CA2948104A1 - 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

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

[0002] 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\ OH

F O IMP
\COH
OH
or a pharmaceutically acceptable salt thereof. Also provided is a use of the compound V H
F\ ga OH

r 0 OH
for promoting chloride transport by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein encoded by the AF508 CFTR gene.

BACKGROUND 01.1"1:11E INVENTION
[00031 ABC
transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenohiotics, as well as anions. ABC transporters are homologous membrane proteins that hind and use cellular adenosine triphosphate (ATP) !Or their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR 1-1) glycoprotein, or the multidrug resistance protein, MRP1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identilial 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 hamiful 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 MR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFIR 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. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R.
et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations in CFTR
resulting in Cystic Fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic Fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF
associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
[0007] In patients with cystic fibrosis, mutations in CPTR 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 CFIR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369;
Dean, M. et al.
(1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080;
Kerem, B-S
et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, > 1000 disease causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.cakftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
[0009] The deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J.
4: 2709-2727). Studies have shown, however, that the reduced numbers of AF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al.
(1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell.
Biochem. 270:
12347-50). In addition to AF508-CFTR, other disease causing mutations in CFTR
that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
[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, Na/2C1-/K+ co-transporter, Natr-ATPase 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 CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via cr channels, resulting in a vectorial transport_ Arrangement of Na+/207K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side.
Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
[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 CFTR. 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 CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD.
Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as Cystic Fibrosis and Sjogrens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/deimatomyositis.
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., TIPS, 21, pp. 466- 469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)]. The diseases associated with the first class of ER malfunction are Cystic fibrosis (due to misfolded AF508-CFTR as discussed above), Hereditary emphysema (due to al-antitrypsin; non Piz variants), Hereditary

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 LI
(due to UDP-glucuronyl-sialyc-transferase), Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus (due to Insulin receptor), Laron dwarfism (due to Growth hormone receptor), Myleoperoxidase deficiency, Primary hypoparathyroidism (due to Preproparathyroid hormone), Melanoma (due to Tyrosinase). The diseases associated with the latter class of ER
malfunction are Glycanosis CDG type 1, Hereditary emphysema (due to al-Antitrypsin (PiZ
variant), Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, II, IV
procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACT
deficiency (due to al-Antichymotrypsin), Diabetes insipidus (DI), Neurophyseal DI (due to Vasopvessin hormone/V2-receptor), Neprogenic DI (due to Aquaporin II), Charcot-Marie Tooth syndrome (due to Peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease ( due to (3APP and presenilins), Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect), Fabry disease (due to lysosornal 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 (1BD).

million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel.
[0019] Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals.
Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
[0020] The most common diarrhea causing bacteria is enterotoxogenic E-coli (EIEC) 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.
[0023] There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.
[0024] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal.
[0025] There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in the cell membrane of a mammal.
[0026] There is a need for methods of treating CFTR-mediated diseases using such modulators of CFTR activity.
[0027] There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal.

[0028] 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) Ri or a pharmaceutically acceptable salt thereof, wherein Ri, 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

or a pharmaceutically acceptable salt thereof, wherein R, RI, R2, R3, Ra, and R5 are defined below.
[0030-1 = 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, abetalipoproteimemia, 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, neumphysiol, nephrogenic, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyorrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
[0031] DETAILED DESCRIPTION OF THE INVENTION
[0032] I. DEFINTIIONS
[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 fiagment 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 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.cakftd, 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 CFTR
anion channel, are called agonists. Compounds that modulate ABC Transporter activity, such as CFTR activity, by decreasing the activity of the ABC Transporter, e.g., CFTR
anion channel, are called antagonists. An agonist interacts with an ABC Transporter, such as CFTR anion channel, to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with an ABC Transporter, such as CFTR, and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

[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 C1-.T1t. anion channel activities. Examples of diseases whose symptoras may be affected by ABC Transporter and/or CF1lit 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 hypercholesterolenna, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type LE, Polyendocrinopadry/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus Neurophysiol DI, Nephrogenic DL Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorabal 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.
[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 El, Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 200L
[0039] As described herein, compounds of the invention may option-ally 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.
[0040] As used herein the terra "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, heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-S024 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 carboxyallcyl (such as HOOC-alkyl, alkoxycarbonylallcyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (allcoxyaryl)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, arylcarbonylanaino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylarnino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl, cyclo alkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylanainocarbonya amino [e.g., aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, or aliphaticsulfonylamind sulfonyl [e.g., alkyl-802-, cycloaliphatic-S02-, or aryl-S02-1, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, arallcyloxy, 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, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-802-, aliphaticamino-S02-, or cycloaliphatic-S02-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylarninocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryflalkoxy.
[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)-R" 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 alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloallcyl)alkylamido, arylamido, aralkylamido, (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, car'boxy, 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 alkynyll; cycloaliphatic;
(cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;
allcoxy;
(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-S02-1;
sulfinyl [e.g., aliphatic-S(0)- or cycloaliphatic-S(0)-j; 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 (alkoxycarbonyparyl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyparyll; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl;
(alkoxy)aryl;
(sulfamoyl)aryl [e.g., (aminosulfonyearyll; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl;
(((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;
(((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl;
(cyanoalkyl)aryl;
(hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.
[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.
[0049] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C1_4 alkyl group) that is substituted with an aryl group. Both "a]kyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycIoallcylcarbonylarnino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamina cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0050] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9, 10, 02 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[3.3.21decyl, 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[3.3.11nonenyl.
[0054] A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., a]kyl, 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)calbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylarnino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-S02- and aryl-S02-], sulfinyl [e.g., alkyl-S(0)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or cathamoyl.
[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[2.2.2]octyl, 1-aza-bicyclo[2.2.2]oetyl, 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, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamimo, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or allcylcarbonyloxy], 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., alkylsulfinyll, 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 heteroatom (e.g., N, 0, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system haying 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, 11-1-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0060] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
[0061] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo[blfuryl, 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 (heteroaraliphatic)carbonyl];
sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl];
sulfanyl [e.g., aliphaticsu]fanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea;
thiourea; sulfamoyl;
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)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl;

(sulfamoyDheteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;
(allcoxyalkyl)heteroaryl;
(hydroxy)heteroaryl; ((carboxy)allcypheteroaryl;
(((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl;
(((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonypalkyl)heteroaryl;
(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroary1};
(alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryIl.
[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, cycloalkyl, (cycloalkyl)alkyl, heterocycloallcyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, allcylcarbonylamino, cycloalkylcarbonylaraino, (cycloalkylalkyl)carhonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, 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-, bi-, 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, adamantanyl, norbomanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyallcyl, hydroxyalkyl, and haloallcyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloaLkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarallcyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocathonyl, alkylcarbonylamino, cycloalkylcarbonylarnino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylallcyl)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 formyl 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 "carbamoyl" group refers to a group having the structure -0-CO-NRxRY or -NRx-00-0-R2, wherein Rx and RY have been defined above and R2 can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0072] As used herein, a "carboxy" 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-NRYR2 when used terminally and -NRx-S(0)2-NRY- when used internally, wherein Rx, RY, and 122 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 "sulftnyl" 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-, (cyc1oaliphatic(amido(a1iphatic)))-S(0)2-or the like.
[0081] As used herein, a "sulfoxy" group refers to -0-SO-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-O-C(0)-.
[0084] As used herein, an "alkoxyalkyl" refers to an alkyl group such as a1ky1-0-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 "arninoalkyl" refers to the structure (Rx)2N-a1ky1-.
[0089] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0090] As used herein, a "urea" group refers to the structure -NRx-CO-NRYRz and a "thiourea" group refers to the structure -NRx-CS-NRYRz when used terminally and -NRx-CO-NRY- or -NRx-CS-NRY- when used internally, wherein Rx, RY, and Rz have been defined above.
[0091] As used herein, a "guanidine" group refers to the structure -N=C(N(RxRY))N(RxRY) 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 carboxy groups used internally.
[00961 As used herein, an "aliphatic chain" refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alicynyl groups). A straight aliphatic chain has the structure -[CH2]v-, where v is 1-12. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ]v- 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 PCl/US2009/0634 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 bound.
[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.

w LAI IWUJ41..16 PCT/U

[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., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 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:

I /
n(R2) or a pharmaceutically acceptable salt thereof.
[00106] Ri 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-, -CO2-, -000-, -NRACO2-, -0-, -NRACONRA-, -OCONRA-, -NRANRA NRACO-, -S-, -SO-, -SO2-, -NRA-, -SO2NRA-, -NRAS02-, or -NRASO2NRA-. Each R4 is independently RA, halo, -OH, -NH2, -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.
[00107] R, is -ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C1_6 aliphatic chain wherein up to two carbon units of ZB
are optionally and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -0O2-, -000-, -NRBCO2-, -0-, -NRBCONRB-, -000NR13_, _NRBNR13_, _NRBC0-, -S-, -SO-, -S02-, 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.
[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:

(R3)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 C1_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_, _NRcc0_, -SO-, -S02-, -NRc-, -SO2NRc-, -NRcS02-, 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 heteicycycloaliphatic, 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, R'3 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 = 0 0 0 \
,or OH
_ N
=
[00112] B. Specific Compounds [00113] 1. Ki Group [00114] Ri is -ZAR4, wherein each ZA is independently a bond or an optionally substituted branched or straight C1..6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -0O2-, -000-, -NRACO2-, -0-, -NRACONRA-, -OCONRA-, -NRANRA-, -NRACO-, -S-, -SO-, -NRA-, -SO2NRA-, -NRAS02-, or -NRASO2NRA-. Each R4 is independently RA, halo, -OH, -NI-12, -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.
[00117] 2. R2 Group [00118] Each R2 is independently -ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C7_6 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -CO-, -CS-, -CONRI3-, -CONRBNRB-, -CO2-, -000-, -NRBCO2-, -0-, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -S02-, -NR8-, -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 C1_6 aliphatic chain. In other examples, R2 is an optionally substituted branched or straight C7_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 C7-6 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 C7_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 C1_5 a]koxy. For example, R2 is a Cj_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, R, is hydroxy, halo, or cyano.
[00122] In several embodiments, R2 is -ZBR5, and ZB is independently a bond or an optionally substituted branched or straight C)_,4 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by -C(0)-, -0-, -S-, -S(0)2-, or -NH-, and R5 is le, 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:
z Z1 Z3,µ
ZZ¨L5 lb [00124] Each of Z1, Z2, 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-, -OCONRD-, -NRDNRD-, -NRDCO-, -S-, -SO-, -S02-, -SO2NRD-, -NRDS02-, or -NRDSO2NRD-. Each R8 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 R7 is independently hydrogen, optionally substituted Ci_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 R7 groups together with the atom or atoms to which they are attached font' 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 R2 groups form an unsubstituted 5-7 membered carbocycle.
[00126] In alternative examples, two adjacent R2 groups form an optionally substituted heterocycle. For instance, two adjacent R2 groups form an optionally substituted 5-7 membered heterocycle having 1-3 heteroatonis independently selected from N, 0, and S. In several examples, two adjacent R2 groups form an optionally substituted 5-6 membered heterocycle having 1-2 oxygen atoms. In other examples, two adjacent 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:
< F2C
><o4 1 I 1 ( I
N

0 "LC

O'sss, Clcss (01s-ss.

0,`-t.z/, (:',1-,67-1._ H
II
.,-0,1-C
N--( ..r3_,..-(.. 1 , Me \ H
0--->1._ N-,..(31:' , and A .

[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 Ro /

Ic [00128] Z1, Z2, Z3, Za, 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, -CH2OH, -CH3, and -0CF3, and/or two adjacent R2 groups together with the atoms to which they are attached form 0-..... C P---,-(.. ><0---)-(.
N--,.......76" I
N---,ti-C
< I F2 C\ i l .....1. , ( I s N', I
0 , sr- , N----0-, , WO 2010/054138 1,1-, II
H
, C
o-c5s:
H

.z/._ .--0 .õ....ØõX
H I p _a_ .i--i-i.
N-,.,i'l-r. i.. i" I
----i. 1 c55 N I
csc, Nc.55, , A , 0 s 5- , 0 , WO OH , , \ H
0--..."(.. N-,--.43-C N--.....
( I s ( I
, and ciL
sss .
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, form 0--P-r._ p--.X.
< 1 F2C, l ,or [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 ..,(1718), sp(R8), vo,, ,.,..0(1R8)õ
\--f (R8)q Rs) '713_2cY , , X81 ' XB2 , XB3 X64 XB5 H
..e.s.e:io-N. (RB)ci "(Rti)c, HN __ (RA
' HN 3 ,ic>5.(RE,), .

H
../....-->er(R8)q (fRE3),, X (Fis)q B (R8)q (R8)q 0 r S

,acz>z.,rHN .7(R8)ci HN (R8) q ( ____________________________________________________ (RB), /
HN
,and ' , , [00137] Each Rs is independently -ZER9, 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-, -000NRE-, -NRENRE-, -NRECO-, -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.

.
.
.

[00139] In other embodiments. ring A is one selected from O.

, and [00140] In several embodiments, ring A is [00141] 4. Ring B
[00142] Ring B is a group having formula Ia:
Fr I /
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-, -0O2-, -000-, -NRcCO2-, -0-, -NRcCONRc-, -000NRc-, -NRCNRC, NRcC0-, -S-, -SO-, -SO-, -NRc-, -SO2NRc-, -NRcS02-, 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, 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 Fr3 R'3 N-Th R'3 (R20)q N-Th \_11 (R3), 11/
(R3) 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_5 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-, -S02-, -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.
[0014-6] For example, ring B is N-Th N-Th >s (R2o)q (R3)1, (R 3)p (R3)) , Sj< ( R3 )p , 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 PC4JUSZUU9/0634 rn 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, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is optionally substituted with aliphatic, halo, hydroxy, nitro. cyano, or combinations thereof. In several alternative examples, 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 O. In still other examples, R3 is an optionally substituted 4-7 membered monocyclic (heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected from N and O. 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(arnino))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(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof.
[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 C16 aliphatic. For example, R3 is an optionally substituted straight or branched CI.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 C1.6 aliphatic or C3_6 cycloaliphatic); 7-F-2-(-(optionally substituted Ci_6 aliphatic or C3_6 cycloaliphatic)), 4F-2-(optionally substituted Ci_6 aliphatic or C3_6 cycloaliphatic); 7-CN-2-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic); 7-Me-2-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic) and 7-0Me-2-(optionally substituted Ci_6 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, -CH2CH2CH3, -NH2, halo, -OCH3, -CN, -CF3, -C(0)0CH2CH3, -S(0)2CH3, -CH2NH2, -C(0)NH2, (:)H

4 [Nil N 4 N
H
io N z,NQ
TH
OH
=

WO 2010/054138 PC'I/U S2009/0634 I
NH I
\ _______________________________________ ---\ --q __ NH / \ __ \
CONH2 0 \ 0 \ OH OH 0 0 OH A_<
__________________ \ -:\ __,µõ..(_0> /

0 OH 0 __________________________________ A--(---NH OEt OH
rz N 1µJ'-kC) 'V( __ / ) /OH
H H N 0 0 0 ___ H N
/ -N
I 1 ,,%<---- CN A_< r\lµ p ________________________________________ --N -,.

ANI---V-''.%-/' .-\`'''k='-,./1 -k---''k,,-/-- / X H
, --µ( X3-(0 ' , and [00153] In another embodiment, two adjacent R3 groups form `,3zz_.=
=
[00154] In several embodiments, R'3 is independently -ZcR6, where each Zc is independently a bond or an optionally substituted branched or straight C1,5 aliphatic chain wherein up to two carbon units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRc-, cNR_, _c02_, -CONR c -0C0-, -NRcCO2-, -0-, -NRcCONRc-, -000NRc-, -NRCNRc_, NRcCO ,-S-, -SO-, -S02-, -NRc-, -SO2NRc_, _NRcs02_, or -NRcSO2NRc-. Each R6 is independently Rc, halo, -OH, -NW, -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, R'3 is is independently -ZcR6, where each Z
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 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_2 aliphatic optionally substituted with -OH, -NH2, or -CN.
[00158] In several embodiments, R'3 is independently selected from one of the following:

-H, -CH3, -CH2CH3, -C(0)CH3, -CH2CH2OH, -C(0)0CH3, ¨K
OH
0 CH2 OH -4- A:Y
, OH 4 A ci-120H A.----------OH Al---.
, NHCOCH AeNHMe -1.--.'`(.0Me --.'s"-"CO H
2 OH , OH , OH '-,N, _NH , -.¨._ _.
.0H , N.z-,--N' --,. 2 .2---*-- --',/ µ-' -.2-'-'..-''") ")C.'''''' CONHMe , r---- 0 0Et , -µ2"rNH2 OH OH
Ae.ThNHCOMe 0 " NH
?7,MCN
-r`-----''CONMe2 OH A OH
H )(Y\O
A--..,..,.NHS02Me A.---y.0O2H A.--...õ.---,tr.N
-." OH --µ,..-'-'rCO2H 0---K
z z , OH , 0 , OH , )24-NHSO2MeNHCO2Me A4Thr-N, NH
.NHCO2Me OH , OH OH Nz---N' , OH
OH H
V'--rf\i'= OH
AM)YOH -µ-rN
OH OH , 0 0HO ...-- A---.,,NHCO2tBu O
N-NAO ..--< OH H N
z\,.......7õ..
"-----'.' NHS02Et )24-,ri-- c7, 1 7.___= NH
OH

, ' O
O _ N0 OH
N
)OH FIN--,---7-. I
H /\--, OH
7---µ N

, and 0 .
[00159] In several embodiments, ring B is one selected from:
H
H H I
I. N/ s-=N, OH
H
ilo N/ 0 N/
140 1>N7<
z / H
, , H H H H

. Na.
, , IP /
=
i H/ o----1 = H

N
= i NO /
H N---\ OH

N
N
NH N N 1µ17- H
N
N/
* 1 \
* I H
= I
* 1 \

H +/OH
N N H OH IN A \N
= i H
OH N
* I I
*
* I
--Y H H N
HN

H2 * I
.N I
*i N
/ N
, ' ' , H
H H N
H N N
N
' ,l * I

, , , .

N
\\
H H
N
--"- LI
=' 10 * NH
/ ¨
\k\ / * NH
H
N H
. NH Mk NH lik ' it . NH = I
.rrcs --..,.
F
. NH
CI ii NH > . NH F NH F 11 , . , , OH
OH
HK
HK HO
\
) N
N
H ir N \\ H
N N
= I F II 1 F 4. j . 1 /11 i H q H;p0H HO
OH HOp H
o/ ( N N F NJ N
= ______________________________________ I F . i =I lik I it 1 , , , =

, I
0:,..,, Li ,, .--._,OH/
HN/
OH _OH \
H \\ \
N F N laNy7----. . I
IIN I

o o -....,õ
= NN = NH NH
, and NH

0 \---.
[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:
R1 R1 Ri R i R
R
SI 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-;
R1 is 1-1 or alkyl;
R2 is H or F;

R3 is H or CN;
R4 is H, -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 II, wherein the compounds set forth below are excluded:

\

F N
H , lir H
N
FX 0 0 0 N \ 1 \OH

LI
OH , N

0 \¨OH N
F 0 F (1)11 N\ I
LA 1101 0 1110 N\1/4 OH, H

0 N <0 * 0 N 110 \
< 00 * \

H
, , 'V 7H
N
0O * \ F.xo * 0 F 110 \

LA \---CH
OH , OH, NH
Fx 0 0 0 \ Fx = 0 * \

l_tH Lt7H
OH, OH , ===00 N
Fsx 110 * \ 101 \
0 =.

HH
, , / ¨0 0¨ o"0 -n m \ o/NO -n m 0" 0 o/N0 0 >40 , 0 * * *
* * 0x 0 na o o * *
44* , .p.
4 * 411 41 .41 0 w o zi o 1 0 0 .4 o 0 oe ZS
zi zi 0 -n ZS -n ZS 0 m ZS.
* * * * ZS . -n ZS
* .
1Z r .*
/.......cz r r rZ r rZ r IZ , rz õ
(--(z i i rl I
.
0 i .. ..
i .
i I
..
.. ¨0 0 o/,.0 . ,-, m X
m m -n n.) 0 0 \

0 .o.

4. '. o 0 ,. 0 0 > 0 co 0 "0 1-, o .o.
-0.

t=-) * 44 .40 * . ,--.
0 N, .

.4 *
41 , (3) A zi 0 zi o zi 0 i , zi * * zi zi -n z i -n zi Z
#
* iz ,,, iz õ... . * 0 zi *
*
1z õ
rz /iz , z , * iz , 0._rZ/
õ
.. 0 rz , in li 0 i . I I
o o 0 i m .
,..
., cN
,., 4:.
,.õ
u, V H

V H FF.,_/

N\ OH
H

0 161 N\
0 H , V H

0 N\ HO V

0 H , V H
<0 so 0 so \

HO HO
Nj , 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 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 -CH2CH2N+(CH3)3. In another embodiment, two R
taken together faun ¨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-, 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, R, is F, R3 is H, and R4 is -CH2OCH2CH(OH)C112011.
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-, 121 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment, the compound is represented by formula Ha:

V H
)(0 F
F 0 0 ,..===,,.*,====-== N

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 fotm a five membered ring.
[00163] In one embodiment of the compounds, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2I\V (CH3)3, or -CH2CH2OH. 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.
[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.

Table 1: Exemplary compounds of the present invention.

H
F N
/

H
oi N

410 A,A0 N is ,47 N
el dim. J H
H
IIP

O
'e 141 cA

o ,,_ . ,..
o 4,0 1,4a 1, / 1 v H <9 lip 0 0 ir H H'N le N N .1114.-P
H
F /
F
F

-.0 ----/---- \, PP
. la N
/ 0 57..rill < I O'CX-1 0 ..-- - ..-- N ' , F>c/ OxLI Cr-,154 A I:i -ii io 1 1 12 ,..t)o_., N H H
N
N IP
0 110 14/ 0 s s 1 A . i t . L.. . , _ ..t4 i 0 . s e, op J /
N
N N u N 1.,0H
AH
H

.0 \s' F

e 0 0 '4, N * N * /
<P0 lb 0 Al N H A H

A H

F fli 0, /--.2 H.
---- (0---0-44 A 0 /
<' H
0 dit.
0 MP 0 nil N
N 411114P / \
_ \
A H N

\--0 N
Ft H
E.!
F
.
Ff2, 0 th Ni N' H Fx,.0 iii, 0 ,N
/

A H F N

-4--- o H

O I N-CE') I \-si '-'0 . ly) (0 * *
N / N
H 0 N ,-, A H W-A H
, c _TV 0 o 0 N
41)177,) Vi ..=,' F_P dal 0 .
,X. N
/
F 0 Mg N
AH

t ft-el 41 H<0 ,(0 rib 0 N '' N

i 7-%. 0 , ,.._ac) 1 1 I ,, / I A H 04 H 0 -= N
H ..-X.' "
..). 33 /--H
0.
H
=-.0 firli N tab,=0 * A
0 ....-O 0 * N \ MI
H
F 0 N / H 0 0 N =
= H

H

N...ip it' 0 H
N
CI' Or I ', I if¨. 0. <roc' 0 WA /
0 ifik, N
A H p , /0 Ala 0,Ç> 1 F"\ 0 WO ri = H

37 38 39 , ÇI

H H
C ish D v..,õ,.., tl, i <o lir 0 ? 7õ, 0 ta AP A H H
A H

Ho H H FCC> I \
H

A H LS g 0 O.
F

H

HO TiZ) H
F _.Ø.... N 0 c0) 4110 i H

0 < . 0 47 A o F p >co 4135 A H N
N F I
N
41.. 11 0 *
µ 0 F '-r-F
46 47 48 .
H
? * C --71`-= i N 0 N'i <

N * FF>(00 F

A H

c H
41......,.r_c3 eo G ZN CCI-V0 i '' 11 0 \--H
52 r:3 54 2 Ai31 Cr/
O =1101 II * / 0 0 I
N

H

1-1011õ).
F
F
MI/ V <P NH H F F

H N --- N
<.0 . 0 /
..
A H
--,_ 0 a µ 0 F

H
N,N
N
o H
F HO .,,,_ N, 1 NI --j-f I
= 11 *

/

A m o .
\-o tl F N
FI14 0 / po.
V H CH
0 hi A 0 0 N
(i H =

O

A H

\-.-0 IL)

6 F ) V H

N HN
RP
dill 0 . 74) 1 0 10 0 . /

N
A H
S-?

.,, Ft Z
H NH
oI H
* 4/ 0 = =,,,i N
A H CI N (s) A H N
<

AH

H
ii o H ) hi /
N
F?
,. P Alt, C 0 ./ 0 N <D 0 o =/
F>p rilb. 0 N /

N"' A H H
. 50 HI H OH
N--.
H

V g (' a /

111161' ' l''' \ I A H

r, --- iki --a 0 N,C --. N
H li( 11 I

Ar. H

H ? _ u I' 0 dab N -, 0 H0 Mr /
H
A H
= H
79 80 81 .
-.NH
cA o Ai ti < , * t4 o O
0 illr pi 7 N
A H
O $4 \--N, <o A I-I

H F

o, 0 tiovii,i) F 40 Nit.
HR F H lah N , -N
14 __,Z) H1,4 4111111113 / 0,.
A
o o F (3 F >c ilk 0 N .., 1 --(y)", I -- A ci 411, A H

o k-o \____0 .

o 4;
O N, . : pl N
.
it H A H OW N * i H

¨I-- H
i 0 <cl * 401 N/ <01.-.)-- 0 N
H

A H
o *
\--0 O 0 Hol,_ c j F
4) O
N di", 0 O * O
0 RIP N / OW< o * /
N
H H A H A H

r--.0 * H
N
\ i 0 N
V o(110 / :GNI
H Aqi, . ) 'W0 i _ CI rttiH
t7 0 0 N, 0 CJIO 8 =
fl it'-c-.1 N
H A H 0- \

,o 0 o H

A
<0 fat 1 0 Ur s'CI
H <0 Atiii 0 Ai, ti,"
o WI N Illtr A H

ii N

=\
0 0 lb N

Fi o HO F
46, N
i ii (P * a nia 8/ i = 110 47 H WI 1 IS
N

A WI
ti o I
FO
F

Ho Y1 . la H
N
H
? ip 0 iii 0 lir N .4114P = H H
H

H
0 * 0 c.,:cti_ ,1 I H
. 0 0 N
0 N, F O Ai o ill N di >C. / F N 41147 /
/ H F 0 WI' N A H
I H

H
. ..- 0 O'o Ill 0 1111. Ni V HSiA1PICO 1 N 11111$11- N
H 1 H ',.
et I \

*
H

_ r F
HN * l H
N eo dab 0 =-=.. 4 o o lir A
A o * NO' li 0 A F i o --,\ -0 F
F

c( F Ho li H H
c ("3 tit o 1 -, I N
Si * /

?0 10 2L =/HN N
N H
H
-H H

* 14/F,,,y lab 0 0 0 \
A
N F**".'0 1111111 1 u H

P H

la ,..-...<53 N pil¨

\_431 A H
H

H *
o, t4 * Neõ 0 I ,, / I

. 0 ii I A ti -N'A---1 A H

ti o Ho\ 4 o H
(la ZN4',81 N

"

<70 N

H

c)\_. r 0;:sz(1) N V H H

< 1/1111 0 iri 0 * \
ti H

r¨
o H
N

0 N A ti I*
N /
H H
c__0' N
=
$
H
'142 143 144 H
F N
H

H %AIN
pa o A

* >c0 0 H

/ F,..7 at. Fl rai. I, N
F-0 uurp A H
FO
F

el H
HN

0 ist 0 iii / = i 0 /
N
< 0 411, õ,.0*/
A
.2'N 11 Si ) H

H H
0 ? 0 N P , =-, 0 , --- N I" /
0 Iliri N HtIM
A H H 0 --- N' 1411111111 N
H H

or-0 *
oI H o Ti; rjrN)-sn4-49 V
* 0 Ati, N./.
,- ../ ,_,, 04_ N ' HN H
N
--s, A H
0 ..., I /

r n o ¨0 H
*A H
N
0 nit 11 = o = r A H 0 N' NH
H

Of _ H

H
HN FH H
H 0iiii da N 0 <
0 iditi 0 dli N
N IP / <
0 LIP N II"
H i < /
I. ola 1,1 A H

Ho r--H
Si F
N:11-114 N H ----%11 101 9k-N 7 0 A 0 H V
t1 14' N
. / 0 CI F)ra F

H
----- F
F N

* t4/ ll H
H
i.

'N. 0 \-0 \-0 166 167 168 .
/ _lo 111,1 0101 /
M
...,ka Fy,: O 0 dilt.
lir / 0 At, 0 dap N
r N <

A H N
el A m O
\-c) 0:sito HN' H

o ':; , P
01:121;ik.. ? I \
N ,-0 o o 411P ,õ N
..c Allk H
172 173 174 .
F l,li Filk! 101 /
V H H C
A c (P 111 0 N I 2I1Ri\l/ F-Ab Mr l C N
y 1 1 A H
N
* 0 I

Cf F
H H
(0 gal 0 rilk N F,../0 rah 0 .ith., 1'4 F *
0 11111111 N WI 1 frµo uip AN MI i V li A H A H
11114111P 0 N * N\
ii N , (,-) HN
\f--N F 0 1/
HO--Z) H
C.) N

*
F,O,riv rib N NI 0 <'co) O N
H A H

\-0 o Ho F
\ H H
<tN4 4 0 alla 7/ 1 0 fCT) I HN
Ho 111211 = H H
0 ill \-0 H
F N I-a I /
I \\_0 HN
H

e N
--= ci go 0 *, 0 411rP
ta H <9 AI
0 asi N
N
o A H
dc- 0 F

r-0 -., itil = H

N H
<01,-)xletN,G1:// _5) <

V H OH 0 Mi-H H
H'N
FO N
/

14 m 0*

e.
0_ N 0 ti A H IV
_ H

H
1 , *101:?\) hil,cyt co t,1.7._ 0 AL,,õ,.. N
41-11 i Cs du 0 * Ni 0 , 0 111, N 0 IMP N
A H A H

_ oH
HCi O
<PO ?
0 111 4; Oqi - H
Ail 0 N;
o N4111PWP N 0 VP N
A. H F)cp taa VP a 403,õ.
/ A H
F a UV N
A. H

Ho F rist N =,.
H N¨

HN WI 7 0 ., 0 ",--;,-N, I
(0 C" 21 N=I(... I 41s -4(12' H 0 '11 0 14 ef \

H
0 *
\-0 H t>
N -(3 I 0 Q \f 0 0 ..- Oi 0 H F, P filb- o o aiti -/ H A

A H , H

F
Ft 11)-) F>P D . / 1 HN illrill /
H A 0 F.>:
0 Illrask i 0AiN N 411V

0 , \-ii N

ti14 H

A 0 a 0 nik. tiz 0 "r-i" N 4WIP Fõ0, lir 0 fah 0 . I H X
F
A H /

\-0 H

NO-F
c) H F
HO/ 1,1 ..- . 0 / N
A H <Oa 1. o . / A .
A H
1.1 o \..-o . _ 214 = 215 216 N 0 H \
? irk 0 iti / N
N,Tr\Z
N 0 4111FP N 41er A H A H

.,- H

o I
CZ) or olir ti i ,r4_ H

o - g {
o tat o Aar N

A t-i A H

HN
\F 0 H
ralt illik 0 lik r'4 I
A H

A H

H H
H 0 1 I 1 Ni -N

<c) 1111 0 101 \ 0 4111=

lik , NN 411117 H N A H
H

F
H H H
0 N --, <0 Ai 0 aN) 1 <f all 0 di 7/ AO o 0 WI 0 IIIIIr N 411111P N
AU A ti A fi mo 1 figh,,, H

..-- 0 H
F, JO gib 0 niti l'::, II 14 . / Ill" N
0 40 0 * /

A S H

H H H
N
e 0 A H O' 0 N F , nil 0 if yi>1 1 Fr-so Ilir tr.l,...õ..- / <. rillii 0 0 WI N LE Oft A H A H

, / Ho O
H
dhN

, lir N I " . /
o * H 0 ,"" N
/
H
H
238 239 240 , /
o .¨o \F
H HN H
/ \ 0 /
=N H1Z4 N
>(4) H A H
F x niu. 0 N
/
F0 4111,- N 4111114P
A m HO
0 .N H ke N F
O N
( 0 - la 0 0 14\
H
N <0 ii 0 WI N -I-----A H

H H H
H} \t'l * 0 iiilkh. N..
F
N
dab 0 * N ir , . . * /
0 t4 N
A H A H

A 1-i \
N --al H
0 =
0 * it CIN; I \ _ 0 0 ca> 1 ti 9.1 0 N
i .
A H

H

r 0 H ( \ _-- 1 H
(C) a lik 0 iti 14 / H F O 0 O 11,P N 411.' .-- N = 10 Ni A H 14 F >(00 * 0 . , 0 N
H A H
hi A ii Ci Cl I
N
H * H N/ C I
* i t 0 VI H
N
a...-^, 41 N
,_ g 256 257 258 .
111.10.CH
C H /

0 0 II' N N
AI 0 illi Ni <
0 * N 0 /
F X.
F 0 lir N 'all& H

A H

H

., N - F
H
(0 AL 0 rak N/ / HN
0 10) * Ni 0 VP 4 4 0-1" N- 0 pirldb. 14/
A H / e 11112 A 0 o Ur tl A H
o \__O
_ r-O
.
o 0 e H V g fah i H 4 < 0 0 * N

HHON
H
il 0\s, H
fiN 0 o dill 3 H
N 4111P I -:,,, 161 N /
N
? 0 * i A H

H
H

H
- C ro CI
H
0 4 . 101 N
301 l \¨C-A /
F_ p rip r r = , .,."'r, , , , 4 1 N
H
FX0 1.10- -K..
- N '----/
A H

\
Ht4 = \) , * * 14/ I
O N
. *N i 0 N

H

H --/V

H0.14 14 ,!;1 HO OH :Ns' , z:0 :31:0 N0,4 F il=

lik 0 lik NI, N F>(:) iglik 0 AIN N
F 0 41111111- N 414-P F,, .2 filk. 0 lio F)(0 RP / F 0 WI VP i A H N N
A H A ti H

H ) 0714,) H
/ 0 = 14/ H y N
/ X I / rit A N F 0 -, N --- /
0 0iNF
H H N 11,11P
H
*

..--H

H
(*) N .CC"ii.
AI 0 lik i a A F".'µ0 F 0 õ., 0 N F
F 0 MP N 41117P 0 `,õ N C I
A H F,,C) *
N
I / F a .--= N' H * F
,--/
A H
282 283 284 .
µ
hi...i{
1:' H
S.,..N \0 0 Ors.. HN ,=1;;c0 H0,4 .s, illt 0 ift ) F.x,0c3 * 1 N 0 Nz 1114*-11111Pj N m".11P.

FA '.) ,, P Ali 0 * 14 i F
A H H A
F 0- Mr 'N
AN

_ H
1 0 O. i 0 \
11 Hi HR
HO ,R7N) 0',"N
CI NI
Fx.C1 1 --... 0 Ai 1,1/ = * 0 1 --; /
F.... p 0 0 CI 1st F.X 0 110 N./
H A H N
AR

H

Ho H H

,--F
A 0 l'- la N, F> 0 la CI O ,fN Ad ' F
H H
0 *
FA-.0 F

fi HO
zs..
.! -0 0 S-11'4 s..
ii.l. -0 N
F.),.0 fa 0 ii, A H Fx0 * 0 =
i F>( 0 N

N
H

Ho "=,-.0 0 N
HO N-IN) N H N /

N * 1 AR
*
F
C I v_ID 0 F F

H
H HN
HO
H
' la la FF0 rib 1 ,....... 0 A H H

0 (Y

P
0 tip F-No 1 , I OH
N IP N N
H H A H

H

r 0 H
q31-il N F
rah Nr*0H
F ,,(3 Alb 0 111/
/ F,,,P
F'µ0 VP
N F
. 411 ' = Ni A H F"-µ0C.21,1,4 111111111 /
0 N" H
A H

o\o HN
%
i?
F
F>( 0 Atyr, '0 A-A H

307 KIE> 309 H
c 0 ti F = ,,-":;z1,- Ft F õ_õ,-,.., ,t,i op, \
-, j-7-0 '`---F'<-3 F F

H H

."
14 ) N
A
_,L, F ' 0 - -,,,-;-;- 0 ..õ,,,f2,- fg E_\õ1,.,. %) , .
( 1 li e `1--' =
q :s...-o F

- F H
t-- : 0 Nt.......24, -c¨F H j..
'1\i"-'':i ' >< 1 I X11N f'`, I
F 0 -- .,.:.;2 0 ..õ,:,-õ=,' -.-ti H N \
1õ ' 'O
H
F" --, k , - 0 -,...
. ...
F

H

H
ki F F i , fõ, b IN
y .--;) I =
..N.- sõ.:"' ---= \-0 0 H --, / i ri r \
...A4 __,... -=::=-4-.--...'7 F,,, ,....õNt ,=,__,,ta i \ õJ-,. ,, ';,..._0 H /4 =e.'; ' .õ1õõ... Art...., ,i ..,,, , 6 0 r v.0 f11/
00 =

H
=

0 = I*

0 FA¨Q

u'd) =
'03-*
0fj: I
'Y
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, CFI}( 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-quinoline-3-carboxamide. 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:

R N \

wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form ¨CH2CH2CH2-, ¨OCH20- or ¨
OCF20-;
R1 is H or alkyl;
R, is H or F;
R3 iS H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2I\14(CH3)3, or -CH2CH2OH; and R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together font.' 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-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form ¨0CF20-, Ri 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-, 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 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, R1 is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.

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 ¨CH,CH2CH2-, R3 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:
H
Fx0 N

Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N (CH3)3, or -CH2CH2OH; and R5 is H, 011, -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, -CH2C112N+(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -CH2OCH2CH(OH)Cf20H, -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 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
\
R

or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form ¨CH2CH2CH2-, ¨OCH20- or ¨
OCF90-;
RI 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 ¨OCF20-, 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 Rq is -CH2CH2W(CF13)3. In another embodiment, two R taken together forrn ¨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 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, R1 is H, R.? is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
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 Rq is H. In another embodiment, at least one R is OCH3, at least two Ri 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 F

Ha or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N4(CI-13)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, -CH2CH2N+(a13)3, or -CH2CH2OH. 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 11, polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, AC'1 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-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:
R1 R1 Ri Ri R N \

R
k R5 wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form ¨CH2CII2CH2-, ¨OCH20- or ¨
OCF,0-;
R1 is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2Nf(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 CF1R.
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 ¨OCF20-, R1 is H, R2 is F, and R3 is H. In another embodiment, two R taken together form ¨OCF20-, R1 is H, R2 is F, R3 is H, and R. 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 ¨

OCF20-. R1 is H. R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, two R taken together font ¨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 foliu ¨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 another embodiment, R is OH, R2 is H, R2 is H, R3 is H, and R4 is -Cl2OCH2CH(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)CH7OH. 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
)(0 ISO
1110 ___________________________________________ Ha or a pharmaceutically acceptable salt thereof, wherein:
R. is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CIL2CH2OH; 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, -CH2CH21\14(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In another embodiment, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH21\r(CH3)3, or -CH2CH2OH; and R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this kit, the compound is selected from Table 1.
[00166] 111. SUBGENERIC 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:

CI
n (R2) k Ic or a pharmaceutically acceptable salt thereof.
[00168] R1, 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 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 H
- N

'32z. 00 \
,or OH
_ N
[00169] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Id:

n (R2) 41, Ri Id or a pharmaceutically acceptable salt thereof.
[00170] RI, R7, 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-, -0O2-, -000-, -NRGCO2-, -0-, -NRGCONRG-, -OCONRG-, -NRGNRG-, -S-, -SO-, -SO2-, -NRG-, -SO2NRG-, -NRGS02-, or -NRGS0,,NRc-, 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 fount an optionally substituted heterocycle.
Futheimore, 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 -ZHR22, where each ZH is independently a bond or an unsubstituted branched or straight C1-3 aliphatic chain wherein up to two carbon units of ZEI are optionally and independently replaced by -CS-, -CONRHNRH, -0O2-, -000-, -NRHCO2-, -0-, -NRHCONRH-, -OCONRH-, -NRHNRH-, -S-, -SO-, -S02-, -S02NRH-, -NREIS02-, or -NRHSO2NRH-, each R22 is independently RH, halo, -OH, -NH2, -NO2, -CN, or -0CF3, and each RH is independently hydrogen, 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:

zrzi

7, 0 (R3) 1, or a pharmaceutically acceptable salt thereof.
[00173] R1, 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

8 modulating ABC transporter activity. The compound has formula Ha:
¨z, R2 Z2 N.A.

Z5 A N l'j"
, Ri p(R3) Ha or a pharmaceutically acceptable salt thereof.
[00175] R1, 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 folinula lb.
[00176] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Ilb:

Z2 NI, R.3 IIb or a pharmaceutically acceptable salt thereof.
[00177] R1, 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.
[00178] Another aspect of the present invention provides a compound that is useful for modulating ABC transporter activity. The compound has formula Hc:
(R2)n NI ) R1 p(R3) He or a pharmaceutically acceptable salt thereof.
[00179] R1, R2 and n are defined above in formula I; and R3, R'3, 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 formula lid:

R'3 O

A(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:
0--...>(.. ,0---)-1, ,0 r_ -.....--< I F2C N,.."11:: N-.......-i,:"
, I A I UL, I N, I , Os 5- , Oiss, , Ocs5, , c-v- , N---ss-5, H
e 2 1.1 0¨._. 7 . C. 0.--.)1", s 0.(0,,17.-C
I U CD, I c I s 0-s7- d N
H

0.,..,..(.
...-- ,.,õØõX_ H
0 ,,,C I
----( Nai//c5 -OXc -css, N e, , N I
0 --.....7"-. sYs. , 0 e- , , Me0 OH , 0---,-11 ( I s ( I
, and XA1 9 XA20 XA21 .
[00182] R'3 is independently selected from one of the following:

A----0, -H, -CH3, -CH2CH3, -C(0)CH3, -CII7CH2OH, -C(0)0CH3, '=
' ¨K
, i---0\ c H2OH
OH OH
A'j"----7 -1--A CH2OH -.4,-OH )(' N H C OC H3 ) ''''''CO2H CcH NHMe )?2,--.-"r0Me , OH
, N ,--0 -µ0H --.. ----.0 NH NH '= .,...,..õ,... 5 '..OH Nz-N' -µ- 2 -1-----CONFIMe '2.
r 0 E0 t A
-µ." JL`)OH

OH
-=)22,---y-''NHCOMe NH
0 A4M-----CN 5_ j A4'...CONMe2 OH Az OH
H Az-0 NHSO2Me A---,T,CO2H ,r,,,...,,¨õiiN, ¨ OH AM-----N-CO2H

, OH , 0 , OH 0---K
, 1 , =AMNHSO2Me N-N`rNHCO2Me , )24N NH
_NHCO2Me OH , OH OH N14 =

9 4 9 OH
OH
OH
150H )1\---"FrH
N'OH
A4 -r-iN
0 _.-= A.-...NHCO2tBu OH OH , 0 HO , 2 , N"
O ..-K. ..< OH
--µS=--C) N 0 N
, "µTh'NHS02Et )("YN N,7. 1 7---NH
OH OH --r-,..----OH H I
t\l)- N
--1\-..--_,õ -.
OH H AThr ----N
\ N
N-0 , 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
..----b ---K -+k 'NE), H H
, , OH .

