AU2013204751A1 - Modulators of ATP-Binding Cassette Transporters - Google Patents

Abstract

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

Description

MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application is a divisional of Australian Patent Application No. 2010249302. The subject matter of this application is related to the applicant's International Patent Application, No. PCT/US2005/022768, filed June 24, 2005 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", the entire contents of which are herein incorporated by cross-reference. The present application claims priority under 35 U. S. C. § 119 to United States Provisional Application No. 60/5 82,676, filed June 24, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", United States Provisional Application No. 60/630,127, filed November 22, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", United States Provisional Application No. 60/635,674, filed December 13, 2004 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", United States Provisional Application No. 60/658,219, filed March 3, 2005 and entitled "MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS", and United States Provisional Application No. 60/661,311, filed March 11, 2005 and entitled "MODULATORS OF ATP BINDING CASSETTE TRANSPORTERS", the entire contents of each of the above applications being incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [002] The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators. BACKGROUND OF THE INVENTION [003] ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR 1-P glycoprotein, or the multidrug resistance protein, MRP 1), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function. - 1 - [004] ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial. (0051 One member of the ABC transporter family commonly associated with disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking. [0061 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. [0071 In patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated -2gene, 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. [008] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, > 1000 disease causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease. [0091 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. (010] 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/2CT/K* co-transporter, Na'-K'-ATPase pump and the basolateral membrane K* channels, that are responsible for the uptake of chloride into the cell. [011] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption -3takes 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 CE channels, resulting in a vectorial transport. Arrangement of Na*/2Cf/K* co-transporter, Na*-K -ATPase pump and the basolateral membrane K+ channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride. [0121 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.. COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis. Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD. Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD. Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include. age, Lasik eye surgery, arthritis, medications, chemical/thenal burns, allergies, and diseases, such as cystic fibrosis and Sj~grens's syndrome. Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sj~grens's syndrome is an autoimmune disease in which the immune system attacks moisture producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, -4for 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. 10131 As discussed above, it is believed that the deletion of residue 508 in AF508 CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. Infact, this cellular phenomenon of defective ER processing of ABC transporters by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is. either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745- 751 (1999); Shastry, B.S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21 pp. 466- 469 (2000); Bross P., et al., Human Mut., _14, pp. 186-198 (1999)]. The diseases associated with the first class of ER malfunction are cystic fibrosis (due to misfolded AF508-CFTR as discussed above), hereditary emphysema (due to al -antitrypsin; non Piz variants), hereditary hemochromatosis, hoagulation-fibrinolysis deficiencies, such as protein C deficiency, Type I hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chytomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to p hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase), polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to insulin receptor), Laron dwarfism (due to growth hormone receptor), myleoperoxidase deficiency, primary hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the latter class of ER malfunction are Glycanosis CDO type 1, hereditary emphysema (due to ccl-Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to aI-antichymotrypsin), Diabetes insipidus (DI), neurophyseal DI (due to vasopvessin honnone/V2-receptor), neprogenic DI (due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus - 5- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease ( due to pAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease (due to lysosomal o-galactosidase A) and Straussler-Scheinker syndrome (due to Prp processing defect). [0141 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 ofsecretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR. [0151 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. [0161 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. [0171 Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16 million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the country and area of travel. [018] 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. [0191 The most common diarrheal causing bacteria is enterotoxogenic E.coli (ETEC) having the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and -6coronavirus. Other infectious agents include cryptosporidium, giardia lamblia, and salmonella, among others, [0201 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. [021] 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. [0221 There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity. [023] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal. 1024] 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. [025] There is a need for methods of treating CFTR-mediated diseases using such modulators of CFTR activity. 1026] There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal. SUMMARY OF THE INVENTION [0271 It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity. These compounds have the general formula I: RI 0

R

2 N -Arl

R

3 * N ReR

R

4 Rk 6 I R567 or a pharmaceutically acceptable salt thereof, wherein R', R2, R3, R 4 , R , R6, R!, and Ar' are described generally and in classes and subclasses below. -7- [028] These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type 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 polyglutarnine 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. DETAILED DESCRIPTION OF THE INVENTION [0291 L General Description of Compounds of the Invention: [0301 The present invention relates to compounds of formula I useful as modulators of ABC transporter activity: R' 0 0 R2 N Ra N R6R R4 R's I or a pharmaceutically acceptable salt thereof, wherein: ArI is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein -8each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar' has m substituents, each independently selected from -WRW; W is a bond or is an optionally substituted C-C 6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by-CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -CO 2 -, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-; RW is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; m is 0-5; each of R', R 2 , Ri, R4, and Rs is indendently -X-RX; X is a bond or is an optionally substituted C-C 6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -CO-, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO 2 -, -NR'-, -SO 2 NR'-, NR'SO-, or -NR'SO 2 NR'-; RX is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; R6 is hydrogen, CF 3 , -OR', -SR', or an optionally substituted C 1 6 aliphatic group;

