R)-2-tert-Buty1-1-((2,2-dimethy1-1,3-dioxotan-4-yOmethyl-1H-indo1-5-amine [00839] To a stirred solution of (R)-2-tert-buty1-14(2,2-diniethyl-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 1 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, SO4, filtered and evaporated under reduced pressure to give (R)-2-tert-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl-1H-indol-5-amine (0_89 g, 98%). 1H NMR (400 MHz, CDC13) 8 7.04 (d, J
= 4 Hz, 1H), 6.70 (d, J = 2.2 Hz, 11-1), 6.48 (dd, J = 2.2, 8.6 Hz, 111), 6.05 (s, 1H,), 4.38-4.1 (m, 21-1), 4.21 (dd, J 7.5, 16.5 Hz, 1H), 3.87 (dd, J = 6.0, 8.6 Hz, 1H), 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).
V
40 - e 1=1,NI
>:110 ts/
FFx:
0 >( 0 0 )<
SOCl2 V
N.
WI OH( =
[00844] NAR)-2-tert-Buty1-1-((2,2-dimethyl-1,3-dioxolan-4-Arnethyl)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00841] To 1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (0.73 g, 3.0 mmol) was added thionyl chloride (660 ttL, 9.0 mmol) and DMF (20 ut) 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 Et3N
(2.1 mL, 15 mmol) were added. A solution of (R)-2-tert-buty1-14(2,2-climethyl-1,3-dioxolan-4-yHmethyl-11/-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 purified by column chromatography on silica gel (ethyl acetate/hexane = 3/7) to give N-((R)-2-tert-buty1-1-((2,2-dimethyl-1,3-dioxolan-4-y1)methyl)-11-1-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide (1.33 g, 84%). 3H NMR
(400 MHz, CDC13) 8 7.48 (d, J = 2 Hz, HI,), 7.31 (dd, J = 2, 8 Hz, 1H), 7.27 (dd, J = 2, 8 Hz, 1H), 7.23 (d, J
= 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.02 (dd, I = 2, 8 Hz, 1H), 6.92 (br s, 1H), 6.22 (s, 1H), 4.38-4.05 (m, 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, I = 8 Hz, 2H).
V H V H
PTSA
FF-x:
N
tsrOH

[00842] NAR)-2-tert-Buty1-1-((2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-dilluorobenzo-[d][1,3]dioxol-5-y1)cyclopropanecarboxamide [00843] To a stirred solution of N-(2-tert-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-ypcyclopropanecarboxamide (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 NaHCO3 (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na2SO4, 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-buty1-14(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzold I 11,31droxol-5-yl)cyclopropanecarboxaraide (0.96 g, 81%). 1H
NMR (400 MHz, CDC13) 8 7.50 (d, .1= 2 Hz, 1H), 7.31 (dd, J = 2, 8 Hz, 1H), 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, 1H,), 6.96 (dd, J = 2, 8 Hz, 11e, 6.23 (s, 111), 4.35 (dd. J = 8, 15 Hz, 1H), 4.26 (dd. J = 4, 15 Hz, 1H,), 4.02-3.95 (m, 1H), 3.60 (dd, J = 4, 1 Hz, 1H), 3.50 (dd, J = 5, 11 Hz, 1H), L75 (q, J = 8 Hz, 3H), 1.43 (s, 9H), L14 (q, J = 8 Hz, 3H).
[00844] Example 73: 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]clioxo1-5-y0cyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropanoic acid AccD\ Of Ac 700Ac V V H
F(C) gh, u, 5K. __________________________ \

\0H
c 0 OH 0"

=
NaHH4 __________________ l= Fx so N

Me0H, RT F o N
1-x0H

AcOs OAc i\o"
H
N dab.
FF,xeo 0 \ 0 F..x.

i DMSO, RT
\cOH
OH

[00845] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarbox-amido)-1H-indol-1-yl)-2-oxopropanoic acid [0084-6] To a solution of N-(2-tert-butyl-1-(2,3-dihydroxypropy1)-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)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 Et0Ac.
The filtrate was partitioned between Et0Ac and water. The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by preparative TLC to yield 3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,31dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-2-oxopropanoic acid that was used without further purification.
V H
V H
0 \
Nal3H, F 0 Ex= a ao Me0H, RT F
Lx0H
o trOH