/

--'''N 1411 H H H

, 0 o o N to T,,_____ ),.,. :2õ-L
NO
, N'''' kl-'1JH
H
OH I
' F
.L.), 0...--------'?-1-(-- 2 C , 3 --µ.O---H-, --µ.--N/ ---kNH I
\ x.õii,N, ,k--.., -3/4'----NH -V---N y0 / \ \ \
CONH2 0 \ 0 \ OH OH 0 0 , OH

' 1\1) %N'1 _________ /
NS o A- < (o0 Et ,-'( ,OH
-k< /OH
A
e' H H N

AtµK
NTh N "
0 )<
N
_______________________________ N
====I

NH
OH

A,OH 0 CO2H
, and [00183] IV. GENERIC SYNTHETIC SCHEMES
[00184] The compounds of formulae (I, Ic, Id, II, 11a, 11b, 11c, and Ild) 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, 11, Ha, 1Tb, 11c, and IId) 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 1.
[00186] Scheme 1:
(R2)n OH
(R2)n A=

0 _____________________________ 11101 o la a (R2)n\
k e 0 lb a) SOC12, DMF (cat.), DCM; b) R141 , pyr.; c) R1--M 415 HATU, 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 R1¨N Co provides compounds of the invention I. Alternatively, the acid la may be directly coupled to the amine using known coupling reagents such as, for example, HATU in the presence of triethylamine.
[00188] Preparation of the acids la may be achieved as illustrated in Scheme 2.
Scheme 2:

cl Br 0 N ____ N

a OH
(R2)n (R2)n (R2)n 2b la 2a a) NaOH, B 'BAC; 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 phenylacetonitiles 2a are commercially available or may be prepared as illustrated in Scheme 3.
Scheme 3 40 Br a CO2Me OH

u _ (R2)n (R2)n (R2)n 3a 3b 3c a CI d = CN
(R2)n (R2)n 3d 2a a) Pd(PPh3)4, CO, Me0H; b) LiA1H4, THF; c) SOC12; d) NaCN
[00191] Referring to Scheme 3, reaction of an aryl bromide 3a with carbon monoxide in the presence of methanol and tetrakis(triphenylphosphine)palladium (0) provides the ester 3b.

Reduction of 3b with lithium aluminum hydride provides the alcohol 3c which is converted to the halide 3d with thionyl chloride. Reaction of 3d with sodium cyanide provides the nitrile 2a.
[00192] Other methods of producing the nitrile 2a are illustrated in schemes 4 and 5 below.
Scheme 4 a (R2)n 4a (R2)n 2a I b d C =
(R2)n 3c (R2)n 3d a) TosMIC; b) NaBH4, THF; c) SOC12; d) NaCN
Scheme 5 = ______________________ a Br 010 ______________________________________________ NC (10 (R2)n (R2)n (R2)n 5a 5b 2a a) NBS, AIBN, CC14; b) NaCN, Et0H
[00193] Preparation of Ri-g 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 R1-11 is illustrated in Scheme 6.
Scheme 6 (R3)p-1 (R3)p-1 (R3)p-1 02 1101 NH2-a 02 N-NH2 __ 02N 411 ek"--R3 6a 6b 6c (R3)p-1 (R3)p,1 6d 6e =tµlH2 (R3)p-1 H (R3)p-1 6f 69 a) NaN07, 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 a0 b \ R3 -(R3)p-1 (R3)0 H (R3)p-1 H
7a 7b 7c (R3)r1 isR3 02N 44Ir ill (R3)p_i H
(R3)p_1 gb7e 1 e\
(R3)1 7d p-R3 1 0\ R3 H H
7i h 7j (R3)p-1 (R3)p-1 \
' f .

021\I\IN H2 02N N-. 2 02N
H H \
7f 7g 7h a) R3aC0C1, Et3N, CH2C12; b) n-BuLi, 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 -p=-"'- a/--...,...,,,.-- b p( R3) 03) I .
N
--.-\

H
p(R3) p(R3) a) 11NO3, H2SO4; b) Me2NCH(OMe)2, DMF; c) H2, Raney Ni, Et0H

[00200] Scheme 9 a b Br Br --., 11101 c p(R3 /,.."..

)"--- p(R3) ,,, p(R3) TMS .
\
02N / NH2 02N N H2N la N
H H
p(R3) (R3) p(R3) a) NBS, DMF; b) KNO3, H2SO4; c) HCC-TMS, Pd(PPh3)2C12, CuI, Et3N, toluene, 1120; d) Cul, DMF; e) H2, Raney Ni, Me0H
[00201] Scheme 10 a -,,,,,,...,.õCO2H --..õ.kCO2H
I b ------a- + '1''''...NO2 02NNO2 __ ',.,,..-.-1CO2H -..,...AG02EtI ,.0O2H b + separation I - -3.-I ''''''.. NO2 02NNO2 __ , I c .. ./ =," , d , K.'NO2-I=NO2 H2Nr----N
R3 R3 CO2Et a) HNO3, 112SO4; b) SOC12; Et0H; e) DMA, DMF; d) Raney Ni, 112, Me0H

[00202] Scheme 11 O 0 2Et /N "--- 0 CO2Et I a =

(R3)p-1 EtO2C 0 b \

H
a) DMA, DMF; b) Raney Ni, 112, Me0H
[00203] Scheme 12 R3 __.4R3 ,-----=.-/ a _ b I , I-12 r) 2, N rsi-'-'",----"--NN'-(R3 ,.., H H

----- ip., _____________________________________ R3 c la \ R3 a) R3aCH2COR3b, AcOH, Et0H; b) H3PO4, toluene; c) H2, Pd/C, Et0H
[00204] Scheme 14 (R3)N = (R3) (R3).1x VR
--\--1 ----\ a ,-\---------) b '''-'----) c 0 N d H H
PG PG
. (R3)p-1 . (R3)p-1 I , e .
n \
1 , f =\ g Fly \
N
H 02¶KJ H 02N N
H

H
a) NaBH3CN; b) When PG= SO2Ph: PhS02C1, Et3N, DMAP, CH2C12; When PG= Ac: AcC1, NaHCO3, CH2C12; c) When Rv= RCO: (RCO)20, A1C13, CH2C12; When Rv=Br: Br2, AcOH;
d) HBr or HO; e) KNO3, H2SO4; f) Mn02, CH2C12 or DDQ, 1,4-dioxane; g) H2, Raney Ni, . Et0H.

WO 2010/054138 PCT[US2009/063475 [00205] Scheme 14 RD
(--' a r------) b* c ... *N
(R3) p-1 SO2R
(R3)p-1 H (R3)p-1 H (R3)p-1 SO2R
RD---''"C----) RD RD *
d e f --1,.."-----N\ '-1--47---N 02N N
(R3)p-1 SO2R (R3)p-1 H
(R3)p,1 H
h RD 0 \

--"-r---------Erl N

(R3)p-1 (R3)p,i a) NaBH3CN; b) RSO2C1, DMAP, Et3N, CH2C12; c) RDC(0)C1, AlC13, CH2C12; d) NaBH4, THF; e) HBr; f) KNO3, H2S02; g) Mn02; g) Raney Ni, H2, Et0H
[00206] Scheme 15 (R3)p_, . (Fup_, - R3 (R3)p,1 11110 \ a , 101 \ b \

02N =N H2N
H
(R3) P-1 CN
(R3)p-Iii: = NCN
,,,,,c.,, =
b \

H H
a) R3X (X=Br, I), zinc triflate, TBAI, DTEA, toluene; b) H2, Raney Ni, Et0H or H2, Pd/C, Et0H or SnC12.2H20, Et0H; c) CISO2NCO, DMF, CH3CN
[00207] Scheme 16 R3 R3,,,,õ,_ __ Rria6 fr\-------c_ a n m_r__\ \ b \
R3 -----).- n 02N¨rce,õ..N R3 -------4"- '-'2' ' 11.,......mi `-'2 WI N
H \
R.3 R'3 a) when X=C1, Br, I, or OTs: R'3X, K2CO3, DMF or CH3CN; b) H2, Pd/C, Et0H or SnC12.2H20, Et0H or SnC12.2H20, DIEA, Et0H.

=
[00208] Scheme 17 02Nx:xBr 02N3r a 0 JLR, c (R3)p-1 (R3)p-1 (R3)p_i H
(R3). 1 R3a (R3)p-1 (R3)p-1 02N Veop 02NtL) R3 H2Ntc>._ . a) Br2, AcOH; b) RC(0)C1, Et3N, CH2C12; c) HC=¨C12.3,õ
Pd(PPh3)2C12, CuI, Et3N; d) TBAF, THF or tBuO1C, DMF or P1(PP1a3)2C12, CuI, DMF; e) F12, Pd/C, Et0H or SnCl2, Me0H or HCO2NH4, Pd/C, Et0H
[00209] Scheme 18 = R3 I a R3 R3 Rs 02N n e H2N
=\
N)L
\ ______________________________________________ 3 R3 Nr H
=

I \=

R3 _______ H2N Rs \ R3 Rufb RD.
=
a) Br2, AcOH, CHC13; Et3N, Pd(PPh3)2C12; RCOC1, Et3N, CH2C12; d) TM
TBAF, DMF; e) Raney Ni, H2, Me0H; f) RO1C, DMF
=
=

=
= =
=
=

100210] Scheme 19 (R3)p-1 R3 a 02N .õ....,....--.õ 02N 0 Br , I
_ b _________________________________________ . 02N 0 %
''''=,-1.-----NH2 NH2 (R3)p-1 (R3)p-1 (R3)p-1 d c 0 \ R3 R3 _______.-____._ N
H H
a) Brz, AcOH; b) HCCR3a, Pd(PPh3) 202, CuI, Et3N; c) Pd(PPh3)2C12, CuI, DMF;
d) H2, Pd/C, Et0H or SnCl2, Me0H or HCO2NH4, Pd/C, Et0H
[00211] Scheme 20 , 02N 0 x I a , I b c -----.--%,.-1-/---F
-7,- . ---yH NH
I
(R3)p-i (R3)p-1 R3 (R3)p-1 R'3 R3 (R3)p-1 02N H2N 434'1 \
02N, 1410 -=-<:''' d \ e , I R3 ___, R3 '%--'"----NH N N

I R.3 a) II2NR'3; b) X=Br: Brz, HOAc; X=I: NIS; c) HCEECR3, Pd(PPh3)2C12, CuI, Et3N;
d) CuI, DMF or TBAF, THF; e) Hz, Pd/C, Et0H or SnC12, Me0H or HCO2NH4, Pd/C, Et0H
[00212] Scheme 21 (R3)p (R3)p o2N _-,/, 02N o2N 0 Br I a b c ---'F -----.- Oil NHR'3 - NHR.3 -p(R3) TMS
d 02N e H2N 40 \ \
I
N N

p(R3) p(R3) R'3 P(R3) R'3 a) R'3N112, DMSO; b) Brz, AcOH; c) TMS-CmCH, CuI, ILA, Pd(PPh3) 202; d) CuI, DMSO;
e) Raney Ni, H2, Me0H

[00213] Scheme 22 02NBr a 02N . /

________________________________________________________________ w ------NHR'3 NHR'3 b (R3)7 p-i (R3)1-1 1 \ C
, \ R3 \ \
(R3)p_i R'3 (R3)p-1 R'3 a) R3a0:----CH, CuI, ILA, Pd(PPh3)2C12; b) 1BAF, THF; c) Raney Ni, Me0H
[00214] Scheme 23 ,õ,-,,,,=Eir Br I a b , 0 I c 401 1 N R N R
(R3)p-1 (R3)p,1 (193)p-1 H (R3)p_1v H
e .
02N =

d ___ , r--R3a _____________________ \ R3 f \ R3 N N
(R3)p-1 H (R 3)p-1 H (R3)p.1 H
a) NaBH4, NiC12, Me0H; b) RC(0)C1; c) Pd(PPh3)C12, HC:.---C-R3, CuI, Et3N; d) tBuOK, DIVIF; e) KNO3, H2SO4; f) NaBH4, NiC12, Me0H
[00215] Scheme 24 a H2N 10 \
, H-.%---N N
(R3)p 43\
(R3)p R,3 a) SnC12, Et0H or Pd/C, HCO2NH4 or H2, Pd/C, Et0H or Raney Ni, 112, Et0H

[00216] Scherne 25 PPh3Br OH a , - 1 PPh Br 3 b 0 o o c N H 2 -INH 2 _________ -N)L-)L0E1 (R3)p-i (R3)p-1 (R3)p.l H
c d iss , 4110 _________________ R
\ R
N CO2Et e N CO2Et (R3)p-1 H (R3)p-1 Boc (R3)p-1 Boc R f R
R
\ (---,õ-- 02N . R 9 '--...=,'N CO2Et N CO2Et (R3)p-1 H (R3)p-1 H

h R
02N .,õ,. R H2N 0 R
\ i \ R
' ---N OH N OH
(R3)p.1 H (R3)0 H
a) PPh3, HBr; b) C1(0)CCH2CO2Et; c) tBuOK; d) (Boc) 20, DMAP; e) KHMDS, R-X;
KHMDS, R-X; f) TEA; g) NaNO3, H2SO4; h) LiA1114, THF; i) SnC12, Et0H
[00217] Scheme 26 a 02N 1 ......_ \ RaRb b 02NRaRb I N NRyRz R3 H R3 tl R3 El 0 C 02N.,..rr, r Rb d LINi \--NRyRz V N NRyZ

a) LOH; b) EDC, HOBt, Et3N, HNRyRz; c) BH3-THF; d) if Rz=H, RC(0)C1(Z=RC(0)-) or RSO2C1 (Z=RS02-) or RO(CO)C1 (Z=--RO(C0)-) or (RO(C0))20 (Z--,_ Z.--R0(C0)-), Et3N, [00218] Scheme 27 02N. a 02N. ,...,,--k.r.
I
I b H2Np---R3 H R3 3.3 R3 iR.3 a) R'3-X (X=Br, I. or OTs), base (K2CO3 or Cs2CO3), DNIF or CH3CN; b) H2, Pd/C, Et0H
or Pd/C, HCO2N1-14 [00219] Scheme 28 R3. R3a a 02N õ..,..
b H2N
R3b 7.--- N 7,------ N 7,------ N
R3 'IR', R3 R3 a) R3aX (X=C1, Br, I), AlC13, CH2C12; b) Raney Ni, H2, Me0H
[00220] Scheme 29 H Boc 02N,õ--s, ,INI.,., I 1 a H2N.,- ----..,...._,..µ (N. b ,. H2Nõ,..,,.--....õ,. I
1--N/ -----.- '1.---1\11 -* '1.%t\l/

a) HCl/Me0H; Pt02, H2; b) (Boe) 20, Et3N, THF
[00221] Scheme 30 02N \ a 02N T\ b C)2N"1--$ c 02Nr---:õD
\
NC HO2C R'3 RO2C R'3 ( NR'3 OH
1 d g t 0 N 73 NRyRz 1 e R, 02N yr- $
( 1'3 NRyRz a) NaOH or Li0H; b) ROH, HC1; c) NaBH4 or LiA1114 or D1BAL-H, THF; d) HNRyRz, HATU, Et3N, Et0H or DMF; e) LiAIH4, THF or BH3=THF; f) H202, H20 (Ry=-Rz=H);
g) H2;
Pd/C

[00222] Scheme 31 ,)c)10 0Ra Rb OR
Fia?/Rb OH
b c d Ra Rb a CI
Rb Raõ./ Rb OH e , Ra Rb OR f Ra / µ
¨ 0 02N.,,...%.,,Br D2N OR 9 'A--7---NH2 1-' 'NH2 R3 n3 Ra Rb -----02N h 02N..õ..--, -\ 2--0R i _ H2N \ OR
I 0 \ __ ,,,.., j.e7NH--4 / N Ra Rb '/...-N Ra Rb a) Ra-X, NaH; Rh-X, NaH; b) PC15, CH2C12; c) NaOH; d) NaNH2, DMSO; e) C1-12N2;

Pd(PPh3)4, CuI, Et3N; g) RC(0)C1, pyr, CH2C12; h) Pd(CH3CN) 2C12, CH3CN; i) Raney Ni, H2, Me0I-I
[00223] Scheme 32 (R2)n R3 1, (1R2)fl R31, a di \ e I µ,õ 0 flii N OH
o OR
H H
b (R2)n R3IP
/ _______________________________________________ _______________________ a \ ____n e lõ. 0 Flii '----- --N IN- Rz H t Ry a) Li0H, THF/H20; b) 1-1NRyRz, HATU, FEA, DMF/CH2C12 [00224] Scheme 33 , -"'.=-...,¨"N OH
a _e H
(R2)n 9 R3 \ '-, _______________ , 1 õ . RI N OR '''.õ,,,a.

b (R2)n IP
--;

H
a) LiBH4, THF/H20 or LiAlHa, THF; b) Ra-Li, TTLF
[00225] Scheme 34 (R2)n 9 (R2)n 9 NO
\ --...
r---47---r---) a \ e Nìb \ I.
i 7 0 Ai L7:/-----N l 7 H H

(R2)n IP NH2 \ N e) n ' 17õ----N

H

a) NaNO2, AcOH/H20; b) Zn, AcOH
[00226] Scheme 35 (R2)n I, (R2)n 9 \ 1--e a __ > \I ..r .-,-,n b v.
l 7 0 ki 17-7-1 I 7 0 Ai L7.----,1 (R2)n 9 (R2)n 11 N

I 1 17....õ...----- /
7 Ri N _____ N, 1 7- 0 Al µCH2R3 µCH2R3 a) NaBH3CN; b) R'3CHO, NaHB(0Ac) 3, TFA, DCE; c) chloranil or CDC13, light or DDO

[00227] Scheme 36 9 (R2)n (R2)n 9 \,.... a _ N¨ì -----''- \ N
n ---H h'3 a) NaH, DIVIT-THF; R3-X (X=C1, Br, I, or OTs) [00228] Scheme 37 (R2)n 9 (R2)n 9 Br \`-... a \I ,.., \ b l , I ' .¨'''' .- 0 ,z,-------N
H H

(R2)n 0 Ar N¨

I \
I .,, o H

a) NBS; b) Ar-B(OR)2, Pd-FibreCat 1007, K2CO3, Et0H
[00229] Scheme 38 , s (R2)n SO2R9 l / 0 Ri H

(R2)n 9 7 1 , b 1 ( 0 y 0 H
-------R2)n OH
HC
R3 ''",..., (R2)n 9 \,, 1 \
\ i 0 Ili iz-----N1 H
(R2)n 0 \......
l 0 flii Lyz-M1 H

1 e CN
(R2)n9 l -H

a) RSO2C1, NaH, THF-DMF; b) R3-X (X=Br, I, or OTs), NaH, THF-DMF; c) ethylene dioxide, InC13; d) P0C13, DMF; e) H2N-OH, CH2C12; Ac20 [00230] Scheme 39 , .

(R2)n IP (R2)n 1, \>
..-(7*-T -- a \'õ, I ,, 0 k ,----,,,, l , 7n \

V \C
(R2)n 9 (R2)n 9 \ -.. N-- \ I
n...----s 1 - 0 A, ly.---N OH o OH
i t71\1 R3 OR R3 \-----(._ OR NRyRz a) NaH, THF-DMF; epichlorohydrin; b) ROH; c) HNRyRz [00231] Scheme 40 (R2)fl ,..., _ (R n 9 \, ip .r.-^
OH_--- I / _NA OH
% Lt R, \--t OH OTs 1,...,....õ....õ>.-= e (R2)n (%)fl (%)n 9 (x, , 0 ,,,, i,./. , N OH I 1 L.--- f \
...v..-÷, % Lc__ ' R1 N OH ---'- 0 N OH
CN % Lt R3 LC
N, NHR
1 c "=-,.......õki i h (R2)n 9 (R2)n 9 (R2)n -=,. f..-----% \
0 Ai 1* N OH I / OH
R, \---(,. CO2H R, I ,,... 0 Flii - N OH
\---(---f-N'NH % \---t_ NN
z a) TsCl, Et3N, CH2C12; b) NaCN, DMF; c) NaOH, Me0H; d) NaN3, NH4C1; e) NaN3, DMF;
f) Pd/C, H2, Me0H (R=H); h) RT(0)C1 (Z-----RT(0)-) or R'SO2C1 (Z=IeS02-) or Rx0(CO)C1 (Z=Rx0(C0)-) or (Rx0(C0)) 20 ( Z--1e0(C0)-), Et3N, CH2C12 [00232] Scheme 41 (R2)n 111 (R2)n 9 --e \ (R2)n b \ ....,...
I 0 11/1 ,-- 0 illi 17 N

(R2)n 1111 (R2)n 9 \
...(X:=>,.
l 0 F1/1 '-'-N I 0 Al N
R3 ? R3 () a) CICH2CHO, NaHB(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 RO(CO)C1 (Z=RO(C0)-) or (RO(C0))20 (Z= RO(C0)-), Et3N, CH2C12.
Scheme 42 0 0 0 0Rb OR
Ra.?/ \K Rb O
Rai H
z ( \\O d OR b OR ¨4' ______________________________________ c 0 ----"-Ra Rb Cl Cl Rb Rb OH Rb OR f Ra Ra.... J., / e Ra/ ________________ ( ___________________________________ , R3 õ,....õ.
..--- OR 9 ¨ 0 ____ o02N 0 0 02N401 Br R2 NH2 02N git \ OR
R2 Litr N Ra Rb H
b) Ra-X, NaH; Rb-X, NaH; b) PCI5, CH2C12; c) NaOH; d) NaNH2, DMSO; e) R-OH, DCC; t) Pd(PP113)2C12, CuI, Et3N; g) PdC12, CH3CN

,. .

Scheme 43 02N 40 x.H2)n-0O2R b) a) 02N 401 \n(H20)- \
CH2OH 02N so n(H2C)-CH2OP
_____________________________________ ) -31.-R2 N Ra Rb H R2 N Ra Rb H R2 N Ra Rb H
c) 02N is \n(H2C)-CH2ORc d) H2N iop \n(H2C)-0H2ORc ----- --).-R2 N Ra Rb R4 R2N Ra Rb n= 0 or I
a) DlEAL-H; b) P-LG; P-= protecting group like PLIDMS and LG= leaving group like Cl; c) Ra-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate, Rc=H
or Re4; d) reducing conditions like Pd/C, H2 or ammonium foimate.
Scheme 43 02N 0 Ra Rb OR 02N 40 OR
\ a) Ra Rb \ b) _____________________________________ )1, c) H2N ioi OH
\
R2 N Ra Rb R4-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate; b) LiA1H4; 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, ADM]NIS 'RATIONS, 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 UtiCo¨,Z,¨

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 prodmg thereof. According to the present invention, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
[00237] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, s-uitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonab]e 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 acciTtable 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, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, soccinic 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, &neonate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, rnalate, maleate, malonate, methanesulfonate, 2-.
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 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 aTicsli metal, alkaline earth metal, ammonium and INT (C1_aa1ky1)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quatemization. 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 additiomdly 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 fomiulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose;
starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;

isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
[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, H, Ha, Ilb, He, and lid) to a subject, preferably a mammal, in need thereof.
[00241] In certain preferred embodiments, the present invention provides a method of treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type H, 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 I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion protein processing defect), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formulae (I, Ic, Id, JI, Ila, Hb, Hc, and Hd), or a preferred embodiment thereof as set forth above.

[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, H, Ha, 11b, IIc, and lid), 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 II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongifonn 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.
[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 hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic 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 foiiii 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.

[002471 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 contract/I 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 foluts 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 dicakium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption 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 stearat_e, 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 foitnulating art.
In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[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 refeired 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; biopsied 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, Hb, He, and Hd). In preferred 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, Ilb, Hc, 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 (NUR) (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 (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPRIm 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, H, lIIa, Ilb, [Ic, and ffd) 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, II, Ha, ilb, IIc, and II(1). In preferred embodiments, the kit is used to measure the density of CFTR.

[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 H
(RxX)x Hal al (RxX)x N _________________________________ )1.
50% NaOH (aq) OH
Hal = CI, 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 CI/--\Br <0 is 0 0 N
O 50% NaOH (a q) 41111 OH
[00274] A mixture of 2-(benw[d][1,3]dioxo1-5-y1)acetonitrile (5.10 g 31.7 mmol), 1-bromo-2-chloro-ethane (9.00 inL 109 mmol), and benzyltriethylammonium chloride (0.181 g, 0.795 mmol) was heated at 70 C and then 50% (wt./wt) aqueous sodium hydroxide (26 mL) was slowly added to the mixture. The reaction was stirred at 70 C for 24 hours and then heated at 130 C for 48 hours. The dark brown reaction mixture was diluted with water (400 mL) and extracted once with an equal volume of ethyl acetate and once with an equal volume of dichloromethane. The basic aqueous solution was acidified with concentrated hydrochloric acid to pH less than one and the precipitate filtered and washed with 1 M
hydrochloric acid. The solid material was dissolved in dichloromethane (400 mL) and extracted twice with equal volumes of 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%) ESI-MS nilz calc. 206.1, found 207.1 (M+1)+. Retention time 2.37 minutes. 1H 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 \
N
NaOH NNaOH OH
Hal CI, 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 nit) 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 HI: Carboxylic Acid Building Block Pd(PPh3)4 rr...".:,.........,,, .0O2Me LiAlH4 t..,.,..

1,..,,,, SOCl2a r .-------''''' NCN
'CI ri----:.--CN
, R- _____________ . R¨

Q..,...,, .....,..,--' CICH2CH2Br R- NaOH
CN _________________________________ R_CO2H
i ' -r . I
[00279] Example 2: 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid 0 xF Br pci,pph3X4 ¨ xLi =-= 1. CO2Me LAI
iH4 F, p 0 OH S0Cl2 F

V
FX 40 ci NaCN Fx0 101 CN CICH2CH2Br o 0 CN NaOH
---...-F 0 =F 0 NaOH F 0 V
FX la CO2H

Fe so Br Pd(PPh3)4 ____________________________________ F = So CO2Me xF=).' X
c0/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 tetralcis(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 z = 0 CO2Me LiAlF14 F 0 ad FA. ______________________________ Alw ?Si)=

[00282] (2,2-Difluoro-benzo[1,3]dioxo1-5-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 (THF) was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 C.
The mixture was then warmed to room temperature. After being stirred at room temperature for 1 hour, the reaction mixture was cooled to 0 C and treated with water (4.1 g), followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography to give (2,2-difluoro-benzo[1,3]dioxol-5-y1)-methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil.
FN/. alp OH SOCl2 F CI
/7\ FX.

[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 InT ) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 raL) 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. Fv" CN
[00286] (2,2-Difluoro-benzo[1,31dioxo1-5-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 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo[1,3]dioxo1-5-ye-acetonitrile (3.3 g) which was used directly in the next step.

CICH2CH2Br V
NaOH A F7 Fve CN __________ EN J. (10 CN \ = PP-F.
[00288] 1-(2,2-Difluoro-benzo[1,3]dioxo1-5-yI)-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-(22-difluoro-benzo[1,3]dioxol-5-y1)-cyclopropanecarbonitrile, which was used directly in the next step.
V NaOH V
Fx/. CN
/\= FX. ' F =
[00291] 1-(2,2-Difluoro-benzo[1,3]dioxol-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]dioxo1-5-y1)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS nilz calc. 242.04, found 241.58 (M+1); 1H NMR (CDC13) 5 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).
[00293] Example 3: 2-(2,2-Dimethylbenzo[d][1,3]dioxo1-5-yDacetonitrile NC so O>BBr3, DCM
311, NC OH 2,2-chmethoxy-propane NC OK
O OH p-Ts0H, toluene 0 N C)> ears, CCM
la NC
'Mr 0 1110 [00294] (3,4-Dihydroxy-phenyl)-acetonitrile [00295] To a solution of benzo[1,3]dioxo1-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH202 (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. HAI) (10 mL) was added to quench the reaction and the CH2C12 layer was separated. The aqueous phase was extracted with CH2C12 (2 x 7 mL). The combined organics were washed with 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. 1H
NMR (DMSO-d6, 400 MHz) 5 9.07 (s, 1 H), 8.95 (s, 1 H), 6.68-6.70 (m, 2 1-1), 6.55 (dd, J =
8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H).
NC OH 2,2-dimethexy-propane NC 1101 OH p-Ts0H, toluene [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 minol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H20, 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 lVfliz) 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 = V
OBn BrCH,CH,CI
__________________________ NC " OBn H2 OH OH
NaOH
____________________________________________________ HOD )1, NC
OBn OBn OH OH
NC
0 OBn BrCH2CH2Cl ___________________ NC
or = OBn OBn OBn [00299] 1-(3,4-Bis-benzyloxy-phenyl)-cyclopropanecarbonitrile [00300] To a mixture of (n-C4H9)4NBr (0.50 g, 1.5 mmol), toluene (7 mL) and (3,4-bis-benzyloxy-phenyl)-acetonitrile (14 g, 42 mmol) in NaOH (50 g) and 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 H20, 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 IVIFIz) 5 7.46-7.30 (m, 10 H). 7.03 (d, f = 8.4 Hz, 1 H), 6.94 (d, = 2.4 Hz, 1 H), 6.89 (dd, J = 2.4, 8.4 Hz, 1 H), 5.12 (d, J= 7.5 Hz, 4H), 1.66-1.62 (m, 2 H), 1.42-1.37 (m, 2 H).
V
OBn H2 OH
NC NC
Pd/C
OBn OH
[00301] 1-(3,4-Dihydroxy-pheny1)-cyclopropanecarbonitrile [00302] To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 28 mmol) in Me0H (50 raL) was added Pd/C (0.5 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 4 h. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give 1-(3,4-dihydroxy-phenyfl-cyclopropanecarbonitrile (4.5 g, 92%). 1H NMR (DMSO 400 MHz) 8 9.06 (br s, 2 H), 6.67-6.71 (m, 2 H), 6.54 (dd, J = 2.4, 8.4 Hz, 1 H), 1.60-1.57 (m, 2 H), 1.30-1.27 (m, 2 H).
V V
OH OH
NC so NaOH HOOC
=
OH OH
[00303] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid [00304] To a solution of NaOH (20 g, 0.50 mol) in 1120 (20 inL) was added 143,4-dihydroxy-phenyfl-cyclopropanecarbonitrile (4.4 g, 25 mmol). The mixture was heated at reflux for 3 h before being cooled to room temperature. The mixture was neutralized with 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-phenyl)-cyclopropanecarboxylic acid (4.5 g crude). From 900 mg crude, 500 mg pure 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic acid was obtained by preparatory HPLC. 1H NMR (DMSO, 300 MHz) 8 12.09 (br s, 1 H), 8.75 (br s, 2 H), 6.50-6.67 (m, 3 H), 1.35-1.31 (m, 2 H), 1.01-0.97 (m, 2 H).
[00305] Example 5: 1-(2-0xo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane-carboxylic acid.

=

HO vMe0H Me0 = v HNO2/Ac200._ Me0 = v NO2 E3Br, 111"11 OMe OMe OMe Me0 du NO2 Ni/H2 Me0 v NH2 trphosgenlei, Me0 N
0 0 IF 0 = OH OH O
DOH HO
0 oo Ho 0 10 Me0H
Me0 0 lb 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 nth) 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, J=
8.8 Hz, 2 H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (q, J= 3.6 Hz, 2 H), 1.15 (q, J= 3.6 Hz, 2 H).

HNO3/Ac20 Me NO2 11101 0 Si OMe OMe [00308] 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester [00309] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylie 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-phenyl)-cyclopropanecarboxylic 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, 1 H), 3.97 (s, 3 H), 3.65 (s, 3 H), 1.68-1.64 (m, 2 H), 1.22-1.18 (m, 2 H).

= Me* V
. = Ili NO2 BBr3 NO2 411111.11 OMe [00310] 1-(4-Hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic 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 mi ) was added 13Br3 (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 'V and stirred at this temperature for 3 hours. Water (50 mL) was added dropwise at ¨20 'V, and the resulting mixture was allowed to warm room temperature before it was extracted with Et0Ac (200 mT x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the cmde 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%). 1H NMR
(CDCI3, 400 MHz) 5 10.5 (s, 1 H), 8.05 (d, J= 2.4 Hz, 1 H), 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 (m, 2 H), 1.20-1.15 (m, 2 H).
V =
Mee NO2 NvH2 M-= NI-i2 ______________________________________________ )0-[00312] 1-(3-Amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00313] To a solution of 1-(4-hydroxy-3-nitro-pheny1)-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 vacuunz to give crude product, which was purified by column chromatography on silica = gel (petroleum ether/ethyl acetate 1:1) to give 1-(3-araino-4-hydroxy-pheriy1)-cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 1H NMR (CDC13,400 MHz) 8 6.77 (s, 1 H), 6.64 (d, J= 2.0 Hz, 2 H), 3.64 (s, 3 H), 1.55-1.52 (m, 2 H), 1.15-1.12 (m, 2 H).
V
Me0 NH2 triphosgen)._e .`"" No IWr OH VP 0 [00314] 1-(2-0xo-2,3-dihydro-benzooxazol-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 mL) was added triphosgene (4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0 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) 5 8.66 (s, 1 H), 7.13-7.12 (m, 2 H), 7.07 (s, 1 H), 3.66 (s, 3 H), 1.68-1.65 (m, 2 H), 1.24-1.20 (m, 2 H).
VL V OH =
Me0 /11=
c, 0 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 mT ) 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 mL x 3). The combined organic layers were dried over anhydrous Na2S0.4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane,carboxylic acid (1.5 g, 84%). 1H NMR
(DMSO, 400 MIL) 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, 1 H), 1.44-1.41 (m, 2 H), 1.13-1.10 (m, 2 H). MS (ESI) m/e (M+H+) 218.1.
[00318] Example 6: 1-(6-Fluoro-benzo[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid BBr OH H BrCH2CIADMI: H 0\ NaBH4 a._ HO o\
OH
soci,a o NaCN NC at 0 BrCH,CH2CI NC $F 0 1 0% NaOH EICX)0 ip 0\

OH
H o BBr3 H
OH
[00319] 2-Fluoro-4,5-dihydroxy-benza1dehyde [00320] To a stirred suspension of 2-fluoro-4,5-dimetboxy-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 so BrCH2CVDMF H 40.) [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 C 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 vacua to give crude product, which was purified by column chromatography on silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDC13) 10.19 (s, 1 H), 7.23 (d, J = 5.6, 1 H), 6.63 (d, J = 9.6, 1 H), 6.08 (s, 2 H).
0> NaBH4 HO 40 o>
H io [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 11101 S0012 Cl 0 \
__________________________________ P c [00324] 5-Ch1oromethy1-6-fluoro-benzo [1,3]dioxole [00325] (6-Fluoro-benzo[1,3]dioxo1-5-y1)-methanol (650 mg, 3.8 mmol) was added to S0C12 (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 S0Cl2 was evaporated under reduced pressure to give the crude product, which was basifted 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 Na2SO4 and evaporated under reduced pressure to give 5-chloromethy1-6-fluoro-ben7o[1,3]dioxole (640 mg, 90%), which was directly used in the next step.

401 0>
NaCN ow_ NC 1101 0F :>
[00326] (6-Fluoro-henzo[1,3]dioxo1-5-y1)-acetonitrile [00327] A mixture of 5-chloromethy1-6-fluoro-benzo[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 (5-10% ethyl acetate/petroleum ether) to afford (6-fluoro-benzoT1,31clioxo1-5-y1)-acetonitrile (530 mg, 70%). IH-NMR (300 MHz, CDC13) 5 6.82 (d, J
=4.8, 1 H), 6.62 (d, 5.4, 1 141. 5.99s. 2 H), 3.65(s, 2 14).
V
NC 11101 BrCH2CH2CI NC
= o) [00328] 1(6-Fluoro-benzo[1,3]dioxol-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 min period. The mixture was allowed to cool to room temperature. Subsequently, the flask was charged with toluene (6 mL), tetrabutyl-ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzoT1,31dioxo1-5-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-benzo[1,3]dioxo1-5-y1)-cyclopropanecarbonitrile (400 mg, 60%). 114 NMR
(300 MHz, CDC13) 8 6.73 (d, J= 3.0 Hz, 1 H), 6.61 (d, J= 9.3 Hz, 1 H), 5.98 (s, 2 H), 1.67-1.62 (m, 2 H), 1.31-1.27 (m, 2 H).
V
NC so 0> 10%NaOH HOOC 110 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 pH < 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[1,3]dioxo1-5-y1)-cyclopropanecarboxylic acid (330 mg, 76%). 1H NMR (400 MHz, DMSO) 8 12.2 (s, 1 H), 6.87-6.85 (m, 2 H), 6.00 (s, 1 H), 1.42-1.40 (m, 2 H), 1.14-1.07 (m, 2 H).
[00332] Example 7: 1-(Benzofuran-5-Acyclopropanecarboxylic acid Br..--'`r Et V
V HO
Me0 0 10 OEt OH NaH, DMF 110 0E, PPA, xylene HO
__________________________ )1, Br'T-OEt He Me0 11101 OH NaH, DMF 0 [101 Et OEt [00333] 144-(2,2-Dietboxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid [00334] To a stirred solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) at 0 C. After hydrogen evolution ceased, 2-bromo-1,1-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 C for 15 hours. The reaction mixture was poured onto ice (100 g) and was extracted with CH2C12. The combined organics were dried over Na2SO4. The solvent was evaporated under vacuum to give 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g), which was used directly in the next step without purification.
Ho PPA, xylene OEt [00335] 1-Benzofuran-5-yl-cyclopropanecarboxylic acid [00336] To a suspension of 144-(2,2-diethoxy-ethoxy)-phenyll-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 HTLC to provide 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 'FINMR (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 4101O Pt02, Me0H HO 0 [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-yficyclopropanecarboxylic acid (155 mg, 42%). 11-1 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 Hz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H).
[00339] Example 9: 1-(3,3-Dimethy1-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid.

VV
Me0 A1013/EtSH Me0 V NIS Me0 dlik. I

ipe OMe OH OH
( Me0 V eau., 0 n Bu3SnH Me0 I LIOH HO v - = A1C13/EtSH .=
0V 1.1 0 401 OMe OH
[00340] 1-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00341] To a solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (10.0 g, 48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mI ) 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%). 1H NMR (400 MHz, CDC13) 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 - =

OH OH
[00342] 1-(4-Hydroxy-3,5-diiodo-phenyl)-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 concentratell 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 MAR (400 MHz, CDC13) 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3 H), 1.59-1.56 (m, 2 H), 1.15-1.12 (m, 2 H).

-= asit. I
Me0 a& I
0 0 wpm OH
[00344] 1 -[3,5-Diiodo-4-(2-methyl-allyloxy)-pheny1]-cyclopropanecarboxylic 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), NaI (0.1 g, 0.7 mmol) in acetone (20 mL) was stirred at 20 C
overnight_ The solid was filtered off and the filtrate was concentrated under vacuum to give 1-[3,5-diiodo-4-(2-methyl-allyloxy)-phenylj-cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). 1H
NTMR (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).
-= 46.6 Bu3Sn H
O

= - =

[00346] 1-(3,3-Dimethy1-2,3-dihydro-benzofuran-5-y1)-cyclopropanecarboxylic acid methyl ester [00347] To a solution of 1-[3,5-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 MEN (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 2e1 (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%). 1H
NMR (400 MHz, CDC13) 6 7.10-7.07 (m, 2 H), 6.71 (d, J= 8 Hz, 1 H), 4.23 (s, 2 H), 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
-=
o 110 = LOH
= =

[00348] 1-(3,3-Dimethy1-2,3-dihydrobenzofuran-5-yDcyclopropanecarboxylic 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 Me0H (10 mL) was added LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40 C overnight. HC1 (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The extracts were washed with 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%).
IH NMR
(400 MHz, CDC13) 8 7.11-7.07 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H), 4.23 (s, 2 H), 1.66-1.63 (m, 2 H), 1.32 (s, 6 H), 1.26-1.23 (m, 2 H).
[00350] Example 10: 2-(7-Methoxybenzo[d][1,3]dioxo1-5-yDacetonitrile.
so OH CH,BrCI 0 Me0 110 OH Me2SO4 Me0 ________________________________________ Me0 5 uA,H4 OH Na2B407 OH 0 OH OMe OMe HO 0, sc.,, Cl soO NaCN NC

OMe OMe OMe Me0 =Me0 OH Me2SO4 0 OH
OH OH
OH Na2B407 [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 mL 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.
Me0 OH CH2Bra _______________________________________________ Me0 40 0>
OH NaOH 0 OMe OMe [00353] Methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate [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 C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 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[d][1,3]dioxole-5-carboxylate (12.6 g, 80%). 1H NMR (400 MHz, CDC13) 6 7.32 (s, 1 H), 7.21 (s, 1 H), 6.05 (s, 2 H), 3.93 (s, 3 H), 3.88 (s, 3 H).

LiAl H4 0) =
Me0 1110 > _______________________ OMe OMe [00355] (7-Methoxybenzo[d][1,3]dioxo1-5-yOmethanol [00356] To a solution of methyl 7-methoxybenzo[d][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 mL) successively. The slurry was filtered off and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzoki][1,3]dioxo1-5-yl)methanol (7.2 g, 52%). 1H
NMR (400 MHz, CDC13) 6 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90 (s, 3 H).
[40 o soa2 a OMe OMe [00357] 6-(Chloromethyl)-4-methoxybenzo[d][1,3]dioxole [00358] To a solution of SOC12 (150 mL) was added (7-methoxybenzo[d][1,31dioxol-5-yl)methanol (9.0 g, 54 mmol) 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 H), 4.51 (s, 2 H), 3.90 (s, 3 H).

Cl ell 0> NaCN NC

OMe OMe [00359] 2-(7-Methoxybenzo[d][1,3]dioxo1-5-yl)acetonitri1e [00360] To a solution of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g, 40 mmol) in DMS0 (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 Na2SO4and evaporated to give the crude product, which was washed with ether to afford methoxybenzo[d][1,31dioxo1-5-yl)acetonitrile (4.6 g, 45%). 1H NNW (400 MHz, CDC13) 5 6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 13C NMR (400 MHz, CDC13) 5 148.9, 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 OMe t-BuOK OMe [00362] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) at ¨78 C. The mixture was stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at ¨78 C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with Et0Ac (100 ni1 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%). 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). 13C NMR
(75 MHz, CDC13) 6 149.6, 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.

N
a BBr3 N 401 OBn a OMe OH
NC= BBr3 N 1101 CI CI
[00364] (4-Chloro-3-hydroxy-phenyeacetonitrile [00365] BBr3 (17 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in dichloromethane (120 m1 ) 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) 8 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Iiz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H), 5.15 (brs, 1H), 3.72 (s, 2 H).
Si Br OHNc OBn K
CO3, CH3CN
a 2 [00366] 2-(3-(Benzyloxy)-4-chlorophenyl)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-methoxyphenyeacetonitrile.

OBn S¨' OBn H 110 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 TosMEC (16.1 g, 82.6 mmol) in TIM (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) dropwise, and continued to stir for 1.5 hours at ¨78 C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with 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-methoxyphenyl)acetonitril (5.0 g, 48%). 1H
NMR (300 MHz, CDC13) 8 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). 13C NMR (75 MHz, CDC13) 6 149.6, 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.
0 Nc it H = Cl 0 NC =CI
t-BuOK OMe [00371] To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mT ) 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) 5 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.
[00372] Example 15: 2-(3-Fluoro-4-methoxyphenypacetonitrile.