R

7 is hydrogen or a C1_ aliphatic group optionally substituted with -X-Rx; R' is independently selected from hydrogen or an optionally substituted group selected from a C 1 .. Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected froin nitrogen, oxygen, or sulfur. [0311 In certain other embodiments, compounds of formula I are provided:

R

1 0 0

R

2 N RW N R6R

R

4 R6 -9or a pharmaceutically acceptable salt thereof, wherein: Ar' is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar' has m substituents each independently selected from -WRw; W is a bond or is an optionally substituted CI-C 6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -CO 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO 2 -, -NR'-, -SO 2 NR'-, NR'SO 2 -, -NR'SO 2 NR'-; Rw is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; m is 0-5; each of R', R 2 , R, R 4 , and R 5 is independently -X-Rx; X is a bond or is an optionally substituted Cr1C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO 2 -, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-; RX is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ;

R

6 is hydrogen, CF 3 , -OR', -SR', or an optionally substituted C1-C8 aliphatic group; Rt is hydrogen or a C1-C6 aliphatic group optionally substituted with -X-Rx; R' is independently selected from hydrogen or an optionally substituted group selected from a CI-C 8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully .unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that: -10i) when R', R 2 , R, R", R', R' and R 7 are hydrogen, then Ar' is not phenyl, 2 methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2 bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxylic acid phenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, 3 carboxylic-acid phenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3 ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl, or 4-ethoxycarbonylphenyl; ii) when R', R 2 , R 3 , R 5 , R 6 and R 7 are hydrogen, and R 4 is methoxy, then Ar' is not 2 fluorophenyl or 3-fluorophenyl; iii) when R', R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, R 2 is 1,2,3,4-tetrahydroisoquinolin-1-yl sulfonyl, then Ar is not 3-trifluoromethylphenyl; iv) when R', R 2 , R , R 4 , R 5 and R 7 are hydrogen, R 6 is methyl, then Ar' is not phenyl; v) when R', RW, RS, R' and R 7 are hydrogen, R 2 and R 3 , taken together, are methylenedioxy, then Ar' is not 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4 carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazol-2-yl. vi) when R', R 4 , i5, R and R 7 are hydrogen, R2 and R 3 , taken together, are methylenedioxy, then Ar is not 4-substituted phenyl wherein said substituent is SO2NHR", wherein R" is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl; vii) when R', R 2 , R 3 , R4, R 5 , R 6 , and R7 are hydrogen, then Ar' is not thiazol-2-yl, 1H 1,2,4-triazol-3-yl, or 1H-1,3,4-triazol-2-yl; viii) when R', R 2 , R?, R, Re, and R7 are hydrogen, and R4 is CF 3 , OMe, chloro, SCF 3 , or

OCF

3 , then Ar' is not 5-methyl-1,2-oxazol-3-yl, -thiazol-2-yL, 4-fluorophenyl, pyrimidin-2-yl, 1 methyl-1,2-(IR)-pyrazol-5-yl, pyridine-2-yl, phenyl, N-methyl-imidazol-2.-yl, imidazol-2-yl, 5 methyl-imidazol-2-yl, 1,3-oxazol-2-yl, or 1,3,5-(lH)-triazol-2-yl; ix) when R', R2, R, R4, RS, R6, and RW each is hydrogen, then Ar' is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2-yl, pyridin-2-yl, or 3,5-dichloro-pyridin-2-yl; x) when R', R 2 , RW, R 4 , R' and R7 each is hydrogen, R 6 is hydroxy, then Ar' is not 2,6 dicbloro-4-aminosulfonyl-phenyl; xi) when R 2 or R 3 is an optionally substituted N-piperazyl, N-piperidyl, or N morpholinyl, then Ar' is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-y, or indazolyl; xii) when R2 is optionally substituted cyclohexylamino, then Arl is not optionally substituted phenyl, pyridyl, or thiadiazolyl; xiii) Ar' is not optionally substituted tetrazolyl; xiv) when R2, R 4 , R5, R6, and R7 each is hydrogen, and R' and R 3 both are simultaneously