[00847] 3-(2-tert-Buty-1-5-(1-(2,2-difluorobenzo[d][1,3]dimcol-5-y1)cyclopropanecarbox-amido)-1H-indol-1-y1)-2-hydroxypropanoic acid [00848] To a solution of 3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-2-oxopropanoic acid (50 mg, 0.10 mmol) in Me0H (1 mL) was added NaBH4 (19 mg, 0.50 minol) at 0 C. The mixture was stirred at room temperature for 15 mm. The resulting mixture was partitioned between Et0Ac and water. The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with brine and dried over anhydrous MgSO4. After the removal of the solvent, the residue was taken up in DMSO and purified by preparative LC/MS to give 3-(2-tert-buty1-5-(1-(2,2-difluorobenin[d][1,3[dioxol-5-yecyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropanoic acid. 1H NMR (400 MHz, CDC13) 8 7.36 (s), 7.27-7.23 (m, 2H), 7.15-7.11 (m, 2H), 6.94 (d, J= 8.5 Hz, 111), 6.23 (s, 1H), 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). 13C NMR
(400 MHz, CDC13) 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 (ES1) link (M+Ir) 501.2.
1008491 Example 74: (R)-N-(2-tert-Butyl-1-(2,3-dihydroxypropy1)-1H-indol-5-yl)-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-ypcyclopropanecarboxamide V
V OH MOH V 0 Br HO H- di _______________ - CD 2 2Dx- , Igh - NaOH
_______________________________________________________ 1.
HO "11114' C p-T5OH Ho 11111r 0 Cs c2CO3, DMF, 120 C
D 0 411111-7 THF-H20, 80 C
H2N 0, N
D0><, 1r OH
p-Ts0H jib.

0 _____________________ 40 HATU, NEt,, DM NF, RT Me0H-H20, 80 C
, = 0 DDX.= 40 40 , N
ccOH
OH
H -,,, OH

I --P-oe( ,1- v 0 P-Ta0H HO

WO 2010/054138 PCl/US2009/063475 [00850] Methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate [00851] To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (190 mg, 1.0 mmol) in Me0H (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 Et0Ac and water. The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with sat. NaHCO3 and brine and dried over MgSO4. After the removal of solvent, the residue was dried in vacuo to yield methyl 143,4-dihydroxyphenypcyclopropanecarboxylate (190 mg, 91%) that was used without further purification. 'H NMR (400 MHz, DMSO-d6) 8 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, 214), 1.08 (q, J = 3.6 Hz, 2H).
V V
H= ao CD2Br2 0 0\
Dx 40 0 _________________________________________ 0 HO Cs2CO3, DMF, 120 C D 0 [00852] Methyl 1-(2,2-dideuteriumbenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylate [00853] To a solution of methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate (21 mg, 0.10 mmol) and CD2Br2 (35 mg, 0.20 mmol) in DMF (0.5 ) was added Cs2CO3 (19 mg, 0.10 mmol). The mixture was heated at 120 C for 30 mm. The reaction mixture was partitioned between Et0Ac and water. The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with 1N NaOH and brine before being dried over MgSO4. After the removal of solvent, the residue was dried in vacuo to yield methyl 1-(2,2-dideuteriumbenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylate (22 mg) that was used without further purification. 1H NMR (400 MHz, CDC13) 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).
= V
OH
Dx. NaOH0 0 ________________________________ 70-Dx 40 D 0 THF-H20, 80 C 0 0 [00854] 1-(2,2-Dideuteriumbenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid [00855] To a solution of methyl 1-(2,2-dideuteriurnbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylate (22 mg, 0.10 mmol) in THF (0.5 naL) was added NaOH
(1N, 0.25 nth, 0.25 rnmol). The mixture was heated at 80 C for 2 h. The reaction mixture was partitioned between Et0Ac and 1N NaOH. The aqueous layer was extracted with Et0Ac twice, neutralized with IN HC1 and extracted with Et0Ac 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][1.31dioxo1-5-yl)cyclopropanecarboxylic acid (21 mg) that was used without further purification.

=V V
OH

D =
HAM, NFt3, DNIF, PT
[00856] (R)-N-(2-tert-Buty1-1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-indol-5-y1)-1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide [00857] To a solution of 1-(2,2-dideuteriumbenzold111,31dioxo1-5-yl)cyclopropanecarboxylic acid (21 mg, 0_10 mmol), (R)-2-tert-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-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 Et0Ac and water.
The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with 1N NaOH, 1N HC1, 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-buty1-1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-indol-5-y1)-1-(2,2-dideuteriumbenzo[d][13]dioxol-5-y1)cyclopropanecarboxamide (24 mg, 49% from methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate). MS (ES1) m/e (M4-1-1+) 493.5.
V 1,1 H
N
DDX:s 0 401 p-Ts0H Dx.