11011 ,411 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 minol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at ¨78 C.
To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with 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-methoxyphenyl)acetonitrile (5.0 g, 58%). 'H NMR (400 MHz, CDC13) 8 7.02-7.05 (m, 2 H), 6.94 (t, J = 8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67 (s, 2 H). 13C NMR
(100 MHz, 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.
110 OH Mel, K2CO3 io OMe NBS Br AIBN, CCI4. OMe NaCN NC 40 OMe Cl ClC H OHlb sal 2 5 Cl H Mel, K2CO3 OMe CH3CN 111'-a Cl [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-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDC13) 7.22 (d, J 7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
OMe OMe NBS Br ______________________________ YIP'"
Al BN, CC14 CI CI
[00377] 4-Bromornethy1-1-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 AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 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 OMe Br Si NC =
NaCN
CI C2H5OH¨

CI
[00379] 2-(4-Chloro-3-methoxyphenyflacetonitrile [00380] To a solution of 4-bromomethy1-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C2H5OH (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 H20.
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-methoxyphenyl)acetonitrile (25 g, 48%). 1H 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 MeO
0 1110 Me0H
0 MOMCI Me al cl Na2CO3 OMe -R4' CS2 OMe 411112--PP OMe V
Me0 Me0 HO
OH TBSCI io OTBS LOH 40 C OH

OMe OMe Me0H/H20 OMe V V
= Me0H 0 0 a 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 mi.) 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) 7.25-7.27 (m, 2 H), 6.85 (d, J =
8.8 Hz, 2 H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (m, 2 H), 1.15 (m, 2 H).
V
Me0 MOMCI Me*
O cs OMe2 OMe [00384] 1-(3-Chloromethy1-4-methoxy-pheny1)-cyclopropanecarboxylic acid methyl ester [00385] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOM (29.1 g, 364 mmol) in CS2 (300 mi ) 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 CILC12 (150 mL x 3). The combined organic extracts were evaporated under vacuum to give 1-(3-chloromethy1-4-methoxy-pheny1)-cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next step without further purification.
Me= V
-=
Cl _1_4...Na C 3 1101 OH

OMe OMe [00386] 1-(3-Hydroxymethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester [00387] To a suspension of 1-(3-chloromethy1-4-methoxy-pheny1)-cyclopropanecarboxylie 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. HCI (2 mol/L) and extracted with Et0Ac (200 inL 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) ö 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).

Me0TBS
/11 e0M

OMe OMe [00388] 113-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]cyclopropane carboxylic acid methyl ester [00389] To a solution of 1-(3-hydroxymethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH2Cl2 (100 mL) were added imidazole (5.8 g, 85 mmol) and TBSC1 (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 to 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%). 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, 2 H), 3.81 (s, 3 H), 3.62 (s, 3 H), 1.57-1.60 (m, 2 H), 1.15- 1.18 (m, 2 H), 0.96 (s, 9 H), 0.11 (s, 6 H).
V V
-=H=

OMe Me0H/1-120 OMe [00390] 1-(3-Hydroxymethy1-4-methoxy-phenyl)-cyclopropanecarboxylic acid [00391] To a solution of 143-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyll-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 mol/L, 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.

= BrCICH2 0 la" H NaBH4/THF
H OMe BBr3 H
0 Mr .µ19 OH OH
CI CI CI
KO AI OH S0Cl2 = VI _ CI NaCN NC oC)>
--a-CI CI CI

ome BBr3 H H 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 'V 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
OH BrCICH2 = 10 H 401 <
=
OH
[00395] 7-Chlorobenzofd][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 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 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) 9.74 (s, 1 H), 7.42 (d, J- 0.4 Hz, 1 H), 7.26 (d, J= 3.6 Hz, 1 H), 6.15 (s, 2 H).

= 4611)) = 114)P
H NaBH4/THF /0 Ilk OH
a [00397] (7-Ch)orobenzo[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 TEE (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-14C1 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][1,31clioxol-5-yl)methanol, which was directly used in the next step.
(6 OH SOCl2 e = a = =
=
a [00399] 4-Chloro-6-(chloromethyl)henzo[d][1,3]dioxole [00400] A mixture of (7-chlorobenzo[d][1,3]-dioxo1-5-y1)methanol (5.5 g, 30 mmol) and S0C12 (5.0 mL, 67 mmol) 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.
= CI NaCN NC IP O\

=
CI Cl [00401] 2-(7-Chlorobenzo[d][1,3]dioxol-5-yeacetonitrile [00402] A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40 C for 1 h 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-chlorobenzo[d][1,3]dioxo1-5-yl)acetonitrile (3.4 g, 58%). 111 NMR 8 6.81 (s, 1 H), 6.71 (s, 1 H), 6.07 (s, 2 H), 3.64 (s, 2 H). 13 C-NMR 8149.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3,23.1.
[00403] Example 19: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarlboxylic acid.

. .

V tnmethylV
Me0 it NH2 orthoformate Me0 0 =
An, HO I\1.

41111" OH 0 0 trimethyl Me0 iso NH2 orthoformate Mee ______________________________________________ v._ OH
[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 e, 14.5 mmol) in DMF 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 mL 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 NMR (CDC13, 400 MHz) 8 8.09 (s, 1), 7.75 (d, J= 1.2 Hz, 1 H), 7.53-7.51 (m, 1 H), 7.42-7.40 (m, 1 H), 3.66 (s, 3 H), 1.69-1.67 (m, 2 H), 1.27-1.24 (m, 2 H).

- = AICI3 H9 )10*-,V

[00406] 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid [00407] To a solution of 1-benzooxaz,o1-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 m1 ) 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 NKR (DMSO, 400 MHz) 8 12.25 (brs, 1 H), 8.71 (s, 1 H), 7.70-7.64 (m, 2 H), 7.40 (dd, J= 1.6, 8.4 Hz, 1 H), 1.49-1.46 (m, 2 H), 1.21-1.18 (m, 2 H). MS
(ESI) ink (M+H+) 204.4.
[00408] Example 20: 2-(7-Fluorobenzo[d][1,3]dioxo1-5-yl)acetonitrile OH
H a.' Bar, H BrCH,Cl/DM; H = (õ) NaBH4 HO = Cj>
OH OH
O
BOC12 CI NaCN NC
OH
H BBr3 H *
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 mI ) was added BBr3 (1.5 mI , 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-benm 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-earbaldehyde [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 nip was added Cs2CO3 (12.6 g, 39 msnol). 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[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR
(300 MHz, CDC13) 5 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).

40 0> NaBH4 ____________________________________ HO 410 o>

[00413] (7-Fluoro-benzo[1,3]dioxo1-5-y1)-methanol [00414] To a solution of 7-fluoro-benzo{1,3]dioxole-5-carbaldehyde (0.80 2, 4.7 mmol) in Me0H (50 mL) was added NaBH4 (0.36 2, 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[1,3]dioxol-5-y1)-methanol (0.80 g, 98%), which was directly used in the next step.
soa2 0 Hs so 00>
O

[00415] 6-Chloromethy1-4-fluoro-benzo[1,3]dioxole [00416] To SOC12 (20 mT ) was added (7-fluoro-benzo11,31dioxol-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 S0Cl2was evaporated under reduced pressure to give the etude 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.
> ________________________ NaCN=
NC >
[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][1,3]dioxo1-5-y1)acetonitrile (530 mg, 70%). 1H NMR (300 MHz.
CDCI3) 6 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 VKr4D3 V V
Ts1- 1 HO ________________________ -= -= Panney 11 110 0_ 1 SI lb.
Ay 0 C,H3OH 0 H2SO4/01-12C12 0 lo V V -= V " SlMe3 Me0 NBS. -= " Br _ sme3 0 .
_______________________________ l= 0 vo. 0 WI
4111)111 NH2 EI3N

V= V
C,u1 -= LiOH
________________________ V. \ _______ I" \

DMF 0 Oil N CH3OH 0 N
H
H
V V
HO 0 Me0 Ts0H
)10-[00420] Methyl 1-phenylcyclopropanecarboxylate [00421] To a solution of 1-phenylcyclopropane,carboxylic acid (25 g, 0.15 mol) in CH3OH
(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) ö 7.37-7.26 (m, 5 H), 3.63 (s, 3 H), 1.63-1.60 (m, 2 H), 1.22-1.19 (m, 2 H).
V V
Me= KNO3 M - =
0 0 {-I 0 /C:1-I r.1111. 0 0 ..2S.._ 4 - -2-.2 [00422] Methyl 1-(4-nitrophenyl)cyclopropanecarboxylate [00423] To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in H2S0.4/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 mL 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 H), 3.64 (s, 3 H), L72-1.69 (m, 2 H), 1.25-1.22 (m, 2 H).
Me0 Ranney Ni Me() O
NO2 _____________________________ 011.-[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-aminophenyficyclopropanecarboxylate (11.38 g, 66%).
1H NMR (300 MHz, CDCI3) 6 7.16 (d, J= 8.1 1-12, 2 H), 6.86 (d, J= 7.8 Hz, 2 H), 4.31 (br, 2 H), 3.61 (s, 3 H), 1.55-1.50 (m, 2 H), 1.30-1.12 (m, 2 H).
Me0 V
Br Me0 [00426] Methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate [00427] To a solution of methyl 1-(4-aminophenyl)cyclopropanecarboxylate (10.38 g, 0.05 mol) in acetonitrile (200 mL) was added NBS (9.3 g, 0.05 mol) at room temperature. The mixture was stirred overnight. Water (200 mL) was added. The organic layer was separated and the aqueous phase was extracted with 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. 11-1 NMR (400 MHz, CDC13) 8 7.38 (d, J = 2.0 Hz, 1 H), 7.08 (dd, J =
1.6, 8.4 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 3.62 (s, 3 H), 1.56-1.54 (m, 2 H), 1.14-1.11(m, 2 H).
V
Me Me* SiMe3 = Br 0 00- ____________ 0 NH2 Et3N NH2 [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 mL x 3).
The filtrate was evaporated under reduced pressure to give a residue, which was purified by chromatography column on silica gel (petroleum ether/ethyl acetate =20:1) to give methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.8 g, 56%). 1H NMR
(300 MHz, CDC13) 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).
V
Me0 SiMe3 Cut Me0 Si [00430] Methyl 1-(1H-indo1-5-yl)cyclopropanecarboxylate [004311 To a degassed solution of methyl 1-(4-amino-3-((trimethylsilyflethynyl)phenyl) cyclopropanecarboxylate (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%). 1H NMR (400 MHz, CDC13) 5 7.61 (s, 1 H), 7.33 (d, J= 8.4 Hz, 1 II), 7.23-7.18 (m, 2 H), 6.52-6.51 (m, 1 H) 3.62 (s, 3 H), 1.65-1.62 (m, 2 H), 1.29-1.23(m, 2 H).
V HO V
Me0 LiOH
\
CH3OH )1' 0 lb [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 CH3OH (50 m L) and water (20 mL) was added LiOH (1.7 g, 0.04 mol).
The mixture was heated at 45 C for 3 hr. Water was added and the mixture was acidified with concentrated HO 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 NMR (300 MHz, DMSO-d6) 7.43 (s. 1 H), 7.30-7.26 (m, 2 H), 7.04 (dd, 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
meo2 me io 0,-i< .2. 0 20% Ha OH Na 0(0.,2 me.2 (:{,, HOOC
OH
=
=

Me02C meo 2 SI ,)OL
'4r OH Na 0 02 [00435] 114-(2-tert-Butoxycarbonyl-ethoxy)-phenA-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 C 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). 1H
NMR (300 MHz, CDC13) 7.24 (d, J.8.7 Hz, 2 H), 6.84 (d,J =8.7 Hz, 2 H), 4.20 (t,J=
6.6 Hz, 2 H), 3.62 (s, 3 H), 2.69 (t, J= 6.6 Hz, 2 H), 1.59-1.56 (m, 2 H), 1.47 (s, 9 H), 1.17-1.42 (m, 2 H).
V V
Me02C Si 0 20% HCI Me02C 101 0 0)(0 0 OH
[00437] 144-(2-Carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester [00438] A solution of 1-[4-(2-tert-butoxycarbonyl-ethoxy)-pheny1]-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 1-[4-(2-carboxy-ethoxy)-phenyl]-cyclopropane,carboxylic methyl ester (5.0 g, 96%). 111 NMR (300 MHz, DMSO) 8 7.23-7.19 (m, 2 H), 6.85-6.81 (m, 2 H), 4.13 (t, J= 6.0 Hz, 2 H), 3.51 (s, 3 H), 2.66 (t, J= 6.0 Hz, 2 H), 1.43-1.39 (m, 2 H), 1.14-1.10 (m, 2 H).
V V
meo2c 0 (C0C1)2 HOOC
411111-Arr 0 OH 0 [00439] 1-(4-0xochroman-6-yl)cyclopropanecarboxylic acid [00440] To a solution of 144-(2-carboxy-ethoxy)-phenyll-cyclopropanecarboxylic methyl ester (5.0 g, 20 mmol) in CH2C12 (50 mL) were added oxalyl chloride (4.8 g, 38 mrnol) and two drops of DMF at 0 C. The mixture was stirred at 0-5 'V 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 C 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-yecyclopropane-carboxylic acid: 1H NMR (400 MHz, DMSO) 6 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-ypcyclopropanecarboxylate: 1H NMR (400 MHz, CDC13) 8 7.83 (d, J = 2.4 Hz, 1 H), 7.48 (dd, J = 2.4, 8.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.55-4.52 (m, 2 H), 3.62 (s, 3 H), 2.80 (t, J= 6.4 Hz, 2 H), 1.62-1.56 (m, 2 H), 1.18-1.15 (m, 211).
[00441] Example 23: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid VLiOH V HO Me =Me02C =

_____________________________________ HOOC
40 .

[00442] 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid [00443] To a solution of methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate (1.0 g, 4.1 mmol) in Me0H (20 mL) and water (20 mL) was added Li01-1.1-120 (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 HC1 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-yl)cyclopropanecarboxylic acid (480 I112, 44%). 1H NMR (400 MHz, CDC13) 8 12.16 (s, 1 H), 7.73 (d, J= 2.0 Hz, 1 H), 7.47 (dd, J = 2.0, 8.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 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, 2H). MS (ESI) miz (M+H ) 263.1.
[00444] Example 24: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyc1opropanecarboxy1ic acid Me00C 00 NaBH4rTFA meopc LOH HOOC
0 $0 =
Me00C =NaBH4/TFA meooc [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 Na2SO4 and evaporated under vacuum to give 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 92%), which was used directly in the next step.
NMR (300 MHz, CDC13) 6 7.07-7.00 (m, 2 H), 6.73 (d, J= 8.4 Hz, 1 H), 4.17 (t, J= 5.1 Hz, 2 H), 3.62 (s, 3 H), 2.79-2.75 (m, 2 H), 2.05-1.96 (m, 2 H), 1.57-1.54 (m, 2 H), 1.16-1.13 (m, 2H).
V V
Me00C 401 LiOH HOOC
=
[00447] 1-(4-Hydroxy-4-methoxychroman-6-yl)cydopropanecarboxylic acid [00448] To a solution of 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 60 mmol) in Me0H (20 mL) and water (20 mL) was added Li01-1.1-120 (1.0 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 HC1 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-methoxyclaroman-6-yl)cyclopropanecarboxylic acid (1.0 g, 76%). 1H
NMR (400 MHz, DMSO) 6 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 (ESI) m/z (M+H+) 217.4.
[00449] Example 25: 1-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid V V V

HOOC 1110 Me0s0H Me00C io = AlC13/AcCI meopc 40 OMe OMe OH
,OH ,OAc V N V V

Me00C 1111 Ac0 111 Me00C Py/DMF ________________ Me00C 110 \ N

OH .411111)rr OH
V
HOOC = N
0' VV
Me00C 01, AlC13/AcCI Me00C 41, 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 min, methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (15 g, 73 mmol) was added. The reaction mixture was heated at reflux for 2 h before ice water was added carefully to the mixture at room temperature. The resulting mixture was extracted with 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) 6 12.28 (s, 1 14), 7.67 (d, J = 2.0 Hz, 1 H), 7.47 (dd, J = 2.0, 8.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 3.64 (s, 3 H), 2.64 (s, 3 H), 1.65-1.62 (m, 2 H), 1.18-1.16(m, 2 H).
N,OH

V V
Me000 = NH2OH so=HCI Me00C
OH OH
[00452] 144-1-1ydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester [00453] To a stirred solution of 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (14.6 g, 58.8 mmol) in Et0H (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)-phenyThcyclopropanecarboxylic methyl ester (14.5 g, 98%), which was used in the next step without further purification. 11-1NMR
(CDC13, 400 MHz) 6 11.09 (s, 1 H), 7.39 (d, J= 2.0 Hz, 1 H), 7.23 (d, J= 2.0 Hz, 1 H), 7.14 (s, 1 H), 6.91 (d, J= 8.4 Hz, 1 II), 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
V N., V
Me00C = Ac20 Me00C io OH OH
[00454] (E)-Methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane carboxylate [00455] The solution of 144-hydroxy-3-(1-hydroxyimino-ethyl)-phenyll-cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac20 (250 mL) was heated at 45 C 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 14341-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%), which was used in the next step without further purification.

N,OAc V V
Me000 110 Py/DMF Me000 401 N
OH
[00456] Methyl 1-(3-methylbenzo[drisoxazol-5-yl)cyclopropanecarboxylate [00457] A solution of (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane carboxylate (10.5 g, 39.6 mraol) and pyridine (31.3 g, 396 mmol) in DMF (150 mL) was heated at 125 'DC for 10 h. The cooled reaction mixture was poured into water (250 mL) and 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 50:1) to give methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate (7.5 g, 82%). 1H NMR (CDC13300 MHz) 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, 211).
V V
LiOH
Me00C (1101 NN ______________________ HOOC = N
[00458] 1-(3-Methylbenzo[d]isoxazol-5-yecyclopropanecarboxylic acid [00459] To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5-yficyclopropanecarboxylate (1.5 g, 6.5 nunol) in Me0H (20 inf ) and water (2 mL) was added Li011.1120 (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 mL 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, DMS0) 8 12.40 (br s, 1 H), 7.76 (s, 1 H), 7.60-7.57 (m, 2 H), 2.63 (s, 3 H), 1.52-1.48 (m, 2 H), 1.23-1.19 (m, 2H). MS (ESI) inh (M+H+) 218.1.
[00460] Example 26: 1-(Spiro[benzo[d][1,3]dioxole-2,1`-cyc1obutane]-5-yl)cydopropane carboxylic acid V V Lr0 OHMeOH OH meooc 40 HOOC
OH OH
V
v-MeCOC HOOC
111.
qr. O \*/ \ LOH IIIP) \/
V V
OH OH
HOOC Me0H Me00C
OH OH
[00461] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester [00462] To a solution of 1-(3,4-dihydroxypheny0cyclopropanecarboxylic acid (4.5 g) in Me0H (30 mL) was added Ts0H (0.25 g, 1.3 mmol). The stirring was continued at overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). 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).
VV
Me00C di OH Eir l\
______________________________ )1. Me00C 0\/\

ir 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 mL) 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-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)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
Me000 LiOH 1101 /x HOOC
\*/ 0 [00465] 1-(Spiro[benzo[d][1,3]dioxole-2,11-cyclobutane]-5-yl)cyclopropane carboxylic acid [00466] To a mixture of methyl 1-(spiro[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]-yl)cyclopropane carboxylic acid (330 mg, 59%). 111-NMR (400 MHz, CDC13) 6 6.78-6.65 (m, 3 H), 2.65-2.58 (m, 4 H), 1.86-1.78 (m, 2 H), 1.63-160 (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 Ail CO2B BrH2CCH2Br co CO2Et LAH r= " OH
= III" = Co 411"
SOCl2 r=
a C2_41 C. All C,N
Co II" = IP
HO CO2Et BrH2GCH2Br c0 CO2Et = )110, =
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 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80 C overnight and then poured into ice-water. The mixture was extracted with 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]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDC13) 6 7.53 (dd, J = 1.8, 7.2 Hz, 2 H), 6.84-6.87 (m, 1 H), 4.22-4.34 (m, 6 H), 1.35 (t, J = 7.2 Hz, 3 1-1).

= 10 CO2Et LAH c OH
[00470] (2,3-Dihydro-benzo[1,4]dioxin-6-yI)-methano1 [00471] To a suspension of LiA1H4 (2.8 g, 74 mmol) in THF (20 m1 ) was added dropwise a solution of 2.3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 C under N7. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling.
The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-y1)-methanol (10.6 g). 1H NMR (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 H).
= sac!, [00472] 6-Chloromethy1-2,3-dihydro-benzo[1,4]dioxine [00473] A mixture of (2,3-dihydro-benzo[1,41dio)dn-6-yl)methanol (10.6 g) in SOC12 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water.
The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3).
The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethy1-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
= NaCN =
CN
=
[00474] 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-Aacetonitrile [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 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL x 4). The combined organic layers were washed with water (50 m1 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][1,41dioxin-6-yl)acetonitrile as a yellow oil (10.2 g, 86%). 111-NMR (300 MHz, CDC13) 8 6.78-6.86 (m, 3 H), 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- Ho carboxylic acid 11 () 1-(2,2-difluorobenzo[1,3]dioxo1-5- H= 0 0,inF
yl)cyclopropane-l-carboxylic acid q o 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic fp, H
acid 4/1 =H
1-(3-methoxyphenyl)cyclopropane-1-carboxylic Ho 0 ()¨

acid 11 =
HO
1-(2-methoxyphenyl)cyclopropane-1-carboxylic =
acid c) 144-(trifluorometboxy)phenyl]cyclopropane-1-Tr carboxylic acid F
Fl"-= HO
1-(2,2-dimethylbenzo[d][1,3]dioxo1-5- = 11 yl)cyclopropanecarboxylic acid = = OH
=
tetrahydro-4-(4-methoxypheny1)-2H-pyran-4- \= =
carboxylic acid =-=-= OH
OH gib 1-phenylcyclopropane-1-carboxylic acid =
1-(4-metboxyphenyl)cyclopropane-1-carboxylic OH
acid 4101 =

Name Structure 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid ci 1-(3-hydroxyphenyl)cyclopropanecarboxylic He 0 OH
acid =
1-phenylcyclopentanecarboxylic acid OH
=
1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5- = OH 14.,,r0 ypcyclopropanecarboxylic acid =o H= 0 1-(benzofuran-5-yl)cyclopropanecarboxylic acid =

1-(4-methoxyphenyl)cyclohexarie,carboxylic acid \= =

= OH
1-(4-chlorophenyl)cyclohexanecarboxylic acid c Ai =
OH
1-(2,3-dihydrobenzofuran-5- H= 0 yl)cyclopropanecarboxylic acid 1-(3,3-dimethy1-2,3-dihydrobenzofuran-5 =
-yl)cyclopropanecarboxylic acid = OH
¨0 1-(7-methoxybenzo[d][1,3]dioxo1-5-=
yl)cyclopropanecarboxylic acid 0 = H=
1-(3-hydroxy-4- = OH OH
methoxyphenyl)cyclopropanecarboxylic acid Name Structure 1-(4-chloro-3- .....
hydroxyphenyl)cyclopropane,carboxylic acid H.
1-(3-(benzyloxy)-4-= 0 chlorophenypcyclopropanecarboxylic acid 'p0 a 1-(4-chlorophenyl)cyclopentanecarboxylic acid c . =
41.-- OH
=1 1- (3-(benzyloxy)-4-.1 A
methoxyphenypcyclopropanecarboxylic acid 0 . .¨

OH
1-(3-chloro-4- ....... 01-1 a methoxyphenyl)cyclopropanecarboxylic acid 1 . R
1-(3-fluoro-4- ...., oi-i F
methoxyphenyl)cyclopropanecarboxylic acid I . R
1-(4-methoxy-3- ...., OH
methylphenyl)cyclopropane,carboxylic acid 1'I. =
c:{
= 0 1-(4-(benzyloxy)-3- 0 .
methoxyphenyl)cyclopropanecarboxylic acid H=
A
1-(4-chloro-3- 01-1 0¨

methoxyphenyl)cyclopropanecarboxylic acid 41 II 1 1-(3-chloro-4- = cm CI
hydroxyphenyl)cyclopropanecarboxylic acid 11 IP OH
1-(3-(hydroxymethyl)-4- ...... OH
OH
methoxyphenyl)cyclopropanecarboxylic acid 1 IF R

Name Structure 1-(4-methoxyphenyl)cyclopentanecarboxylic = =
acid = OH
1-phenylcyclohexanecarboxylic acid =
= OH
1-(3,4-dimethoxyphenyl)cyclopropanecarboxylic 4,, OH 0--acid 4 II ck H. CL-7 1-(7-chlorobenzo[d][1,3]dioxo1-5-o yl)cyclopropanecarboxylic acid 1-(benzo[d]oxazol-5-ypcyclopropane,carboxylic H= 0 acid H.
1-(7-fluorobenzo[d][1,3]dioxo1-5-o = O
yl)cyclopropanecarboxylic acid 1-(3,4-difluorophenyl)cyclopropanecarboxylic H. F
acid 11 F
H.
1-(1H-indo1-5-yl)cyclopropanecarboxylic acid 111 NH
1-(1H-benzo[d]imidazol-5- H. 0 r\.7 /I NH
yl)cyclopropanecarboxylic acid 4 1-(2-methyl-1H-benzo[d]imidazol-5- H.
yl)cyclopropanecarboxylic acid q NH
1-(1-methyl-1H-benzokijimidazol-5- H. o yl)cyclopropanecarboxylic acid 4 11 Nj`

Name Structure 1-(3-methylbenzo[d]isoxazol-5- Ho ¨N
yl)cyclopropanecarboxylic acid 84 1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutanej- H. j:i 5-yl)cyclopropanecarboxylic acid 1-(1H-benzo[d][1,2,3]triazol-5- H. 0 /
.NH
yl)cyclopropanecarboxylic acid if 1-(1-methyl-1H-benzo[d][1,2,3]triazol-5- H.
yl)cyclopropanecarboxylic acid 1-(1,3-dihydroisobenzofuran-5- H= o yl)cyclopropanecarboxylic acid 11 IP
H= C) '3-3 1-(6-fluorobenzo[d][1,3]dioxo1-5-lik yl)cyclopropanecarboxylic acid 111 F
1-(2,3-dihydrobenzofuran-6- H. il yl)cyclopropanecarboxylic acid 4 IP
H. o 1-(chroman-6-yl)cyclopropanecarboxylic acid 4 lik =
-.. OH
1-(4-hydroxy-4-methoxychroman-6- =
H.
yl)cyclopropanecarboxylic acid 4 4/ =
=
1-(4-oxochroman-6-yl)cyclopropanecarboxylic= o \
acid If II =
1-(3,4-dichlorophenyl)cyclopropanecarboxylic H. I
/1, a acid 4 Name i Structure 1-(2,3-dihydrobenzo[b])1,4]dioxin-6- H= 0 o yl)cyclopropanecarboxylic acid 41).
= =
H =
1-(benzofuran-6-yl)cyclopropanecarboxylic acid WI
[00477] Specific Procedures: Synthesis of aminoindole building blocks [00478] Example 28: 3-Methy1-1H-indo1-6-amine 411 NaNO2/HCI
N,N
SnCl2 02N NH2 HCI

Akt 401 I H2/Pd-C Oi i earl I +02N N H2N
NaNO2/HCI
N,NH2_ Ha SnCl2 02N

[00479] (3-Nitro-phenyl)-hydrazine hydrochloride salt [00480] 3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in the mixture of H20 (40 mL) and 37% HO (40 mL). A solution of NaNO2 (13.8 g, 0.2 mol) in H20 (60 mL) was added to the mixture at 0 C, and then a solution of SnC12.H20 (135.5 g, 0.6 mol) in 37% HC1 (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)hydra zine hydrochloride (27.6 g, 73%).
4111 NH2. HO _______ )10. ,N

[00481] N-(3-Nitro-phenyl)-N'-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 mL) until pH 6.
Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol).
After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain (E)-1-(3-nitropheny1)-2-propylidenehydrazine, which was used directly in the next step.
No2 = H? 4 41111 4_ 01 I

[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 %
H3PO4 (20 raL) 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 g in total, 86 %, two steps from (3-nitrophenyl)hydrazine hydrochloride] which was used to the next step without further purification.

el I H2/Pd-C

= + 02N N H2N
[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 H, (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%). 1H NMR
(CDC13) 8 7.59 (br s. 1H), 7.34 (d, J=e 8.0 Hz, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.57 (m, 1H), 3.57 (brs, 2H), 2.28 (s, 3H); MS (ESI) Ink (M+H+) 147.2.
[00487] Example 29: 3-tert-Butyl-1H-indo1-5-amine Raney Ni/H2 =
N a3/CH202 1110 N
02N Ali \ 8+ 0.02N Ali N n03cF4202 [00488] 3-tert-Butyl-5-nitro-1H-indole [00489] To a mixture of 5-nitro-1H-indole (6.0 g, 37 mmol) and AlC13 (24 g, 0.18 mol) in CH2C12 (100 mL) at 0 C was added 2-bromo-2-methyl-propane (8.1 g, 37 mmol) dropwise.
After being stirred at 15 C overnight, the mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with 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-buty1-5-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDC13, 400 MHz) 5 8.49 (d, J =
1.6 Hz, 1 H), 8.31 (brs, 1 H), 8.05 (dd, J = 2.0, 8.8 Hz, 1 II), 7.33 (d, J = 8.8 Hz, 1 H), 6.42 (d, J = 1.6 Hz, 1 H), 1.42 (s, 9 H).
02N is Raney Ni/H2 H2N =
N
[00490] 3-tert-Butyl-1H-indo1-5-amine [00491] To a solution of 3-tert-butyl-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) 6 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 H), 6.09 (d, J= 1.6 Hz, 1 H), 1.37 (s, 9 H); MS (ESI) m/e (M+1-1+) 189.1.
[00492] Example 30: 2-tert-Butyl-6-fluoro-1H-indo1-5-amine and 6-tert-butoxy-2-tert-butyl-1H-indo1-5-amine 0,N Br 0 __ = \c- 0.2 WI N =
<2' Ail Br2 tAlk -';'.-111111r1 NH2 NH2 F NH2 H
02N H2N so TBAF \ NI \
DMF N
F ill 1 N H
H
-Yr.-L \ BuOK 02N idu \ NI
H2N flail 7 MIPP-- N = I.' H
H

0 Br Br2 -Ix-[00493] 2-Bromo-5-fluoro-4-nitroanitine [00494] To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise 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-nitroaniline (9 g, 90%). 1H-NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J= 9.6 Hz, 1H).
02N 40, Br = __ ----02N, [00495] 2-(3,3-Dimethylbut-1-yny1)-5-fluoro-4-nitroaniline [00496] A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(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-dimethylbut-1-yny1)-5-fluoro-4-nitroaniline (4.2 g, 46%). 1H-NMR (400 MHz, DMSO-d6) 8 7.84 (d, J = 8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J= 14.4 Hz, 1H), 1.29 (s, 9H).

02N ra F lir NH2 [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 mL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmoI) 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-1-yny1)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was used in the next step without further purification.

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-nitrophenyl)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 niL 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-1H-indole (1.5 g, 65%). 1H-NMR (400 MHz, CDC13) 5 8.30 (d, Jr 7.2 Hz, 11-1), 7.12 (d, J= 11.6 Hz, 1H), 6.35 (d, J = 1.2 Hz, 111), 1.40 (s, 9H).
o2N

F F 41111"
[00501] 2-tert-Butyl-6-fluoro-1H-indo1-5-amine [00502] A suspension of 2-tert-buty1-6-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-1H-indo1-5-amine (520 mg, 38%). 1H-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, 911);
MS (ESI) m/e 206.6.
cD2N
02N BuOK
0 111.
F 411111"
[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 mL) was heated at 70 C
for 2 h. The mixture was poured into water and then extracted with Et0Ac (50 inL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), 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 MHz, DMSO-d6) 8 11.35 (brs, 1H), 7.99 (s, 1H), 7.08 (s, HI), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
o2N
14411I Raney Ni H2N afah [00505] 6-tert-Butoxy-2-tert-butyl-1H-indo1-5-amine [00506] A suspension of 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 0.36 mmol) and Raney Ni (0.5 g) in Me0H (15 mI ) 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 MHz, 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 H284¨ 02N _ 02N =
02N at Br2 / AcOH 02N 0 Br 411" NH _____________________________ NH
F
Pd(PPl-13)2012 NH

Cul, DMF 31101 \ Raney NC H2 N
H2N¨K-- 02N so 02N aoNH
[00508] N-tert-Buty1-4-nitroaniline [00509] A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75 C overnight. The mixture was poured into water (10 mL) and extracted with 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%). 1H NMR (CDC13, 400 MHz) 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
02N o2N Br Br2 / AcOH
NH _______________________________ NH
[00510] (2-Bromo-4-nitro-phenyl)-tert-butyl-amine [00511] To a solution of N-tert-buty1-4-nitroaniline (1 g, 5.1 mmol) in AcOH
(5 mL) was added Br2 (0.86 g, 54 mmol) dropwise at 15 C. After addition, the mixture was stirred at 30 C for 30 min and then filtered. The filter cake was basified to pH 8-9 with aqueous 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 (CDC13, 400 MIL) 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).

Si, 02N so Br - __________________ /1_ a 02N
NH
Pd(PPh3)2C12 NH
[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 Na2SO4 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) 8 8.20 (d, J = 2.4, 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.

Cul, DMF 02N 40 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 mmol) in DMF (2 mL), 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-butyl-5-nitro4H-indole (7 mg, 93%). 1H-NMR (CDC13, 300 MHz) 8 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 _________________________________ )01, [00516] 1-tert-Butyl-1H-indo1-5-amine [00517] To a solution of 1-tert-buty1-5-nitio-1H-indole (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 (PE/Et0Ac 1:2) to give 1-tert-buty1-1H-indol-5-amine (2.5 g, 45%). 1H-NMR (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, 111), 1.67 (s, 9H).
MS (ESI) m/e (M+H+) 189.2.
[00518] Example 32: 2-tert-Butyl-1-methyl-1H-indol-5-amine 02N " 02N" Br NH LIW NH
Br2/HOAc 02N "
111)111 NH
Ni/H, H2N

=
N
02N 02N Br = Br2/HOAc ________________________________ 11.
NH NH
[00519] (2-Bromo-4-nitro-phenyl)-methyl-amine [00520] To a solution of methyl-(4-nitro-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 m1 x 3), and the combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-amine (2-bromo-4-nitro-phenyfi-methyl-amine (23.0 g, 99%), which was used in the next step without further purification. 1H NMR (300 MHz, CDC13) 5 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, J =
5.4 Hz, 3 H).
Br =.2N 40 __________________________________ 02N ilk =
NH
NH
[00521] [2-(3,3-Dimethyl-but-1-ynyI)-4-nitro-pheny1]-methyl-amine [00522] To a solution of (2-bromo-4-nitro-phenyl)-methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) were added 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 mmol) successively under N2 protection. The mixture was heated at 70 C for 3 hours and then cooled down to room temperature. The resulting mixture was extracted with Et0Ac (100 m1 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, 3H), 1.35 (s, 9H).
0 TBAF .2N io 2N id.
1111111" 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-amine (5.0 g, 22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THF (50 mL) was heated at reflux overnight.
The solvent was removed by evaporation under vacuum and the residue was dissolved in brine (100 mL) and 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 Hz, 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).
.2N 40 H2N
Raney Ni/H2 [00525] 2-tert-Butyl-1-methyl-1H-indol-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 ovemight. The mixture was filtere,d through a Celite pad and the filtrate was evaporated under vacuum.
The crude residue was purified by column chromatography on silica gel (P.E/Et0Ac 20:1) to give 2-tert-butyl-1-methy1-1H-indo1-5-amine (1.7 g, 66%). 1H NMR (300 MHz, CDCI3) 8 7.09 (d, J =
8.4 Hz, 1H), 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 (ESI) m/e (M+1-1+) 203.1.
[00527] Example 33: 2-Cyclopropy1-1H-indol-5-amine 02N Br2, HOAc 02N = Br ¨,11 02N =
butyryl chloride ________________ Yrs NH2 r.t. NH, Cul, Et3N NH2 Pd(PPh3)C12 H2N io 02N = 02N =

Raney Ni 0 TBAF \ 1 110 \ A, ___________________________________ 02N 40 02N Br Br2, HOAc NH 2 r.t. N H2 [00528] 2-Bromo-4-nitroaniline [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 ml), 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-nitroaniline (30 g, 80%), which was directly used in the next step.
02N io Br 02N
NH2 Cul, Et3N 4" NH2 Rd(RITh3)C12 [00530] 2-(CyclopropylethynyI)-4-nitroaniline [00531] 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 triethylanaine (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 mg, 23%). 1H NMR (300 MHz, CDC13) 8 8.14 (d, J = 2.7 Hz, 1H), 7.97 (dd, J= 2.7, 9.0 Hz, 1H), 6.63 (d, J= 9.0 Hz, lIT), 4.81 (brs, 2H), 1.55-1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).

butyryl chloride. 02N

[00532] N-(2-(Cyclopropylethynyl)pheny1)-4-nitrobutyramide [00533] To a solution of 2-(cyclopropylethyny1)-4-nitroaniline (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 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 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 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, 111), 2.46 (t, J= 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 1.59-1.53 (m, 1H), 1.06 (t, J
7.2 Hz, 3H), 1.03-1.01 (m, 2H), 0.91-0.87 (m, 2H).

02N rai 0 110 \
tq"
[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 inL) 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-1H-indole (1.3 g, 64%). 1H NMR (400 MHz, CDC13) 8 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 =
Raney NI
H2N =
\ \ 4 [00536] 2-Cyclopropy1-1H-indo1-5-amine [00537] To a solution of 2-cyclopropy1-5-nitro-1H-indole (1.3 g, 6.4 mmol) in Me0H (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-Buty1-1H-indo1-5-amine o2N soBr _______________ 02N Raney Ni/H2 H2N =

=Br __________________________________ 02N
N Al0L3/01-12012 N
[00539] 3-tert-Butyl-5-nitro-111-indole [00540] To a mixture of 5-nitro-1H-indole (6 g, 36.8 nunol) and A1C13 (24 g, 0.18 mol) in CH2C12 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 numol) 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 mT 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%). 111 NMR (CDC13, 400 MHz) 8 8.49 (d, J= 1.6 Hz, 111), 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, 111), 1.42 (s, 9H).

02N 40 Raney NI/H2 H2N
=
[00541] 3-tert-Butyl-111-indo1-5-amine [00542] To a solution of 3-tert-buty1-5-nitro-1H-indole (2.5 g, 11.6 mmol) in Me0H (30 mI ) 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) 8 7.72 (brs, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.0 I-1z, 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-1-1-1+) 189.1.
[00543] Example 35: 2-Phenyl-1H-indo1-5-amine Ph 0 02N 02N Br 02N
= __ Ph Br2 _________________________________ W.-NH2 AcOH NH2 Et3N

Ph 02N H2N so Ph so 0 TBAF
101 N\ ph Raney Ni __________________________________________ VP-02N so Br2/HOAC 02N so Br [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.

rttuNZUU9/06.14 /3 Ph 02N Br _____________________________ Ph __________________________________ )11.-NH2 Et3N

[00546] 4-Nitro-2-(phenylethynyl)aniline [00547] To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), 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 tarnol) 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)aniline (340 mg, 14%). 1H NNW (300 MHz, CDCI3) 6 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H), 7.56-7.51 (m, 211), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95 (brs, 2H).
Ph Ph [00548] N-(2-(Phenylethynyl)pheny1)-4-nitrobut3Tramide [00549] To a solution of 4-nitro-2-(phenylethynyl)aniline (17 g, 0.07 mum') 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 CH2C12 (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-(phenylethyny1)pheny1)-4-nitrobutyramide (12 g, 55%). 1H NMR (400 MHz, CDC13) 6 8.69 (d, J =9 .2 Hz, 111), 8.39 (d, J=2.8 Hz, 111), 8.25-8.20 (m, 2H), 7.58-7.55 (m, 211), 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 0,N
0 TBAF 110 \ Ph N") [00550] 5-Nitro-2-phenyl-1H-indole [00551] A mixture of N-(2-(phenylethynyl)pheny1)-4-nitrobutyramide (5.0 g, 0.020 mol) and IBAF (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-phenyl-1H-indole (3.3 g, 69%). 1H NMR (400 MHz, CDC13) 6 8.67 (s, 1H), 8.06 (dd, J = 2.0, 8.8 Hz, 1H), 7.75 (d, J
=7.6 Hz, 2H), 7.54 (d, J =8.8 Hz, 1H), 7.45 (t, J =7.6 Hz, 2H), 7.36 (t, J =
7.6 Hz, 1H). 6.95 (s, 1H).

\ ph Raney Ni H2N 401 \ Ph [00552] 2-Phenyl-1H-indo1-5-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-indo1-5-amine (1.6 g, 77%). 111 NMR (400 MHz, CDC13) 6 7.76 (d, J=7.6 Hz, 2H), 7.39 (t, J= 7.6 Hz, 2H), 7.24 (t, J= 7.6 Hz, 1H), 7.0'7 (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 (ESD m/e (M-1-1-1+) 209Ø
[00554] Example 36: 2-tert-Butyl-4-fluoro-1H-indo1-5-amine Br NaBH4/NiC12,.... io Brrd,L.
________________________________ a Br 0 Pd(PPh3)2a2 lir NO, Me0H
NH2 NH)C,'", CuVEt3N
r-BuOK KNo, 02N is NaBH4/Nia2 H2N 401 DMF H2SO4 N Me0H
di Br NaBH4/NiC120 Br Ill" NO2 Me0H

[00555] 2-Bromo-3-fluoroaniline [00556] To a solution of 2-bromo-l-fluoro-3-nitrobenzene (1.0 g. 5.0 mmol) in CH3OH (50 mL) was added NiC12 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0 C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with 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%). 1H
NMR
(400 MHz, CDC13) 8 7.07-7.02 (m, 1 H), 6.55-6.49(m, 1 H), 4.22 (br s, 2 H).

di Br Ct)'-'"- Br 0 NH-[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 (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0 C.
The mixture was stirred at room temperature for 24 h. Water (20 rnL) 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.
F
13r 0 Pd(PPh3)2CIi.
111- Cul/Et3N
[00559] N-(2-(3,3-Dimethylbut-1-yny1)-3-fluorophenyflbutyramide [00560] To a solution of N-(2-bromo-3-fluorophenyl)butyrarnide (2.0 g, 7.0 mmol) in Et3N
(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%). 1H NMR (400 MHz, CDC13) 8 8.20 (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
JU t-BuOK
NH DMF
[00561] 2-tert-Butyl-4-fluoro-1H-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-1H-indole (5.8 g, 97%). 1H NMR (400 MHz, CDC13) 8 8.17 (br s, 1 H), 7.11 (d, J=7.2 Hz, 1 H), 7.05-6.99 (m, 1 H), 6.76-6.71 (m, 1 H), 6.34 (m, 1 H), 1.41 (s, 9 H).

[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 H2SO4 (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-buty1-4-fluoro-5-nitro-1H-indole (900 mg, 73%). 1H NMR (400 MHz, CDC13) 8 8.50 (br 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 \
Me0H
[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 (4.2 g, 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.

NaCl and water, dried over anhydrous Na2SO4, evaporated under vacuum to give 2-tert-buty1-4-fluoro-1H-indo1-5-amine (900 mg, 50%). 1H NMR (300 MHz, CDC13) 8 7.80 (brs, 1 H), 6.91 (d, J= 8.4 Hz, 1 H), 6.64 (dd, J= 0.9, 2.4 Hz, 1 H), 6.23 (s, 1 H), 1.38 (s, 9 H).
[00567] Example 37: 2,3,4,9-Tetrahydro-1H-carbazol-6-amine 02N =
SnCl2 H2N
[00568] 2,3,4,9-Tetrahydro-1H-carbazol-6-amine [00569] 6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol.
Tin(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-indo1-5-amine a 0 BT-24-lOAc 02N it NH2 ________________ fo- 02N
Cul,Pd(PPh3)2C12, E13N so11.- Py,CH2C1, NH2 41111" N1-12 02N = 0 t-BuOK, DMF

02N 0 ___________________________ Br2/1-10Ac 02N __________________ a ________________________________ VP= NH2 [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 H), 4.88 (brs, 2 H).
02N Ali Br 02N
gifil NH2 Cul,Pd(PPh3)2C12, Et3N WI NH2 [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 Cul (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-dimethyl-but-1-yny1)-6-fluoro-4-nitro-phenylamine (4.0 g, 36%). 1H NMR (400 MHz, CDC13) 6 8.02 (d, J = 1.2 Hz, 1 11), 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-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide [00576] To a solution of 2-(3,3-dimethyl-but-1-yny1)-6-fluoro-4-nitro-phenylamine (4.0 g, 17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous C112C12 (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]-butyrarnide (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 H), 7.22 (brs, 1 H), 2.45 (t, J = 7.5 Hz, 2 H), 1.82 (m, 2 H), 1.36 (s, 9 H), 1.06 (t, J = 7.5 Hz, 3 H).