CF

3 , chloro, methyl, or methoxy, then Arl is not 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or [3,5-bis(trifluoromethyl)-IH-pyrazol- 1 -yllphenyl; xv) when R', R 4 , R, Re, and R7 each is hydrogen, and Ar' is thiazol-2-yl, then neither R2 nor R 3 is isopropyl, chloro, or CF 3 ; xvi) when Ar' is 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then: a) when R', R(2, R 4 , R 5 , R 6 , and R( each is hydrogen, then R 3 is not methoxy; or b) when R', R , R4, R5, R 6 , and R7 each is hydrogen, then R2 is not chloro; or c) when R', R2, R, R 5 , R6, and R7 each is hydrogen, then R4 is not methoxy; or d) when when R', R3, R 4 , R6, and R7 each is hydrogen, and R5 is ethyl, then R 2 is not chloro; e) when R1, R2, R5, R1R, and R7 each is hydrogen, then R3 is not chloro; xvi) when R', R, R4, R 5 , R, and R' each is hydrogen, and R2 is CF 3 or OCF 3 , then Ar' is not [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl; xvii) when R', R2, R 4 , R, R, and R7 each is hydrogen, and R3 is hydrogen or CF3, then Arl is not a phenyl substituted with -OCH 2

CH

2 Ph, -OCH 2

CH

2 (2-trifluoromethyl-phenyl), OCH2CH 2 -(6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl; and xviii) the following two compounds are excluded: -12- M NH 1 0 NH HF F c1 and [0321 2. Compounds and Definitions: [033] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. (034] The term "ABC-transporter" as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vitro. The term "binding domain" as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al., . Gen. Physiol. (1998): 111(3), 477-:90. [035] The term "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/ for CFTR mutations). [036] The term "modulating" as used herein means increasing or decreasing by a measurable amount. [037] 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, 75d Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and - 13 - "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0381 As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." 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 Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", 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. [039] The term-"aliphatie" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C 3 -Cs hydrocarbon or bicyclic or tricyclic - 14 -

C

8

-C

14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo octyl, or bridged tricyclic such as adamantyl. [040] The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups. [0411 The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members. [042] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or, a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR* (as in N substituted pyrrolidinyl)). [043] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation. [044] The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom. -15- [045] The terms "haloaliphatic" and "haloalkoxy" means aliphatic or alkoxy, as the case may be, substituted with one or more halo atoms. The term "halogen" or "halo" means F, Cl, Br, or I. Examples of haloaliphatic incude -CHF 2 , -CH 2 F, -CF3, -CF 2 -, or perhaloalkyl, such as, -CF 2 CF3. [0461 The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow. [047] The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". [0481 An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including beteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halo; ~R-; -OR*; -SR*; 1,2-methylene-dioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R*; -O(Ph) optionally substituted with R*; -(CH2)I 2 (Ph), optionally substituted with R*; -CH=CH(Ph), optionally substituted with R*; -NO 2 ; -CN;

-N(R*)

2 ; -NR*C(O)R*; -NR*C(O)N(R*) 2 ; -NR*CO 2 R*; -NR*NR*C(O)R*; NR*NR*C(O)N(R*) 2 ; -NR*NR*CO 2 R"; -C(O)C(O)R*; -C(O)CH 2 C(O)R*; -CO 2 R*; -C(O)R*; C(O)N(R*) 2 ; -OC(O)N(R*)2; -S(O) 2 R*; -SO 2

N(R*)

2 ; -S(O)R*; -NR*SO2N(R*) 2 ; -NR*S0 2

R

0 ;

-C(=S)N(R")

2 ; -C(=NH)-N(R*) 2 ; or -(CH 2 )o.2NHC(O)R* wherein each independent occurrence of R* is selected from hydrogen, optionally substituted C 1 . aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, notwithstanding the definition above, two independent occurrences of R", on the same substituent or different substituents, taken together with the atom(s) to which each R* group is bound, form a 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms -16independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R* are selected from NH 2 , NH(Cl.aliphatic), N(C, 4 aliphatic) 2 , halo, C1.aliphatic, OH, O(C-aliphatic), NO 2 , CN, CO 2 H, CO 2 (C,-aliphatic), O(haloC 1 4 aliphatic), or haloC. 4 aliphatic, wherein each of the foregoing C, 4 aliphatic groups of R* is unsubstituted. [049] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =0, =S, =NNHR*, =NN(R) 2 , =NNHC(O)R*, =NNHCO 2 (alkyl), =NNHSO 2 (alkyl), or =NR*, where each R* is independently selected from hydrogen or an optionally substituted Ct aliphatic. Optional substituents on the aliphatic group of R* are selected from NH 2 ,

NH(C

1 4 aliphatic), N(CI- 4 aliphatic), halo, C1 aliphatic, OH, O(CIA aliphatic), NO 2 , CN,

CO

2 H, C0 2

(C

1 4 aliphatic), O(halo CM aliphatic), or halo(C 1 4 aliphatic), wherein each of the foregoing CI 4 aliphatic groups of R* is unsubstituted. [050] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R*, -N(R*) 2 , -C(O)R, -CO 2 R*, -C(O)C(O)R, -C(O)CH 2 C(O)R*, -SO 2 R*,

-SO

2 N(R*)2, -C(=S)N(R*) 2 , -C(=NH)-N(R:)2, or -NRSO 2 R*; wherein R is hydrogen, an optionally substituted C- aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH 2 (Ph), optionally substituted -(CH 2 )1.