Me0H-H20, 80 C D
CC'H
OH
[00858] (R)-N-(2-tert-Buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-dideuterium-benzo[d][1,3]dioxol-5-yOcyclopropanecarboxamide [00859] To a solution of (R)-N-(2-terr-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-indol-5-y1)-1-(2,2-dideuterium-benzo[d][1,3]dioxol-5-y1)cyclopropanecarboxanaide (24 mg, 0.050 trunol), 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 Et0Ac and water. The aqueous layer was extracted with Et0Ac twice and the combined organic layers were washed with sat NaHCO3 and brine before being dried over MgSO4. After the removal of solvent, the residue was purified by preparative HPLC to yield (R)-N-(2-tert-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yHmethyl)-1H-indol-5-y1)-1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide (12 m2, 52%). 1H NMR (400 MHz, CDCI3) 8 7A4 (d, J =
2.0 Hz, 111), 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, 1H), 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, .1= 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). 13C NMR (400 MHz, CDC13) 6171.4, 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) nVe (M+H+) 453.5.
[00860] It is further noted that the mono-deuterated analogue for this compound can be synthesized by substitution the reagent CHDBR2 for CD2BR2 and following the procedures described in example 74. Furthermore, mono-deuterated analogues of other compounds of the present invention can be synthesized by substituting the reagent CHDBR2 for CD23R2 and following the steps described herein.
[00861] Example 75: 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cydopropanecarboxamido)-indol-2-y1)-4-methylpentanoic acid H
=
y /IP V
v H ..I) SOCl2,DMF N
= CN

CN
= IP
V H
N
KOH
OH
=
= V H
(.0 dmiON i)SCCI,DMF
' 0 VP) 0 ii) H21,1 ON
[00862] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indol-5-ypcyclopropanecarboxamide [00863] To 1-(benzo[d][1,3]clioxol-5-ypeyclopropanecarboxylic acid (0.068 2-, 0.33 ramol) was added thionyl chloride (72 0.99 mmol) and DMF (20 L) 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 Et3N (230 [IL, 1.7 mmol) were added. A solution of 4-(5-amino-1H-indo1-2-y1)-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 1 N HC1 (2 x 2 mL), saturated aqueous NaHCO3 (2 x 2 mL) and brine (2 x 2 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 1-(benzo[d][1,3]clioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indol-5-yl)cyclopropanecarboxamide.
V H V H

(00 a 0 N

4111,13 N 0 OH

[00864] 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)-4-methylpentanoic acid [00865] A mixture of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5 mmol) in 50% Et0H/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][1,3Jdioxo1-5-ypcyclopropanecarboxamido)-1H-indol-2-y1)-4-methylpentanoic acid. 1H NMR (400 MHz, DMSO-d6) 8 11.98(s, 1H), 10.79 (s, 111), 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, 411), 1.41-1.38 (m, 211), 1.30 (s, 611), 1.04-1.02 (m, 2H).
[00866] Example 76: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-y1)-indo1-5-yecyclopropanecarlboxamide .2 0 2 LiAl HI, 02 di s 114P'P N = sna22Hp H H
+ A OH = HBTI.J, Et3N
N = = 14tF 0 02 go LiAIF-14 C 2Et [00867] 2-(5-Nitro-1H-indo1-2-yl)propan-1-ol WO 2010/054138 UUSZUllY/M3J4 /J
[00868] To a cooled solution of LiA1R4 (LO 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-indo1-2-yl)propanoate (0.20 g, 0.76 mmol) in my (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 Na2SO4, 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-1H-indo1-2-yl)propan-l-ol (0.14 g, 81%).

SnC12.2H20 OH OH
[00869] 2-(5-Amino-1H-indo1-2-yl)propan-l-ol [00870] To a solution of 2-(5-nitro-1H-indo1-2-y1)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 C for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO3 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 Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indo1-2-yl)propan-1-ol (0.093 g, 82%).
H,N
lir 'NsHBTU, Etpl, eerN N

= H (D0-1).A..icH 0 [00871] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-y1)-1H-indoi-5-yDeydopropanecarboxamide [00872] To a solution of 1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) were added MTH (0.185 g, 0.49 mmol) and Et3N (205 [IL, 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-1H-indo1-2-yl)propan1-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 1 N HC1 (1 x 3 mL) and saturated aqueous NaHCO3 (1 x 3 mL). The organic layer was dried over Na2SO4, , =