1-BuoK, DMF 02N
di [00577] 2-tert-ButyI-7-fluoro-5-nitro-1H-indole [00578] To a solution of N-12-(3,3-dimethyl-but-1-yny1)- 6-fluoro-4-nitro-pheny1]-butyramide (3.2 g, 10 mmol) in DMF (20 mI ) was added t-BuOK (2.3 g, 21 mmol) at room temperature. The mixture was heated at 120 C for 2 g before being cooled down to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with 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) 6 9.95 (brs, 1 H), 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 [00579] 2-tert-Buty1-7-fluoro-1H-indo1-5-amine [00580] To a solution of 2-tert-butyl-7-fluoro- 5-nitro-1H-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%). 111 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+11 ) 207.
[00581] Example 39: 5-Amino-2-tert-butyl-1H-indole-7-carbonitrile 02N 40 Br 02N 1 02N H2N
TBAF 1101 NICI,/NaBH4 10 N
Cul ,Pd(PP h3),C12, Et3 Nt* =
NH, NH, CN CN CN CN

02N Br 02N =
Cu I, Pd(P Ph3)2C12, BP?' CN CN N
[00582] 2-Amino-3-(3,3-dimethylbut-1-yny1)- 5-nitrobenzonitrile [00583] To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g, 10 mmol) in dry Et3N (60 naL) was added CuI (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%). 1H NMR (300 MHz, CDCI3) 8 8.28 (d, J= 2.7 I-1z, 1 H), 8.27 (d, J = 2.7 Hz, 1 H), 5.56 (br s, 2 H), 1.37 (s, 9 H).

CN CN
[00584] 2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile [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.
0,N
NiCl2/NaBH4 H2N
_______________________________ PP-N
CN CN
[00586] 5-Amino-2-tert-buty1-1H-indo1-7-carbonitrile WO 2010/054138 /USZ0(19/06..i4 [00587] To a solution of crude product 2-tert-butyl-5-nitro-1H-indole-7-carbonitrile (0.87 g, 3.6 mmol) in Me0H (10 mL) was added NiC12.6H20 (1.8 g, 7.2 mmol) at -5 C.
The reaction mixture was stirred for 30 min, then NaBH4 (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-buty1-1H-indo1-7-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, J = 2.4 Hz, 1 H), 6.14 (d, J = 2.4 Hz, 1 H), 3.57 (br s. 2 H), 1.38 (s, 9 H). MS (ESI) mlz: 214 (M+fr).
[00588] Example 40: Methyl 5-amino-2-tert-buty1-1H-indole-7-carboxylate KOH, Et0H 02N 40 Me0H
SOCl2 CN =OH

.2N 40 Raney-NVH2 10) N\
= 0 = 0 KOH, Et0H 2N 110 eN H
ir OH
[00589] 2-tert-Butyl-5-nitro-1H-indole-7-carboxylic acid [00590] 2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile (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-buty1-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 77%). 11-1 NMR (CDC13, 300 MHz) 6 10.79 (brs, 1 H), 8.66 (s, 1 H), 8.45(s, 1 H), 6.57 (s, 1 H), 1.39 (s, 9 H).
0.2N 40 Me0H 02N
SOCl2 = OH o' [00591] Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate [00592] S0C12 (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-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%). 1H NMR
(CDC13, 300 MHz) 5 9.99 (brs, 1 H), 8.70 (d, J= 2.1 Hz, 1 H), 8.65 (d, J= 2.1 Hz, 1 H), 6.50 (d, J= 2.4 Hz, 1 H), 4.04 (s, 3H), 1/1/1(s, 9H).

Raney-Ni/H2 = 0' = 0"
[00593] Methyl 5-amino-2-tert-butyl-1H-indole-7-earboxylate [00594] A solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.0 g, 7.2 mmol) and Raney Nickel (200 mg) in CH3OH (50 mL) was stirred for 5 h at the room temperature under H, atmosphere. The catalyst was filtered off through a celite pad and the filtrate was evaporated under vacuum to give methyl 5-arnino-2-tert-butyl-1H-indole-7-carboxylate (1.2 g, 68%) 1H NMR (CDC13,400 MHz) ö 9.34 (brs, 1H), 7.24 (d, J = 1.6 Hz, 11-1), 7.10 (s, 1H), 6.12 (d, J= 1.6 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H).
[00595] Example 41: (5-Amino-2-tert-butyl-1H-indoI-7-yl)methanol o2N N
DII3AL-H 02 Raney NVH2 H2N
N "urr. N N
00¨ OH OH

DIBAL-Hip 02N
N 40I'vr N
= 0---- OH
[00596] (2-tert-Butyl-5-nitro-1H-indo1-7-y1) methanol [00597] To a solution of methyl 2-tert-butyl-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 cC.
The mixture was stirred for 1 h before water (10 mL) was added slowly. The resulting mixture was extracted with Et0Ac (120 mL 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.

o2N Raney Ni/I-12 H2N
N
411111" N
OH OH
[00598] (5-Amino-2-tert-butyl-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 H2. 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 MHz) 8.53 (br s, 111), 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-indol-5-amine n-E3uLi \Si ___________ <TBAF
Me2SO4 si ____________________________________________ 00-Pk.
02N B-2/HoAe 02N Br ¨
______________________________________ 02N di NH2 NH2 Pd(PPh3)202 1111111" NH2 butyryl chloride Tr =
=
0 _________________ 113AF
N

\ A Raney 1\i/H2 4 N
NH¨c_ Sin-BuLi \= _______________ ¨ < ___________ 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 rnmol) was added dropwise at ¨10 C. The resulting solution was stirred at 10 C and then at 20 C for 30 min each. The reaction was quenched by adding a mixture of sat. aq.
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 mL) 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
[00603] 1-Ethyny1-1-methyl-cyclopropane [00604] To a solution of trimethyl-(1-methyl-cyclopropylethyny1)-silane (20 g, 0.13 mol) in THF (250 mL) was added 1BAF (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 mL). The combined organic layers were dried over anhydrous Na2SO4 and distilled under atmospheric pressure to obtain 1-ethyny1-1-methyl-cyclopropane (7.0 g, contained 1/2 THF, 34%). 1H NMR (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 Iso Br2/1-10AC 02N Br [00605] 2-Bromo-4-nitroaniline [00606] To a solution of 4-nitro-phenylarnine (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 = Br =_ ON =NI-12 Pd(PPh3)2012 NH2 [00607] 2-((1-Methylcyclopropypethyny1)-4-nitroaniline [00608] To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethyny1-1-methyl-cyclogropane (630 mg, 8.0 mmol) in triethylamine (20 mL) 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%). 1H NMR (300 MHz, CDC13) 8.15-8.14 (m, 1 H), 7.98-7.95 (m, 1 H), 6.63 (d, J = 6.9 Hz, 1 H), 4.80 (brs, 2 H), 1.38 (s, 3 H), 1.04-1.01 (m, 2 H), 0.76-0.73 (m, 2 H).
=
02N io 02N

NH2 butyryl chloride NI I
[00609] N42-(1-Methyl-cyclopropylethyny1)-4-nitro-pheny1]-butyramide [00610] To a solution of 2((1-methylcyclopropyHethyny1)-4-nitroaniline (220 mg, LO
mmol) and pyridine (160 mg, 2.0 mol) in CH2C17 (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 Na2SO4 and evaporated under reduced pressure to obtain N42-(1-methyl-cyclopropyl-ethyny1)-4-nitro-phenyThbutyrannide (230 mg, 82%), which was directly used in the next step.
Yr so 0 TBAF \
NI __________________ I
[00611] 2-(1-Methylcyclopropy1)-5-nitro-1H-indole [00612] A mixture of N42-(1-methyl-cyclopropylethyny1)-4-nitro-phenyThbutyramide (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 2-(1-methylcyclopropy1)-5-nitro-1H-indole (0.70 g, 71%). 1H 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 Hz, 1 H),L52 (s, 3 H), 1.03-0.97 (m, 2 H), 0.89-0.83 (m, 2 H).
02N lei Raney H2N
\ 4 WI-12 110 \ 1 N N
H H
[00613] 2-(1-Methyl-cyclopropy1)-1H-indo1-5-ylamine [00614] To a solution of 2-(1-methylcyclopropy1)-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) 8 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 H), 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 KOMe )-)LY. Mel, Nall., Axkome Pa5 ¨ _____ \ aq. NaOH
0 ____ by OMe CH2Cl2 CI
OH
_________________ No' )/ ( _________ OH CH 2N2 ,-al ,2. '.2 0 )0- 27' ___ ( DMSO ¨ 0 0 CI
0 (1-..

ail "-%
0 02N si -,,00 ______________________ ,.._ tip mi_i NH2 butyryl chloride NI I
Pd(PPh3)4, Cul, ET3N 2 \

Pd(CH3CN)2Cl2 02N 40 0 Haney Ni H2N iii 0 _______________ 10, \ \ _ \ \
N

H
H

AA Mel, NaH ).Lx11,....
--0Me __________________________ 00 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 MeI (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. MeI (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 mL 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.
0 0 /OMe )1X)0Me CH2Cl2 Cl [00618] Methyl 3-chloro-2,2-dimethylbut-3-enoate [00619] To a suspention of PC15 (270 g, 1.3 mol) in CH2C12 (1000 mL) 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 CH2C12 (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%). Ili NMR (400 MHz, CDC13)13 5.33 (s, 1 H), 3.73 (s, 3 H), 1.44 (s, 6 H).
OMe aq. NaOH <OH
_____________________ 0 ________________ 0 [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 NMR (400 MHz, CDC13) 8 7.90 (brs, 1 H), 5.37 (dd, J= 2.4, 6.8 Hz, 2 H), 1.47 (s, 6 H).
,( OH
______________________ O y NaNH2 /OH
DMSO
¨
CI
[00622] 2,2-Dimethyl-but-3-ynoic acid [00623] Liquid NH3 was condensed in a 3-neck, 250 mL round bottom flask at -78 'C. Na (3.98 g, 0.173 mol) was added to the flask in portions. The mixture was stirred for 2 h at -78 C before anhydrous DMSO (20 mL) was added dropwise at - 78 C. The mixture was stirred at room temperature until no more NH3 was given off. A solution of 3-chloro-2,2-dirnethyl-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. 1H NMR (400 MHz, CDC13) 8 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.
1H NMR (400 MHz, CDC13) 8 3.76 (s, 3 H), 2.28 (s, 1 H), 1.50 (s, 6 H).

02N ipo Br ___________________________________ 02N.::

DIP

Pd(PPh3)4, Cul, Et3N
[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 mmol) under N2. 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 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to obtain methyl 4-(2-amino-5-nitropheny1)-2,2-dimethylbut-3-ynoate (900 mg, 9%).

(400 MHz, CDC13) 5 8.17 (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 I-1), 1.60 (s, 6 H).

o2N
0,N 0 NH2 butyryl chloride NH
[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 mol) in CH2C12 (20 mi ) 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 CH2C12 (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. 1H NMR (400 MHz, CDC13) 6 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 H), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J= 6.8 Hz, 3 H).

0 Pd(oH3oN)2a2 02N 0 lir NI I
[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-yl)propanoate (320 mg, 23%). 1H N-WIR (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 0 \
[00632] Methyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropanoate [00633] A suspension of methyl 2-methyl-2-(5-nitro-1H-indo1-2-y1)propanoate (60 mg, 0.23 mmol) and Raney Nickel (10 mg) in Me0H (5 mL) was hydrogenated under hydrogen (1 atrn) 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%). 1H NMR (400 MHz, CDC13) 8 8.37 (br 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) Ede (MAT) 233.2.
[00634] Example 44: 2-Isopropyl-1H-indo1-5-amine TBA 02NF/DMF Raney N
\

4111) _______ NF I\
02N fah 02N
lir __ 00 TE3AF/DMF
NI I
[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%). 111 NMR (400 MHz, CDC13) c 8.68 (s, 1 H), 8.25 (br s, 1 H), 8.21 (dd, J= 2.4, 10.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1 H), 6.41 (s, 1 H), 3.07-3.14 (m, 1 H), 1.39 (d, J= 6.8 Hz, 6 H).
.2N so =
Raney Ni H2N
[00637] 2-Isopropyl-1H-indo1-5-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%).
111NMR (400 MHz, CDC13) S 7.69 (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) m/e (MAT-) 175.4.
[00639] Example 45: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxy-2-methylpropan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide PPh3Br 40 OEt. 40, Nyt joEt , OH PPh3 HE3! CI

(Boc),y \ KHMDS
KOt-By * \ DMAP 02Et Mel r = 2Et 02Et hoc Boc TFA, NaNO3 02N
N CO2Et conc. H2S104 N CO2Et = OH P Ph3 HBr 1101 PPh3Br [00640] Tripheny1(2-aminobenzyl)phosphonium 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 naixture 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 "Ph3Br ___ NH2 OEt [00642] Triphenyl((ethyl(2-earbamoyl)acetate)-2-benzyl)phosphonium bromide [00643] To a suspension of tripheny1(2-aminobenzyl)phosphonium bromide (190 g, 0.43 mol) in anhydrous diehloromethane (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 dichlorornethane (approximately 700 mL) under heating and evaporated. The solid was dried overnight at 50 C under vacuum to give triphenyl((ethyl(2-carbamoyl)acetate)-2-benzy1)-phosphonium bromide (139 g, 58%).
PPh3Br K Ot-Bu =\
OEt 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 min) to give ethyl 2-(1H-indo1-2-yl)acetate (9.12 g, 78%).
\ (Boc)20,.
DMAP
CO2Et N CO2Et Boo [00646] tert-Butyl 2-((ethoxycarbonyl)methyl)-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-1-carboxylate (20.0 g, 91%).
\ KHMDS $o CO2Et Mei N CO2Et Boc Boc [00648] tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-y1)-1H-indole-1-carboxylate [00649] tert-Butyl 2-((ethoxycarbonyl)methyl)-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 nth, 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-l-carboxylate (17.1 g, 94%).
gr" CO2Et 1'1-A
ICL-1)-1 4;02Et 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 mT ) 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 dichlorornethane 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%).
NaNO3 02N loi 1100 N CO2Et conc. H2S 04 N CO2Et [00652] Ethyl 2-methy1-2-(5-nitro-1H-indo1-2-yppropanoate [00653] Ethyl 2-(1H-indo1-2-y1)-2-methylpropanoate (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (6 mL) and cooled to ¨10 C (salt/ice-mixture). A
solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 min. Stirring was continued for another 30 min at ¨10 C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% Et0Ac in hexane) to give ethyl 2-methy1-2-(5-nitro-1H-indo1-2-yl)propanoate (0.68 g, 57%).
02N io 02N =
LiA1H4 N CO2Et N OH
[00654] 2-Methy1-2-(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 warm 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 mil) and water (4 mL).
The mixture was stirred at room temperature for 0.5 h and was filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over 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-y1)propan-1-ol (0.098 g, 58%).
02N = H2N io SnC12.2H20 =H OH
[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 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-y1)-2-methylpropan-1-ol (0.080 g, 98%).
[00658] Example 46: 2-(Pyridin-2-y1)-1H-indo1-5-amine N
)0, 02N 401 t-BuOK/DMF
NH2 pd(pPh3)2012/0u1 Sna2 H2N
________________________________ VP-I
02N ioN
___________________________________ 02N so , NH2 Pd(PPh3)2C12/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 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 4-nitro-2-(pyridin-2-ylethynyeaniline (1.5 g, 60%). 1H 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 IT), 7.87-7.80 (m, 2 H), 7.42-7.39 (m, 1 H), 7.05 (brs, 2 H), 6.80 (d, J = 6.9 Hz, 1 H).
, N
02N so t-BuOK/DMF o2N

[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) 8 12.40 (s, 1H), 8.66 (d, J = 2.1 Hz, 1 H), 8.58 (d, = 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 H2N., N-N N
[00663] 2-(Pyridin-2-y1)-1H-indo1-5-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)-1H-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)-1H-indo1-5-amine 02N 0 0õ,OTBDMS 02Ndui I 02N

o 0,N H2N
Pd02/CH3CN io 02N so= DIBAL-H. H2RaneY-1 N
H
H
OH OH
OH
02N soI -0TBDMS 02N
NH mOTBDMS

[00666] [2-(tert-Butyl-dimethyl-silanyloxy)-ethy1]-(2-iodo-4-nitro-pheny1)-amine [00667] To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added HA (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 )2-(tert-butyl-dimethyl-silanyloxy)-ethyl)-(2-iodo-4-nitro-pheny1)-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, J= 5.4 Hz, 2 H), 3.35 (q, J = 5.4 Hz, 2 H), 0.93 (s, 9 H), 0.10 (s, 6 H).
o2N
cp,N la"
=111111}P
[00668] 54242-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyll-3,3-dimethyl-pent-4-ynoic acid ethyl ester [00669] To a solution of [2-(tert-butyl-dimethyl-silanyloxy)-ethyl)-(2-iodo-4-nitro-pheny1)-amine (800 mg, 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 5-12-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-pheny1)-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 H), 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 Hz, 3 H), 0.84 (s, 9 H), 0.00 (s, 6 H).

pda2,0H30N , [00670] 341-(2-Hydroxy-ethyl)-5-nitro-1H-indo1-2-yl]-3-methyl-butyric acid ethyl ester [00671] A solution of 542- [2-(te rt-butyl-dimethyl-silanyloxy)-ethylarnino]-5-nitro-pheny1}-3,3- dimethyl-pent-4- ynoic acid ethyl ester (600 mg, 1.34 mmol) and PdC12(650 mg) in CIT3CN (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 mi ) and fBAF (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 H), 0.03 (s, 6 H).
O
0,N =

0 o2N
DIBAL-H_ OH
=
OH
[00672] 311-(2-Hydroxy-ethyl)-5-nitro-1H-indo1-2-y11-3-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 THF (25 mL) was added DIBAL-H (1.0 M, 4.2 mL, 4.2 mmol) at -78 C. The mixture was stirred at room temperature for 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 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-methyl-butan-l-ol (300 mg, 49%). 1H
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 (m ,2 H), 3.24-3.21 (m, 2 H), 1.42 (s, 6 H).

H2/Raney-Ni OH OH
OH OH
[00674] 345-Amino-1-(2-hydroxy-ethyl)-1H-indol-2-y1]-3-methyl-butan-1-ol [00675] A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indo1-2-y1]-3-methyl-butan-1-o1 (300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH3OH (30 mL) was stirred for 5 h at room temperature under a 112 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 315-amino-1-(2-hydroxy-ethyl)-1H-indo1-2-y1]-3-methyl-butan-1-ol (70 mg, 26%). 111NMR (300 MHz, CDC13) .5 7.07 (d, J = 8.7 Hz, 1 H), 6.83 (d, J = 2.1 Hz, 1 H), 6.62 (dd, J = 2.1, 8.4 Hz, 1 H), 6.15 (s, 1 H), 4.47 (t, J= 5.4 Hz, 2 H), 4.07 (t, J= 5.4 Hz, 2 H), 3.68 (t, J= 5.7 Hz, 2 H), 2.16 (t, J = 5.7 Hz, 2 H), 4.00-3.91 (m, 4 H), 2.76 (s, 2 H), 1.61 (s, 6 H), 1.42 (s, 6 H).
[00676] Example 48: tert-Butyl 2-(5-amino-1H-indo1-2-y1)piperidine-1-earboxylate pt021-42 H2N
Ail \7-->
Boc 0 H N
HN--) 2 2 = _________________________________________________________ \
111, N

Q _________________________ Pt020-12 H2N- )\ .cHN¨) [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 atm) at room temperature for 2 h. The catalyst was filtered through a celite pad and the solvent was evaporated under vacuum to afford 2-(piperidin-2-y1)-1H-indo1-5-amine (1.0 g), which was directly used in the next step.
HW-N H N
BoO 2 Et3N
[00679] tert-Butyl 2-(5-amino-1H-indo1-2-yppiperidine-1-carboxylate [00680] To a solution of 2-(piperidin-2-y1)-1H-indo1-5-amine (1.0 g) in Et3N
(25 mL) and THF (25mL) was added Boc20 (640 mg, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous 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 te rt-butyl 2-(5-amino-1H-indo1-2-y1)piperidine-1-carboxylate (15 mg, 1%
over 2 steps). 1H N1VIR (400 MHz, CDC13) 8 8.82 (s, 1 H), 7.58 (s, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.02 (d, J= 1.6, 8.0 Hz, I 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), L70-1.58 (m, 2H), 1.53 (s, 9 1-1).
[00681] Example 49: 6-amino-1H-indole-2-carbonitrile 40 NaNO2/Ha SnC12 02 140 NH2 Ha (302E1 ), 02N N CO2EI
f,Hr"
02N= NH2 PPA
011 1 NaOH
01 ,s0 ,.2 el 02N Çij N CO2Et = 002H 2, NH3 H20 02 N CONH2 (CF30)20 =i Raney NM, 01 N __________________________________________ IP' H2 N CN
NaNO2/HCI
N, NH2 HC1 02N NH2 Sna2 02N
[00682] (3-Nitrophenyl)hydrazine hydrochloride [00683] 3-Nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H20 (40 mL) and 37% HC1 (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% HC1 (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-niqophenyl)hydrazine hydrochloride (28 g, 73%).

OCOEt f NH FICI __ P. 02N N , -0,N N.- 2.
[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-nitrophenyl)hydrazono)propanoate, which was used directly in the next step.
410 ,N CO2Et PPA 4101 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%).
el I NaOH
el I
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 %
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%).
01 I 1. soci2 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-carboxamide [00691] A mixture of 6-nitro-1H-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 S0C12 was removed under reduced pressure. The residue was dissolved in anhydrous CH2C12 (250 mL) and NH3.H20 (22 g, 0.32 rnol) 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.
lel I (cF3c0)20 el I
02N N cow, 02N N CN

= WO 2010/054138 [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 CH7C12 (200 mL). Et3N (24 g, 0.24 mol) 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%).
401 I Raney Ni/H2 01 I
02N CN Fi2N N CN
[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 H2 (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) 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, f= 8 Hz, 1 H); MS (ESI) ink (M+H+) 158.2.
[00696] Example 50: 6-Amino-1H-indole-3-carbonitrile CN
CN
= CISO2NCO 4111 1-12/Pd-C
1 le=

I l 02 0,2N H2 11111i _________________________________ [00697] 6-Nitro-1H-indole-3-carbonitrile [00698] To a solution of 6-nitroindole (4.9 g 30 mmol) 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 Na.2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

CN
H2/Pd-C 01 I
l I ________ ).

CN
o2N e [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 H2 (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. 1H 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 (ESI) m/e (M+H ) 157.1.
[00701] Example 51: 2-tert-Butyl-1H-indo1-6-amine ao i NH2 Rtyk 0 n-BuLi NaBH4/Ac3H 111.
C
111111" N
KNO3M-2S0i.
40 io

11 N
0 N DCQ Raney NVH2 NH2 =
________________________________ = N

[00702] N-o-Tolylpivalamide [00703] To a solution of o-tolylamine (21 g, 0.20 mol) and Et3N (22 g, 0.22 mol) 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%). 11-1 NMR
(300 MHz, CD03) 6 7.88 (d, J= 7.2 Hz, 1 H), 7.15-7.25 (m, 2 H), 7.05 (t, J= 7.2 Hz, 1 H), 2.26 (s, 3 H), 1.34 (s, 9 H).
so Ny< n-BuLi =

[00704] 2-tert-Butyl-1H-indole [00705] To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol ) in dry THF
(100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15 C. After addition, the mixture was stirred overnight at 15 C. The mixture was cooled in an ice-water bath and treated with saturated NR4C1. 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) 8 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 _________________________________ to [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 f120 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.
=KNO3/H2S 4).= N
N
[00708] 2-tert-buty1-6-nitroindoline and 2-tert-butyl-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 Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g, 31% over two steps). 1H NMR (300 MHz, CDC13) 5 7.52 (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 H).

=DDQ =
_________________________________ )1P.-N

[00710] 2-tert-Butyl-6-nitro-1H-indole [00711] To a solution of 2-tert-butyl-6-nitroindoline (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ (6.9 g, 30 mmol) at room temperature. The mixture was heated at reflux for 2.5 h before being filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-buty1-6-nitro-1H-indole (1.6 g, 80%). 1H
NMR (300 MHz, CDC13) 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 Ni/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) 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, 2H), 1.24 (s, 9 H); MS (ESI) m/e (M+H+) 189.1.
[00714] Example 52: 3-tert-Butyl-1H-indo1-6-amine *Br 70- Raney Ni-H2 ___________________________________________ 70-02N =N zinc triflate 01 \ 401 TBAI, DIEA 02 le I ) __ Br VP-\
02 N zinc tiflate 01 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 DMA (1.5 g, 11 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 min at 120 C, WO 2010/054138 ,e1. 1/
U3ZUtIV/Ub.,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. 1H-NMR (CDC13) ö 8.32 (d, J = 2.1 Hz, 111), 8.00 (dd, J = 2.1, 14.4 Hz, 1H), 7.85 (d, J
= 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).
Raney Ni-H2 02N OI\ N

[00717] 3 -tert-Butyl-11-1-indo1-6-amine [00718] A suspension of 3-tert-buty1-6-nitro-1H-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-butyl-1H-indo1-6-amine (2.0 g, 77%) as a gray solid. 1111NMR (CDC13) 8 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz, 1H), 6.66 (s, 1H), 6.57(dd, J= 0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
[00719] Example 53: 5 -(Trilluoromethyl)-1H-indo1-6-amine õ, 111. DMA F3 1111 Raney Ni/H2 F3C
H2SO4 02N 441P. NO2 02N 111" NO2 H2N
F3C = F3, H2SO4 02N=NO2 [00720] 1-Methyl-2,4-dinitro-5-(trifluoromethyl)benzene [00721] To a mixture of HNO3 (98%, 30 naL) and H2S0.4 (98%, 30 mL) was added dropwise 1-methy1-3-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 so N

[007221 (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 CE)-2-(2,4-dinitro-5-(trifluoromethyl)pheny1)-N,N-dimethylethenamine (2.1 g, 86%).
F3 op N., Raney Ni/H2 F,C
=

[00724] 5-(Trifluoromethyl)-1H-indo1-6-amine [00725] A suspension of (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyI)-N,N-dimethylethenamine (2.1 g, 6.9 mmol) and Raney Nickel (1 g) in ethanol (80 mL) was stirred under H2 (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-indo1-6-amine (200 mg, 14%). III NMR (DMSO-d6) 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 (ESI) mie (M+H ): 200.8.
[00726] Example 54: 5-Ethyl-1H-indo1-6-amine O

Ac,OACia/CH2C12 NaBH/THF
____________________________________________ )1}. 48%HBr H El2NADMAFICH2a2 T"
e'41, 4Ik \

KNO2+12SOõ
N Si MnO2 Raney [CI 40 Eto DmA P/C H 21'a 2 [00727] 1-(PhenylsulfonyDindoline [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 PC1/U52009/00.54 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%).
o Ac,o/AdcycH2ct2 OSOrQ
_________________________________ =
o =
[00729] 1-(1-(Phenylsulfonyl)indolin-5-yl)ethanone [00730] To a suspension of AlC13 (144 g, 1.08 mol) in CH2C12 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes before a solution of (phenylsulfonyl)indoline (46.9 g, 0.180 mol) in C112C12 (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 CH2C12.
The combined organics were washed with saturated aqueous NaHCO3 and brine, dried over Na.2SO4, and concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (42.6 g).
o [00731] 5-Ethyl-1-(phenylsulfonyl)indoline [00732] To 11-,A (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-(phenyIsulfonyl)indolin-5-yl)ethanone (40.0 g, 0.133 mol) in TFA (700 mL) over 1 h. The mixture was then stirred overnight at 25 C. After dilution with 1-120 (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 Na9SO4 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 [00733] 5-Ethylindoline [00734] A mixture of 5-ethyl-1-(phenylsulfonyl)indoline (15 g, 0.050 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH
to pH 9 and then it was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethylindoline (2.5 g, 32%).
KNO3/H2s04 1110 N ____________________________ [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%).
MnO 2 ).
n 4111 N __________________________ -2-N 02N 00) N
[00737] 5-Ethyl-6-nitro-111-indole [00738] To a solution of 5-ethyl-6-nitroindoline (1.9 g, 9.9 mmol) in CH2C12 (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).
4110 \ Raney Ni/H20.

[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). 1H NMR
(CDC13) 7.90 (br 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) m/e (M-4-1-) 161.1.
[00741] Example 55: Ethyl 6-amino-1H-indole-4-carboxylate 02N COOH 02N CO2Et COON HNO3 s002;
H2SO4 Et0H
NO2 No2 GEt No2 / o2 DNINDMF /N SnCl2 C-02Et [00742] 2-Methy1-3,5-dinitrobenzoic acid [00743] To a mixtu_re of HNO3 (95%, 80 mL) and H2SO4 (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%).
02N 40 COOH 02N 40 .02Et soa2;
Et0H
1\02 NO2 [00744] Ethyl 2-methyl-3,5-dinitrobenzoate [00745] A mixture of 2-methyl-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 CH7Cl2 (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 mL). The combined extracts were washed sat. Na2CO3 (80 naL), water (2 x 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to dryness to give ethyl 2-methy1-3.5-dinitrobenzoate (50 g, 88%) 02Nso 002a 1402 N
DMDMF
--O.- 02 c 2Et [00746] (E)-Ethyl 2-(2-(dimethy1amino)vinyI)-3,5-dinitrobenzoate [00747] A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 C for 5 h. The mixture was poured into ice-water and the precipitated solid was filtered and washed with water to give (E)-ethyl 2-(2-(dimethylamino)viny1)-3,5-dinitrobenzoate (11 g, 48%) C
No2 / O2Et SnC12 CO2Et [00748] Ethyl 6-amino-1H-indole-4-carboxylate [00749] A mixture of (E)-ethyl 2-(2-(dimethylamino)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%). 11-INMR
(DMSO-d6) 8 10.76 (br s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (m, 1 H), 6.67-6.68 (m, 1 H), 4.94 (br s, 2 H), 4.32-4.25 (q, J = 7.2 Hz, 2 H), 1.35-1.31 (t, J= 7.2, 3 H);
MS (ESI) m/e (M+Ir) 205Ø
[00750] Example 56: 5-Fluoro-1H-indo1-6-amine F \N¨r _________________________ Vir F 02N r402 F N
H2/Raney-N F

=

`--2"m [00751] 1-Fluoro-5-methyl-2,4-dinitrobenzene [00752] To a stirred solution of HNO3 (60 mL) and H9SO4 (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 mi ). 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-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).
\N-( __ , 0 F N
02N NO2 02N 1 m ..02 [00753] (E)-2-(5-Fluoro-2,4-dinitrophenyI)-N,N-dimethylethenamine [00754] A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100 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%).
N 41111:1 N H2/Raney-Ni ________________________________________ Air H2N lei I

[00755] 5-Fluoro-111-indo1-6-amine [00756] A suspension of (E)-2-(5-fluoro-2,4-clinitropheny1)-N,N-dimethy1ethenamine (8.0 g, 31 mmol) and Raney Nickel (8 g) in Et011 (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 2, 16%) as a brown solid. 1FINMR (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 (ES1) m/e (M+14+) 150.1.
[00757] Example 57: 5-Chloro-1H-indo1-6-amine = WO

\N¨e¨

HNo3m,so4 0¨

________________________________________________________ or, Ci m=N 2 arem ,A,õ
H2/Raney-Ni aN Ig I I

HNO3/H2SO4 Ci [00758] 1-Chloro-5-methy1-2,4-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 ml). The resulting precipitate was collected by filtration and purified by recrystallization to give 1-chloro-5-methy1-2,4-dinitrobenzene (26 g, 60%).
a ail N

[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 mmol), DMA
(11.9 g, 100 mmol) in DMF (50 mL) was heated at 100 C for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected by filtration, washed with water, and dried to give (E)-2-(5-chloro-2,4-dinitropheny1)-N,N-dimethylethenamine (9.84 g, 72%).
a ci RIP H2/Raney-Ni [00762] 5-Chloro-1H-indo1-6-amine [00763] A suspension of (E)-2-(5-chloro-2,4-dinitrophenye-N,N-dimethylethenamine (9.8 g, 36 mmol) and Raney Nickel (9.8 g) in Et0H (140 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether/ethyl acetate 10:1) to give 5-chloro-1H-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, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, 1H); MS (ESI) m/e (M+H+) 166Ø
[00764] Example 58: Ethyl 6-amino-1H-indole-7-carboxylate so..2, 1. piNO3l,2s04 NO2 032, 1. so.,2 2. SOC12/Et01-1 40 NO2 2. Et0H
No2 c,o2Et DMA 02 II / NI\ Ni N

NO2 Et02c NO2 CO2E-1 401 CO2H 1. HNO3/H2SO4 NO2 co 2. S00I2/Et0H
No2 [00765] 3-Methyl-2,6-dinitrobenzoic acid [00766] To a mixture of HNO3 (95%, 80 mL) and ILS04 (98%, 80 inL) 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 mol) in Et0H (150 mL) was added dropwise SOC12 (54 g, 0.45 mol).
The 'mixture was heated at reflux for 2 h before being concentrated to dryness under reduced pressure. The residue was partitioned between Et0Ac (100 mL) and aq. Na2CO3 (10%, 120 mL). The organic layer was washed with brine (50 mL), dried over Na sn 2- - 4, and concentrated to dryness to obtain ethyl 5-methy1-2,4-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, 401 ..2, 1. soci2 Go2B
2. Et0H

[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 mL) was heated at reflux 4 h. The excess S0C12was evaporated off under reduced pressure and the residue was added dropwise to a solution of Et0H (100 mL) and Et3N (50 mL). The mixture was stirred at 20 C for 1 h and then concentrated to dryness. The residue was dissolved in Et0Ac (100 rid), washed with Na2CO3 (10 %, 40 mL x 2), water (50 niL x 2) and brine (50 mL), dried over Na2SO4 and concentrated to give ethyl 3-methy1-2,6-dinitrobenzoate (20 g, 53%).
No, api co2 Et DMA 02 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 342-(dimethylamino)viny1)-2,6-dinitrobenzoate (25 g, 58%).
/ N\ Raney N Ni/H2 2 o, H2N

Et02C NO2 CO2Et [00771] Ethyl 6-amino-1H-indole-7-earboxylate [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 (3.2 g, 16%). 1H NMR (DMSO-d6) 5 10.38 (s, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 6.98 (t, J = 3.0 Hz, 1 H), 6.65 (s, 2 H), 6.48 (d, J =
8.7 Hz, 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 oo,a DMA 02 al No2 Eto2c N
Raney N
= lir No2 Et02 N H2N

Et02 [00774] (E)-Ethyl 5-(2-(dimethylamino)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 5-(2-(dimethylamino)viny1)-2,4-dinitrobenzoate (15 g, 28%).
02N NO2 Et02 Raney Ni Et02 NI/ H2N 111" N
[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 Et0H (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%). 11-1NMR (DMSO-d6) 8 10.68 (s, 1 H), 7.99 (s, 1 H), 7.01-7.06 (m, 1 H), 6.62 (s, 1 H), 6.27-6.28 (m, 1 H), 6.16 (s, 2 H), 4.22 (q, J= 7.2 Hz, 2 H), 1.32-1.27 (t, J= 7.2 Hz, 3 H).
[00778] Example 60: 5-tert-Butyl-1H-indo1-6-amine t-Bu t-Bu = (Et0)2P(0)CVNaH
! LL/NH3 t-Bu 40 HNO3/H3.4 H= Et01- OEt t-Bu WI ahn t-Bu * >4)- teu 2 sna 2 t-eU

t-Bu t-Bu (E10)2P(0)CVNaH lir ________________________________________ 0 HO =EY0¨ P¨OEt I

[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 THF
(200 mL) was added dropwise a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol) in THF (100 mL) at 0 C. The mixture was stirred at 0 C for 15 min and then phosphorochloridic acid diethyl ester (37 g, 0.21 mol) was added dropwise at 0 C. After addition, the mixture was stirred at ambient temperature for 30 min. The reaction was quenched with sat.
N1-14C1 (300 mL) and then extracted with Et20 (350 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S0.4, 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 Li/NH3 t-Bu 401 =
Et0-13-0Et O
[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. NR4C1 until 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.
No2 t-Bu HNO3/H2SO4 t-Bu t-Bu =

[00783] 1-tert-Butyl-5-methy1-2,4-dinitrobenzene and 1-tert-buty1-3-methy1-2,4-dinitro-benzene [00784] To HNO3 (95%, 14 mL) was added H2SO4 (98 %, 20 mL) at 0 C and then 1-tert-butyl-3-methylbenzene (7.4 g, -50 mmol, crude from last step) dropwise to the with the temperature being kept below 30 C. The mixture was stirred at ambient temperature for 30 min, poured onto crushed ice (100 g), and extracted with 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-tert-buty1-5-methyl-2,4-dinitrobenzene and 1-tert-buty1-3-methyl-2,4-dinitrobenzene (2:1 by NMR) as a yellow oil (9.0 g, 61%).

t-Bu t-Bu \N--( t-Bu _____________________________________ )1k.
02 NO2 r\l 2 02N NO2 [00785] (E)-2-(5-tert-Butyl-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 mmol, 2:1 by NMR) and DMA (5.4 g, 45 mmol) in DMF (50 mL) was heated at reflux for 2 h before being cooled to room temperature. The reaction mixture was poured into water-ice and extracted with 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-dinitropheny1)-N,N-dimethylethen-amine (5.0 g, 68%).
t-Bu N SnCl2 t-Bu = \

[00787] 5-tert-Butyl-1H-indo1-6-amine [00788] A solution of (E)-2-(5-tert-butyl-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 CH2C12 to afford a yellow powder, which was purified by column chromatography to give 5-tert-buty1-1H-indo1-6-amine (0.40 g, 12%). 11-1NMR (DMSO_d6) 8 10.34 (br s, 1 H), 7.23 (s, 1 H), 6.92 (s, 1 H), 6.65 (s, 1H), 6.14 (s, 1 H), 4.43 (br s, 2 H), 2.48 (s, 9 H); MS (ESI) ra/e (M+14 ) 189.1.
[00789] General Procedure IV: Synthesis of acylaminoindoles RN
(RxX)x OH RN
HNI , HATU (RxX)x NArl I B
I B -"At Et3N, DMF 0 = =

[00790] One equivalent of the appropriate carboxylic acid and one equivalent of the appropriate amine were dissolved in NA-dimethylformamide (DMF) containing triethylamine (3 equivalents). 0-(7-Azabenzotriazol-1-y1)-NdV,NcN'-tetramethyluronium hexafluorophosphate (HATU) was added and the solution was allowed to stir. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product.
[00791] Example 61: N-(2-tert-Buty1-1H-indo1-5-y1)-1-(4-methox ypheny1)-cyclopropanecarboxamide DMF
HATU
/0 N/ Et3N

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 (28 4, 0.20 mmol). 0-(7-Azabenzotriazol-1-y1)-N,N,NcN'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found 363.3 (M+1)4; Retention time 3.48 minutes.
[00793] General Procedure V: Synthesis of acylaminoindoles (R.)6 RN
RN
OH soci2 (RxX)x pyridine (RxX)x \ a +
B Arl \ N',Art it) DMF I B I B

[00794] 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-dimethylformamide were added and the solution was allowed to stir for 20 minutes at 60 C. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in a minimum of anhydrous pyridine. This solution was slowly added to a stirred solution of one equivalent the appropriate amine dissolved in a minimum of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110 C. The mixture was evaporated to dryness, suspended in dichloromethane, and then extracted three times with IN HC1. The organic layer was then dried over sodium sulfate, evaporated to dryness, and then purified by column chromatography.

[00795] Example 62: Ethyl 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate (Compd. 28) K 1) SOCl2 0 N 0 DMF
0 OH 2) dichloromethane 0 NI OEt Et3N A H
N

[00796] 1-Benzo[1,3]dioxo1-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under N2. N,N-dimethylfoimamide (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 HC1, 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]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate as a gray solid (3.44 g, 88 %). ESI-MS m/z calc. 392.4; found 393.1 (M+1) Retention time 3.17 minutes. 11-1 NNW (400 MHz, DMSO-d6) 8 11.80 (s, 1H), 8.64 (s, 1H), 7.83 (m, 1H), 7.33-7.26 (m, 2H), 7.07 (m, 1H), 7.02 (m, 1H), 6.96-6.89 (m, 2H), 6.02 (s, 2H), 4.33 (q, J= 7.1 Hz, 2H), 1.42-1.39 (m, 2H), 1.33 (t, J= 7.1 Hz, 3H), 1.06-1.03 (m, 2H).
[00797] Example 63: 1-(Benzo[d][1,3]dioxol-5-y1)-N-(2-tert-butyl-1H-indo1-5-ypeyelopropaneearboxamide Cl 011 0 SOCl2 0 DMF N Et3N

=-=-=
[00798] 1-Benzo[1,3]dioxo1-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 nil of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of N,N-dimethylformamide (DME) 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-buty1-11/-indo1-5-amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mL,

12.1 mmol). The resulting solution was allowed to stir for 10 minutes. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a gradient of 5-50 % ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a pale pink powder (1.24 g 62%).
ESI-MS m/z calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 1H NMR (400 MHz, DMSO) 6 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J= 1.4 Hz, 1H), 7.15 (d, J= 8.6 Hz, 1H), 7.05 - 6.87 (m, 4H), 6.03 (s, 3H), 1.44 - 1.37 (m, 2H), 1.33 (s, 9H), 1.05-1.00 (m, 2H).
[00799] Example 64: 1-(Benzo[d][1,3]dioxo1-5-yl)-N-(1-methyl-2-(1-methylcyclopropy1)-11-1-indol-5-yecyclopropanecarboxamide HATU
V o OH H2N Et3N V
<o o0 =0 N 40 , =
=
[00800] 1-Methyl-2-(1-methylcyclopropy1)-1H-indol-5-amine (20.0 mg, 0.100 mmol) and 1-(benzo[d][1,3]dioxo1-5-yflcyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in N,N-dirnethylformamide (1 mr ) containing triethylamine (42.1 pL, 0.300 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,/V,NcN'-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-yficyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M-I-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]indo1-7-y1)cyclopropaneearboxamide V H
V

H2N io Et3N
( OH * = 140 0 \

[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 pL, 0.600 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,N,N,AP-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]clioxol-5-y1)-N-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]-indo1-7-yflcyclopropane,carboxamide. ESI-MS nilz calc. 388.2, found 389.2 (M+1)+. Retention time of 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) 8.41 (s, 1H), 7.59 (d, J= 1.8 Hz, 1H), 7.15 (d, J= 8.6 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.96 -6.90(m, 2H), 6.03 (s, 2H), 5.98 (d, J= 0.7 Hz, 1H), 4.06 (t, J= 6.8 Hz, 2H), 2.35 (t, J=
6.8 Hz, 2H), 1.42-1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
[00803] Example 66: Methyl 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropaneearboxamido)-2-tert-butyl-1H-indole-7-earboxylate H
H2N gab <:Et3N V N
0 v <o = N
0 N\
=

[00804] 1-(Benzo[d][1,3]dioxo1-5-yecyclopropanecarbonyl 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 /V,N-ditnethylfounarnide (2 alL) containing a magnetic stir bar and triethylarnine (0.084 mT , 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-yl)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-yl)cyclopropanecarboxamide V H

H
<C3Dtpxy,.._ OH HBTU, Et3N = dith 0 N
N = 0 0 Mill" N = H
[00806] To a solution of 1-(benzo[d][1,31dioxo1-5-yl)cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol) and 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-l-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 HCI

(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-(benzo[d][1,31dioxol-5-y1)-N-(2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-yflcyclopropanecarboxamide (0.11 g, 75%). 1H NMR (400 MHz, DMSO-d6) 6 10.64 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04-6.90 (m, 4H).
6.06 (s, 1H), 6.03 (s, 2H), 4.79 (t. J = 2.7 Hz, 1H), 3.46 (d, J = 0.0 Hz, 2H), 1.41-1.39 (m, 2H), 1.26 (s, 6H), 1.05-1.02 (m, 2H).
[00807] Example 67: 1-(Benzo[d][1,3]dioxol-5-y1)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide HATU

(0 qr. OH
______________________________________ <o 111 [00808] 2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,3]dioxo1-5-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)-N,N,NR'-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) 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, 2H), 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[d][1,3]dioxo1-5-ypeyelopropanecarbox-amido)-1H-indol-2-yl)piperidine-l-carboxylate V a _________________ o 1401 0 v H
I 1\14(11_ _____ ( JO 0 140 N\ __ C40, N
\ Et3N

[00810] 1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19 mmol) and te rt-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 N,N-dimethylformamide, and then purified by preparative HPLC using a gradient of 0-99%
acetonitrile in water containing 0.05% trifluoroacetic acid to yield tert-butyl 44541-(benzo[d][1,31dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)piperidine-1-carboxylate. ESI-MS trz/z calc. 503.2, found 504.5. (M+1)+. Retention time of 1.99 minutes.
[00811] Example 70: Ethyl 2-(5-(1-(benzo[d][1,31dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)propanoate ghiõ, KFINA DS TFA NaN 03 02N
N\ CO2Et "el co2E1 N CO2Et conc. H2SO4 N
CO2Et Boc Boc SnCl2 2H20, H2N V H
N CO2Et T (C) so 1. H BTU, Ei3N, <0 401 N gib A OH 0 0 41111PF N co CO2Et Mel CO2Et Boc Boc [00812] tert-Butyl 2-(1-ethoxy-1-oxopropan-2-y1)-1H-indole-1-carboxylate [00813] tert-Butyl 2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THE (29 mL) and cooled to ¨78 C. A 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal temperature stayed below ¨60 C. Stirring was continued for 1 h at ¨78 'C. Methyl iodide (727 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%).