2 (Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R, on the same substituent or different substituents, taken together with the atom(s) to which each R group is bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R* are selected from NH 2 , NH(C 1 4 aliphatic), N(C 14 aliphatic) 2 , halo, C1 aliphatic, OH, O(CM aliphatic), NO 2 , CN, CO 2 H, CO 2 (C[4 aliphatic), O(halo CJ 4 aliphatic), or halo(C 1 4 aliphatic), wherein each of the foregoing CI 4 aliphatic groups of R is unsubstituted. [0511 The term "alkylidene chain" refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of -17attachment to the rest of the molecule. The term "spirocycloalkylidene" refers to a carbocyclic ring that may be fully saturated or have one or more units of unsaturation and has two points of attachment from the same ring carbon atom to the rest of the molecule. [0521 As detailed above, in some embodiments, two independent occurrences of R" (or R*, or any other variable similarly defined herein), are taken together together with the atom(s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Exemplary rings that are formed when two independent occurrences of R' (or R*, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R" (or R*, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R*)2, where both occurrences of R* are taken together with the nitrogen atom to form a piperidin- 1 -yl, piperazin 1-yl, or morpliolin-4-yl group; and b) two independent occurrences of R* (or R+, or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two OR* occurrences of OR - OR, these two occurrences of R* are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring: O . It will be appreciated that a variety of other rings can be formed when two independent occurrences of R* (or R, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting. 10531 A substituent bond in, e.g., a bicyclic ring system, as shown below, means that the substituent can be attached to any substitutable ring atom on either ring of the bicyclic ring system: - 18- [0541 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. E.g., when R 5 in compounds of formula I is hydrogen, compounds of formula I may exist as tautomers: .RI O O RI OH 0 R2 NR Ar2 Ar ! -Ar' ___N N 1 RK3 :N R6R R 3 N RR

R

4 H R4 I I 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 I 3 C- or 1 4 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. [055] 3. Desoription of Exemplary Compounds: [056] In some embodiments of the present invention, Ar' is selected from: (WRw)m or(WRW)m a-i a-il; wherein ring Al 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Al and A 2 , together, is an 8-14 aromatic, bicyclic or tricyclic aryl ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. -19- [057] In some embodiments, A, is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein said heteroatom is nitrogen. In some embodiments, At is an optionally substituted phenyl. Or, A, is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or, A, is an optionally substituted pyrazinyl or triazinyl. Or, A, is an optionally substituted pyridyl. [0581 In some embodiments, A, is an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, wherein said heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, A, is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In one embodiment, A, is an optionally substituted 5-membered aromatic ring other than thiazolyl. [059] In some embodiments, A 2 is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein said heteroatom is nitrogen. In some embodiments, A 2 is an optionally substituted phenyl. Or, A 2 is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or triazinyl. [0601 In some embodiments, A 2 is an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, wherein said heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, A 2 is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In certain embodiments, A 2 is an optionally substituted pyrrolyl. [0611 In some embodiments, A 2 is an optionally substituted 5-7 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, or oxygen. Exemplary such rings include piperidyl, piperazyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, etc. [062] In some embodiments, A 2 is an optionally substituted 5-10 membered saturated or unsaturated carbocyclic ring. In one embodiment, A 2 is an optionally substituted 5-10 membered saturated carbocyclic ring. Exemplary such rings include cyclohexyl, cyclopentyl, etc. [063] In some embodiments, ring A 2 is selected from: H (WRW)m \ Rw H (WRwf (WRW)m H N N i ii iii iv -20- 0 WRW)m N (WRW)m N__f~m(R) 0 NH 0= 0 V Ai vii viii 0 (WR)m N (WRW)m ,-X(W) N- WR, S 0 ix x xi. xii H (WRW)m <(RW)m (WRW)m (WRW)m. AiixV xv xvi N(WWmWRW)m (WRW)m H xvii xviii xix .(RW)(WRW)m, (WRW)m m(R W) F N(R~i 77 xx xiii xxiii (WRW)m (WRW)m, (WRW)m WRW).. N N) (0ITF N H H H xxiv xxv xxvi xxviii -21- BOC N (WR(WRW )WRw) (WRW)m -/,/ (WRWN (WRw) N1 OCIH NN H H H xxix xxx xxxi xxxii; wherein ring A 2 is fused to ring Al through two adjacent ring atoms. [064] In other embodiments, W is a bond or is an optionally substituted C 1