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][1,31dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-y1)-1H-indo1-5-yecyclopropanecarboxamide (0.095 g, 51%).
1H NMR (400 MHz, DMSO-d6) 510.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s,11-1)õ 6.02 (s, 2H), 4.76 (t, J = 5.3 1-1z, 1H), 3.68-3.63 (m, 1H), 3.50-3.44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1.26 (d, J =
7.0 Hz, 3H), 1.05-1.02 (m, 2H).
[00873] Example 77: 1-(l3enzo[d][1,3]dioxol-5-y1)-N-(2-tert-butyl-1H-indo1-5-y1)-N-methyleyelopropanecarboxamide LI
HAT V I
V HN El3N
HO 40 _________ -eo 40 [00874] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-1H-indol-5-y1)-N-methyleyelopropaneearboxamide [00875] 2-tert-Butyl-N-methyl-1H-indo1-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo 1411,3 Idioxo1-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (42.1 pt, 0.300 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,N,NW-tetramethyluronium 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]clioxo1-5-y1)-N-(2-tert-butyl-1H-indol-5-y1)-N-methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+.
Retention time of 3.41 minutes.
[00876] Example 78: N-(2-tert-Buty1-1-methy1-1H-indol-5-y1)-1-(benzo[d][1,3]dioxol-6-y1)-N-methylcyclopropanecarboxamide / DMF
1) NaH -4t N __ 0 ilk 0 = H 2) CH3I
[00877] 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-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxol-6-ypcyclopropanecarboxamide (0.250 g, 0.664 mmol) in a mixture of 4.5 mL of anhydrous tetrahydrofuran (THF) and 0.5 mL of anhydrous N,N-dimethylformamide (DMF). The resulting suspension was allowed to stir for 2 minutes and then iodomethane (0.062 int, 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 I 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.
[00878] Example 79: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(hydroxymethyl)-1H-indol-ybcyclopropanecarboxamide LiBH4, THF/H20 e 0 fib N/ ( _________________ 0 is N 0E1 25 'C. 16 hrs 0 N OH
H
[00879] 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 LiBH4 (132 mg, 6.0 mmol) in THF
(10 mL) and water (0.1 ad). 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 1 N HC1. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(hydroxymethyl)-1H-indol-5-y1)cyclopropaneearboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. ESLMS ,2/z calc. 350.4, found 351.3 (M+1) ;
retention time 2.59 minutes.
[00880] Example 80: 5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-N-tert-bnly1-1H-indole-2-carboxamide LION
110 o OEt A 1-60 ; 1,4-dioxane = OH HATU, Et,N, ( Fl A H
0 liw voLx j?..N so 0 LiOH = is - 0 0E1 H20 / _________________________________ cxkOH 1,4-dioxane =
A H
[00881] 5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid [00882] Ethyl 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (392 mg, 1.0 mmol) and LiOH (126 me, 3 mmol) were dissolved in 1-170 (5 mL) and 1,4-dioxane (3 ml). The mixture was heated in an oil bath at 100 'V 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 Na2 S 04 and evaporated to yield 5-(1-(benz,o[d][1.3[-dioxo1-5-ypcyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase IIPLC. ESI-MS rri/z calc. 364.1, found 365.1 (M+1)+;
retention time 2.70 minutes.
(0 wain 0 so N 0 A K. 40 0 io N 0 OH HATU, El3N, DMF = A N I IN
H
[00883] 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropaneearboxamido)-N-tert-butyl-lII-indole-2-earboxamide [00884] 5-(1-(Benzo[d][1,3]dioxo1-5-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 N,N-dimethylfomiamide (1.0 mL) containing triethylamine (28 pt, 0.20 mmol).
0-(7-Azabenzotriazol-1-y1)-N,N,AP,A7-tetramethyluronium hexafluorophosphate (46 nig, 0.12 mmol) 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 541-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-N-tert-butyl-1H-indole-2-carboxamide. ESI-MS rtilz calc. 419.2, found 420.3 (M+1); retention time 3.12 minutes.
[00885] Example 81: N13-Amino-2-tert-butyl-111-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-ypeyelopropanecarboxamide * 40 Ao 40 =
Ig < aNO2 < o N
N AcOH/H20 H =
A H NO
Zn <6 401 ail AcOH = A N "41111114v.

[00886] A solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-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 NaNO2 (9 mg) in H20 (0.03 mL).
The mixture was allowed to stir for 30 min at 45 C before the precipitate was collected and washed with Et20. This material was used in the next step without further purification. To DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE. Pour les tomes additionels. veillez contacter le Bureau Canadien des Brevets.
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Claims (4)

CLAIMS:

1. The compound:

2. A pharmaceutically acceptable salt of the compound of claim 1.

3. A pharmaceutical composition comprising the compound:
or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier.

4. Use of the compound:
for promoting chloride transport by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein encoded by the .DELTA.F508 CFTR gene.