* . WO 2010/054138 TFA
CO2Et C t,C)co2Et H
Boc [00814] Ethyl 2-(1H-indo1-2-yl)propanoate [00815] tert-Butyl 2-(1-ethoxy-1-oxopropari-2-y1)-1H-indole-1-carboxylate (2.77 g, 8.74 mmol) was dissolved in dichloromethane (25 mL) before TFA (9.8 mL) was added.
The mixture was stirred for 1.5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with sat. aq. sodium bicarbonate, water, and brine.
The product was purified by column chromatography on silica gel (0-20% Et0Ac in hexane) to give ethyl 2-(1H-indo1-2-yl)propanoate (0.92 g, 50%).
N CC CO2Et>4 NaNO3 02N
conc. H2S6 4 N CO2Et H H
[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%).
02N ai õN
\ Sn C12.2H20 \
N CO2Et N CO2Et H H
[00818] Ethyl 2-(5-amino-1H-indo1-2-yl)propanoate [00819] To a solution of ethyl 2-(5-nitro-1H-indo1-2-y1)propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The mixture was heated in the microwave at 120 C for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous 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%).

= 0 N G0 Et H

4 (C) II HETU, Et3fµl =

A
[00820] Ethyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)propanoate [00821] To a solution of 1-(benzo[d][1,3]dioxo1-5-y0cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et3N
(160 AL, 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-yl)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 mL) and then 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 ethyl 2-(5-(1-(benzo[d][1,3[dioxo1-5-y0cyclopropane,carboxamido)-1H-indo1-2-y1)propanoate (0.081 g, 50%). 111 NMR (400 MHz, CDC13) 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, 1H), 6.28 (s, 1H), 6.06 (s, 2H), 4.25-4.17 (m, 2H), 3.91 (q, J = 7.2 Hz, 1H), 1.72-1.70 (m, 2H), 1.61 (s, 2H), 1.29 (t, J = 7.1 Hz, 4H), 1.13-1.11 (m, 211).
[00822] Example 71: tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarbox-amido)-1H-indol-2-y1)-2-methylpropylcarbamate LiOH 02 =\ EDC, HOBt 02N 116 N CO2Et N CO2H NEt3, NH4C1 N H2 id&
THFC)2N 02N Boc20 \ Pci/C H2N
H2 NEt3HBoc HBoc HCO2NH4 V H
EDC, HOBt, NEt3, /6 , N
= \ID N \--NHBoc = 46 OH
=

IP

LICH
CO2Et [00823] 2-Methyl-2-(5-nitro-1H-indo1-2-y1)propanoic acid [00824] Ethyl 2-methyl-2-(5-nitro-1H-indo1-2-yl)propanoate (4.60 g, 16.7 mmol) was dissolved in THF/water (2:1, 30 mL). LiORH20 (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 HC1. 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-indo1-2-y1)propanoic acid (4.15 g, 99%).
0,N
\ EDC, HOBt 02N * \
CO2H Et3N, NH4CI

H 0'/
[00825] 2-Methyl-2-(5-nitro-1H-indo1-2-yl)propanamide [00826] 2-Methyl-2-(5-nitro-1H-indo1-2-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 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) were added and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Combined organic phases were washed with brine, dried over magnesium sulfate and dried to give 2-methyl-2-(5-nitro-1H-indo1-2-yl)propanamide (4.3 g, 99%).
02N soBH3TH F

H ' [00827] 2-Methyl-2-(5-nitro-1H-indo1-2-yl)propan-1-amine [00828] 2-Methyl-2-(5-nitro-1H-indo1-2-yepropanamide (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
HC1. 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-y1)propan-1-amine (82 mg, 43%).

02 io B.20 02 H2 NEt3, THF HBOC
[00829] tert-Butyl 2-rnethy1-2-(5-nitro-1H-indol-2-yl)propylcarbamate [00830] 2-Methy1-2-(5-nitro-1H-indo1-2-yl)propan-1-amine (137 mg, 0.587 mmol) was dissolved in THF (5 mL) and cooled to 0 C. Et3N (82 pL, 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-y1)propylcarbamate (131 mg, 67%).

Pd/C
HBoc HCO2NH4 HBoc [00831] tert-Butyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropylcarbamate [00832] To a solution of tert-butyl 2-methy1-2-(5-nitro-1H-indo1-2-y1)propylcarbamate (80 mg, 0.24 mmol) in THF (9 mL) and water (2 mL) was added ammonium formate (60 mg, 0.96 mmol) followed by 10% Pd/C (50 mg). The mixture was stirred at room temperature for 45 minutes. Pd/C was filtered off and the organic solvent was removed by evaporation. The remaining aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to give tert-butyl 2-(5-amino-1H-indo1-2-y1)-2-methylpropylcarbamate (58 mg, 80%).
H

EDC, HOBt, NEt3 = ao ( N ritki NHBoc = V 0 UPI N\ NHBoc OH
<
= 0 [00833] tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-y1)cyclopropaneearboxamido)-indo1-2-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-yl)cyclopropanecarboxylic acid (47 mg , 0.23 nunol), EDC
(45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (80 1., 0.57 mmol) were dissolved in DMF (4 mL) and stirred overnight at room temperature. The mixture was diluted with water and extracted with ethylacetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (10-30% ethylacetate in hexane) to give tert-butyl 2-(5-(1-(benzoId} [1,3jdioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)-2-methylpropyl-carbamate (88 mg, 94%). 111 NMR (400 MHz, CDC13) 5 8.32 (s, 1H), 7.62 (d, J =
1.5 Hz, 1H), 7.18 - 7.16 (m, 2H), 7.02 - 6.94 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 6.19 (d, J = 1.5 Hz, Hi), 6.02 (s, 21-1). 4.54 (m, 1H), 3.33 (d, J = 6.2 Hz, 2H), 1.68 (dd, J =
3.7, 6.8 Hz, 2H), 1.36 (s, 91-1), 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-y1)cyclopropanecarboxamide OTs cc.00><

N\ NH4F7C0C2-Cs2CO3 ccoOK
co0)<
V a F/4' V H V H

111 PTSA =
40 N` FFx= = N
Et3N FTho 0 0 ccOH
cr=
o OH
OTs ccOx 02 aot cs20030 ao 100830 (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 mmol) 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)methyl 4-methylben7Pnesulfonate (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 = 1.5/1) to give (R)-2-tert-buty1-1-((2,2-dimethy1-1,3-dioxolan-4-y0methyl)-5-nitro-1H-indole (1.0 g, 66%). 3H NMR (400 MHz, CDC13) 5 8.48 (d, J
= 2.2 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 (m, 3H), 4.12 (dd, J = 6.0, 8.6 Hz, 1H), 3.78 (dd, J = 6.0, 8.6 Hz, 1H), 1.53 (s, 311), 1.51 (s, 911), 1.33 (s, 3H).

02 Pd/C ).= \/
N NI-14+CO2 [00838] (R)-2-tert-Butyl-1-((2,2-dimethy1-1,3-dioxolan-4-y1)methyl-1H-indo1-5-amine [00839] To a stirred solution of (R)-2-tert-buty1-14(2,2-dimethy1-1,3-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 Na2SO4, 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, 1H), 6.48 (dd, J 2.2, 8.6 Hz, 111), 6.05 (s, 1H,), 4.38-4.1 (m, 2H), 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 H
N Et3N
V FFxs.
N/
a rrx:
ooK (),o)<
soc12 V
OH
FFx:
[00840] N-OR)-2-tert-Buty1-1-((2,2-dimethyl-1,3-dioxolan-4-yOrnethyl)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide [00841] To 1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (0.73 g, 3.0 mmol) was added thionyl chloride (660 [IL, 9.0 mmol) and DMF (20 !IL) 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-dimethy1-1,3-dioxolan-4-yl)methyl-1H-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-te rt-buty1-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide (1.33 g, 84%). 1H NMR
(400 MHz, CDC13) 8 7.48 (d, J = 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 (dd, J = 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, J = 8 Hz, 2H).
V H V H
Frx:

40 FFx:
N
ccOH

[00842] N-((R)-2-tert-Buty1-1-((2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)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-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide (0.96 g, 81%). 1H NMR
(400 MHz, CDC13) 8 7.50 (d, J = 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, 1H), 6.23 (s, 1H), 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, 11 Hz, 1H), 3.50 (dd, J = 5, 11 Hz, 1H), 1.75 (q, J = 8 Hz, 3H), 1.43 (s, 9H), 1.14 (q, J = 8 Hz, 3H).
[00844] Example 73: 3-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-ypcyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropanoic acid AGO\ PAc Is-0Ac 0 V H V H
FX
40 N 0 Fx.
N

DMSO, RT

0c)H

V H
NaBH4 .xF. = , Me0H RT F 0 OH

Ac0,1pAL
,0 H V H
N .446.
Fa4 10 0 , 0 Fx., tgi ______________________________________ F 0 [USD, RT
'N,.-OH

IrOH

[00845] 3-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbox-amido)-1H-indol-1-y1)-2-oxopropanoic acid [00846] To a solution of N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropane-carboxamide (97 mg, 0.20 mmol) in DMSO
(1 mL) was added Dess-Martin periodinane (130 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 h. The solid was filtered off and washed with 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] [1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-2-oxopropanoic acid that was used without further purification.
V H
V H
, N Ahh NaBH4 F 0 µ1 =0 Me0H, RT F =
Lx0H
IrOH

[00847] 3-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y0cyclopropanecarbox-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 mT ) was added NaBH4 (19 mg, 0.50 nunol) at 0 C. The mixture was stirred at room temperature for 15 min. 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-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-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, 1H), 6.23 (s, Hi), 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 (ESI) m/e (M+H+) 501.2.
[00849] Example 74: (R)-N-(2-tert-Butyl-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-ypcyclopropanecarboxamide V
HO irk V OH H= V 0,, CD213r2 10, Dx= 0 NaOH
HO p-Ts0H HO Cs2CO3, DMF, 120 C 0 0 THF-H20, 80 C
H2N os V

p-Ts0H
lo HATU, NEt3, DMF, Me0H-H20, 80 C
t \c0x, DDx.. io o 411 , (rOH
OH

H=I V OH ____ Ai õ.._meoH HO =
HO l_W p-Ts0H HO WI 0 [00850] Methyl 1-(3,4-dihydroxyphenypcyclopropanecarboxylate [00851] To a solution of 1-(3,4-dihydroxyphenypcyclopropanecarboxylic 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-dihydroxyphenyl)cyclopropane,carboxylate (190 mg, 91%) that was used without further purification. 1H NMR (400 MHz, DMSO-d6) 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 V
He goO CD2Br2 0 HO Cs2CO3, DMF, 120 C D><b 11 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 mniol) and CD2Br2 (35 mg, 0.20 mmol) in DMF (0.5 mT ) was added Cs2CO3 (19 mg, 0.10 mmol). The mixture was heated at 120 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 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
NaOH0 D.>( 40 \,0 411r1 THF-H20, 80 C D 0 [00854] 1-(2,2-Dideuteriumbenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid [00855] To a solution of methyl 1-(2,2-dideuteriumbenzo[d][1,31dioxo1-5-y1)cyclopropanecarboxylate (22 mg, 0.10 mmol) in THF (0.5 mL) was added NaOH
(1N, 0.25 nth, 0.25 mmol). 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][1.3]dioxo1-5-yl)cyclopropanecarboxylic acid (21 mg) that was used without further purification.

V =V H
OH N
Dx D = 4.11-1'. 0 0 DDX:
HATU, N Et3, DMF, RT
[00856] (R)-N-(2-tert-Buty1-14(2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-1H-indol-5-y1)-1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxarnide [00857] To a solution of 1-(2,2-dideuteriumbenzo[d][1,3]dioxo1-5-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][1,3]dioxo1-5-yl)cyclopropanecarboxamide (24 mg, 49% from methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate). MS (ESI) age (M+1-1+) 493.5.
V v H
x p-Ts0H
Me0H-H20, 80 C DX.D 0 CCH
OH
[00858] (R)-N-(2-tert-Buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-dideuterium-benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide [00859] To a solution of (R)-N-(2-tert-buty1-142,2-dimethyl-1,3-dioxolan-4-yemethyl)-1H-indol-5-y1)-1-(2,2-dideuterium-benzo[d][1,3]dioxol-5-y1)cyclopropanecarboxanaide (24 mg, 0.050 mmol), in methanol (0.5 mL) and water (0.05 mL) was added 4-methylbenzenesulfonic acid (2.0 mg, 0.010 mmol). The mixture was heated at 80 C for 30 min. The reaction mixture was partitioned between 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-yOmethyl)-1H-indol-5-y1)-1-(2,2-dideuteriumbenzo[d][1.3]dioxol-5-ypcyclopropanecarboxamide (12 1112, 52%). 1H NMR (400 MHz, CDC13) 8 7.44 (d, J= 2.0 Hz, 1H), 7.14 (dd, J = 22.8, 14.0 Hz, 2H), 6.95-6.89 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.14 (s, 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, J = 11.3, 4.0 Hz, 1H), 3.45 (dd, J = 11.3, 5.4 Hz, 1H), 1.60 (q, J = 3.5 Hz, 2H), 1.35 (s, 9H), 1.02 (q, J = 3.5 Hz, 2H). 13C NMR (400 MHz, CDC13) 8 171.4, 149.3, 147.1, 146.5, 134.8, 132.3, 129.2, 126.5, 123.6, 114.3, 111.4, 110.4, 109.0, 107.8, 98.5, 70.4, 63.1, 46.6, 31.6, 30.0, 29.8, 15.3. MS (ESI) m/e (M+H+) 453.5.
[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. Furthennore, mono-deuterated analogues of other compounds of the present invention can be synthesized by substituting the reagent CHDBR2 for Cla213K2 and following the steps described herein.
[00861] Example 75: 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-indol-2-y1)-4-methylpentanoic acid V V H
4, õ SOCl2,DMF =
( ____________________________________ 7 /
f WI
= 0 ii) H = 2N 0 /CN
CN
V H
N
KOH
(' =
OH
=
= = H
<0 au OH SCCI2,DMF<00 N
0 lir 0 10 H2N

CN I.
[00862] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide [00863] To 1-(benzo[d][1,3]dioxo1-5-y1)cyclopropanecarboxylic acid (0.068 a, 0.33 mmol) was added thionyl chloride (72 pt, 0.99 mmol) and DMF (20 p.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 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]dioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide.
V H
V I
<t-41 KOH
110 0 I N\ /ON <C) 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-indo1-5-yl)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 DMS0 (1 mL), filtered, and purified by reverse phase preparative HPLC to give 4-(5-(1-(benzo[d][1,3]dioxo1-5-ypcyclopropanecarboxamido)-1H-indol-2-y1)-4-methylpentanoic acid. 1H NMR (400 MI-Iz, DMSO-d6) 8 11.98 (s, 1H), 10.79 (s, 1H), 8.44 (s, 1H), 7.56 (s, 1H), 7.15 (d, J = 8.6 Hz, 11-1), 7.03-6.90 (m, 4H), 6.05 (s, 111), 6.02 (s, 2H), 1.97-1.87 (m, 4H), 1.41-1.38 (m, 2H), 1.30 (s, 6H), 1.04-1.02 (m, 2H).
[00866] Example 76: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-y1)-indo1-5-yl)cyclopropanecarlboxamide .2 0 002ET LiAl H a2 4 __ ' N (--OH Sna22H20 V H
H2Ny.....) Cal <4:=

A OH = HBTU, Et3N = Ail 0 40 N, __ ( \¨OH
02 io LiAIH4 2N,Cc) K¨OH
[00867] 2-(5-Nitro-1H-indo1-2-yl)propan-1-ol .

1/USZUllY/U0..)=4 /J
[00868] To a cooled solution of LiA1H4 (LO M in THF, 1.2 inL, 1.2 mmol) in THF
(5.3 mL) at 0 C was added a solution of ethyl 2-(5-nitro-111-indo1-2-yl)propanoate (0.20 g, 0.76 mmol) in THF (3.66 mL) dropwise. After addition, the mixture was allowed to warm up to room temperature and was stirred at room temperature for 3 h. The mixture was cooled to 0 C. Water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at room temperature for 0.5 h and was then filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over 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-1-ol (0.14 g, 81%).
0, SnC12.2H20 _____________________________________ H2N 401 OH OH
[00869] 2-(5-Amino-1H-indo1-2-yl)propan-1-ol [00870] To a solution of 2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.13 g, 0.60 mmol) in ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). The mixture was heated in the microwave at 120 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%).
V H

IV =H HBTU, Et3N, e 110 N

(DOIC)...2'0H 0 [00871] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-31)-1H-indoi-5-yl)cydopropanecarboxamide [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 HBTU (0.185 g, 0.49 mmol) and Et3N (205 itL, 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)propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was stirred at room temperature for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 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 2e1 (ethyl acetate/hexane = 13/7) to give 1-(benzo[d][1,31dioxo1-5-y1)-N-(2-(1-hydroxypropan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide (0.095 g, 51%).
IH NMR (400 MHz, DMSO-d6) 10.74 (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, 1H)õ 6.02 (s, 2H), 4.76 (t, J = 5.3 Hz, 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-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indol-5-y1)-N-methyleyelopropaneearboxamide V
OH HNI HATU I

(0 +
[00874] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-1H-indol-5-y1)-N-methylcyclopropaneearboxamide [00875] 2-tert-Butyl-N-methyl-1H-indo1-5-amine (20.2 mg, 0.100 mmol) and 1-(benzo [d][1,31dioxo1-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) were dissolved in /V,N-dimethylformamide (1 mL) containing triethylamine (42.1 RL, 0.300 mmol) and a magnetic stir bar. 0-(7-Azabenzotriazol-1-y1)-N,N,NcY-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]dioxo1-5-y1)-N-(2-tert-buty1-1H-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-indoll-5-y1)-1-(benzo[d][1,3]dioxol-6-y1)-N-methylcyclopropanecarboxamide 11 os THF / DMF
N , 1) NaH
= 0 2) CH,I 0 [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][1,31dioxol-6-y1)cyclopropanecarboxamide (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 = 1 resulting suspension was allowed to stir for 2 minutes and then iodomethane (0.062 mL, 1.0 mm-l) was added to the reaction mixture. Two additional aliquots of sodium hydride and iodomethane were required to consume all of the starting material which was monitored by LC / MS. The crude reaction product was evaporated to dryness, redissolved in a minimum of DMF and purified by preparative LC / MS chromatography to yield the pure product (0.0343 g, 13%) ESI-MS m/z calc. 404.2, found 405.3 (M+1)+. Retention time of 3.65 minutes.
[00878] Example 79: 1-(Benzo[d][1,3]dioxo1-5-311)-N-(2-(hydroxymethyl)-1H-indol-5-ybcyclopropanecarboxamide < 0 N LiBH4, THF/H20 0 0 N OD 25 '0, 16 hrs <0 N OH
H 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 mL). The mixture was allowed to stir for 16h at 25 C
before it was quenched with water (10 mL) and slowly made acidic by addition of 1 N HC1. The mixture was extracted with three 50-mL portions of ethyl acetate. The organic extracts were dried over Na?Sat and evaporated to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(hydroxymethyl)-1H-indo1-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was further purified by reverse phase HPLC. FSI-MS nilz 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-butyl-1H-indole-2-carboxamide H2N,]<
< 1, goy 0 LiOH OH N HATU, Et,N, OMF = IV A N
1111.. = VI
HN
H OEt H20 1,4-dioxane A H H
<6 0 LiOH dib- 0 0 Op ____________________________________________ =
OEt H20 / 1,4-dioxane = W
A H 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 H20 (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 1N 1IC1 and it was extracted with three 20 mL portions of dichloromethane. The organic extracts were dried over Na2S 04 and evaporated to yield 5-(1-(benz,o[d][1,3]-dioxo1-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small amount was further purified by reverse phase HPLC. ESI-MS m/z calc. 364.1, found 365.1 (M+1)+;
retention time 2.70 minutes.
H2N1.
(0o 40 _________________________________________ < A 0 N , HN 0 N 116 40 :H HATU, Et3N, DMF = H =
ii 40 H
[00883] 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-N-tert-butyl-indole-2-carboxamide [00884] 5-(1 - (B enzo[d] (1,3]dioxo1-5-yl)cyclopropane-carboxamido)-1H-indole-carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12 mmol) were dissolved in N,N-dimethylforrnamide (1.0 mL) containing triethylamine (28 L, 0.20 mmol).
0-(7-Azabenzotriazol-1-y1)-N,N,AP,AP-tetramethyluronium hexafluorophosphate (46 mg, 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 nilz calc. 419.2, found 420.3 (M+1)+; retention time 3.12 minutes.
[00885] Example 81: N-(3-Amino-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide 40 0 io NaNO2 j 0 di AcOH/H20 = 4111F N
A H A H NO
Zn -0 0 1111 AcOH = .11111ir N '111119.7"
= H NH2 [00886] A solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-5-y1)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 the crude material, 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-nitroso-1H-indol-5-y1)cyclopropanecarboxamide, was added AcOH (2 mL) and Zn dust (5 mg). The mixture was allowed to stir for lh at ambient temperature. Et0Ac and H20 were added to the mixture. The layers were separated and the organic layer was washed with sat.
aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was taken up in DMF
(1 mL) and was purified using prep-HPLC. LCMS: miz 392.3; retention time of 2.18 min.
[00887] Example 82: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-3-(methylsulfony1)-1H-indol-5-ypeyclopropaneearboxamide V ill 1) NaH V H SO2Me (' 40 40 DMF-THF
(*. N
= 2) MeS02C1 [00888] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-(methylsulfony1)-1H-indol-5-y0cyclopropanecarboxamide [00889] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-y1)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to ¨15 C and a solution of methanesulfonyl chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for 30 min at ¨15 C then for 6 h at room temperature. Water (0.5 m1 ) was added at 0 C, solvent was removed, and the residue was diluted with Me0H, filtrated and purified by preparative HPLC to give 1-(Benzo[d][1,31dioxo1-5-y1)-N-(2-tert-butyl-3-(methylsulfonyl)-1H-indol-5-y1)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO) 8 11.6 (s, 1H), 8.7 (s, 1H), 7.94 (d, J=1.7 Hz, 111), 7.38 (d, J=8.7 Hz, 1H), 7.33 (dd, J1 =1.9 Hz, J2 =8.7 Hz, 1H), 7.03 (d, J
=1.7 Hz, 1H), 6.95 (dd, J1 =1.7 Hz, J2 =8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.02 (s, 2H), 3.07 (s, 3H), 1.56-1.40 (m, 911), 1.41 (dd, J1 =4.0 Hz, J2 =6.7 Hz, 2H), 1.03 (dd, J1 =4.0 Hz, J2 =6.7 Hz, 2H). MS (ESI) Ink (M+11 ) 455.5.
[00890] Example 83: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(3-phenyl-1H-indo1-5-y1)cyclopropane earboxamide OH
HO V
op NBS H
Br (CHO 0 = TN 0 40 \

N FibreCat 1001 0 _________________________________________________ e 0 v H V ,H Br NBs e N \ <0 [00891] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(3-bromo-1H-indo1-5-yl)cyclopropanecarboxamide [00892] Freshly recrystallized N-bromosuccinimde (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(1H-indol-5-yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylfaiinamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes.
The resulting green solution was poured into 40 rnI of water. The grey precipitate which formed was filtered and washed with water to yield 1-(benzo[d][1,31dioxo1-5-y1)-N-(3-bromo-1H-indo1-5-y0cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc.
398.0, found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6) 11.37(s, 1H), 8.71 (s, 1H), 7.67(d, J= 1.8 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.22 (dd, J= 2.0, 8.8 Hz, 1H), 7.02 (d, J= 1.6 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.03 (s, 2H), 1.43 - 1.40 (m, 2H), 1.09 - 1.04 (m, 2H).
OH
HO
ft H
v H Br 0 e 110 N
0 w 0 N FibreCat 1001 - 0 [00893] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(3-pheny1-1H-indo1-5-y1)cyclopropanecarboxamide [00894] Phenyl boronic acid (24.6 mg, 0.204 inmol) was added to a solution of (benzo [d][1,3]-dioxo1-5-y1)-N-(3-bromo-1H-indo1-5-y1)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130 C in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo [d][1,3]dioxo1-5-y1)-N-(3-pheny1-1H-indo1-5-yl)cyclopropane carboxamide. ESI-MS
m/z calc. 396.2, found 397.3 (M+1) . Retention time of 3.52 minutes. 1H NMR
(400 MHz, DMSO-d6) 8 11.27 (d, J= 1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40(m, 2H), 7.31 (d, J= 8.7 Hz, 1H). 7.25-7.17 (m, 2H), 7.03 (d, J=
1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
[00895] Example 84: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-3-cyano-1H-indol-5-yl)eyclopropanecarboxamide <00 0 N A = POCI3, DMF = A H (C) H2N-OH, DCM
________________________________ 0 <AO
Ac20 N
H A H
<= 0 40 POCI3, DMF <0 idu lir ___________________________________ 0 N/
0 =A N A H
H

[00896] 1-(Benzo[d][1,3]dioxo1-5-yl)-N-(2-tert-butyl-3-formy1-1H-indo1-5-y1)cyclopropane-earboxamide [00897] P0C13 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at ¨20 'C.
After the addition was complete, the reaction mixture was allowed to warm to 0 'DC and was stirred for 1 h. 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25 'C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h.
The mixture was then heated at 100 C for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL
dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-fonnyl-1H-indo1-5-y1)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS rn/z calc.
404.5, found 405.5 (M+1)+; retention time 3.30 minutes. 1H NMR (400 MHz, DMSO-d6) 11.48 (s, 1H), 10.39 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97-6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H).
<
0 rat 0 141" 0 N N =
=
H2N-OH, DCM A < 40 0 40 N
H H

[00898] (Z)-1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-3-((hydroxyimino)methyl)-1H-indol-5-ypcyclopropanec_arboxamide [00899] To a solution of 1-(benzo[d][1,31dioxo1-5-y1)-N-(2-tert-buty1-3-formy1-1H-indo1-5-yflcyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate/hexanes) to yield (Z)-1-(benzo[d][1,31dioxo1-5-y1)-N-(2-tert-buty1-3-((hydroxyimino)methyl)-1H-indol-5-y1)cyclopropanecarboxamide (81 mg, 77%). ESI-MS
m/z calc. 419.5, found 420.5 (M+1)'; retention time 3.42 minutes. 1H NMR (400 MHz, DMSO-d6) 5 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 1.43 (s, 9H), 1.40-1.38 (m, 2H), 1.04-1.01 (m, 2H).
(00 A 0 N/ Ac20 (0 0 N IµPj = 41"" N
Hla A H
HO-N/
[00900] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-cyano-1H-indol-5-ypcyclopropane-carboxamide [00901] (Z)-1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-((hydroxyimino)-methyl)-1H-indol-5-y1)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and the precipitate was collected and washed with water. The solid was further dried under high vacuum to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-cyano-1H-indo1-5-ypcyclopropanecarboxamide. ESI-MS m/z calc. 401.5, found 402.5 (M+1)+;
retention time 3.70 minutes. 111NMR (400 MHz, DMSO-d6) 5 11.72 (s, 1H), 8.79 (s, 1H), 7.79 (s, 1H), 7.32 (m, 2H), 7.03-7.02 (m, 1H), 6.95-6.89 (m, 2H), 6.03 (s, 2H), 1.47 (s, 9H), 1.43-1.41 (m, 2H), 1.06-1.04 (m, 2H).
[00902] Example 85: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-3-methyl-1H-indol-5-y1)cyclopropanecarboxamide = giti 0 AN/ Mel,DMF 0 lib A H AL H
[00903] A solution of 1-(benzo[d][1,3]dioxol-5-y1)-N-(2-tert-buty1-1H-indo1-5-ypcyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 pL, 2.0 mmol) in NN-dimethylformamide (1 mL) was heated at 120 'V in a sealed tube for 24 h.
The reaction was filtered and purified by reverse phase HPLC. ESI-MS in/z calc. 390.5, found 391.3 (M+1)+; retention time 2.04 minutes. 1H NMR (400 MHz, DMSO-d6) 6 10.30 (s, 1H), 8.39 (s, 1H), 7.51 (m, 1H), 7.13-7.11 (m, 1H), 7.03-6.90 (m, 4H), 6.03 (s, 2H), 2.25 (s, 3H), 1.40-1.38 (m, 11H), 1.03-1.01 (m, 2H).
[00904] Example 86: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-3-(2-hydroxyethyl)-1H-indol-5-y0cyclopropanecarboxamide <0 "FL N = AI N
0 IVN / InC13, DCM <oMAP N
Ai H A H
OH
[00905] Approximately 100 1.1.L of ethylene dioxide was condensed in a reaction tube at ¨78 C. A solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-5-y1)cyclopropanecarboxamide (200 mg, 0.50 mmol) and indium trichloride (20 mg, 0.10 mmol) in diehloromethane (2 mL) was added and tbe reaction mixture was irradiated in the microwave for 20 min at 100 C. The volatiles were removed and the residue was purified by column chromatography (0-100 % ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-3-(2-hydroxyethyl)-1H-indol-5-y1)cyclopropanecarboxamide (5 mg, 3%).
ESI-MS m/z calc. 420.5, found 421.3 (M+1)+; retention time 1.67 minutes. 1H
NMR (400 MHz, CD3CN) 8 8.78 (s, 1H), 7.40 (m, 1H), 7.33 (s, 1H), 7.08 (m, 1H), 6.95 -6.87 (m, 3H), 6.79 (m, 1H), 5.91 (s, 211), 3.51 (dd, J = 5.9, 7.8 Hz, 2H), 2.92 - 2.88 (m, 2H), 2.64 (t, J = 5.8 Hz, 1H), 1.50 (m, 2H), 1.41 (s, 9H), 1.06 (m, 2H).
[00906] Example 87: 2-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxainido)-1H-indol-2-ypacetic acid V H LiOH H20 V H
40 * TH F/H20 < = 40 0 0 N CO,Et N CO2H
[00907] To a solution of ethyl 2-(5-(1-(benzo[d][1,31dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-yeacetate (0.010 g, 0.025 mmol) in THF
(0.3 mL) were added Li0H.H20 (0.002 g, 0.05 mrnol) and water (0.15 naL) were added. The mixture was stirred at room temperature for 2 h. dichloromethane (3 mL) was added to the reaction mixture and the organic layer was washed with 1 N HCI (2 x 1.5 mL) and water (2 x 1.5 mL).
The organic layer was dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give 2-(5-(1-(benzo[d1[1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-2-y1)-acetic acid. 1I-1 NMR (400 MHz, DMSO-d6) 8 12.53 (s, 1H), 10.90 (s, 1H), 8.42 (s, 1H), 7.57 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.17 (s, IFI), 6.02 (s, 211), 3.69 (s, 21-I), 1.41-1.39 (m, 214), 1.04-1.02 (m, 2H).
[00908] Example 88: 5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylic acid V H V H

(0 OO O
LOH 3. (00 :Iv ______________________________________ 0 ? 0 OH
[00909] Methyl 5-(1-(benzo[d][1,3]dioxo1-5-yficyclopropanecarboxamido)-2-tert-buty1-1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (2 mL) containing a magnetic star bar and lithium hydroxide (30 mg, 0.71 mmol). The resulting solution was stirred at 70 C for 45 minutes. The crude product was then acidified with 2.6 M hydrochloric acid and extracted three times with an equivalent volume of dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimum of N,N-dimethylformamide and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-(benzo [d][1,31dioxo1-5-yficyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylic acid. ESI-MS trilz calc. 434.2, found 435.5. Retention time of 1.85 minutes.
1H NMR (400 MHz, DMSO-d6) 8 13.05 (s, 1H), 9.96 (d, J= 1.6 Hz, 111), 7.89 (d, J= 1.9 Hz, 1H), 7.74 (d, J= 2.0 Hz, 1H), 7.02 (d, J= 1.6 Hz, 111), 6.96-6.88 (m, 2H), 6.22 (d, J= 2.3 Hz, 111), 6.02 (s, 2H), 1.43 - 1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 211).
[00910] Example 89: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(1,3-dihydroxypropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide v H v H H

< 40 0 40 N
Na(0Ac)313 _______________________ <I=
* ON * N Chloranil __________________________________________________ * 0 40 =
( WO 2010/054138 PC1711S2009/06.34 V H Na(0Ac)3BH V kl <=
0 o <= 0N
=
(OH

[00911] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yOindolin-5-yecyclopropaneearboxamide [00912] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in dichloroethane (0.20 mL) and 2,2-dimethy1-1,3-dioxan-5-one (0.20 raL). Trifluoroacetic acid was added (0.039 mL) and the resulting solution was allowed to stir for 20 minutes. Sodium triacetoxyborohydride was added (55 mg, 0.26 mmol) and the reaction mixture was stirred for 30 minutes. The crude reaction mixture was then evaporated to dryness, dissolved in N,N-dimethylformamide and purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid.
v H
lor H Chioranil 0 <() 1.1 0 *N
___________________________________ < 40 *

C)MOH (HOH
OH
OH
[00913] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yI)-1H-indol-5-yl)cyclopropanecarboxamide [00914] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(1,3-dihydroxypropan-2-yl)indolin-5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100 'V in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in a 1 mL of N,N-dimethylformamide and purified by purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield 1-(benzo [d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(1,3-dihydroxypropan-2-y1)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS nilz calc.
450.2, found 451.5 (M+1)+. Retention time of 1.59 minutes.
[00915] Example 90: N-(7-(Aminomethyl)-2-tert-butyl-1H-indo1-5-y1)-1-(benzo[d][1,31-dioxol-5-yfleyclopropanecarboxamide V H Pd / C V
N
(0 MI 0 *I \

= N
_____________________________________ <c) 101 0 [00916] N-(7-(Aminomethyl)-2-tert-butyl-1H-ivadol-5-y1)-1-(benzo[d][1,3]dioxo1-ypcyclopropanecarboxamide [00917] 1 -(B enzo [d] [1,31dioxo1-5-y1)-N-(2-tert-buty1-7-cyano-1H-indo1-5-y1)cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of ethyl acetate.
The solution was recirculated through a continuous flow hydrogenation reactor containing 10% palladium on carbon at 100 'V under 100 bar of hydrogen for 8 h. The crude product was then evaporated to dryness and purified on 12 g of silica gel utilizing a gradient of 0-100% ethyl acetate (containing 0.5% triethylamine) in hexanes to yield N-(7-(aminomethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]-dioxo1-5-y1)-cyclopropanecarboxamide (121 mg, 32%). ESI-MS m/z calc. 405.2, found 406.5 (M+1)+. Retention time of 1.48 minutes.
[00918] Example 91: 5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butyl-W-indole-7-carboxamide <o 110 0 la \ (o la 0 110 [00919] 5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropaneearboxamido)-2-tert-butyl-indole-7-carboxamide [00920] 1 -(B enzo[d][1,3]dioxol-5-y1)-N-(2-tert-buty1-7-cyano-1H-indo1-5-y1)-cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of methanol (1.8 mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium hydroxide (0.150 mL). The resulting suspension was stirred for 72 h at room temperature.
The hydrogen peroxide was then quenched with sodium sulfite. The reaction mixture was diluted with 0.5 mI of N,N-dimethylformamide, filtered, and purified by preparative HPLE
using a gradient of 0,99% acetonitTile in water containing 0.05%
trifluoroacetic acid to yield 5-(1-(benzo [6] [1,3]dioxo1-5-yflcyclopropane-carboxamido)-2-tert-butyl-1H-indole-7-carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M-I-1)+. Retention time of 1.74 minutes.
[00921] Example 92: 1-(BenzoM[1,31dioxol-5-y1)-N-(2-tert-butyl-7-(methylsultonarnido-methyl)-1H-indol-5-yl)cyclopropanecarboxamide WO 2010/054138 FL 1/ Li zukfiyiuo..,4 0 0 ( Et3N KO Si 0 N 40 ao Is _____________________________________ 0 0-.1 [00922] 1-(Benzo[d][1,31dioxo1-5-y1)-N-(2-tert-buty1-7-(methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide [00923] N-(7-(Aminornethyl)-2-tert-buty1-1H-indol-5-y1)-1-(benzo[d][1,31dioxol-yl)cyclopropanecarboxamide (20 nig, 0.049 mmol) was dissolved in DIVIF (0.5 mL) containing triethylamine (20.6 [IL, 0.147 mmol) and a magnetic stir bar.
Methanesulfonyl chloride (4.2 lit, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-7-(methylsulfonamidomethyl)-1H-indol-5-y1)cyclopropanecarboxamide. ESI-MS m/z calc.
483.2, found 484.3 (M+1)+. Retention time of 1.84 minutes.
[00924] Example 93: N-(7-(Acetarnidomethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,31-dioxo1-5-yl)cyclopropanecarboxamide = N
*1 0 = \
Et3N 0 ____________________________________ < 0 101 \

o [00925] N-(7-(Aminomethyl)-2-tert-buty1-1H-indol-5-y1)-1-(benzo[d][1,3]dioxol-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 11.1,õ 0.147 mmol) and a magnetic stir bar.
Acetyl chloride (4.2 p,L, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative I-IPLC
using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield N-(7-(acetamidomethyl)-2-rert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxo1-5-yflcyclopropanecarboxamide. ESI-MS tn/z calc. 447.2, found 448.3 (M+1) .
Retention time of 1.76 minutes.
[00926] Example 94: N-(1-Acety1-2-tert-butyl-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxol-5-y1)-cyclopropanecarboxamide V H 1) NaH V H
DMF-THF

= =2) AcCI =
[00927] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-ypcyclopropane,carboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL, 1:9) was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After 30 min under N2, the suspension was cooled down to ¨15 C and a solution of acetyl chloride (1.1 eq.) in DMF (0.5 ) was added dropwise. The reaction mixture was stirred for 30 min at ¨
15 C then for 6 h at room temperature. Water (0.5 mL) was added at 0 C, solvent was removed, and the residue was diluted with Me0H, filtrated and purified by preparative HPLC
to give N-(1-acety1-2-tert-buty1-1H-indo1-5-y1)-1-(henzo[d][1,3]dioxol-5-y1)cyclo-propanecarboxamide. 1H NMR (400 MHz, DMSO) 8 8.9 (s, 1H), 7.74 (d, J =2.1 Hz, 1H), 7.54 (d, J =9 .0 Hz, 1H), 7.28 (dd, J1 =2.1 Hz, J2 =9.0 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.93 (dd, J 1 =1.7 Hz, J2 =8.0 Hz, 111), 6.89 (d, J =8 .0 Hz, 1H), 6.54 (bs, 1H), 6.02 (s, 2H), 2.80(s, 3H), 1.42-1.40 (m, 11H), 1.06-1.05 (m, 21-1). MS (EST) ink (1VI-f-fr) 419.3.
[00928] Example 95: N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)cyclopropanecarboxamide V H H

F 110 N= TFA, CH2C12,' \

H
ICH,CDOCIsiF1 R
EN ___________ F . SI 0 10 Api) V
lath F/\= 11, 40' TFA, CH202 F
= = V H
= ito \Th \Th [00929] N-(1-(2-Aminoethyl)-2-tert-butyl-6-fluoro4H-indol-5-y1)-1-(2,2-difluorobenzo-[d][1,3]clioxol-5-y1)eyclopropanecarboxamide " WO 2010/054138 [00930] To a solution of tert-butyl 2-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yflcyclopropanecarboxamido)-6-fluoro-1H-indo1-1-y1)ethylcarbamate (620 mg, 1.08 mmol) in CH2C12 (8 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 1.5 h before being neutralized with solid NaHCO3. The solution was partitioned between H20 and CH2C12. The organic layer was dried over MgSO4, filtered and concentrated to yield the product as a cream colored solid (365 mg, 71%). 1H NMR (400 MHz, DMSO-d6) 6 8.38 (s, 111), 7.87 (br s, 3H, NH3), 7.52 (s, 1H), 7.45-7.38 (m, 31i), 7.32 (dd, J = 8.3, 1.5 Hz, 1H), 6.21 (s, 1H), 4.46 (m, 2H), 3.02 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H), 1.14 (m, 2H).
HPLC ret. time 1.66 min, 10-99 % CH3CN, 3 min run; ESI-MS 474.4 m/z (MAP).
V H V H
10 0 CH,COC1 Et3N, DMF 1110 40 =
H

[00931] N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-y1)-1-(2,2-difluorobenzo [d][1,3]dioxo1-5-yl)cyclopropanecarboxamide [00932] To a solution of N-(1-(2-aminoethyl)-2-tert-buty1-6-fluoro-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et3N
(28 [IL, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 L, 0.10 mmol). The mixture was stirred at room temperature for 1 h before being filtered and purified by reverse phase HPLC (10 ¨ 99 % CH3CN/ H20) to yield N-(1-(2-acetamidoethyl)-2-tert-buty1-6-fluoro-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-ypcyclopropanecarboxamide.
1H NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1H), 8.15 (t, J = 5.9 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m, 2H), 1.41 (s, 9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99 % CH3CN, 3 min run; ESI-MS
516.4 m/z (M+IP).
[00933] Example 96: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-hydroxy-methoxy-propy1)-1H-indol-5-yl)cyclopropenecarboxamide 1. NaH, DMF-THF