-

6 alkylidene chain wherein one or two methylene units are optionally and independently replaced by 0, NR', S, SO, SO 2 , or COO, CO, SO 2 NR', NR'SO 2 , C(O)NR', NR'C(O), OC(O), OC(O)NR', and Rw is R' or halo. In still other embodiments, each occurrence of WRw is independently -Cl-C3 alkyl, C1-C3 perhaloalkyl, -O(Cl-C3alkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, Cl, -Br, or -COOR', -COR', -O(CH 2

)

2 N(R')(R'), -O(CH 2 )N(R')(R'), -CON(R')(R'), (CH 2

)

2 0R', -(CH 2 )OR', optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, -N(R')(R'), (CH 2

)

2 N(R)(R-), or -(CH2)N(R')(R'). [0651 In some embodiments, m is 0. Or, m is 1. Or, m is 2. In some embodiments, m is 3. In yet other embodiments, m is 4. [0661 In one embodiment, R 5 is X-R. In some embodiments R 5 is hydrogen. Or, R 5 is an optionally substituted Cig aliphatic group. In some embodiments, R 5 is optionally substituted C1.4 aliphatic. Or, R' is benzyl. [067] In some embodiments R is hydrogen. Or, R6 is an optionally substituted Ci-s aliphatic group. In some embodiments, R is optionally substituted C 4 aliphatic. In certain other embodiments, R 6 is -(O-C1.4 aliphatic) or -(S-C 14 aliphatic). Preferably, R 6 is -OMe or SMe. In certain other embodiments, R6 is CF 3 . [0681 In one embodiment of the present invention, R', R 2 , R(, and R 4 are simultaneously hydrogen. In another embodiment, R 6 and R'' are both simultaneously hydrogen. [069] In another embodiment of the present invention, R1, R 2 , R, R 4 , and R' are simultaneously hydrogen. In another embodiment of the present invention, R', R2, R, R, R and R 6 are simultaneously hydrogen. -22- [070] In another embodiment of the present invention, R2 is X-Rx, wherein X is SO 2 NR'-, and Rx is R'; i.e., R 2 is -SO 2

N(R')

2 . In one embodiment, the two R' therein taken together form an optionally substituted 5-7 membered ring with 0-3 additional heteroatoms selected froni nitrogen, oxygen, or sulfur. Or, R , R', R , R' and R are simultaneously hydrogen, and R 2 is SO 2

N(R')

2 . [0711 In some embodiments, X is a bond or is an optionally substituted C1.

6 alkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by 0, NR', S, SO2, or COO, CO, and Rx is R' or halo. In still other embodiments, each occurrence of XRx is independently -Cj- 3 alkyl, -O(Cj.

3 alkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, Cl, -Br, OH, -COOR', -COR', -O(CH 2

)

2 N(R')(R'), -O(CH 2 )N(R')(R'), -CON(R')(R'), (CH 2

)

2 OR', -(CH 2 )OR', optionally substituted phenyl, -N(R')(R'), -(CH 2

)

2 N(R')(R'), or (CH 2 )N(R')(R'). [0721 In some embodiments, R 7 is hydrogen. In certain other embodiment, R 7 is C 1 4 straight or branched aliphatic. [0731 In some embodiments, RW is selected from halo, cyano, CF 3 , CHF 2 , OCHF 2 , Me, Et, CH(Me) 2 , CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, 0-fluorophenyl, 0 difluorophenyl, 0-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF 3 , SCHF 2 , SEt, CH 2 CN, NH 2 , NHMe, N(Me) 2 , NHEt, N(Et) 2 , C(O)CH 3 , C(O)Ph, C(O)NH 2 , SPh, S0 2 -(amino-pyridyl),

SO

2

NH

2 , SO 2 Ph, SO 2 NIh, S0 2 -N-morpholino, S0 2 -N-pyrrolidyl, N-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4-dihydro-pyrazol-3 one-2-yl, benzimidazot-2yl, furan-2-yl, 4-methyl-4H-[1,2,4]triaz'ol-3-yl, 3-(4'-chlorophenyl) [1,2,4]oxadiazol-5-yi, NHC(O)Me, NHC(O)Et, NHC(O)Ph, NHSO 2 Me, 2-indolyl, 5-indolyl, CH 2

CI

2 OH, -OCF 3 , O-(2,3-dimethylphenyt), 5-methylfuryl, -S02-N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO 2 C(Me) 3 , CO 2 C(Me) 3 , isopropenyl, n-butyl, O-(2,4-dichlorophenyl),

NHSO

2 PhMe, 0-(3-chloro-5-trifluoromethyl-2-pyridyl), phenylhydroxymethyl, 2,5 dimethylpyrrolyl, NHCOCH 2 C(Me) 3 , 0-(2-tert-butyl)phenyl, 2,3-dimethylphenyl, 3,4 dimethylphenyl, 4-hydroxymethyl phenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl, 3 trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-cyanomethylphenyl, 4-isobutylphenyl, 3 pyridyl, 4-pyridyl, 4-isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6 -23dimethoxyphenyt, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF 3 -phenyl, 3 trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2 fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5-isopropyl-2-methoxyphenyl, 2 fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5 difluorophenyl, 3-chloro-4-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3 dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl, 4 methoxycarbonyl phenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3 methylphenyl, 4-methanesulfimyl-phenyl, 4-methanesulfonyl-phenyl, 4-N-(2-N,N dimethylaminoethyl)carbamoylphenyl, 5-acetyl-2-thienyl, 2-benzothienyl, 3-benzotlienyl, furan 3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N'-phenylcarbonyl-N-piperazinyl,

-NHCO

2 Et, NHCO 2 Me, N-pyrrolidinyl, -NHSO 2

(CH

2 )2 N-piperidine, -NHSO 2

(CH

2

)

2 N-morpholine, NHSO 2

(CH

2

)

2 N(Me) 2 , COCH 2 N(Me)COCH 2 NHMe, -CO 2 Et, O-propyl, CH 2

CH

2

NHCO

2 C(Me) 3 , hydroxy, aminomethyl, pentyl, adamantyl, cyclopentyl, ethoxyethyl, C(Me) 2

CH

2 OH, C(Me) 2

CO

2 Et, -CHOHMe, CH 2

CO

2 Et, -C(Me) 2

CH

2 NHCQ2C(Me) 3 ,

O(CH

2

)

2 OEt, O(CH 2

)

2 0H, CO 2 Me, hydroxymethyl,, 1-methyl-1-cyclohexyl, 1-methyl-1 cyclooctyl, 1-methyl-I -cycloheptyl, C(Et) 2 C(Me) 3 , C(Et) 3 , CONHCH 2 CH(Me) 2 , 2-aminomethyl phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyt, cyclohexyl, 4-methylpiperidinyl, -OCO 2 Me, C(Me) 2

CH

2

NHCO

2

CH

2 CH(Me) 2 , -C(Me) 2

CH

2

NHCO

2

CH

2

CH

2

CH

3 , -C(Me) 2

CH

2

NHCO

2 Et, C(Me) 2

CH

2

NHCO

2 Me, -C(Me) 2

CH

2

NHCO

2

CH

2 C(Me) 3 , -CH 2

NHCOCF

3 , -CH 2

NHCO

2 C(Me) 3 , -C(Me) 2

CH

2

NHCO

2

(CH

2

)

3

CH

3 , C(Me) 2

CH

2

NHCO

2

(CH

2

)

2 OMe, C(OH) (CF 3

)

2 , C(Me)2CH2NHCO 2

CH

2 -tetrahydrofurane-3-yl, C(Me) 2

CH

2 0(CH 2

)

2 OMe, or 3-ethyl-2,6 dioxopiperidin-3-yl. [074] In one embodiment, R' is hydrogen. [075] In one embodiment, R' is a CI-C8 aliphatic group, optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF 3 , or OCHF 2 , wherein up to two methylene units of said CI-C8 aliphatic is optionally replaced with -CO-, -CONH(CI-C4 alkyl)-, -C0 2 -, -OCO-, -N(Cl-C4 alkyl)CO 2 -, -0-, -N(CI-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(CI-C4 alkyl)CO-, -S-, -N(Cl-C4 alkyl)-, -SO 2 N(C1-C4 alkyl)-, N(Cl-C4 alkyl)SO 2 -, or -N(CI-C4 alkyl)SO 2 N(Cl-C4 alkyl)-. - 24- 10761 In one embodiment, R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF3, OCHF 2 , or CI-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-,