<
Me0H

[00934] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-5-y1)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N2. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction mixture was cooled to ¨15 C before a solution of epichlorohydrin (79 pt, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at ¨15 C, then for 8 h at room temperature. Me0H (1 mL) was added and the mixture was heated for 10 min at 105 C in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzokl][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-hydroxy-3-methoxy-propy1)-1H-indol-5-yl)cyclopropanecarboxarnide. 1H NMR (400 MHz, DMSO-d6) 8 8.44 (s, 1H), 7.59 (d, J¨ 1.9 Hz, 1H), 7.31 (d, J= 8.9 Hz, 1H), 7.03 (dd, J=
8.7, 1.9 Hz, 2H), 6.95 (dd, J= 8.0, 1.7 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.16(s, 1H),6.03 (s, 2H), 4.33 (dd, J = 15.0, 4.0 Hz, 1H), 4.19 (dd, J= 15.0, 8.1 Hz, 1H), 4.02 (ddd, J= 8.7, 4.8 Hz, 1H), 3.41-3.32 (m, 2H), 3.30 (s, 3H), 1.41 (s, 9H), 1.41-1.38 (m, 2H), 1.03 (dd, J= 6.7, 4.0 Hz, 2H). MS (ESI) ink (M+H+) 465Ø
[00935] Example 97: 1-(Benzo[d][1,31clioxo1-5-y1)-N-(2-tert-butyl-1-(2-hydroxy-(methyl-amino)propy1)-1H-indol-5-y1)cyclopropanecarboxamide 1. NaH, DMF-THF

* 0 NI\
00 0 a MeNFi2 0 HN
[00936] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-5-y1)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture composed of anhydrous DMF (0.5 mL) and anhydrous THF (5 mL) under N2. NaH (60% in mineral oil, 120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the reaction mixture was cooled to ¨15 C before a solution of epichlorohydrin (79 !IL, 1.0 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for 15 min at ¨15 C, then for 8 h at room temperature. MeNH2 (2.0 M in Me0H, 1.0 mL) was added and the mixture was heated for 10 min at 105 C in the microwave oven. The mixture was cooled, filtered and purified by preparative HPLC to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-hydroxy-3-(methylamino)propy1)-1H-indol-5-yl)cyclopropanecarboxamide.
1H NMR (400 MHz, DMSO-d6) 8 8.50 (s, 111), 7.60-7.59 (m, 1H), 7.35 (dd, J =.
14.3, 8.9 Hz, 1H), 7.10 (d, J 8.8 Hz, 1H), 1H), 6.94 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J =
7.9 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 6.03 (s, 2H), 2.82 (d, J = 4.7 Hz, 1H), 2.72 (d, J =
4.7 Hz, 1H). 2.55 (dd, J = 5.2, 5.2 Hz, 1H), 2.50 (s, 3H), 1.43 (s, 9H), 1.39 (dd, J = 6.4, 3.7 Hz, 2H), 1.04 (dd, J
= 6.5, 3.9 Hz, 2H). MS (ESI) m/e (MA-) 464Ø
[00937] Example 98: (S)-N-(1-(3-Amino-2-hydroxypropy1)-2-tert-butyl-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide H
F..,)<==

V VH
=
ÇJ TsQ, TEA, DCM Fx. io 0 so NaN3 F =
OTs V H
V H
=
110 0 N\ PdfC FFX. 40 \

CCH

V H V H
=
F =
40 TsCi, TEA, DCM F 40"
OH OTs [00938] (R)-3-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarbox-amido)-1H-indol-1-y1)-2-hydroxypropyl-4-methylbenzenesulfonate [00939] To a stirred solution of (R)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indo1-5-y1)-1-(2,2-difluoro-benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide (3.0 g, 6.1 mmol) in dichloromethane (20 mL) was added triethylamine (2 mL) and para-toluenesulfonylchloride (1.3 g, 7.0 mmol). After 18 hours, the reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified using column chromatography on silica gel (0-60% ethyl acetate/hexane) providing (R)-3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropy1-4-methyl-benzenesulfonate (3.21 g, 86%). LC/MS (M + 1) = 641.2. 111 NMR (400 MHz, CDC13) 6 7.77 (d, 211, J= 16 Hz), 7.55 (d, 1H, J= 2 Hz), 7.35 (d, 2H, J = 16 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, 1H, J = 2, 8 Hz), 6.22 (s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J=
6, 15 Hz), 4.28 (dd, 1H, J= 11, 15 Hz), 4.18 (m, 1H), 3.40 (dd, 1H, J= 3, 6 Hz), 3.36 (dd, 1H, J= 3, 6 Hz), 2.46 (s, 3H), 2.40 (br s, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2 H).

v H V H
Ail = =N N3N3 F,x.
___________________________________ F = 411, 0 \/
OH OH
--OTs [00940] (R)-N-(1-(3-Azido-2-hydroxypropy1)-2-tert-butyl-1H-indo1-5-y1)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00941] To a stirred solution (R)-3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,31dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropyl-4-methylbenzenesulfonate (3.2 g, 5.0 mmol) in DMF (6 mL) was added sodium azide (2.0 g, 30 mmol). The reaction was heated at 80 C for 2 h. The mixture was partitioned between 20 mL ethyl acetate and 20 mL water. The layers were separated and the organic layer was evaporated. The residue was purified using column chromatography (0-85% ethyl acetate/hexane) to give (R)-N-(1-(3-azido-2-hydroxypropy1)-2-tert-buty1-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)-cyclopropanecarboxamide (2.48 g). LC/MS (M + 1) = 512.5. 1H NMR (400 MHz, CDC13) 7.55 (d, 1H, J= 2 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, 1H, J= 2, 8 Hz), 6.22 (s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J= 6, 15 Hz), 4.28 (dd, 1H, J¨ 11, 15 Hz), 4.18 (m, 1H), 3.40 (dd, 1H, J = 3, 6 Hz), 3.36 (dd, 1H, J = 3, 6 Hz), 2.40 (br s, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2 H).
V H
V H
=
Fx Al 0 is õõ.
Pd/C
F = =0 1110 N
F = 1111111-4-.
OH

[00942] (S)-N-(1-(3-Amino-2-hydroxypropy1)-2-tert-buty1-1H-indo1-5-y1)-1-(2,2-difluoro-benzo[d][1,3]clioxol-5-y1)cyclopropanecarboxamide [00943] To a stirred solution (R)-N-(143-azido-2-hydroxypropy1)-2-tert-butyl-1H-indo1-5-y1)-1-(2,2-difluorobenzo [d][1,31dioxo1-5-ypcyclopropanecarboxamide (2.4 g, 4.0 mmol) in Me0H (25 mL) was added 5 % Pd/C (2.4 g) under a Hydrogen gas filled balloon.
After 18 h, the reaction mixture was filtered through celite and rinsed with 300 mL
ethyl acetate. The organic layer was washed with 1 N HC1 and evaporated to give (S)-N-(1-(3-amino-hydroxypropy1)-2-tert-buty1-1H-indo1-5-y1)-1-(2,2-difluoro-benzo[d][1,3]-dioxol-5-y1)cyclopropane-carboxamide (1.37 g). MS (M + 1) = 486.5.

[00944] Example 99: (S)-Methyl 3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y0cyclopropanecarboxamido)-1H-indol-1-y1)-2-hydroxypropylcarbantate V H
F(. H 40 \ Me0C(op 11-SO
Fl o N
? \
=0 M, TEA
11\,-,AOH
OH
NH

[00945] To a stirred solution (R)-N-(1-(3-amino-2-hydroxypropy1)-2-tert-buty1-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide (0.10 g, 0.20 mmol) in methanol (1 mL) was added 2 drops of triethylamine and methylchloroformyl chloride (0.020 mL, 0.25 mmol). After 30 min, the reaction mixture was filtered and purified using reverse phase HPLC providing (S)-methyl 3-(2-te rt-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclo-propanecarboxamido)-1H-indol-1-y1)-2-hydroxypropylcarbamate. The retention time on a three minute run is 1.40 min. LC/MS (M + 1) = 544.3. 1H NMR (400 MHz, CDC13) 8 7.52 (d, 1H, J = 2Hz), 7.30 (dd, 1H, J 2, 8 Hz), 7.28(m, 1H), 7.22 (d, 1H, J = 8 Hz), 7.14 (d, 1H, J = 8 Hz), 7.04 (br s, 1H), 6.97 (dd, 1H, J = 2, 8 Hz), 6.24 (s, 1H), 5.19 (1H, br s), 4.31 (dd, 1H, J = 6, 15 Hz), 4.28 (dd, 1H, J = 11, 15 Hz), 4.18 (m, 1H), 3.70 (s, 314), 3.40 (dd, 1H, J 3, 6 Hz), 3.36 (dd, 111, J = 3, 6 Hz), 3.26 (m, 1H), 1.74 (m, 2H), 1.40 (s, 9 H), 1.11 (m, 2 H).
[00946] Example 100: 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-y1)butanoic acid H V H
<

NaBH3ON, AcOH = diAiiih N 0 \= O 0 10 ttp 0 Up = 0 C = NaBH3CN, Me0H-AcOH
H V H
CDCf3, fight N
K: open air /6 s 0 VP- \
OH OH
V H V H
. 40 NaBH,CN, AcOH = alb, N

o w 0 IP

[00947] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-y0cyclopropanecarboxamide [00948] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1H-indo1-5-y1)cyclo-propanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 mL) was added NaBH3CN (309 mg, 4.91 mmol) at 0 C. The reaction mixture was stirred for 5 min at room temperature after which no starting material could be detected by LCMS. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (5-40% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (760 mg, 89%).
LThr V H OH
<6 I. 00 - =0= N
0 NaBH3CN, =0 Me0H-AcOH
OH
[00949] 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yDbutanoic acid [00950] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol (6.5 mL) and AcOH (65 pt) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 min of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0 C and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,31dioxo1-5-yficyclopropanecarboxamido)-2-tert-butylindolin-l-y1)butanoic acid (130 mg, 30%).
V cools, light V H
* N open air <* \
= =
OH OH
[00951] 4-(5-(1-(Benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-yObutanoic acid [00952] 4-(5-(1-(Benzo[d][1.3]dioxo1-5-yficyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 0.28 mmol) was taken up in a mixture of acetonitrile-H20-TFA.
The solvent was removed under reduced pressure and the residue obtained was dissolved in CDC13. After a brief exposition to daylight (5-10 min), the solution turned purple. The mixture was stirred open to the atmosphere at room temperature until complete disappearance of the starting material (8 h). Solvent was removed under reduced pressure and the residue was purified by reverse pharse HPLC to give 4-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-buty1-1H-indo1-1-yl)butanoic acid. 1H NMR
(400 MHz, CDC13) 8 7.52 (d, J = 1.9 Hz, 1H), 7.18 (d, J -= 2.1 Hz, 1H), 7.16 (s, 1H), 7.03 (dd, J =-- 9.4, 1.9 Hz, 1H), 7.00-6.98 (m, 2H), 6.85 (d, J = 7.9 Hz, 1H), 6.16 (s, 1H), 6.02 (s, 2H), 4.29-4.24 (m, 2H), 2.48 (dd, J = 6.9, 6.9 Hz, 2H), 2.12-2.04 (m, 2H), 1.69 (dd, J = 6.8, 3.7 Hz, 2H), 1.43 (s, 9H), 1.09 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) mie (M+H+) 463Ø
[00953] Example 101: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(4-(2-hydroxyethyl-amino)-4-oxobuty1)-1H-indol-5-ypeyclopropanecarboxamide HBTU, Et3N, /41' N.1 0 DMF
' = 0 go =
1 ethanolarnne OH
[00954] To a solution of 4-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-y1)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were successively added Et3N (9.5 mL, 0.069 mmol) and BETU (8.2 mg, 0.022 minol).
After stirring for 10 min at 60 C, ethanolamine (1.3 tiL, 0.022 mmol) was added, and the mixture was stirred for another 4 h at 60 C. 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(4-(2-hydroxyethyl-amino)-4-oxobuty1)-1H-indo1-5-y1)cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) ink (M+H+) 506Ø
[00955] Example 102: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-(dimethylamino)-2-oxoethyl)-1H-indol-5-yeeyelopropanecarboxamide 1. NaH, DMF-TFIF

H
H
el =
. 0= 1 0 le \
2_ DMF, Pd-C = 401 [00956] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-yftcyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 nth) and THF (1 mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N2.
After 30 min of stirring, the reaction mixture was cooled to 0 C and 2-chloro-N,N-dimethylacetamide (11 mL, 0.14 mmol,) was added. The reaction mixture was stirred for 5 min at 0 C and then for 10 h at room temperature. The mixture was purified by preparative HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of Pd-C (10 mg). The mixture was stirred open to the atmosphere overnight at room temperature. The reaction mixture was filtrated and purified by preparative HPLC providing 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-1-(2-(climethylamino)-2-oxoethyl)-1H-indol-5-yftcyclopropanecarboxamide. MS (ESI) mie (M+H+) 462Ø
[00957] Example 103: 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)cyclo-propanecarboxarnido)-111-indol-1-y1)propanoic acid V H H
N 1. NaBH(OAc), NaCN, DMF, up- DCM F.õ7 rik 0 KI, BOH-H20_ F = IMP 0 \O IMP 1111127 N
a H
= e1. 50%aq KOH H 0 N N 1,4-aioxane µ0 41PP "g1W". Rx. ifik 40 \
, CDCI3, fight, __________________ air V H 1. NaBH(OAc)a H
F.x. Ali 0 F = gittlir 41Irvir N DCM
F =0 N ,ditIPb a a [00958] N-(2-tert-Buty1-1-(2-chloroethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]clioxol-5-yl)cyclopropanecarboxamide WO 2010/054138 PC 1 / UJ.L.UUSVUO.,4 /3 [00959] To a solution of N-(2-tert-buty1-1-(2-cyanoethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yi)cyclopropanecarboxamide (71 mg, 0.17 mmol) in anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 pt, 0.41 mmol) at room temperature under N2. After 20 min of stirring, NaBH(OAc)3 (90 mg, 0.42 mmol) was added in two portions. The reaction mixture was stirred overnight at room temperature. The product was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2- ten-buty1-1-(2-chloroethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane,carboxamide (51 mg, 63%).
V N H
= aCN, DMF, =V
=
N
Et0H-H20_ 4110 FF><0 N KI, N
a [00960] N-(2-tert-Buty1-1-(2-cyanoethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00961] N-(2-tert-buty1-1-(2-chloroethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane,carboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and Kr (cat) in Et0H
(0.6 mL) and water (0.3 mL) were combined and heated at 110 C for 30 min in the microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2-tert-buty1-1-(2-cyanoethyl)indolin-5-y0-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yUcyclopropanecarboxamide (24 mg, 48%).
V V H
N
N 42.1,h 0 1. 50%aq KOH X N
1,4-dioxane 011 0 F = %Pi CDCI3, light, air [00962] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclo-propanecarbox-amido)-1H-indol-1-y1)propanoic acid [00963] N-(2-tert-buty1-1-(2-cyanoethyl)indolin-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cycIopropane-carboxamide (24 mg, 0.050 mmol) was taken up in 50% aq. KOH
(0.5 mL) and 1,4-dioxane (1 mL). The mixture was heated at 125 C for 2 h. The solvent was removed and the residue was purified by preparative HPLC. The residue was dissolved in CDC13 (1 mL) then briefly exposed to daylight. The purple solution that formed was stirred until complete disappearance of the starting material (1 h). The solvent was removed under reduced pressure and the residue was purified by preparative HPLC providing 3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,31dioxol-5-yl)cyclo-propanecarboxarnido)-1H-indol-ylipropanoic acid. MS (ESI) ink (M+H+) 485Ø
[00964] Example 104: 1-(Benzo[d][1,3]dioxo1-5-yI)-N-(2-tert-butyl-6-fluoro-1-(2-hydroxy-ethyl)-1H-indo1-5-yl)cyclopropenecarboxamide 1. o 0 V H
j<H = V H
(' 40 N dikh ' 0 N
C> giP < NaBH3CN ________ = Vdoh P F IWP N
Me0H-AcOH
CDC13, light, air [00965] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoroindolin-5-yl)cyclopropanecarboxamide (340 mg, 0.86 mmol) in anhydrous Me0H (5.7 mL) containing 1% of acetic acid was added glyoxal 40% in water (0.60 mL, 5.2 mmol) at room temperature under N2. After 20 min of stirring, NaBH3CN (120 mg, 1.9 mmol) was added in one portion and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue obtained was purified by column chromatography on silica gel (10-40% ethyl acetate/hexanes) providing a pale yellow oil which was treated with 50/50 CH3CN-H20 containing 0.05% TFA and CDC13. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20-35% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-1-(2-hydroxyethyl)-1H-indol-5-y1)cyclopropanecarboxamide. 1H
NMR (400 MHz, CDC13) 8 8.02 (d, J = 7.7 Hz, 11I), 7.30 (d, J = 2.1 Hz, 1H), 6.93 (dd, J
= 1.6, 7.9 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.08 (s, 1H), 5.92 (s, 2H), 4.21 (dd, J = 6.9, 6.9 Hz, 2H), 3.68 (m, 211), 2.28 (s, 1H), L60 (dd, J = 3.7, 6.7 Hz, 2H), 1.35 - 1.32 (m, 9H), 1.04 (dd, J = 3.7, 6.8 Hz, 2H). MS (ESI) (M+1-1+) 439Ø
[00966] Example 105: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxy-propyl)-1H-indo1-5-yl)cyclopropanecarboxamide 1. ri V H V H
F

0 1.11 NaBH(OAc)3, DCM = N
= CDCI3, light, air =
3. Pd-C, H2, Me0H
FKD

/USZumub.s4 tn OH PCC, DCM
, OBn [00967] 3-(Benzyloxy)propanal 1009681 To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous dichloromethane (8 mL) at room temperature under N, was added a solution of 3-benzyloxy-1-propanol (310 mg, 1.88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred overnight at room temperature, filtrated through Celite, and concentrated. The residue was purified by column chromatography on silica gel (1-10% ethyl acetate/hexanes) to give 3-(benzyloxy)propanal (243 mg, 79%).
1.
OBn V = H V H
NaBH(OAc)3, DCM 40 <. 0 0 N\
= F N CDCI3, light, air =
3. Pd-C, H2, Me0H
HO
[00969] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-1-(3-hydroxypropy1)-1H-indol-5-yl)cyclopropaneearboxamide [00970] To a solution of 1-(benzo[d][1,3]dioxo1-5-ye-N-(2-tert-buty1-6-fluoroindolin-5-yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After 10 min of stirring, NaBH(OAc)3 (140 mg, 0.65 mmol) was added in one portion and the reaction naixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was taken-up in a mixture of 50/50 CH3CN-1120 containing 0.05%
11-A. The mixture was concentrated to dryness and the residue was dissolved in CDC13 (5 mL) and briefly exposed to daylight. The purple solution was stirred open to the atmosphere at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with Pd-C (10 mg) in Me0H (2 mL) under 1 atm of H2 for 2 h. The catalyst was filtered through Celite and the solvent was removed under reduced pressure.
The residue was purified by preparative TLC 30% ethyl acetate/hexanes to provide 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-1-(3-hydroxypropy1)-1H-indol-5-yl)cyclopropanecarboxamide (18 mg, 8% from 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoroindolin-5-yl)cyclopropane-carboxamide). 1H NMR (400 MHz, CDC13) 8 8.11 (d, J =
7.8 Hz, 1H), 7.31 (d, J = 2.2 Hz, 111), 6.94 (dd, J = 7.9, 1.7 Hz, 1H), 6.91 (d, J = 1.6 Hz, 111), 6.85 (d, J = 11.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.10 (s, 1H), 5.94 (s, 2H), 4.25-4.21 (m, 2H), 3.70 (dd, J = 5.7, 5.7 Hz, 2H), 1.93-1.86 (m, 2H), 1.61 (dd, J = 6.8, 3.7 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453Ø
[00971] Example 106: N-(1-(2-Acetamidoethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide NaBH(OAc), V H
1. PciaciF11 atm H
N
:s 0 N DCM0 - <6 2. Et,N, THF, (.40 N\
Aca 2 CDC13, light, N3 NH
3 NaN,, Nal, DMF
V H H
1. NaB1-1(0Ac)3 = N
<.= 40 0 SN
DCM
= 0 IP \
CCa CDC13, light, ar 3 NaN,, Nal, DMF
[00972] N-(1-(2-azidoethyl)-2-tert-buty1-1H-indol-5-y1)-1-(benzo[d][1,3]dioxol-5-y1)-cyclopropanecarboxamide [00973] To a solution of 1-(benzo[d][1,31dioxo1-5-y1)-N-(2-tert-butylindolin-5-yl)cyclopropane-carboxamide (73 mg, 0.19 mmol) in anhydrous dichloromethane (1.2 mL) was added chloroacetaldehyde (60 [IL, 0.24 mmol) at room temperature. After 10 min of stirring, NaBH(OAc)3 (52 mg, 0.24 mmol) was added in one portion and the reaction mixture was stirred for another 30 min at room temperature. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the indoline, which oxidized to the corresponding indole when taken-up in CDC13. The resulting indole was treated with NaN3 (58 mg, 0.89 mmol) and Nal (cat) in anhydrous DMF (0.8 mL) for 2 h at 85 C. The reaction mixture was purified by preparative HPLC providing N-(1-(2-azidoethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxol-5-. yl)cyclopropanecarboxamide (15 mg, 18% from 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-butylindolin-5-yl)cyclopropane-carboxamide).
V H 1. Pd-C, H2 V H
Me0H-Ao0H
( 1.1 0 N _______________________________ ' 411 El3N, THF, = ¨ 0 N
Aca o iNH

[00974] N-(1-(2-Acetamidoethyl)-2-tert-buty1-111-indol-5-y1)-1-(benzo[d][1,3]-dioxol-5-y0cyclopropanecarboxarnide [00975] A solution of N-(1-(2-azidoethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxol-5-y1)cyclopropamecarboxamide (13 mg, 0.029 mmol) in Me0H-AcOH
(0.2 mL, 99:1) in the presence of Pd-C (2 mg) was stirred at room temperature under 1 atm of H2 for 2 h, filtered through Celite, and concentrated under reduced pressure.
The crude product was treated with AcC1 (0.05 mL) and Et3N (0.05 mL) in anhydrous THF
(0.2 mL) at 0 C for 30 min and then 1 h at room temperature. The mixture was purified by preparative HPLC providing N-(1-(2-acetamidoethyl)-2-tert-buty1-1H-indo1-5-y1)-1-(benzo[d][1,3]-dioxol-5-y1)cyclopropanecarboxamide. MS (ESI) m/e (M+H ) 462Ø
[00976] Example 107: N-(2-tert-Buty1-1-(3-cyano-2-hydroxypropy1)-111-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-ypcyclopropanecarboxarnide F =
V H
NIccr)if_ Fxxx--vy" TsCI, EteJ * wicQ4_ NaCN F--,2VCIVY
u N '""ilir 0 Fia.)/) DCM
HOI) DMFHO
HO Ts0 = H V H
00 0 ip Tsai, Et,N_ F,x= 40 0 010 \
Ha)) DCM F =
HO Ts0 [00977] 3-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbox-amido)-1H-indol-1-y1)-2-hydroxypropyl-4-methylbenz,enesulfonate [00978] To a solution of N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,31-dioxol-5-y1)cyclopropanecarboxamide (172 mg, 0.35 mmol) in anhydrous dichloromethane (1.4 mL) at 0 C in the presence of Et3N (56 pi, 0.40 mmol) was added TsC1 (71 mg, 0.37 mmol). The reaction mixture was stirred for 2 h at room temperature before being cooled to 0 C and another portion of TsC1 (71 mg, 0.37 mmol) was added. After 1 h of stirring at room temperature, the mixture was purified by column chromatography on silica gel (10-30% ethyl acetate/hexanes) providing 3-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-hydroxypropyl-4-methylbenzene-sulfonate (146 mg, 64%).

Fx= fa 0 \ N a C NI, DMF Fx.
F = lir= F =
HO)) Ts0 [00979] N-(2-tert-Buty1-1-(3-cyano-2-hydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00980] N-(2-tert-Buty1-1-(3-cyano-2-hydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-cyclopropanecarboxamide (145 mg, 0.226 mmol) was treated with powdered NaCN (34 mg, 0.69 mmol) in anhydrous DMF (1.5 mL) at 85 C for 2 h. The reaction mixture was cooled down to room temperature before it was diluted with dichloromethane (10 mL) and aq. sat. NaHCO3 (10 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with brine, dried with sodium sulfate, filtered then concentrated. The residue was purified by column chromatography on silica gel (25-55% ethyl acetate/hexanes) providing N-(2-tert-buty1-1-(3-cyano-2-hydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,31dioxo1-5-y1)cyc1opropanecarboxamide (89 mg, 79%). 1H NMR
(400 MHz, CDC13) 7.43 (d, J = 1.9 Hz, 1H), 7.20-7.16 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.94 (s, 1H), 6.88 (dd, J = 8.7, 2.0 Hz, 1H), 6.16 (s, 1H), 4.32-4.19 (m, 3H), 2.83 (s, 1H), 2.40 (dd, J = 5.2, 5.2 Hz, 2H), 1.62 (dd, J = 6.6, 3.6 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J = 6.9, 3.9 Hz, 2H). MS (ESI) mle (M+1-1+) 496Ø
[00981] Example 108: N-(2-tert-Buty1-1-(2-hydroxy-3-(2H-tetrazol-5-yOpropy1)-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-Acyclopropanecarboxamide Nat4.3, NH4a FS
N
o \

NtHlii [00982] To a solution of N-(2-tert-buty1-1-(3-cyano-2-hydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054 mmol) in anhydrous DMF (1.2 mL) were successively added NH4C1 (35 mg, 0.65 mmol) and NaN3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h at 110 C in the microwave, at which stage 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to provide N-(2-tert-butyl-1-(2-hydroxy-3 -(2H-tetrazol-5 -yl)propy1)-1H-in dol- 5-y1)- 1- (2,2-difluorobenzo-[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539Ø
[00983] Example 109: 4-(2-tert-Buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclo-propanecarboxamido)-1H-indol-1-y1)-3-hydroxybutanoic acid H

V H
Me0H, NaOH 40 \
el HO-?) [00984] A solution of N-(2-ten-buty1-1-(3-cyano-2-hydroxypropy1)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-ypcyclopropanecarboxamide (14 mg, 0.028 mmol) in methanol (0.8 mL) and 4 M NaOH (0.8 mL) was stirred at 60 C for 4 h. The reaction mixture was neutralized with 4 M PIC1 and concentrated. The residue was purified by preparative HPLC to provide 4-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamido)-1H-indol-1-y1)-3-hydroxybutanoic acid. MS (EST) nile (M+H ) 515Ø
[00985] Example 110: N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-y1)-1-(benzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamide V H NaCN, l V H 1. NH4CI, NaN, DMF = /RI
(.0 410 140 Et0H-H20 <" 40 40 2. MCI, light, =
air t\r'1,1 V H NaCN, K1 V H
K. 401 Et0H-1-120 = = N viat=r.

=
a [00986] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-cyanoethypindolin-5-y1)-cyclopropanecarboxamide [00987] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol (0.8 mL) and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room temperature.
The reaction mixture was stirred for 30 min at 110 C in the microwave before being purified by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 77%).
V H 1. NH4CI, NaN3, V H
(' 40 DMF
.
a CDCI3, light, =
air [00988] N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-y1)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide [00989] To a solution of 1-(benzo[d][1,31dioxo1-5-y1)-N-(2-tert-buty1-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF
(2.6 mL) was added NH4C1 (230 mg, 4.3 mmol) and NaN3 (280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110 C in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDC13 (3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide. MS (ESI) rate (M+H ) 473Ø
[00990] Example 111: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)-111-indol-5-yl)cyclopropanecarboxamide V [1 1.NaBH(OAc)3, V H
<. le) 40 0 =\

LO) 2. CDCl3 [00991] To a solution of 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoroindolin-5-Acyclopropane-carboxamide (150 mg, 0.38 mmol) in anhydrous dichloromethane (2.3 mL) at room temperature under N2 was added tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol). After 20 min of stirring, NaBH(OAc)3 (110 mg, 0.51 mmol) was added in one portion at room temperature. The reaction Mixture was stirred for 6 h at room temperature before being purified by column chromatography on silica gel (5-20% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)indolin-5-yl)cyclopropane,carboxamide (95 mg, 50%). CDC13 was added to the indoline and the solution was allowed to stir overnight at ambient temperature. The solution was concentrated to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-6-fluoro-((tetrahydro-2H-pyran-3-y1)methyl)-1H-indol-5-y1)cyclopropanecarboxamide. MS
(ESI) mie (M+1-) 493Ø
[00992] Example 112: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(2-hydroxypropan-2-y1)-indol-5-ypeyclopropanecarboxamide = H V H
<0 AliN 0 CH3Li(= OH
0 \
0 gipP-[00993] Methyl 5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclopropane-carboxamido)-1H-indole-2-carboxylate (100 mg, 0.255 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL) under an argon atmosphere. The solution was cooled to 0 'V in an ice water bath before methyllithium (0.85 mL, 1.6 M in diethyl ether) was added by syringe. The mixture was allowed to warm to room temperature. The crude product was then partitioned between a saturated aqueous solution of sodium chloride (5 mL) and dichloromethane (5 mL). The organic layers were combined, dried over sodium sulfate, filtered, evaporated to dryness, and purified on 12 g of silica gel utilizing a gradient of 20-80% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(2-hydroxypropan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide (35 mg, 36%) as a white solid. ESI-MS m/z calc.
378.2, found 379.1 (M+1) . Retention time of 2.18 minutes. iff NMR (400 MHz, DMSO-d6) 8 10.78 (s, 11-1), 8.39 (s, 1H), 7.57 (d, J¨ 1.7 Hz, 1H), 7.17 (d, J= 8.6 Hz, 1H), 7.03 -6.90 (m, 4H), 6.12 (d, J= 1.5 Hz, 1H), 6.03 (s, 2H), 5.18 (s, 1H), 1.50 (s, 6H), 1.41 - 1.38 (m, 211), 1.05-0.97 (m, 2H).
[00994] Example 113: N-(2-(1-Amino-2-methylpropan-2-y1)-1H-indo1-5-y1)-1-(benzo[d][1,3]-dioxol-5-ypeyelopropanecarboxamide = H = H
0 N.CCD¨e-N NH Boc TFA =
t4CD¨e_ = [Nli NH2 [00995] Trifluoroacetic acid (0.75 mf ) was added to a solution of tert-butyl 2-(5-(1-(benzo[d][1,31dioxo1-5-3/1)cyclopropanecarboxamido)-1H-indol-2-y1)-2-methylpropylcarbarnate (77 mg, 0.16 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give N-(2-(1-amino-2-methylpropan-2-y1)-1H-indo1-5-yl)-1-(benzo[d][1,3]dioxo1-5-y1)cyclopropane,carboxamide (53 mg, 86%). 1H NMR
(400 MHz, CDC13) 8 9.58 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.18 - 7.15 (m, 2H), 7.02 - 6.94 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 6.14 (d, J = 1.2 Hz, 1H), 6.02 (s, 2H), 2.84 (s, 2H), 1.68 (dd, J
= 3.6, 6.7 Hz, 2H), 1.32 (s, 6H), 1.08 (dd, J -= 3.7, 6.8 Hz, 2H).
[00996] Example 114: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-(dimethylamino)-2-methyl-propan-2-y1)-1H-indol-5-yl)cyclopropanecarboxamide V H Mel = K2CO3 =
0 WI 0 NA_14,_,2 O gP

e2 [00997] To a solution of N-(2-(1-amino-2-methylpropan-2-y1)-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxo1-5-y1)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF
(1 mL) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 !.LL, 0.11 mmol).
The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate, evaporated, coevaporated with toluene (3x) and purified by silica gel chromatography (0-30% Et0Ac in hexane) to give 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(1-(dimethylamino)-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide (7 mg, 33%). 1H NMR (400 MHz, CDC13) S
9.74 (s, 1H), 7.58 (d, J = 1.9 Hz, 111), 7.20 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.01 - 6.95 (m, 3H), 6.85 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s, 214), 2.24 (s, 6H), 1.68 (dd, J = 3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J = 3.7, 6.8 Hz, 2H).
[00998] Example 115: N-(241-Acetamido-2-methylpropan-2-y1)-1H-indol-5-y1)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide 0 =

V H = V H
=
2 " = =
NCQ-eNH AC2 Nit Nnre-NHAc [00999] To a solution of N-(2-(1-amino-2-methylpropan-2-y1)-1H-indo1-5-y1)-1-(benzo[d][1,3]dioxo1-5-y1)cyclopropanecarboxamide (21 mg, 0.054 mmol) in dichloromethane (1 mL) was added pyridine (14 ).11_, 0.16 mmol) followed by acetic anhydride (6.0 !.IL, 0.059 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane, evaporated, coevaporated with toluene (3x) and purified by silica gel chromatography (60-100% ethylacetate in hexane) to give N-(2-(1-acetamido-2-methylpropan-2-y1)-1H-indo1-5-y1)-1-(benzo[d][1,3]-dioxo1-5-yl)cyclopropanecarboxamide (17 mg, 73%). IH NMR (400 MHz, DMSO) .5 10.79 (s, 111), 8.39 (s, 1H), 7.66 (t, J = 6.2 Hz, 111), 7.56 (d, J = 1.7 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.02 -6.89 (m, 4H), 6.08 (d, J = 1.5 Hz, 1H), 6.03 (s, 2H). 3.31 (d, J .= 6.2 Hz, 2H), 1.80 (s, 3H), 1.41 - 1.38 (m, 2H), 1.26 (s. 6H), 1.04 - 1.01 (m, 2H).
[001000] Example 116: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(2-methyl-4-(1H-tetrazol-5-yl)butan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide V H V H
<AO // NH4C1 N
NaN, 0 41111-1'.'"
_-N
HN, .2N1 [001001] 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(4-cyano-2-methylbutan-2-y1)-1H-indo1-5-y1)cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in N,N-dimethylformarnide (1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol), and a magnetic stir bar. The reaction mixture was heated at 110 'V for 40 minutes in a microwave reactor. The crude product was filtered and then purified by preparative HPLC
using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-(2-methy1-4-(1H-tetrazol-5-yl)butan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide. ESI-MS miz calc. 458.2, found 459.2 (M+1) .
Retention time of 1.53 minutes. 1H NMR (400 MHz, CD3CN) 9.23 (s, 1H), 7.51 - 7.48 (m, 2H), 7.19 (d, J=
8.6 Hz, 1H), 7.06 - 7.03 (m, 2H), 6.95 - 6.89 (m, 2H), 6.17 (dd, J= 0.7, 2.2 Hz, 1H), 6.02 (s, 2H), 2.61 - 2.57 (m, 2H), 2.07 - 2.03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s, 6H), 1.12-1.09 (m, 2H).
[001002] Example 117: 1-(Benzo[d][1,3]dioxo1-5-y1)-N-(2-(piperidin-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide = TFA N H
40 <
. N
[001003] tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxo1-5-yl)cyclo-propanecarboxamido)-1H-indol-2-y1)piperidine-1-carboxylate (55 mg, 0.11 mmol) was dissolved in dichloromethane (2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was stirred for 6 h at room temperature. The crude product was purified by preparative H:PLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield I-(benzo [d][1,3]dioxol-5-y1)-N-(2-(piperidin-2-y1)-1H-indol-5-yl)cyclopropaneearboxamide.
ESI-MS tn/z cale. 403.2, found 404.4 (M+1)+. Retention time of 0.95 minutes.
[001004] Example 118: 5-tert-Butyl-1H-indo1-6-ylamine HCCSIMe3 = NBS, DMF = Br., H2so = Br Pd(PHh3)2Cl2 NH2 NH2 02N NH2 Cul, Et3N
Tol, H20 Si 1 02N NH2 Cul, DMF

\ H2, Raney Ni 40 100NBS DMF Br [001005] 2-Bromo-4-tert-butyl-phenylamine [001006] To a solution of 4-tert-Butyl-phenylamine (447 g, 3.00 mol) in DMF
(500 mL) was added dropwise NBS (531 g, 3.00 mol) in DMF (500 mI ) at room temperature.
Upon completion, the reaction mixture was diluted with water and extracted with Et0Ac. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
Br Br KNO,, H2S01.
'14'11.' NH2 02N 41(11111P. NH2 [001007] 2-Bromo-4-tert-butyl-5-nitro-phenylamine [001008] 2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H2SO4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to ¨5 to ¨10 'C. A solution of KNO3 (83 g, 0.82 mol) in H2SO4 (410 mL) was added dropwise while the temperature was maintained between ¨5 to ¨10 C. Upon completion, the reaction mixture was poured into ice / water and extracted with Et0Ac. The combined organic layers were washed with 5% Na2CO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by a column chromatography (ethyl acetate/petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%).
HCCSiMe3 = Br Pd(PPh3)2a 2 02N NH2 Cul, Et3N
Tof , H20 02N NH2 [001009] 4-tert-Butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine [001010] To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et3N (27.9 mL, 200 mmol), Pd(PPh3)2C12 (2.11 g, 3.00 mmol), Cur (950 mg, 0.500 mmol) and trimethylsily1 acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 'V in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with Et0Ac. The combined filtrate was washed with 5% NH4OH solution and water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0 ¨ 10 % ethyl acetate/petroleum ether) to provide 4-tert-buty1-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous liquid (25 g, 81 %).
O N
¨
02N NH2 õ2¨

A
[001011] 5-tert-Butyl-6-nitro-1H-indole [001012] To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added Cut (8.2 g, 43 mmol) under a nitrogen atmosphere.
The mixture was heated at 135 C in a sealed pressure flask overnight, cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with Et0Ac. The combined filtrate was washed with water, dried over Na2SO4 and concentrated.
The crude product was purified by column chromatography (10 ¨ 20 % ethyl aetate/hexane) to provide 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69 %).
H2, Raney Ni =\

[001013] 5-tert-Butyl-1H-indo1-6-ylamine [001014] Raney Nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (15 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30 C for 3 h. The catalyst was filtered off. The filtrate was dried over Na2SO4 and concentrated. The crude dark brown viscous oil was purified by column chromatography (10 ¨ 20 % ethyl acetate/petroleum ether) to give 5-tert-buty1-1H-indo1-6-ylamine as a gray solid (11 g, 87 %).
1H NMR (300 MHz, DMSO-d6) 8 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, 1H), 4.4 (br s, 211), 1.3 (s, 9H).

1-(2,3-Dihydro-1H-inden-5-yDcyclopropanecarboxylic acid V V
d) 00 Cl e) aô CN f) 00 CN g) OH

a) Ac20, AlC13, CH2C12; b) NaC10; c) LiA11-14, THF, -78 C; d) S0C12, CHCI3; e) NaCN, DMSO; BrCH2CH2C1, NaOH, Bu4NBr, toluene; g) NaOH
[001] Step a: 1-(2,3-Dihydro-1H-inden-6-yl)ethanone [002] A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of AlC13 (272.0 g, 2.04 mol) in CILC12 (1000 ml) at 0 C over a period of 3h. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated in vacuo. The residue that was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to give the product (120.0 g, 88%). 1H NMR (400 MHz, CDC13) 5 2.08-2.15 (m, 2H), 2.58 (s, 3H), 2.95 J= 7.2, 4 H), 7.28 (d, J= 8.0, 1H), 7.75 (d, J= 8.0, 1H) 7.82 (s,1H).
[003] Step b: 2,3-dihydro-1H-indene-5-carboxylic acid [004] To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol, 6%) at 55 C was added 1-(2,3-dihydro-1H-inden-6-y1) ethanone (120.0 g,0.75 mol) and the mixture was stirred at 55 C for 2 h. After cooling to room temperature, saturated NaHCO3 solution was added until the solution became clear. The produced precipitate was filtered, washed several times with water and dried to afford the desired product (120.0 g, 99%). 1H NMR (CDC13, 300MHz) 6 2.07-2.17 (m, 2H), 2.96 (t, J= 7.5Hz, 4H), 7.30 (d, J
=7.8, 1H,), 7.91 (d, J= 7.8, 1H), 7.96 (s, 1H).
[005] Step c: (2,3-dihydro-1H-inden-5-yl)methanol [006] To a stirred solution of LAH (72.8 g, 1.92 mol) in THF (2.5 L) at 0 C
was slowly added 2,3-dihydro-1H-indene-5-carboxylic acid (100.0 g, 0.62 mol).
The reaction mixture was stirred at 0 C for 1h. Then the reaction was quenched with H20 (72 ml) and NaOH (68 ml, 20%). The mixture was filtered and the organic layer was dried over Na2SO4, evaporated in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the desired product (82.0 g, 90%). 111 NMR (CDC13, 300MHz); 2.03-2.13 (m, 2H), 2.91 (t, J= 7.5Hz, 4H), 4.64 (s, 2H), 7.13 (d, J=
7.5, 1H), 7.18-7.24 (m, 2H).
[007] Step d: 5-(chloroinethyl)-2,3-dihydro-1H-indene [008] Thionyl chloride (120 ml, 1.65 mol) was added drop-wise to a rapidly stirred mixture of (2,3-dihydro-1H-inden-5-yl)methanol (81.4 g, 0.55 mol) in chloroform (500 ml) at 0 C. After the addition was complete, the resulting mixture was allowed to wami to room temperature and the stirring was continued for an additional 12 h. The chloroform was evaporated under reduced pressure to give a residue, that was purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) to afford 5-(chloromethyl)-2,3-dihydro-1H-indene (90.5 g, 99%). 1H NMR (300 MHz, CDC13) 2.06-2.19 (m, 4H), 2.93 (t, J= 7.5, 4H), 4.54 (s, 2H), 7.15-7.31 (m, 3H).
[009] Step e: 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile [010] To a stirred solution of 5-(chloromethyl)-2,3-dihydro-1H-indene (90.0 g, 0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08mol) at 0 C portion wise. The reaction mixture was then stirred at room temperature for 3 hours.
The reaction was quenched with water (1000 ml), extracted with ethyl acetate (3 x 250 mL).
The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to afford 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (82.2 g, 97%), that was used in the next step without further purification.
[011] Step f: 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile [012] To a stirred solution of 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (50.0 g, 0.32 mol) in toluene (150 mL) was added sodium hydroxide (300 mL, 50 percent in water W/W), 1-bromo-2-chloroethane (92.6 m1,1.12 mol) and (n-Bu)4NBr (5 g, 15.51 mmol). The mixture was heated at 60 C overnight. After cooling to room temperature, the reaction mixture was diluted with water (400 nth) and extracted with Et0Ac (3 x 200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to yield 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3 g,16%).
114 NWIR. (CDC13,300MHz) 6 1.35-1.38 (m, 2H), 1.66-1.69 (m, 2H), 2.05-2.13 (m.
211), 2.87-294 (m, 4H), 7.07-7.22 (m,3H).