-CO

2 -, -OCO-, -N(CI-C4 alkyl)C0 2 -, -0-, -N(CI-C4 alkyl)CON(Cl-C4 alkyl)-, -OCON(CI C4 alkyl)-, -N(Cl-C4 alkyl)CO-, -S-, -N(CI-C4 alkyl)-, -SO 2 N(C1-C4 alkyl)-, N(Cl-C4 alkyl)S0 2 -, or -N(C1-C4 alkyl)SO 2 N(C1-C4 alkyl)-. [077] In one embodiment, R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF 3 , OCHF 2 , or CI-C6 alkyl, wherein up to two methylene units of said Cl-C6 alkyl is optionally replaced with -CO-, -CONH(C1-C4 alkyl)-, -C02-, -OCO-, -N(C1-C4 alkyl)CO 2 -, -0-, -N(Cl-C4 alkyl)CON(C1-C4 alkyl)-, -OCON(Cl C4 alkyl)-, -N(Cl-C4 alkyl)CO-, -S-, -N(CI-C4 alkyl)-, -SO 2 N(C1-C4 alkyl)-, N(CI-C4 alkyl)S0 2 -, or -N(C 1-C4 alkyl)SO 2 N(C I -C4 alkyl)-. [0781 In one embodiment, two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF 3 , OCHF 2 , or Cl-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, CONH(CI-C4 alkyl)-, -C02-, -OCO-, -N(CI-C4 alkyl)CO 2 -, -0-, -N(C1-C4 alkyl)CON(CI-C4 alkyl)-, -OCON(C1-C4 alkyl)-; -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -SO 2 N(Cl-C4 alkyl)-, N(CI-C4 alkyl)SO 2 -, or -N(C1-C4 alkyl)SO 2 N(C1-C4 alkyl)-. [079] According to one embodiment, the present invention provides compounds of formula HA or formula IHB: - 25 - R 2R 0 10 A 1 (WRw6m R 2 R' 0 0 A 1

A

2 WW) NI(WRw m N N (WRw)m R3 - R R 4 *H R4H IIA IIB (080] According to another embodiment, the present invention provides compounds of formula lIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE: "X 2 0 0 'X RX---(WRW)m H ~ N H IIA 00 0 0 X 1 )3

R-X

5 (WRw)m RX-X (WRw)m XHRxX+I H A ,W X H H IILB Inc 0 0 A (Ww)m 0 0 X X5 RX-X-0 H x 5 RX-X H A WRw)m H RID IHE wherein each of X 1 , X 2 , X 3 , X 4 , and Xs is independently selected from CH or N; and

X

6 is 0, S, or NR'. [081) In one embodiment, compounds of formula IHA, formula IHB, formula IHC, formula HID, or formula ILE have y occurrences of substituent X-Rx, wherein y is 0-4. Or, y is 1. Or, y is 2. [082] In some embodiments of formula IIIA, X 1 , X 2 , X 3 , X 4 , and X 5 taken together with WRw and m is optionally substituted phenyl. - 26 - 10831 In some embodiments of formula 1IHA, X 1 , X 2 , X 3 , X 4 , and X 5 taken together is an optionally substituted ring selected from: CI F N C1 OMe MeO N OMe CI a-i a-il a-iii a-iv a-v r0 MeO N N CF 3 N C CH 3 N N N

CH

3 a-xi a-xii a-xiii a-xiv a-xy a-xvi FF F N OFFCH3 a-xvii a-xviii a-xix a-xx a-xxi N a-xxii a-xxiii a-xxiv a-xxy [084] In some embodiments of formula 1IIIB, formula IIIC, formula IIID, or formula IIE, X 1 , X 2 , X 3 , X 4 , X5, or X 6 , taken together with ring A 2 is an optionally substituted ring selected from: H H N~ N tO HN(N - 27 b-i b-ii b-ill b-iv b-v THH