[013] Step g: 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid

[014] To a stirred 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3 g,50.8 mmol) in methanol (40 mL) was added a solution of 150 mL of sodium hydroxide (25% NaOH w/w in water). The mixture was heated at 100 C for 8 hours. After cooling to room temperature, the reaction mixture was poured over ice-water (0 C), the pH was adjusted to pH=4 with hydrogen chloride (1 N) and the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The residue that was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid (4.8 g,47%). 1H NMR (CDC13, 400 MI-lz) 6 1.23-1.26 (m, 2H), 1.62-1.65 (m, 2H), 2.03-210 (m, 2H), 2.81-2.91 (m, 4H), 7.11-7.21 (m, 3H).
5-Amino-2-tert-butyl-1H-indole-4-carbonitrile = 92N =
b) H2N
a) KCN, DMSO; b) Pd/C, Et0Ac

[015] Step a: 2-tert-buty1-5-nitro-1H-indole-4-carbonitrile

[016] To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (4.0 g, 17 mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred at 70 C for 3 hours, and poured into water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (7% Et0Ac in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (2.2 g, 53%). 1H NMR (DMSO, 300 MHz) 8 12.23 (br s, 1 H), 8.09 (d, J = 9.0 Hz, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 6.50 (s, 1 H), 1.38 (s, 9 H). MS (ESI) m/z: 244.2 [M+H
].

[017] Step b: 5-amino-2-tert-butyl-1H-indole-4-carbonitrile

[018] To a solution of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (550 mg, 2.3 mmol) in Et0Ac (10 mL) was added Raney Ni (0.1 g) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 h. The catalyst was filtered over Celite and the filtrate was evaporated in vacua to afford 5-amino-2-WO 2010/054138 PCTiUS2009/0634 7 5 tert-butyl-1H-indole-4-carbortitrile (250 mg, 51%). 1I1 NMR (DMSO, 300 MHz) 8 10.93 (br s, 1 H), 7.25 (d, J= 8.7 Hz, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 5.94(cIJ = 2.1 Hz, 1 H), 5.40 (br s, 2 H), 1.30 (s, 9 H). MS (ESI) ink: 214.0 [M+H].
N-(2-tert-buty1-4-cyano-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide V
V H CN
Fx0 16O H2 N =
Et3N, DMF Fx0 F F N \ 0 lir 0 0 110j-P 0 111112-9 N

[019] Step a: N-(2-tert-buty1-4-cyano-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,31dioxol-5-y1)cyclopropanecarboxamide

[020] 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-Acyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-buty1-1H-indole-4-carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 ut, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature overnight, then filtered and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,31clioxol-5-y1)cyclopropanecarboxamide. ESI-MS m/z calc.
437.2, found 438.7 (M+1)+. Retention time 2.10 minutes. 1H NMR (400 MHz, DMSO-d6) 8 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 111), 7.32 (dd, J = 1.5, 8.3 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 1.51 - 1.49 (m, 2H), 1.36 (s, 9H), 1.18 - 1.16 (m, 2H).
N-(2-tert-buty1-4-cyano-1-(2-hydroxyethyl)-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,31dioxol-5-y1)cydopropanecarboxamide cN CN CN
02N so .2N is H2N
1/'10H H2, Pd-C
CsCO3, gMF
Et0H
0H oH
V H N
Fx0 gft v CI
F 0 Fx0 N\
F
Et3N, CH2Cl2 OH

[021] Step a: 2-tert-buty1-1-(2-hydroxyethyl)-5-nitro-1H-indole-4-carbonitrile

[022] A mixture of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (200 mg, 0.82 mmol), 2-iodoethanol (77 1.1.1õ 0.98 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (1.3 mL) was heated to 90 C overnight. Then more 2-iodoethanol (77 !IL, 0.98 mmol) was added and the reaction was stirred at 90 C for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then the combined ethyl acetate layers were washed with water (x3) and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (50 - 100% CH2C12- Hexanes) to yield the product as a yellow solid (180 mg, -25% purity by NMR, product co-elutes with the indole starting material). ESI-MS m/z calc.
287.1, found 288.5 (M+1)+. Retention time 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) 8 12.23 (s, 1H), 8.14 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 6.60 (s, 1H), 5.10 (t, J =
5.5 Hz, 1H), 4.55 (t, J = 6.3 Hz, 2H), 3.78 - 3.73 (m, 2H) and 1.49 (s, 9H) ppm.

[023] Step b: 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H-indole-4-carbonitrile

[024] To a solution of 2-tert-buty1-1-(2-hydroxyethyl)-5-nitro-lH-indole-4-carbonitrile (180 mg, 0.63 mmol) in ethanol (6 mL) under N2 atmosphere was added Pd-C
(5% wt, 18 mg). The reaction was flushed with N2 (g) and then with H2 (g) and stirred under H2 (atm) at room temperature for 1.5 hours. The reaction was filtered over Celite and concentrated to yield the product (150 mg, 93 %). ESI-MS m/z calc. 257.2, found 258.5 (M+1)+. Retention time 1.26 minutes.

[025] Step c: N-(2-tert-buty1-4-cyano-1-(2-hydroxyethyl)-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

[026] 1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-buty1-1-(2-hydroxyethyl)-1H-indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 1.., 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N
HC1 solution (x2), saturated NaHCO3 solution (x2), brine, dried over MgS0.4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-buty1-4-cyano-1-(2-hydroxyethyl)-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc.
481.2, found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) 8 8.93 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33 (d, J =
1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.28 (s, 111), 5.05 (t, J = 5.6 Hz, 111), 4.42 (t, J =
6.8 Hz, 2H), 3.70 - 3.65 (m, 2H), 1.51 - 1.48 (m, 211), 1.44 (s, 9H), 1.19 - 1.16 (m, 21-1).

2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y0cyclopropanecarboxamido)-6-fluoro4H-indol-1-y1)-N,N,N-trimethylethanaminium chloride OH H2N 40 SOCI, DMF H41111111" F N\ F
411111.9 Fx0 F
Et3N, DCM Fx/0 " , HN
\Th H 01¨
i) Mel, Et,N, DMF
0 =4Ir H
TFA/DCM y3 41" N
HCl/Me0H F
N
- X

0 1111111" 0 NH2 jr,L._

[027] Step a: tert-Butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-y1)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-y1)ethylcarbamate

[028] To 1-(2,2-difluorobenzo[d][1,31dioxo1-5-yflcyclopropanecarboxylic acid (90A4 mg, 0.3722 mrnol) in thionyl chloride (81,28 pL, 1.117 mmol) was added N ,N -dimethyl founamide (8.204 uL, 0.1064 mmol). The reaction mixture was stirred at room temperature for 30 minutes before excess thionyl chloride and N,N -dirnethyl formamide were removed in vacuo to yield the acid chloride. The acid chloride was then dissolved in dichloromethane (1.5 mL) and added slowly to a solution of tert-butyl 2-(5-amino-2-tert-buty1-6-fluoro-1H-indo1-1-yl)ethylcarbamate (156.1 mg, 0.4467 mmol) and triethylamine (155.6 uL, 1.117 mmol) in dichloromethane (1.5 mL). The resulting reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HC1 (5 nit) and a saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield tert-butyl 2-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y1)cyclopropanecarboxamido)-6-fluoro-1H-indo1-1-yl)ethylcarbamate as a white solid (140 mg, 66%). ESI-MS rrt/z calc. 573.2, found 574.7 (M+1)+. Retention time 2.41 minutes. 1H NMR (400.0 MHz, DMSO) d 8.35 (s, 1H), 7.53 (s, 1H), 7.44 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.13 - 7.10 (m, 1H), 6.17 (s, 1H), 4.24 -4.20 (m, 2H), 3.20 - 3.17 (m, 2H), 1.48-1.45 (m, 2H), 1.41 (s, 18H) and 1.15-1.12 (m, 21-1)

[029] Step b: N-(1-(2-aminoethyl)-2-tert-buty1-6-fluoro-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxamide

[030] To a solution of tert-butyl 2-(2-tert-butyl-5-0-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarl)oxamido)-6-fluoro-1H-indo1-1-yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 rrtL) was added trifluoroacetic acid (444 p.L, 5.8 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indo1-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxarnide as a white solid (93.7 mg, 82%). ESI-MS m/z calc.
473.19, found 474.5 (M+1)+. Retention time 1.61 minutes.

[031] Step c: 2-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indo1-1-y1)-N,N,N-trimethylethanaminium chloride

[032] To a clear solution of N-(1-(2-arainoethyl)-2-tert-buty1-6-fluoro-1H-indol-5-y1)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (50 mg, 0.1056 mmol) in IV,N -dimethyl formamide (1 mL), methyl iodide (336.8 mg, 147.7 pL, 2.37 mmol) and triethylamine (106.9 mg, 147.2 p.L, 1.05 mmol) were added and the mixture was heated at 80 C for 2 hours. The crude product was purified by reverse phase preparative HPLC. 22 mg of this product were dissolved in 1.25 M HC1 in methanol (112 [IL, 0.14 mmol) and heated at 60 C for 1 hour. The reaction was cooled to room temperature. The product was first dried and then dissolved in dichloromethane and dried again. This procedure was repeated four times to yield 2-(2-tert-buty1-5-(1-(2,2-difluorobenzo[d][1,31dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indo1-1-y1)-N,N,N-trimethylethanaminium chloride. ESI-MS m/z calc. 516.25, found 516.7 (M+1)+. Retention time 1.69 minutes. 1H
NMR (400.0 MHz, DMSO) d 8.43 (s, 1H), 7.53 (s, 1H), 7.45 - 7.41 (m, 2H), 7.36 -7.31 (m, 2H), 6.27 (s, 1H), 4.74 - 4.70 (m, 2H), 3.57 - 3.53 (m, 2H), 3.29 (s, 9H), 1.48 - 1.42 (m, 11H), and 1.15 (dd, J = 3.9, 6.8 Hz, 2H) ppm.
2-(4-(Tert-butyldimethylsilyloxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole 02N io HCI lo 02N Br .....0)<-10Et Br2 ), Ali 0 t0 NH NH2 Pd(PBh3)202/Et3 02NN F

PdC12/CH3CN 02N so \ DIBAL 02N =
= TBSCI, imidazole 02N
H O H
OH DOM
OEt OTBS

[033] Step a: 3-fluoro-4-nitroaniline

[034] A mixture of N-(3-fluoro-4-nitro-phenyl)-2, 2-dimethyl-propionamide (87.0 g, 0.36 mol) in CJ-12C12 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 30: 1) to afford.3-fluoro-4-nitroaniline (56.0 g, 99 %). 1H
NMR (300 MHz, CDC13) 8 8.07 (t, J= 8.7 Hz, 1 H), 7.86 (dd, J= 2.1, 13.2 Hz 1 H), 7.59 (brs, 2 H), 7.22 (s, I H).

[035] Step b: 2-bromo-5-fluoro-4-nitroaniline To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5 C in an ice bath. The reaction mixture was basified with saturated Na2CO3 and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether /
ethyl acetate 10: 1) to give the 2-bromo-5-fluoro-4-nitroaniline ( 45.6 g, 84 % ) as a yellow solid. 1H NMR (400 MHz, CDC13) 8 8.29 (d, J= 7.6 Hz, 1 H), 653 (d, J= 12.4 Hz, 1 H), 4.94 (br s, 2 H).

[036] Step c: ethyl 5-(2-amino-4-fluoro-5-nitropheny1)-3,3-dimethylpent-4-ynoate

[037] To a solution of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and ethyl 3,3-dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added Pd(PPh3)2C12 (13.8 g, 0.02 mol) and Cul (3.6 g, 0.02 mol) under N.,. The reaction mixture was stirred at 70 C for 8 hours. The reaction mixture was diluted with 500 mL
of ethyl acetate and 1500 mL of water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (500 mLx3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl

38 PCT/US2009/063475 acetate 10: 1) to give ethyl-5-(2-amino-4-fluoro-5- nitropheny1)-3.3-dimethylpent-4-ynoate (34.5 g, 57 %). 1H NMR (300 MHz, CDC13) 8 8.05 (d, J= 8.1Hz, 1 H), 6.36 (d, J
= 13.2 Hz, 1 H), 5.60 (brs, 2 H), 4.16 (q, J= 7.2 Hz, 2 H), 2.51 (s, 2 H), 1.40 (s, 6 H), 1.28 (t, J= 7.2 Hz, 3H).
[038] Step d: ethyl 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutanoate

[039] To a mixture of ethyl 5-(2-amino-4-fluoro-5-nitr=opheny1)-3, 3-dimethylpent-4-ynoate (34.5 g, 0.11 mol) and PdC12(10.4 g, 58.6 nmol) in CH3CN
(350 mL) was heated to reflux for L5 hours. The reaction mixture was cooled down to room temperature. Ethyl acetate (300 mL) was added, the precipitate was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 40: 1) to give ethyl 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutanoate (34.0 g, 98 %) as a deep yellow solid. 1H NMR (300 MHz, CDC13) c 10.11 (brs, 1 H), 8.30 (d, J= 7.2 Hz, 1 H), 7.14 (d, J= 11.7 Hz, 1 H), 6.35 (d, J= 1.5 Hz, 1 H), 4.17 (q, J= 7.2 Hz, 2 H), 2.69 (s, 2 H), 1.51 (s, 6 H), 1.25 (t, .1= 7.2 Hz, 3 H).

[040] Step e: 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-o1

[041] To a solution of ethyl 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutanoate (34 g, 0.11 mol) in dry CH2C12 (400 mL) was added drop-wise DMAL-H
(283.4 ml , 0.27 mol) over 2 hours at -78 C. The reaction mixture was stirred for 10 hours at -78 C and then quenched by adding water (200 mL). The precipitate was filtered off and washed with methanol. The filtrate was extracted with CH2C12 (200 mLx3), the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol (6.6 g, 22 %). 111 NMR (400 MHz, CDC13)15 9.35 (brs, 1 H), 8.30 (d, J=
7.6 Hz, 1 H), 7.11 (d, J= 12.0 Hz, 1 H), 6.35 (d, J= 1.2 Hz, 1 H), 3.74 (t, J=
6.4 Hz, 2 14), 1.9 (t, J= 6.4 Hz, 2 H), 1.4 (s, 6 H).

[042] Step f: 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole

[043] To a solution of 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol (6.6 g, 25 mmol) in CH2C12 (80 mL) was added IBSCI (3.7 g, 25 nmol) and imidazole (4.2 g, 62 nmol) at 0 C. The reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered off and washed with the methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica 2e1 (petroleum ether / ethyl acetate 10: 1) to give the desired product as a brown solid (5.0 g, 53 %). H NMR (300 MHz, CDC13) 8 9.80 (brs, 1 H), 8.30 (d, J = 7.2 Hz,1 H), 7.05 (d, J = 11.7 Hz, 1 H), 6.33 (t, J== 1.2 Hz, 1 H), 3.7 (t, J= 6.0 Hz, 2 H), 1.91 (t, J= 6.0 Hz, 2 H), 1.42 (s, 6 H), 0.94 (s , 9 H), 0.12 (s , 6 H). MS (ESI) m/z (M-414): 381.1.
Benzyl 2,2-dimethylbut-3-ynoate o o o 0 CI 0 ).
NaH, Mel )\.,11PCI5, CH2Cl Na0H, H20 )L
0 0 reflux )(ILC I 0 aNsH02 0 BnOH
H m OH DCC, CH2Cl2 OCH2Ph

[044] Step a: methyl 2,2-dimethy1-3-oxobutanoate

[045] To a suspension of NaH (28.5 g, 0.718 niol, 60%) in THF (270 mL) was added dropwise a solution of 3-oxo-butyric acid methyl ester (78.6 g, 0.677 mol) in THF (70 rni ) at 0 C. The mixture was stirred for 0.5 hours at 0 C. MeI (99.0 g, 0.698 mol) was added dropwise at 0 C. The resultant mixture was warmed to room temperature and stirred for 1 hour. NaH (28.5 g, 0.718 mol, 60%) was added in portions at 0 C and the resulting mixture was continued to stir for 0.5 h at 0 C. MeI (99.0 g, 0.698 mol) was then added dropwise at 0 C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into ice water. 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 methyl 2,2-dimethy1-3-oxobutanoate (52 g, 53%), which was used directly in the next step.

[046] Step b: methyl 3-chloro-2,2-dimethylbut-3-enoate

[047] To a suspention of PC15 (161 g, 0.772 mol) in dichloromethane (600 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (52 g, 0.361 mol, crude from last step) at 0 C, followed by the addition of approximately 20 drops of dry DMF. The mixture was heated at reflux overnight. After cooling, the reaction mixture was slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO3 solution and dried over anhydrous Na2SO4. The solvent was evaporated to give the product, methyl 3-chloro-2,2-dimethylbut-3-enoate which was used without further purification (47 g, 82%).

[048] Step c: 3-chloro-2,2-dimethylbut-3-enoic acid

[049] A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (42.0 g, 0.26 mol) and NaOH (12.4 g, 0.31 mol) in water (300 mL) was heated at reflux overnight.
After cooling, the reaction mixture was extracted with ether. The organic layer contained 20g of methyl 3-chloro-2,2-dinlethylbut-3-enoate (48 % recovered). The aqueous layer was acidified with cold 20% HC1 solution and was extracted with ether (250 mT x 3). The combined organic layers were dried and evaporated under reduced pressure to give 3-chloro-2,2-dimethylbut-3-enoic acid (17 g, 44 %), which was used directly in the next step.

[050] Step d: 2,2-dimethylbut-3-ynoic acid

[051] To a three-neck flask (500 mL) was added NaNH2 (17.8 g, 0.458 mmol, pellets) and DMS0 (50 m1). The mixture was stirred at room temperature until no more NH3 (g) was given off. A solution of 3-chloro-2,2-dimethylbut-3-enoic acid (17.0 g, 114 mmol) in DMS0 (50 mL) was added dropwise at 0 C. The mixture was warmed and stirred at 50 C for 5 hours, then stirred at room temperature overnight. The mixture was poured into cold 20% HC1 solution, and then extracted three times with ether. The ether extracts were dried over anhydrous Na2SO4 and concentrated to give a 6:1 ratio of starting material and alkyne product. The residue was re-dried using ether and Na2SO4 and re-subjected to the reaction conditions above. The reaction mixture was worked up in the same manner to provide 2,2-dimethylbut-3-ynoic acid (12.0 g, 94 %).

[052] benzyl 2,2-dimethylbut-3-ynoate

[053] To a stirred solution of 2,2-dimethylbut-3-ynoic acid (87.7 g, 0.782 mmol) and benzyl alcohol (114.6 g, 0.938 mol) in dichloromethane (800 mL) was added DCC
(193.5 g, 0.938 mmol) at -20 C. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (2% ethyl acetate in petroleum ether as eluant) to afford benzyl 2,2-dimethylbut-3-ynoate (100 g, 59 % yield). 1H NMR (CDC13, 400 MHz) 8 7.37-7.36 (m, 5 H), 5.19 (s, 2 H), 2.28 (s, 1 H), 1.52 (s, 6 H).
2-(1-(Tert-butyldimethylsilyloxy)-2-methylpropan-2-y1)-6-fluoro-5-nitro-11-1-indole 02N Br 0 )11. 02N so pdc12 NH2 Pd(PPh3)2C12/E13N
NH2 ph 02N 40 .2N
02N io DIBAL-H TBSCI
0 ---)1""
NF N
H HO CH2Cl2 H TBSO
H OCH2Ph

[054] Step a: benzyl 4-(2-amino-4-fluoro-5-nitropheny1)-2,2-dimethylbut-3-ynoate

[055] To a solution of 2-bromo-5-fluoro-4-nitroaniline (23.0 g, 0.1 mol) in Et3N
(250 mL) was added benzoic 2,2-dimethylbut-3-ynoic anhydride (59.0 g, 0.29 mol), CuI
(1.85 g) and Pd(PPh3)2C12 (2.3 g) at room temperature. The mixture was stirred at 80 C
overnight. After cooling to room temperature, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% ethyl acetate in petroleum ether) to give benzyl 4-(2-amino-4-fluoro-5-nitropheny1)-2,2-dimethylbut-3-ynoate (20.0 g,

56%). 1H NMR
(400 MHz, CDC13) 8.05 (d, J = 8.4 Hz, 1 H), 7.39-7.38 (m, 5 H), 6.33 (d, J=
13.2 Hz, 1 H), 5.20 (s, 2 H), 4.89 (br s, 2 H), 1.61 (s, 6 H).
[056] Step b: benzyl 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate

[057] To a solution of benzyl 4-(2-amino-4-fluoro-5-nitropheny1)-2,2-dimethylbut-3-ynoate (20.0 g, 56 mmol) in acetonitrile (100 mL) was added PdC12 (5.0 g, 28 mmol) at room temperature. The mixture was stirred at 80 C overnight. The mixture was filtered off and the solvent was evaporated in vacuo, the residue was purified by chromatography on silica gel (10% Et0Ac in petroleum ether) to give benzyl 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-niethylpropanoate (18.0 g, 90%). 1H NMR (300 MHz, CDC13) 8.96 (br s, 1 H), 8.33 (d, J=
7.2 Hz, 1 H) 7.35-7.28 (m, 5 H) 7.08 (d, J= 11.7 Hz, 1 H), 6.47 (s, 1 H), 5.18 (s, 2 H) 1.69 (s, 6H).

[058] Step c: 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol To a solution of benzyl 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate (18.0 g, 0.05 mol) in CH202(100 mL) was added DLEIAL-H (12 mL) at -78 C. The mixture was stiffed for 1 h at that temperature and was warmed to room temperature. The reaction was quenched with water and the aqueous layer was extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% Et0Ac in petroleum ether) to dye 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol (10.0 g, 77%). 11-1 NMR
(300 MHz, CDC13) 9.37 (s, 1 H), 8.32 (d, J= 7.2 Hz, 1 H), 7.11 (d, J= 11.7 Hz, 1 H), 6.36 (s, 1 H), 3.73 (d, J = 5.1 Hz 2 H), 1.97 (t, J= 5.1 Hz, 1 H), 1.39 (s, 6 H).

[059] Step d: 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-y1)-6-fluoro-5-nitro-1H-indole

[060] To a stirred solution of 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol (10.0g) in CH2C12 was added IBSCI (8.9 g), imidazole (8.1g, 0.12 mol) at room temperature. The mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (10% Et0Ac in petroleum ether) to give 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-y1)-6-fluoro-5-nitro-1H-indole (5.3 g, 38 %). 1H NMR (300 1V111z, CDC13) 9.51 (s, 1 H), 8.31 (d, J = 7.5 Hz, 1 H), 7.02 (d, J =
11.7 Hz, 1 H), 6.32 (s, 1 H), 3.63 (s, 2 H), 1.35 (s, 6 H), 0.99 (s, 9 H), 0.11 (s, 6 H).
6-fluoro-1,1-dimethy1-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole, (R)-3-(14(2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-l-ol, 2-(4-4(R)-2,2-dimethy1-1,3-dioxolan-4-yOmethoxy)-2-methylbutan-2-y1)-1-(((R)-2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-111-indole, 3-(6-fluoro-5-nitro4H-indo1-2-y1)-3-methylbutan-1-ol and (R)-2-(4-((2,2-dimethy1-1,3-dioxolan-4-yOmethoxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole Ori 02N '''Cick CsCO3, DMF 02N 02NFcci)___FI C2Nrtc-Nhe N N
oTeDms CciCck 0)\ y OH

FI:X14/-71

[061] Step a: 6-fluoro-1,1-dimethy1-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole, (R)-3-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol, 2-(4-(((R)-2,2-dimethy1-1,3-dioxolan-4-yOmethoxy)-2-methylbutan-2-y1)-1-(((R)-2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-6-fluoro-5-nitro-1H-indole, 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol and (R)-2-(4-((2,2-dimethy1-1,3-dioxolan-4-yOmethoxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole

[062] To a solution of 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole (1.9 g, 5.0 mmol) and (S)-(2,2-dimethy1-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2.86 g, 10.0 mmol) in DMF (10 mL) was added Cs2CO3 (4.88 g.
15.0 mmol). The mixture was heated at 90 'V for 24 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-50% ethyl acetate -hexane) to afford 6-fluoro-1,1-dimethy1-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 48%). ESI-MS m/z calc. 248.1, found 249.2 (M+1)+. Retention time 2.00 minutes; 2-(4-(((R)-2,2-dimethy1-1,3-dioxolan-4-yHmethoxy)-2-methylbutan-2-y1)-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indole (270 mg, containing some (R)-2-(4-((2,2-dimethy1-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole).
ESI-MS rn/z calc. 494.2 and 380.2, found 495.4 and 381.4 (M+1) . Retention time 2.12 and 1.92 minutes; (R)-3-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol (1.0 g, containing some 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-o1). ESI-MS m/z calc. 380.2 and 266.1, found 381.2 and 267.2 (M+1)+.
Retention time 1.74 and 1.48 minutes.
(R)-2-(14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-11uoro-5-nitro-1H-indol-2-y1)-2-methylpropan-1-ol and 3-(6-fluoro-5-nitro-1H-indol-2-y1)-3-methylbutan-1-ol OTs 02N 02N 0 OH 02N ilk N' OH
F OTBDMS CsCO3, DMF F

[063] A mixture containing (R)-2-(1-((2,2-dimethy1-1,3-dioxolan-4-yHmethyl)-6-fluoro-5-nitro-1H-indol-2-y1)-2-methylpropan-1-ol and 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol was obtained following the procedure shown above starting from 2-(1-(tert-butyldimethylsiIyloxy)-2-methylpropan-2-y1)-6-fluoro-5-nitro- 1H-indole. (R)-2-(14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-y1)-2-methylpropan-1-ol, ESI-MS m/z calc. 366.2, found 367.2 (M+1) . Retention time 131 minutes; 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol, ESI-MS m/z calc. 252.1, found 253.4 (M+1)+.
Retention time 1.42 minutes.
1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-1,1-dimethy1-2,3-di1ydro-1H-pyrrolo[1,2-a]indol-7-y1)eyelopropanecarboxarnide 02N so KIH4.0O2 H2N PF)<X30r H N F F N
___________________ = ________________ XC'DOYY= 0 Pd-C, Et0H HAT1J, Et3N, MAP

[064] Step a: 6-fluoro-1,1-dimethy1-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine

[065] To a solution of 6-fluoro-1,1-ditnethy1-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 2.4 mmol) in ethanol (15 mL) was added ammonium foiniate (600 mg, 9.5 mmol) and Pd/C (10%, 129 mg, 0.12 mmol). The mixture was refluxed for 10 min. The Pd catalyst was removed via filtration through Celite and washed with ethanol.
The filtrate was concentrated and purified by column chromatography (20-40%
ethyl acetate-hexanes) to provide 6-fluoro-1,1-dimethy1-2,3-dihydro-1H-pyrrolo[1,2-a]indo1-7-amine (260 mg, 49 %). ESI-MS m/z calc. 218.1, found 219.2 (M+1)+. Retention time 1.01 minutes.

[066] Step b: 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-1,1-dimethy1-2,3-dihydro-1H-pyrrolo[1,2-a]indo1-7-yl)cyclopropane,carboxamide

[067] To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yffcyclopropanecarboxylic acid (346 mg,1.4 mmol), 6-fluoro-1,1-dimethy1-2,3-dihydro-1H-pyrrolo[1,2-a]indo1-7-amine (260 mg, 1.2 mmol) and HATTJ (543 mg, 1.4 mmol) in DMF (5 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water.
The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% ethyl acetate - hexanes) to afford 142,2-difluorobenzo[d][1,3]dioxol-5-y1)-N-(6-fluoro-1,1-dimethy1-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yffcyclopropanecarboxamide (342 mg, 65 %). ESI-MS m/z calc. 442.2, found 443.5 (M+1) . Retention time 2.30 minutes. 1H NMR (400 MHz, DMSO-d6) 5 8.20 (d, J =
7.6 Hz, 1H), 7.30 - 7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 11.1 Hz, 1H), 6.01 (d, J = 0.5 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 1.75 (dd, J =
3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J = 3.9, 6.9 Hz, 2H) ppm.
(R)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide OH
NE.L.c02 H2N)cchc-1 FF00H )00ecr:N
p HATU, Et2N, DMF
Pd-C, Et0H F

OH
pTSA H20 __ . FFX0r Me0H, H20 F)CCN1-7=4 CCOH
OH

[068] Step a: (R)-3-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yffmethyl)-6-fluoro-1H-indol-2-y1)-3-methylbutan-1-ol

[069] To a solution of (R)-3-(1-((2.2-dimethy1-1,3-dioxolan-4-yffmethyl)-6-fluoro-5-nitro-1H-indol-2-y1)-3-methylbutan-1-ol containing some 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-l-ol (500 mg, 1.3 mmol) in ethanol (10 mL) was added ammonium formate (500 mg, 7.9 mmol) and Pd/C (10%, 139 mg, 0.13 mmol). The mixture was refluxed for 5 min. The Pd catalyst was removed via filtration through Celite and washed with ethanol. The filtrate was evaporated to dryness and purified by column chromatography (30-50% ethyl acetate-hexanes) to provide (R)-3-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yffmethyl)-6-fluoro-1H-indo1-2-y1)-3-methylbutan-1-ol (220 mg, 48 %, contains some 3-(5-amino-6-fluoro-1H-indo1-2-y1)-3-methylbutan-1-off. ESI-MS
171/Z calc.
350.2 found 351.4 (M+1) . Retention time 0.94 minutes.

[070] Step b: (R)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(14(2,2-dimethy1-1,3-dioxolan-4-yffmethyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-yffcyclopropanecarboxamide

[071] To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yffcyclopropanecarboxylic acid (183 mg, 0.75 mmol), (R)-3-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yffmethyl)-6-fluoro-1H-indol-2-y1)-3-methylbutan-1-ol containing some 345-amino-6-fluoro-1H-indo1-2-y1)-3-methylbutan-1-ol (220 mg, 0.63 mmol) and HATU
(287 mg, 0.75 mmol) in DMF (3.0 mL) was added triethylamine (0.21 m1 , 1.5 turnoff. The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-40% ethyl acetate - hexanes) to afford (R)-1-(2,2-difluorobenzo[d][1,31dioxo1-5-yff-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yffmethyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-yffcyclopropanecarboxamide (315 mg, 87 %, contains some 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide). ESI-MS m/z calc.
574.2 found 575.7 (M+1)+. Retention time 2.08 minutes.

[072] Step c: (R)-1-(2,2-difluorobenzo[d][1,31dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-yffcyclopropanecarboxamide

[073] To a solution of (R)-1-(2,2-difluorobenw[d][1,3]dioxo1-5-yff-N-(1-((2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide containing some 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indo1-5-yl)cyclopropane,carboxanaide (315 mg, 0.55 mmol) in methanol (3 mL) and water (0.3 mL) was added p-Ts0H.H20 (21 mg, 0.11 mmol). The mixture was heated at 80 C for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated. NaHCO3 solution and brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-80% ethyl acetate - hexanes) to provide (R)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide (92 mg, 31%). ESI-MS
m/z calc.
534.2, found 535.5 (M+1)+. Retention time 1.72 minutes. 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 7.53 (d, J = 1.0 Hz, 1H), 7.43 - 7.31 (m, 411), 6.17 (s, 1H), 4.97 - 4.92 (m, 2H), 4.41 (dd, J = 2.4, 15.0 Hz, 1H), 4.23 (t, J = 5.0 Hz, 1H), 4.08 (dd, J = 8.6, 15.1 Hz, 1H), 3.87 (s, 1H), 3.48 - 3.44 (m, 1H), 3.41 - 3.33 (m, 1H), 3.20 (dd, J = 7.4, 12.7 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.48 - 1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15 - 1.12 (m, 2H) ppm.
1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(44(S)-2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-1-((R)-2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-y1)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(4-(2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-6-fluoro4H-indo1-5-y1)cyclopropanecarboxamide HO HO
Hy v H 0-j V H
N 46.6 Fz\F\z:

Fx=
F = WI 01 0 OH

[074] 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(44(S)-2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-14(R)-2,3-dihydroxypropy1)-6-fluoro-1H-indol-5-yl)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(4-(2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-6-fluoro-1H-indo1-5-yl)cyclopropane,carboxamide

[075] 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(44(S)-2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-14(R)-2,3-dihydroxypropy1)-6-fluoro-1H-indo1-5-y1)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(4-(2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-6-fluoro-1H-indo1-5-y1)cyclopropanecarboxamide were made following a scheme similar as shown above starting from 2-(4-a(R)-2,2-climethy1-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-y1)-1-(((R)-2,2-dimethy1-1.3-dioxolan-4-yOmethyl)-6-fluoro-5-nitio-1H-indole containing some (R)-2-(44(2,2-dimethy1-1,3-dioxolan-4-y1)methoxy)-2-methylbutan-2-y1)-6-fluoro-5-nitro-1H-indole).
difl uorobenzo [d] [1 ,3]di oxo1-5-y1)-N-(2-(4-((S)-2,3-dihydro xypropoxy)-2-methylbutan-2-y1)-14(R)-2,3-dihydroxypropy1)-6-fluoro-1H-indol-5-y1)cyclopropanecarboxamide, ESI-MS m/z calc. 608.2, found 609.5 (M+1)+. Retention time 1.67 minutes. 111NMR (400 MHz, d6) 8 8.32 (s, 1H), 7.53 (s, 1H), 7.43 - 7.31 (m, 4H), 6.19 (s, 1H), 4.95 -4.93 (m, 2H), 4.51 (d, J 5.0 Hz, 1H), 4.42 - 4.39 (m, 2H), 4.10 - 4.04 (m, 1H), 3.86 (s, 1H), 3.49 - 3.43 (m, 2H), 3.41 - 3.33 (m, 1H), 3.30 - 3.10 (m, 6H), 2.02 - 1.97 (m, 2H), 1.48 -1.42 (m, 8H) and 1.13 (dd, J = 4.0, 6.7 Hz, 2H) ppm ; (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(2-(4-(2,3-dihydroxypropoxy)-2-methylbutan-2-y1)-6-fluoro-1H-indo1-5-y0cyclopropanecarboxamide, ESI-MS m/z calc. 534.2, found 535.5 (M+1)+.
Retention time 1.81 minutes. 1H NMR (400 MHz, DMSO-d6) 8 10.91 (d, J = 1.5 Hz, 1H), 8.30 (s, 1H), 7.53 (s, 1H), 7.42 - 7.33 (m, 3H), 7.03 (d, J = 10.9 Hz, 1H), 6.07 (d, J = 1.6 Hz, 1H), 4.56 (d, J =
5.0 Hz, 1H), 4.43 (t, J = 5.7 Hz, 1H), 3.51 - 3.46 (m, 1H), 3.31 - 3.13 (m, 6H), 1.88 (t, J = 7.3 Hz, 211), 1.48 - 1.45 (m, 2H), 1.31 (s, 6H) and 1.15 - 1.12 (m, 2H) ppm.
1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indo1-5-yDcyclopropanecarboxamide H
OH
A

[076] 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indo1-5-yflcyclopropanecarboxamide

[077] 1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide was made following the scheme shown above starting from a mixture containing (R)-2-(14(2,2-dimethy1-1,3-dioxolan-4-yflmethyl)-6-fluoro-5-nitro-1H-indol-2-y1)-2-methylpropan-1-ol and 3-(6-fluoro-5-nitro-1H-indo1-2-y1)-3-methylbutan-1-ol. ESI-MS m/z calc. 446.2, found 447.5 (M+1)+.
Retention time 1.88 minutes. 1H NMR (400 MHz, CDC13) 8 8.68 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.30 - 7.21 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 11.2 Hz, 1H), 6.18 (s, 1H), 3.64 (s, 214), 1.75 (dd, J = 3.8, 6.8 Hz, 2H), 1.34 (s, 6H) and 1.14 (dd, J =
3.9, 6.9 Hz, 2H) ppm.

(R)-1-(2,2-Difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-.
fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indo1-5-yl)cyclopropanecarboxamide 0,N AI 73c- '"
\

LIA/H,,THF 0,N gith \
F = OCH,PhÇ0DMF F N F N F N
H

H2NOH F F F ==

= 1,1 =
H2, Ptd-C \ SOCI,, DM F F io 0 N, OH pr.) FFx0c,= F N\ 0, F N
DOH
ir 2) Et,N CN2C12 Me0H, H20 OH
[0781 Step a: (R)-Benzyl 2-(1-((2,2-dimethy1-1,3-dioxolan-4-yflmethyl)-6-fluoro-5-nitro-1H-indol-2-y1)-2-methylpropanoate and ((S)-2,2-Dimethy1-1,3-dioxolan-4-yOmethyl 2-(1-(((R)-2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate [079] Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate (3.0 g, 8.4 mmol) and (S)-(2,2-dimethy1-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (7.23 g, 25.3 mmol) in DMF (17 mL). The reaction was stirred at 80 C for 46 hours under nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product, a viscous brown oil which contains both of the products shown above, was taken directly to the next step without further purification. (R)-Benzyl 2-(1-((2,2-dimethy1-1,3-dioxolan-4-yflmethyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate, ESI-MS m/z calc. 470.2, found 471.5 (M+1) .
Retention time 2.20 minutes. ((S)-2,2-Dimethy1-1,3-dioxolan-4-y1)methyl 2-(1-a(R)-2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate, ESI-MS m/z calc. 494.5, found 495.7 (M+1) . Retention time 2.01 minutes.
[080] Step b: (R)-2-(14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol [081] To the crude reaction mixture obtained in step (a) was dissolved in THF (42 mL) and cooled in an ice-water bath. LiA1H4 (16.8 mL of 1 M solution, 16.8 mmol) was added drop-wise. After the addition was complete, the reaction was stirred for an additional 5 minutes. The reaction was quenched by adding water (1 mL), 15%
NaOH
solution (1 mL) and then water (3 mL). The mixture was filtered over Celite, and the solids were washed with THF and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate- hexanes) to obtain the product as a brown oil (2.68g, 87 % over 2 steps). ESI-MS m/z calc. 366.4, found 367.3 (M+1)+.
Retention time 1.68 minutes. 1H NMR (400 MHz, DMSO-d6) 8 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J
= 13.4 Hz, 1H), 6.5'7 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H). 4.52 -4.42(m, 2H), 4.16 -4.14 (m, 1H), 3.76 - 3.74 (m, 1H), 3.63 - 3.53 (m, 2H), 1.42 (s, 3H), 1.38 -1.36 (m, 6H) and 1.19 (s, 3H) ppm [082] Step c: (R)-2-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indo1-2-y1)-2-methylpropan-1-ol [083] (R)-2-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitTo-1H-indo1-2-y1)-2-methylpropan-1-01 (2.5 g, 6.82 mmol) was dissolved ethanol (70 mL) and the reaction was flushed with N2. Then Pd-C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was re-subjected to the conditions above. After 2 hours LCMS
indicated complete conversion to product. The reaction mixture was filtered through Celite.
The filtrate was concentrated to yield the product as a black solid (1.82 g, 79 %). ESI-MS
m/z calc. 336.2, found 337.5 (M+1)+. Retention time 0.86 minutes. 11-1NMR (400 MHz, DMSO-d6) 8 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, IH), 4.79 - 4.76 (m, 1H), 4.46 (s, 2H), 4.37 - 4.31 (m, 3H),4.06 (dd, J = 6.1, 8.3 Hz, 1H), 3.70 -3.67 (m, 11-1), 3.55 - 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
[084] Step d: (R)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(14(2,2-dimethyl-1,3-dioxolan-4-yOmethyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide [085] DMF (3 drops) was added to a stirring mixture of 142,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indo1-2-y1)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichlorornethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HC1 solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (3g, 100%).
ESI-MS m/z calc. 560.6, found 561.7 (M+1) . Retention time 2.05 minutes. 1H
NMR (400 MHz, DMSO-d6) 8 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm [086] Step e: (R)-1-(2,2-difluorobenzo[d][1,31dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide [087] (R)-1-(2,2-difluorobenzo[d][1,3[dioxo1-5-y1)-N-(14(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-Ts0H.H20 (204 mg, 1.1 mmol). The reaction was heated at =80 C for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100 %
ethyl acetate -hexanes) to yield the product as a cream colored foamy solid. (1.3 g, 47 %, e,e >98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 minutes.

(400 MHz, DMSO-d6) 8 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.38 (m, 2H), 7.33 -7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J =
5.8 Hz, 1H), 4.40 (dd, J = 2.6, 15.1 Hz, 1H), 4.10 (dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65 - 3.54 (m, 21-1), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 -1.11 (m, 2H) ppm.
(S)-1-(2,2-Difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-rnetbylpropan-2-y1)-1H-indol-5-ypcyclopropanecarboxamide OQO
1.H THF
DA:COH
C5CO, Dmf F Zs N
Pd-C pTsA H20 ,Rx:thNyve,,,r, EION B,N, CHz01, F MOH HOF'sk-"Lcro:

[088] Step a: (S)-Benzyl 2-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate and ((R)-2,2-Dimethy1-1,3-dioxolan-4-yl)methyl 2-(1-(((S)-2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-y1)-2-methylpropanoate [089] Cesium carbonate (2.74 g, 8.4 mmol) was added to a mixture of benzyl 2-(6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate (1.0 g, 2.8 mmol) and (S)-(2,2-dimethy1-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (3.21 g, 11.2 mmol) in DMF
(5.6 mL). The reaction was stirred at 80 C for 64 hours under nitrogen atmosphere. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product, a viscous brown oil which contains both of the products shown above, was taken directly to the next step without further purification. (S)-Benzyl 2-(142,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-111-indol-2-y1)-2-methylpropanoate, ESI-MS m./z calc. 470.2, found 471.5 (M+1)+.
Retention time 2.22 minutes. ((R)-2,2-Dimethy1-1,3-dioxolan-4-yl)methyl 2-(1-(((S)-2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate, ESI-MS nilz calc. 494.5, found 495.5 (M+1)+. Retention time 2.03 minutes.
[090] Step b: (S)-2-(1-((2,2-Dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol [091] The mixture of crude reaction mixture of (S)-benzyl 2-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-11-1-indol-2-y1)-2-methylpropanoate and ((R)-2,2-dimethy1-1,3-dioxolan-4-yemethyl 2-(1-(((S)-2,2-dimethy1-1,3-dioxolan-yl)methyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropanoate was dissolved in THF (15 mL) and cooled in an ice-water bath. LiA11-14 (2.8 mL of 1 M solution, 2.8 mmol) was added dropwise. After addition was complete the reaction was stirred for 5 minutes.
The reaction was quenched by adding water (0.5 mL), 15% NaOH solution (0.5 nil ) and then water (1.5 mL). The mixture was filtered over Cate, and the solids were washed with THF
and ethyl acetate. The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate- hexanes) to obtain the product as a brown oil (505 mg, 49 % over 2 steps). ESI-MS
m/z calc. 366.4, found 367.3 (M+1)+. Retention time 1.68 minutes. 1H NMR (400 MHz, DMSO-d6) 5 8.34 (d, J = 7.6 Hz, 1H), 7.65(d, J = 13.5 Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 - 4.42 (m, 2H), 4.14 (dd, J = 6.2, 8.4 Hz, 1H), 3.74 (dd, J
7.0, 8.3 Hz, 1H), 3.63 - 3.53 (m,2H), 1.42 (s, 3H), 1.37 (m, 6H) and 1.19 (s, 3H) ppm.

[092] Step c: (S)-2-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indo1-2-y1)-2-methylpropan-1-ol [093] (S)-2-(14(2.2-dimethy1-1,3-dioxolan-4-yernethyl)-6-fluoro-5-nitro-1H-indo1-2-y1)-2-methylpropan-1-ol (500 mg, 1.4 mmol) was dissolved ethanol (15 mL) and the reaction was flushed with N2. Then Pd-C (50 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 1 hour only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was resubjected to the conditions above. After 1 hour LCMS
indicated complete conversion to product. The reaction mixture was filtered through Celite.
The filtrate was concentrated to yield the product as a black solid (420 mg, 91 %). ESI-MS
m/z calc. 336.2, found 337.5 (M-i-1). Retention time 0.90 minutes. 1H NMR (400 MHz, DMSO-d6) 8 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, 1H), 4.78 (br s, 1H), 4.46 (s, 2H), 4.41 - 4.27 (in, 3H), 4.06(dd, J = 6.1, 8.3 Hz, 1H), 3.70 - 3.67 (m, 1H), 3.53 (dd, J = 10.7, 17.2 Hz, 2H), 1.40 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
[094] Step d: (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-((2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxarnide [095] DMF (3 drops) was added to a stirring mixture of 142,2-ditluorobenzo[d][1,3]dioxo1-5-yl)cyclopropanecarboxylic acid (187 mg, 0.8 mmol) and thionyl chloride (0.13 mL, 1.8 mmol). After 30 minutes a clear solution had founed. A small amount was mixed piperidine to test that the acid chloride had been formed.
The solution was concentrated on the rotovap and then toluene (1 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (2 mL) and added to a mixture of (S)-2-(5-amino-14(2,2-dimethy1-1,3-dioxolan-4-yOmethyl)-6-fluoro-lH-indol-2-y1)-2-methylpropan-1-ol (200 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (4 mL). The reaction was stirred at room temperature for 45 minutes. The reaction was washed with 1N HCI solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (320 mg, 96 %). ESI-MS m/z calc. 560.6, found 561.5 (M+1)+. Retention time 2.05 minutes. 1H
NMR (400 MHz, DMSO-d6) 6 8.31 (s, 1H), 7.53 (s, IH), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.84 (t, J = 5.5 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.41 - 4.32 (m, 2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.71 - 3.67 (m, 1H), 3.58 - 3.50 (m, 2H), 1.48 - 1.45 (m, 2H), 1.40 (s, 3H), 1.34 - 1.33 (m. 61-1), 1.18 (s, 3H) and 1.14 - 1.12 (m, 21-1) ppm.
[096] Step e: (S)-1-(2,2-difluorobenzo[d][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide [097] (S)-1-(2,2-difluorobenzo[d][1,31dioxo1-5-y1)-N-(14(2,2-dimethy1-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1)cyclopropanecarboxamide (290 g, 0.5 mmol) was dissolved in methanol (5 mL).
Water (0.5 mL) was added followed by p-Ts0H.1-120 (20 mg, 0.1 mmol). The reaction was heated at 80 C for 45 minutes. The solution was then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated.
The residue was purified by column chromatography (50-100 % ethyl acetate -hexanes) to yield the product as a cream colored foamy solid. (146 mg, 54 %, ee >97% by SFC). ESI-MS
m/z calc. 520.5, found 521.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400 MHz, DMSO-d6) 6 8.31 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.33 -7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, .1= 5.0 Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.75 (t, J =
5.8 Hz, 1H), 4.42 -4.38 (m, 1H), 4.10 (dd, J = 8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64 - 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 - 1.11 (m, 2H) ppm.
(R)-1-(benzo[d][1,3]dioxo1-5-y -N-(2-tert-butyl-1-(2,3-dihydroxypropy1)-6-fluoro-111-indol-5-y1)cyclopropanecarboxamide $1 OH
[098] (R)-1-(benzo[d][1,3]dioxo1-5-y1)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-fluoro-1H-indo1-5-yl)cyclopropane,carboxamide was prepared using an experimental procedure similar to example 72 from 1-(benzo[d][1,3]dioxo1-5-yl)cyclopropane,carboxylic acid and 2-tert-buty1-6-fluoro-5-nitro-1H-indole.
(S)-1-(benzo[d][1,3]dioxol-5-y1)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-6-fluoro4H-indo1-5-y1)cyc1opropanecarboxamide = H
<00 110 0 \
*OH
OH
[099] (S)-1-(benzo[d][1,31dioxo1-5-y1)-N-(2-tert-butyl-1-(2,3-dihydroxypropy1)-fluoro-lH-indol-5-y1)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(benzo[d][1,31dioxol-5-yl)cyclopropanecarboxylic acid and 2-tert-butyl-6-fluoro-5-nitro-1H-indole.
(R)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(3,4-dihydroxyphenyl)cyclopropanecarboxamide / H
HO

N\
.00H
OH
[0100] (R)-N-(2-tert-buty1-1-(2,3-dihydroxypropy0-1H-indol-5-y1)-1-(3,4-dihydroxyphenyl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid and 2-tert-buty1-5-nitro-1H-indole.
(R)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,3-dihydro-1H-inden-5-ypcyclopropanecarboxamide / H

.s0H
OH
[001015] (R)-N-(2-tert-buty1-1-(2,3-dihydroxypropy1)-1H-indol-5-y1)-1-(2,3-dihydro-11-1-inden-5-yl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxylic acid and 2-tert-buty1-5-nitro-11-1-indole.
[001016] A person skilled in the chemical arts can use the examples and schemes along with known synthetic methodologies to synthesize compounds of the present invention, including the compounds in Table 3, below.

Table 3: Physical data of exemplary compounds.

Compoun LC/MS LC/RT NIvIR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
1 373.3 2.49 11 452.3 2.51 2 469.4 3.99 12 527 2.36 3 381.3 3.69 13 498 1.85 4 448.3 1.75 14 404.5 1.18 389.3 3.3 15 369.2 3.81 6 463 1.87 16 419.2 2.24 7 363.3 3.7 17 389.2 2.02 H NMR (400 MHz, DMSO) 8 405.5 3.87 8.41 (s, 1H), 7.59 9 487.3 2.12 H NMR (400 (d, J
= 1.8 Hz, MHz, DMSO-d6) 1H), 7.15 (d, J =
8.65 (s, 1H), 7.55 8.6 Hz, 1H), 7.06 (d, J = 1.7 Hz, - 7.02 (m, 2H), 1H), 7.49 (d, J = 6.96 - 6.90 (m, 1.4 Hz, 1H), 7.38 2H), 6.03 (s, 2H), (d, J = 8.3 5.98 (d, J = 0.7 Hz,1H), 7.30-7.25 Hz, 1H), 4.06 (t, J
(m, 2H), 7.08 (dd, = 6.8 Hz, 2H), J =8.8, 1.9 Hz, 2.35 (t, J = 6.8 1H),6.11 (s, 1H), Hz, 2H), 1.42-4.31 (t. J = 7.4 1.38 (m, 2H) , Hz, 2H), 3.64 (t, J 1.34 (s, 6H), = 7.3 Hz, 2H), 1.05-1.01 (m, 2H) 3.20 (t, J = 7.6 Hz, 2H), 1.92 (t, J
= 7.6 Hz, 2H), 1.45 (m, 2H), 1.39 (s, 6H), 1.10 (m, 2H) 388 3.34 Compotm LC/MS LC/RT NMR Compoun LCfMS LC/RT NMR
M+1 Min M+1 Min No. No.
18 395.3 3.6 H NMR (400 22 421.14 1.53 MHz, DMSO) 23 363.3 3.62 10.91 (s, 1H), 24 378.5 2.66 7.99 (s, 1H), 7.67 (d, J = 7.7 Hz, 25 417.5 3.53 1H), 7.08-6.92 26 454.3 3.18 (m, 4H), 6.09 -6.03 (m, 3H), 27 596.2 2.58 1.47 - 1.42 (m, 28 379.3 2.92 2H), 1.31 (d, J =
29 481 1.69 7.3 Hz, 9H), 1.09-1.05 (m, 2H) 30 504.2 1.95 19 457.2 1.97 H NMR (400 31 517 1.92 MHz, CD3CN) 32 403.5 3.5 11 NMR (400 7.50 (d, J = 1.9 MHz, DMSO) Hz, 1H), 7.41 (d, 10.76 (s, 1H), J = 1.6 Hz, 2H), 8.72 (s, 1H), 7.79 7.36 (dd, J = 1.7, (d, J = 2.3 Hz, 8.3 Hz, 1H), 7.29 1H), 7.62 (dd, J =
- 7.24 (m, 2H), 2.4, 8.6 Hz, 1H), 7.02 (dd, J = 2.1, 7-55 (d, J = 1.5 8.8 Hz, 1H),6.24 Hz, 1H), 7.14 (d, (s, 1H), 4.40 (t, J
J = 8.6 Hz, 1H), = 7.1 Hz, 2H), 7.05 - 7.01 (m, 3.80 (t, J = 7.1 2H), 6.03 (d, J =
Hz, 2H), 1.59-1.6 Hz, 1H), 4.54 1.55 (m, 2H), (t, J = 6.4 Hz, 1.50 (s, 9H), 2H), 2.79 (t, J =
1.15-1.12 (m, 2H) 6.4 Hz, 2H), 1.44 20 375.5 3.71 (m, 2H), 1.32 (s, 9H), 1.03 (m, 2H) 33 321.3 2.98 Compoun LC/MS LC/RT NNW Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
34 450.2 2.02 41 397.3 3.41 H NMR (400 35 395.1 MHz, DMSO) 3.59 11.44 (s, 1H), 36 509 2.01 8.52 (s, 11-1), 7.85 37 447.2 2.02 (d, J = 1.2 Hz, 2H), 7.71 (d, J =
38 379.1 2.16 H NMR (400 1.7 Hz, 1H), 7.47 MHz, DMSO) - 7.43 (m, 2H), 10.78 (s, 1H), 7.32 - 7.26 (m, 8.39 (s, 1H), 7.57 2H), 7.12 (dd, J =
(d, J = 1.7 Hz, 2.0, 8.7 Hz, 1H), 1H), 7.17 (d, J =
7.04 (d, J = 1.6 8.6 Hz, 1H), 7.03 Hz, 1H), 6.97 -- 6.90 (m, 4H), 6.90 (m, 2H), 6.12 (d, J = 1.5 6.84 (d, J = 1.3 Hz, 1H), 6.03 (s, Hz, 1H), 6.03 (s, 2H), 5.18 (s, 1H), 2H), 1.43 - 1.40 1.50 (s, 6H), 1.41 (m, 2H), 1.07-1.05-0.97 (m, 2- 1.38 (m, 2H), 1.03 (m, 2H) H) 39 373.3 3.74 40 372.8 3.8 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+ 1 Min No. No.
42 505.3 2.23 - H NMR (400 46 391.3 3.41 MHz, DMSO-d6) 47 377.5 3.48 8.33 (s, 1H), 7.52 48 427.5 4.09 (s, 1H), 7.42-7.39 (m, 2H), 7.33- 49 402.2 3.06 7.25 (m, 2H), 50 421.1 1.81 6.14 (s, 1H), 4.99 (s, 1H), 4.31-4.27 51 407.5 3.34 (m, 3H), 3.64 (t, J 52 464.3 2.87 = 7.0 Hz, 2H), 53 405.3 3.65 3.20 (t, J = 7.6 Hz, 2H), 1.91 (t, J 54 375 1.84 = 7.6 Hz, 2H), 55 505.4 1.96 1.46 (m, 2H), 1.39 (s, 611), 1.13 56 335.3 3.18 (m, 2H) 57 445.2 3.27 43 505.4 1.97 58 491 1.88 44 407.7 1.76 H NMR (400 59 478 1.98 MHz, DNB 0) 60 413.3 3.95 10.31 (s, 1H), 8.34 (s, 1H), 7.53 61 402.5 3.71 (d, J = 1.8 Hz, 62 393.3 1.98 1H), 7.03 (d, J =
63 407.2 2.91 1.6 Hz, 1H), 6.97 - 6.90 (in, 3H), 64 505.4 1.98 6.05 - 6.03 (m, 65 377.5 3.53 3H), 4.72 (s, 2H), 1.40 - 1.38 (m, 66 417.5 4.06 2H), 1.34 (s, 9H), 67 333.3 3.53 1.04-1.00(m, 2H) 68 397.3 3.86 45 497.2 2.26 69 506 1.67 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
70 501 2.1 94 377.5 3.41 71 335.3 3.22 95 375.3 3.43 H NMR (400 72 487 1.93 MHz, DMSO) 10.52 (s, 1H), 73 417.5 3.88 8.39 (s, 11-1), 7.46 74 395 1.95 (d, J = 1.8 Hz, 1H), 7.10- 6.89 75 548 1.64 (m, 5H), 6.03 (s, 76 418.3 2.9 2H). 2.68 - 2.65 77 377.3 3.87 (m, 2H), 2.56 -2.54 (m, 2H),

78 363.3 3.48 1.82 - 1.77 (m,

79 476 1.8 4H), 1.41 - 1.34 (m, 2H), 1.04-

80 447.3 2.18 0.97 (m, 2H)

81 492.4 2 96 346.1 3.1

82 564.3 1.35 97 367.3 3.72

83 467.3 1.72 98 440.3 3.26

84 445.2 3.08

85 389.5 3.86

86 374.3 3.11

87 435 3.87

88 465 1.89

89 411.3 3.89

90 449.3 3.92

91 393.3 3.12

92 469.6 1.75

93 476.5 2.88 WO 2010/054138 Ft_ 1/uzutlY/uo..14 /3 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
99 393.1 3.18 H NMR (400 101 387.5 2.51 MHz, DMSO-d6) 102 479 3.95 11.80(s, 1Ff), 8.64 (s, 1H), 7.83 103 420.3 3.12 (m, 1H), 7.33- 104 469.5 3.97 7.26 (m, 2H), 105 391.3 2.04 7.07 (m, 1H), 7.02 (m, 111), 106 375.2 2.82 6.96-6.89 (m, 107 349.3 3.33 2H), 6.02 (s, 2H), 4.33 (q, J = 7.1 108 503.3 1.88 Hz, 2H), 1.42- 109 451.5 1.59 1.39 (m, 2H).
110 361.5 3.7 1.33 (t, J = 7.1 Hz, 311), 1.06- 111 391.3 3.65 1.03 (m, 2H) 112 335.3 3.03 100 421.3 1.85 H NMR (400 113 496.5 1.68 MHz, DMSO) 114 381.5 3.72 13.05 (s, 111), 9.96 (d, J = 1.6 115 390.3 3.22 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.22 (d, J =
2.3 Hz, 111), 6.02 (s, 2H), 1.43 -1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H) Compoun LC/MS LC/RT N1WR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
116 397.3 3.52 H NNIR (400 126 459.2 1.53 H NMR (400 MHz, DMSO-d6) MI3z, CD3CN) 11.27 (d, J = 1.9 9.23 (s, 1H), 7.51 Hz, 1H), 8.66 (s, - 7.48 (m, 2H), 1H), 8.08 (d, J = 7.19 (d, J = 8.6 1.6 Hz, 1H), 7.65- Hz, 1H), 7.06 -7.61 (m, 311), 7.03 (m, 2H), 7.46-7.40 (m, 6.95 - 6.89 (m, 2H), 7.31 (d, J = 2H), 6.17 (dd, .1=
8.7 Hz, 1H), 7.25- 0.7, 2.2 Hz, 1H), 7.17 (m, 2H), 6.02 (s, 2H), 2.61 7.03 (d, J = 1.6 - 2.57 (m, 2H), Hz, 1H), 6.98- 2.07 - 2.03 (m, 6.87 (m, 2H), 2H), 1.55-1.51 6.02 (s, 2H), (m, 2H), 1.39 (s, 1.43-1.39 (m, 6H), 1.12-1.09 2H), 1.06-1.02 (m, 2H) (m, 2H) 127 408.5 2.48 117 377.5 3.77 128 393 3.26 118 515.3 2.3 129 420.2 2.16 119 381.3 3.8 130 406.3 2.88 120 464.2 2.1 131 473.3 4.22 121 465 1.74 132 417.3 3.8 122 395.2 3.74 133 465 1.74 123 383.3 3.52 134 464.3 2.91 124 388.5 3.56 135 347.3 3.42 125 411.3 3.85 136 511 2.35 137 .455.5 3.29 Compoun LC/MS LC/RT NMR Compoun LC/MS
LC/RT NMR
d d M+1 Min M+1 Min No. No.
138 393.3 3.54 162 475 2.06 139 335.1 3.08 163 437.2 2.35 140 434.5 2.74 164 379.2 2.76 _ 141 381.3 2.91 165 462 3.44 142 431.5 3.97 166 465.2 2.15 143 539 1.89 167 455.2 2.45 144 515 ' 1.89 168 451 1.65 145 407.5 3.6 169 528 1.71 146 379.5 1.51 170 374.3 3.4 147 409.3 4 171 449.5 1.95 148 392.2 1.22 172 381.3 3.8 149 375.3 3.37 173 346.3 2.93 150 377.3 3.61 174 483.1 2.25 151 377.22 3.96 175 411.2 3.85 152 504.5 1.99 176 431.5 4.02 153 ' 393.1 3.47 177 ' 485.5 4.02 154 363.3 3.52 178 528.5 1.18 155 321.3 3.13 179 473 1.79 156 407.5 3.2 180 479 2.15 157 406.3 1.43 181 387.5 2.56 _ 158 ' 379.3 1.89 182 365.3 3.13 159 451 3.34 183 493 2.3 _ 160 375.3 3.82 161 355.1 3.32 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
184 461.3 2.4 H NMR (400 190 435.5 3.67 H NMR (400 MHz, DMSO-d6) MHz, DMSO) 10.89 (s, 1H), 11.83 (s, 1H), 8.29 (s, 1H), 7.52 10.76 (s, 1H), (s, 1H), 7.42-7.37 8.53 (s, 1H), 7.93 (m, 2H), 7.32 (dd, (d, J'= 1.8 Hz, J = 8.3, 1.4 Hz, 1H), 7.60 (dd, J =
H), 7.01 (d, J = 2.3, 8.5 Hz, 1H), 10.9 Hz, 1H), 7.53 (d, J = 1.4 6.05 (d, J = 1.7 Hz, 1H), 7.14 (d, Hz, 1H), 4.29 (t, J J = 8.6 Hz, 1H), = 5.0 Hz. 1H), 7.02 - 6.97 (m, 3.23 (m, 2H), 2H), 6.02 (d, J =
1.81 (t. J = 7.7 1.5 Hz, 1H), 3.71 Hz, 2H), 1.46(m, (t, J = 6.2 Hz, 2H), 1.29 (s, 6H), 2H), 3.37 (t, J =
1.13 (m, 2H) 6.2 Hz, 2H), 3.25 (s, 3H), 1.44 (m, 185 377.5 3.63 2H), 1.32 (s, 9H), 186 464 1.46 1.08 (tn, 2H) 187 339.1 3.2 191 421.3 3.32 188 435.5 1.64 192 404.4 0.95 189 392.3 2.18 193 451 1.71 194 465 1.69 195 434.2 2.29 196 363.3 3.4 197 501 1.91 198 411.2 3.14 199 439 1.89 ______________________________________________________________________ -Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
d d M+1 Min M+1 Min No. No.
200 434.4 1.53 211 381.3 3.69 __________ _ -201 462 3.22 212 461 2.04 202 351.3 2.59 213 469 1.72 203 495.2 2.71 214 363.3 3.48 204 435 ' 3.94 215 432.3 - 3.07 ' _ 205 397.3 3.69 216 403.5 3.94 206 - 493 2.26 217 420.4 1.27 __________ .
207 487 1.87 218 475 2.2 -208 391.3 2.94 219 484.3 ' 1.84 209 397.2 3.3 220 419.3 3.87 210 487.2 1.85 H NMR (400 221 486.3 0.91 -MHz, CD3CN) 222 391.3 3.01 7.50 (d, J = 2.0 Hz, 1H), 7.41 (d, 223 398.3 1.3 J = 1.6 Hz, 2H), 224 349.2 2.54 7.37-7.32 (m, 225 375.5 - 3.74 2H), 7.25 (d, J =
8.3 Hz, 1H), 6.98 226 377.5 3.47 H NMR (400 (dd, J = 2.1, 8.8 MHz, DMSO-d6) Hz, 1H), 6.27 (d, 10.76 (s, 1H).
J = 0.6 Hz, 1H), 8.39 (s, 1H), 7.55 4.40 - 4.28 (in, (s, 1H), 7.15-7.13 2H), 4.12 - 4.06 (m, 1H), 7.03-(m, 1H), 3.59 - 6.89 (m, 4H), 3.51 (m, 2H), 6.03 (m, 311), 1.59- 1.50(m, 1.41-1.38 (m, 2H), 1.47 (s, 9H), 2H), 1.32 (s, 9H), 1.15- 1.12(m, 1.04-1.01 (m, 211) 2H) 227 393.3 2.03 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
d d M+1 Min M+1 Min No. No.
228 398.3 1.24 248 407.3 1.52 H NMR (400 229 487.2 1.78 MHz, DMSO) 10.74 (d, J = 1.2 230 361.1 3.47 Hz, 1H), 8.40 (s, 231 435.5 2.12 1H), 7.54 (d, I =
1.8 Hz, 1H),7.15 232 321.3 2.91 (d, J = 8.6 Hz, 233 413.3 3.77 1H), 7.03 - 6.90 234 393.3 1.58 (m, 4H), 6.03-6.00 (m, 3H), 235 465 1.92 3.26 - 3.22 (m, 236 361.3 3.18 2H), 1.85-1.80 (m, 2H), 1.41 -237 421 1.8 1.38 (m, 2H), 238 405.5 3.79 1.31 (s, 6H), 239 544.3 1.4 1.05-1.01 (m, 2H) 240 405.3 3.9 249 393.3 3.32 241 462 1.74 250 406.2 2.08 242 550 1.68 251 511 2.39 243 395.2 1.98 252 379.3 3.3 244 517.3 1.94 253 383 3.46 245 372.2 3.59 254 401.2 3.26 246 361.3 3.58 255 398.3 1.38 247 490 1.95 256 512.5 1.96 257 389.2 3.05 258 321.3 3.02 259 392.1 2.74 260 462 1.81 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
N4+1 Min M+1 Min No. No.
261 453 1.91 264 421.3 1.66 H NMR (400 MHz, CD3CN) 262 349.3 3.22 8.78 (s. 1H), 7.40 263 391.1 3.67 H NMR (400 (m, 1H), 7.33 (s, MHz, DMSO) 1H), 7.08 (m, 1.01-1.05 (dd, J = 1H), 6.95 - 6.87 4.0, 6.7 Hz. 2H), (m, 3H), 6.79 (m, 1.41 - 1.39 (m, 1H), 5.91 (s, 2H), 11H), 3.81 (s, 3.51 (dd. J = 5.9, 3H), 6.03 (s, 2H), 7.8 Hz, 2H), 2.92 6.15 (s, 1H), 6.96 - 2.88 (m, 2H), - 6.90 (m, 2H), 2.64 0, 7 = 5.8 7.02 (d, J -= 1.6 Hz, 1H), 1.50 (m, Hz, 1H), 7.09 (dd, 2H), 1.41 (s, 9H), .1-= 2.0, 8.8 Hz, 1.06 (m, 2H) 1H), 7.25 (d, J =
265 475 2.15 8.8 Hz, 1H), 7.60 (d, J = 1.9 Hz, 266 347.3 3.32 1H),8.46 (s, 111) 267 420.5 1.81 268 416.2 1.76 269 485 2.06 270 395.3 3.89 271 492 1_59 272 405.5 3.96 273 547.2 1.65 274 631.6 1.91 275 590.4 2.02 276 465.7 - 1.79 277 411.3 2.14 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
278 385.3 1.99 288 512.5 1.89 H NMR (400 279 425.3 2.19 MHz, DMSO) 8.77 (s, 1H). 7.97 280 473.2 1.74 (s, IH), 7.51 (s, 281 469.4 2.02 H NMR (400 1H), 7.43 - 7.40 MHz, DMSO) (m, 2H), 7.33 (d, 8.82 (s, 1H), 7.84 J = 8.2 Hz, 1H), (d, J = 1.7 Hz, 6.36 (s, 111), 4.99 1H), 7.55 - 7.51 - 4.97 (m, 2H), (m, 2H), 7.40- 4.52(d, J = 13.1 7.35 (m, 2H), Hz, 1H), 4.21 (dd, 7.29 (dd, J = 1.7, J = 9.2, 15.2 Hz, 8.3 Hz, 1H), 7.04 1H), 3.86 (m, (s, 1H), 4.98 (t, j 11-1), 3.51 - 3.36 -= 5.6 Hz, 1H), (m, 2H), 1.51 -4.27 (t, J = 6.1 1.48 (m, 2H), Hz, 2H), 3.67 (q, 1.43 (s, 9H), 1.17 J = 6.0 Hz, 2H), -1.15 (m, 2H) 1.48 (dd, J = 4.0, 289 437.3 1.6 6.7 Hz, 2H), 1.13 (dd, J = 4.1, 6.8 Hz, 2H) 282 644.4 1.83 283 544.6 1.97 284 465.4 1.56 285 485.2 1.8 286 475.2 1.87 287 564.2 1.95 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
290 499.5 1.81 H NMR (400 291 455.4 2.02 H
NMR (400 MHz, DMSO) MHz, DMSO) 8.82 (s, 1H), 7.83 8.62 (s, 1H), 7.56 (d. J = 1.7 Hz, (s, 1H), 7.50 (s, 1H), 7.55 - 7.50 1H), 7.38 (d, J =
(m, 2H), 7.39 - 8.3 Hz, 1H), 7.29 7.28 (m, 3H), (dd, J = 1.5, 8.3 7.03 (s, 1H), 4.97 Hz, 1H), 7.23 (d, (d, J = 5.6 Hz, J = 8.7 Hz, 1H), 1H), 4.83 (t, J = 7.06 (dd, J = 1.7, 5.6 Hz, 1H),4.33 8.7 Hz, 1H),6.19 (dd, J = 3.4, 15.1 (s, 1H), 4.86 (t, J
Hz, 1H), 4.09 (dd, = 5.4 Hz, 1H), 1=8.7, 15.1 Hz, 4.03 (t, J = 6.1 1H), 3.80 - 3.78 Hz, 2H), 3.73 (qn, (m, 1H), 3.43 - J = 8.5 Hz, 1H), 3.38 (m, 1H), 3.57 (q, J = 5.9 3.35 - 3.30 (in, Hz, 2H), 2.39 -1H), 1.49 - 1.46 2.33 (m, 2H), (m, 2H), 1.14 - 2.18 - 1.98 (m, 1.11 (m, 2H) 3H), 1.88 - 1.81 (m, 1H), 1.47 -1.44 (m, 2H), 1.11 - 1.09(m, 2H) 292 578.4 1.99 293 630.4 1.8 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
294 443.4 1.98 H NMR (400 295 482.3 2 H NMR (400 Mliz, DMSO) MEz, DMSO) 8.62 (s, 1H), 7.55 8.78 (s, 1H), 7.92 (d, J = 1.8 Hz, (s, 1H), 7.51 (s, 1H), 7.50 (d, J = 1H), 7.45 (s, 1H), 1.5 Hz, 1H), 7.38 7.41 (d, J = 8.3 (d, J = 8.3 Hz, Hz, 111), 7.33 (d, 1H), 7.30 - 7.24 J = 8.4 Hz, 1H), (m, 2H), 7.05 (dd, 6.34 (s, 1H), 5.01 J = 2.0, 8.8 1-1z, (t, J = 5.7 Hz, 1H), 6.13 (s, 1H), 1H), 4.41 (t, J =
4.88 (t. J = 5.5 6.6 Hz, 2H), 3.68 Hz, 1H), 4.14 (t, J (m, 2H), 1.51 -= 6.1 Hz, 2H), 1.47 (m, 2H), 3.61 (m, 2H), 1.42 (s, 9H), 1.19 3.21 (septet, J = - 1.15 (m, 2H) 6.8 Hz, 1H), 1.47 296 438.7 2.12 H NMR (400 - 1.44 (m, 2H), MHz, DMSO) 1.26 (d, J = 6.8 11.43(s, 1H), Hz, 6H), 1.11 -8.74 (s, 1H), 7.63 1.08 (m, 2H) (s, 1H), 7.51 (s, 1H), 7.45 - 7.40 (m, 2H), 7.33 (dd, J = 1.4, 8.3 Hz, 1H), 6.25 (d, J =
1.5 Hz, 1H), 1.51 - 1.48 (m, 2H), 1.34 (s, 9H), 1.17 -1.14 (m, 2H) 297 449.3 1.6 298 517.5 1.64 Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
M+1 Min M+1 Min No. No.
299 391.5 2.05 304 425.1 2.04 H NMR
(400 300 449.3 1.59 DMSO) 12.16(s. 111).
301 501.2 1.93 8.80 (s, 1H), 7.83 302 503.5 1.63 (s, 1H), 7.51 (d, J
= 1.4 Hz, 1H), 303 437.3 1.6 7.39 - 7.28 (m, 4H), 6.95 (s, 1H).
1.48 (dd, J = 4.0, 6.6 Hz, 2H), 1.13 (dd, J = 4.0, 6.7 Hz, 2H) 305 459.2 1.67 306 558.4 2.05 Cmpd. LC/MS LC/RT NMR
No. M+1 Min 307 447.5 1.93 308 516.7 1.69 'H NMR (400 MHz, DMSO-d6) 6 8.32 (s, 1H), 7.53 (s, 1H), 7.43 - 7.31 (m, 4H), 6.19 (s, 1H), 4.95 - 4.93 (m, 2H), 4.51 (d, J = 5.0 Hz, 1H), 4.42 - 4.39 (m, 2H), 4.10 - 4.04 (m, 1H), 3.86 (s, 1H), 3.49 - 3.43 (m, 2H), 3.41 -3.33 (m, 1H), 3.30 - 3.10 (m, 6H), 2.02 - 1.97 (m, 2H), 1.48 - 1.42 (m, 8H) and 1.13 (dd, J 4.0, 6.7 Hz, 2H) ppm 309 535.7 1.79 1H NMR (400.0 MHz, DMSO) d 8.43 (s, 1H), 7.53 (s, 1H), 7.45 - 7.41 (m, 2H), 7.36 - 7.31 (m, 2H), 6.27 (s, 1H), 4.74 - 4.70 (m, 2H), 3.57 - 3.53 (m, 2H), 3.29 (s, 9H), 1.48 - 1.42 (m, 11H), and 1.15 (dd, J = 3.9, 6.8 Hz, 2H) ppm.
310 609.5 1.64 311 535.7 1.7 1H NMR (400 MHz. DMS0-d6) 6 8.32 (s, 1H), 7.53 (d, J = 1.0 Hz, 1H), 7.43 - 7.31 (m, 4H), 6.17 (s, 1H), 4.97 - 4.92 (m, 2H), 4.41 (dd, J = 2.4, 15.0 Hz, 1H), 4.23 (t, J = 5.0 Hz, 1H), 4.08 (dd, J = 8.6, 15.1 Hz, 1H), 3.87 (s, 1H), 3.48 - 3/1/1 (m, 1H), 3.41 - 3.33 (m, 1H), 3.20 (dd, J = 7.4, 12.7 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.48 - 1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15 - 1.12 (m, 2H) ppm.
312 413 2.31 '1-1NMR (400 MHz, DMSO-d6) 6 8.93 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J =- 5.6 Hz, 1H). 4.42 (t, J = 6.8 Hz, 2H), 3.70 - 3.65 (m, 2H), 1.51 - 1.48 (m, 2H), 1./1/1 (s, 9H), 1.19 - 1.16 (m, 2H) ppm.
313 521.5 1.69 1H NMR (400.0 MHz, CD3CN) d 7.69 (d, J = 7.7 Hz, 1H), 7/14 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 1.7, 8.3 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.20 (d, J
12.0 Hz, 1H), 6.34 (s, 1H), 4.32 (d, J = 6.8 Hz, 2H), 4.15 - 4.09 (m, 1H), 3.89 (dd, J = 6.0, 11.5 Hz, 1H), 3.63 - 3.52 (m, 3H). 3.42 (d, J = 4.6 Hz, 1H), 3.21 (dd, J = 6.2, 7.2 Hz, 1H), 3.04 (t, J = 5.8 Hz, 1H), 1.59 (dd, J = 3.8, 6.8 Hz, 2H), 1.44 (s, 3H), 1.33 (s, 3H) and 1.18 (dd, J = 3.7, 6.8 Hz, 2H) ppm 314 447.5 1.86 11-1NMR (400 MHz, DMSO-d6) 6 8.20 (d, J = 7.6 Hz, 1H), 7.30 - 7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 11.1 Hz, 1H), 6.01 (d, J = 0.5 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.37 (t, J -= 6.8 Hz, 2H), 1.75 (dd, J = 3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J = 3.9, 6.9 Hz, 2H) ppm.
315 482.5 1.99 H NMR (400 MHz, DMSO) 8.93 (s, 1H), 7.71 (d, J =
8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.42 (t, J = 6.8 Hz, 2H), 3.70 - 3.65 (m, 2H), 1.51 - 1.48 (m, 2H), 1.44 (s, 9H), 1.19 - 1.16 (m, 2H) 316 438.7 2.1 H NMR (400 MHz, DMSO) 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 1.5, 8.3 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 1.51 - 1.49 (m, 2H), 1.36 (s, 9H), 1.18 - 1.16 (m, 2H) ppm.
317 439.4 1.36 318 469.016 1.66 319 469.016 1.66 - 320'-' 320 465.7 1.79 H NMR (400 MHz, DMSO) 9.26 (s, 1H), 7.65 (d, J -=
1.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 1.9. 8.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.14 (s, 1H), 4.42 - 4.37 (m, 1H), 4.16 - 4.10 (m, 1H), 3.90 - 3.88 (m, 1H), 3.73 (s, 3H), 3.46 - 3.42 (m, 2H), 1.41 (s, 9H), 1.36 (d, J 5.0 Hz, 1H), 1.21 (s, 3H), 0.99 (d, J = 5.0 Hz, 1H), 0.84 (s, 3H) 321 391.5 2.05 H NMR (400 MHz, DMSO) 10.73 (s, 1H), 9.23 (s, 1H), 7.61 (d, J 1.5 Hz, 1H), 7.49 (d, J 8.8 Hz, 2H), 7.13 (s, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.02 (d, J = 1.8 Hz, 1H), 3.73 (s, 3H), 1.36 (d, J = 5.0 Hz, 1H), 1.31 (s, 9H), 1.22 (s, 3H), 0.98 (d, J =-5.0 Hz, 1H), 0.84 (s, 3H) 322 521.5 1.67 1H NMR (400.0 MHz, DMSO) d 8.31 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.30 (m, 2H), 6.22 (s, IH), 5.01 (d, J = 5.0 Hz, 1H), 4.91 (t, J
5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.42 - 4.38 (m, 1H), 4.10 (dd, J = 8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64 - 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 - 1.11 (m, 2H) ppm Assays for Detecting and Measuring AF508-CFTR Correction Properties of Compounds Membrane potential optical methods for assaying AF508-CFTR modulation properties of compounds.
The assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR 111, Molecular Devices, Inc.) as a readout for increase in functional AF508-CFTR in NTH 3T3 cells. The driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
Identification of Correction Compounds To identify small molecules that correct the trafficking defect associated with AF508-C1-"IR; a single-addition HTS assay format was developed. Assay Plates containing cells are incubated for ¨2-4 hours in tissue culture incubator at 37oC, 5%CO2, 90%
humidity. Cells are then ready for compound exposure after adhering to the bottom of the assay plates.
The cells were incubated in serum-free medium for 16-24 hrs in tissue culture incubator at 37oC, 5%CO2, 90% humidity in the presence or absence (negative control) of test compound. The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with a voltage sensing redistribution dye. To activate AF508-CFTR, 10 tM forskolin and the CFTR
potentiator, genistein (20 uM), were added along with C1--free medium to each well. The addition of Cr-free medium promoted Cl- efflux in response to AF508-CFIR activation and the resulting membrane depolarization was optically monitored using voltage sensor dyes.
Identification of Potentiator Compounds To identify potentiators of AF508-CFTR, a double-addition HTS assay format was developed. This HTS assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential on the FLIPR III as a measurement for increase in gating (conductance) of AF508 CFTR in temperature-corrected AF508 CFTR NIH 3T3 cells. The driving force for the response is a Cl- ion gradient in conjunction with channel activation with forskolin in a single liquid addition step using a fluoresecent plate reader such as FLIPR TR after the cells have previously been treated with potentiator compounds (or DMSO vehicle control) and subsequently loaded with a redistribution dye.
Solutions:
Bath Solution #1: (in mM) NaC1 160, KC1 4.5, CaC12 2, MgC12 1, HEPES 10, pH
7.4 with NaOH.
Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts.
Cell Culture NTH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 C in 5%
CO2 and 90 %
humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10 %
fetal bovine serum, 1 X NEAA, f3-ME, 1 X pen/strep, and 25 m1VI HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at ¨20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 C before culturing at 27 C for 24 hrs.
for the potentiator assay. For the correction assays, the cells are cultured at 27 C or 37 C
with and without compounds for 16 ¨ 24 hours.
Electrophysiological Assays for assaying AF508-CFIR modulation properties of compounds.
1.Ussing Chamber Assay Ussing chamber experiments were performed on polarized airway epithelial cells expressing AF508-CFIR to further characterize the AF508-CFTR modulators identified in the optical assays. Non-CF and CF airway epithelia were isolated from bronchial tissue, cultured as previously described (Galietta, L.J.V., Lanier , S.. Gazzolo, A., Sacco, O., Romano, L., Rossi, G.A., &
Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar SnapwellTm filters that were precoated with NIH3T3-conditioned media. After four days the apical .media was removed and the cells were gown at an air liquid interface for >14 days prior to use. This resulted in a monolayer of fully differentiated columnar cells that were ciliated, features that are characteristic of airway epithelia. Non-CF HBE were isolated from non-smokers that did not have any known lung disease. CF-HBE were isolated from patients homozygous for CF1 R.
HBE grown on Costar SnapwellTM cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the transepithelial resistance and short-circuit current in the presence of a basolateral to apical Cr gradient (Isc) were measured using a voltage-clamp system (Department of Bioengineering, University of Iowa, IA). Briefly, HBE were examined under voltage-clamp recording conditions (Vhoid = 0 mV) at 37 C. The basolateral solution contained (in mM) 145 NaC1, 0.83 K2HPO4, 3.3 KI-14304, 1.2 MgC12, 1.2 CaC12, 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145 NaGluconate, 1.2 MgC12, 1.2 CaCh, 10 glucose, 10 FIEPES
(pH adjusted to 7.35 with NaOH).
Identification of Correction Compounds Typical protocol utilized a basolateral to apical membrane Cr concentration gradient. To set up this gfadient, normal ringer was used on the basolateral membrane, whereas apical NaC1 was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large CI
concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate AF508-CFTR, forskolin (10 uM), PDE inhibitor, TBMX (100 iniv1) and CFTR potentiator, genistein (50 1.1M) were added to the apical side.
As observed in other cell types, incubation at low temperatures of FRT cells and human bronchial epithelial cells isolated from diseased CF patients (CF-HBE)expressing AF508-CFIR
increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with test compound for 24-48 hours at 37 C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated Isc in compound-treated cells was normalized to 37 C controls and expressed as percentage activity of CFTR activity in wt-HBE. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated Isc compared to the 37 C controls.
Identification of Potentiator Compounds Typical protocol utilized a basolateral to apical membrane cr concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane, whereas apical NaC1 was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large CI
concentration gradient across the epithelium. Forskolin (10 tiM) and all test compounds were added to the apical side of the cell culture inserts. The efficacy of the putative AF508-CFTR
potentiators was compared to that of the known potentiator, genistein.
2. Patch-clamp Recordings Total current in AF508-NIH3T3 cells was monitored using the perforated-patch recording configuration as previously described (Rae, J., Cooper, K., Gates, P., Sz Watsky, M.
(1991) J. Neurosci. Methods 37, 15-26). Voltage-clamp recordings were performed at 22 C
using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). The pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-C1, 2 MgC12, 2 CaC12, EGTA, 10 HEPES, and 240 u.g/m1 amphotericin-B (pH adjusted to 7.35 with HC1).
The extracellular medium contained (in mM) 150 NMDG-C1, 2 MgC12, 2 CaC12, 10 HEPES
(pH

adjusted to 7.35 with HC1). Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). To activate AF508-C1-I R, 10 p.M forskolin and 20 p/1 genistein were added to the bath and the current-voltage relation was monitored every 30 sec.
Identification of Correction Compounds To determine the activity of correction compounds for increasing the density of functional AF508-CFIR in the plasma membrane, we used the above-described perforated-patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 101.1M forskolin and 20pM
genistein were added to the cells. Under our recording conditions, the current density following 24-hr incubation at 27 C was higher than that observed following 24-hr incubation at 37 C. These results are consistent with the known effects of low-temperature incubation on the density of AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFI R current density, the cells were incubated with 10 ptM of the test compound for 24 hours at 37 C and the current density was compared to the 27 C and 37 C controls (%
activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 pIVI of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37 C
controls.
Identification of Potentiator Compounds The ability of AF508-CFTR potentiators to increase the macroscopic AF508-CFIR
current (L.F5o8) in NIH3T3 cells stably expressing AF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IAF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated En (-28 mV).
Cell Culture NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for whole-cell recordings. The cells are maintained at 37 C in 5% CO2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X
NEAA, p-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For whole-cell recordings, 2.500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 C for measuring the activity of correctors.
3.Single-channel recordings Gating activity of wt-CFIR and temperature-corrected AF508-CFTR expressed in NTH3T3 cells was observed using excised inside-out membrane patch recordings as previously described (Dalemans, W., Barbry, P., Champiany, G., Jallat, S., Don, K., Dreyer, D., Crystal, R.G., Pavirani, A., Lecoeq, J-P., Lazdunski, M. (1991) Nature 354, 526 ¨ 528) using an Axopatch 200B
patch-clamp amplifier (Axon Instruments Inc.). The pipette contained (in mM):
150 NMDG, 150 aspartic acid, 5 CaC12, 2 MgC12, and 10 HEPES (pH adjusted to 7.35 with Tris base). The bath contained (in mM): 150 NMDG-C1, 2 MgC12, 5 EGTA, 10 TES, and 14 Tris base (pH
adjusted to 7.35 with HCI). After excision, both wt- and AF508-CF1R were activated by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of CAMP-dependent protein kinase (PKA;
Promega Corp. Madison, WI), and 10 mM NaF to inhibit protein phosphatases, which prevented current rundown. The pipette potential was maintained at 80 mV. Channel activity was analyzed from membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of AF508-CFIR activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with rnultigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (Po) were determined from 120 sec of channel activity. The Po was determined using the Bio-Patch software or from the relationship Po =1/i(N), where I = mean current, i =
single-channel current amplitude, and N = number of active channels in patch.
Cell Culture NIE3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 C in 5% CO, and 90 %

humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10 %
fetal bovine serum, 1 X NEAA, P-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 C before use.
[001017] The compounds of Table 1 were found to exhibit Correction activity as measured in the assay described above.
[001018] Compounds of the invention are useful as modulators of ATP binding cassette transporters. Using the procedures described above, the activities, i.e., EC50s, of compounds of the present invention have been measured to be from about 3.8 nIVI to about 13.5 p.M.
Furthermore, using those methods described above, the efficacies of compounds of the present invention have been measured to be from about 35 % to about 110 %.
In Table 4, the following meanings apply:
EC50: "1 } 1" means <2 uM; "" means between 2 uM to 5 uM; "+" means between 5 uM to 25 uM.
% Efficacy: "+" means < 25%; "+F" means between 25% and 100%; "¨H-" means >
100%.

Table 4.
Cmpd. EC50 Binned Max Binned No. ECSO Efficacy Max Efficacy 307 0.981 I 160 308 3.095 -H- 100 309 0.0381 -H-F 122 310 0.1595 t 120.5 311 0.08175 -H-4 126 312 0.181 iI 117.5 313 0.2835 4++ 102 =
314 0.2285 -I-1¨F 124.5 315 0.272 -H-+ 106 316 0.285 +++ 126.5 317 4.525 -H- 65.5 ++
318 0.06595 +++ 132 I f 319 0.03905 i I 4 125.5 320 4.315 ++ 94 ++
321 1.81 +++ 76 -H-322 None [001019] OTHER EMBODIMENTS
[001020] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (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.