-

,N b-vi b-vii b-viii b-ix b-x N N xN /

CH

3 b-xi b-xii b-xiii b-xiv b-xv NH N N NN b-xvi b-xvil b-xviii b-xix b-xx

CH

3 N-- HN- -\ S N

N

H 00 b-xxi b-xxil b-xxiii b-xxiv b-xxv

CH

3

CH

3 N.,N 0 CH 3 NH N O'CH .00 b-xxvi b-xxvii b-xxvii b-xxix b-xxx H HON4 HN N 0Np H bxxxi b-xxxii b-xxxi b-xxxiv -28-

N-

0

CH

3 H\N b-xxxv b-xxxvi b-xxxvii I K 'I N N~ ~ H [jH H H b-xxxviii bxxxix b-xL b-xLi b-xLii 0 FF 0 0 F N N HH H H b-xLili b-xLiv b-xbv b-xLvi /l 0 N N H N N H H H HN) b-xLvlli b-YxLvmi b-xLix b-L N N 1 N N H H H b-Li b-Lui b-Liii b-Liv -29 - N' N N, H H H H b-Lv b-Lvi b-Lvii b-Lviii 0 H H H H b-Lix b-Lx b-Lxi b-Lxii 0~J oJ H H HH b-Lxiii b-Liy b-Lxv b-Lxvi N N HH H 0 0 b-Lxvil b-LxvW b-Lxix b-Lxx 0N H N b)-Lxxi bi-Lxxii b-Lll b-Lxxi-v -.30- N H H H b-Lxxv b-Lxxvi b-Lxxvii b-Lxxvffi NN NN N b-Lxxii b-Lxxxi b-L-xxxv b-Lxxx 'I0 N) N5 N -\:Zl\NO b-Lxxxii b-Lxxxix b-xCx b-xxxv N\C 6N 0 H , .- H Y - H k .

H t b-xCi b-xCii b-xchi b-xCiv H HJOCx b-xCv b-xCvi b-xCvii b-xCvii -31- -,ZZ 0--HO F 0F HO' O OH b-xCix b-C b-Ci b-Cii. [085] In some embodiments, Rw is selected from halo, cyano, CF 3 , CHF 2 , OCHF 2 , Me, Et, CH(Me) 2 , CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, 0-fluoropheny, 0 difluorophenyl, 0-methoxyphenyl, 0-tolyl, 0-benzyl, SMe, SCF 3 , SCHF 2 , SEt, CH 2 CN, NH 2 , NHMe, N(Me) 2 , NHEt, N(Et) 2 , C(O)CH 3 , C(O)Ph, C(O)NH 2 , SPh, SO2-(amino-pyridyl), S0 2

NH

2 , SO 2 Ph, SO 2 NHPh, S0 2 -N-morpholino, S0 2 -N-pyrrolidyl, N-pyrrolyl, N morpholino, I -piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4 dihydro-pyrazol-3-one-2-yl, benzimidazol-2y, furan-2-yl, 4-methyl-4H-[1,2,4]triazol-3-yl, 3 (4'-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, or NHSO 2 Me [0861 In some embodiments, X and RX, taken together, is Me, Et, halo, CN, CF 3 , OH, OMe, OEt, SO 2 N(Me)(fluorophenyl), SOr(4-methyl-piperidin-1-yl, or S0 2 -N-pyrrolidinyl. [0871 According to another embodiment, the present invention provides compounds of formula WA, formula JVB, or formula WC: 0 0-(WRw RH _WRWim IVA 00-X- (WR)m 00 N-- (WRW) RX X, H i Rx-X H H H IVB WYC [0881 In one embodiment compounds of formula WA, formula VB, and formula IWC have y occurrences of substituent X-R, wherein y is 0-4. Or, y is 1. Or, y is 2. [0891 In one embodiment, the present invention provides compounds of formula WA, formula IVB, and formula IC, wherein X is a bond and RX is hydrogen. 32- [0901 In one embodiment, the present invention provides compounds of formula formula IVB, and formula IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic seven membered ring with 0-3 heteroatoms selected from 0, S, or N. Exemplary rings include azepanyl, 5,5-dimethyl azepanyl, etc. [091] In one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic six membered ring with 0-3 heteroatoms selected from 0, S, or N. Exemplary rings include piperidinyl, 4,4-dimethylpiperidinyl, etc. [0921 In one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic five membered ring with 0-3 heteroatoms selected from 0, S, or N. [0931 In one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted five membered ring with one nitrogen atom, e.g., pyrrolyl or pyrrolidinyl. [0941 According to one embodiment of formula IVA, the following compound of formula VA-1 is provided: WRW5 0 0 WR1 N OI H WRw2 RN-XW H VA-1 wherein each of WRw2 and WRw 4 is independently selected from hydrogen, CN, CF 3 , halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from 0, S, or N, wherein said WRw2 and WR0 4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , SR', S(O)R', SO 2 R', -SCF 3 , halo, CN, -COOR', -COR', -O(CH 2

)

2 N(R')(R'), -O(CH 2 )N(R')(R'), CON(R')(R'), -(CH 2

)

2 0R', -(CH 2 )OR', CH 2 CN, optionally substituted phenyl or phenoxy, N(R')(R'), -NR'C(O)OR', -NR'C(O)R', -(CH 2

)

2 N(R')(R'), or -(CH 2 )N(R')(R'); and WRWS is selected from hydrogen, -OH, NH 2 , CN, CHF 2 , NHR', N(R') 2 , -NHC(O)R', -NHC(O)OR', NHSO 2 R', -OR', CH 2 OH, CH2N(R') 2 , C(O)OR', SO 2 NHR', SO 2

N(R')

2 , or -33-

CH

2 NHC(O)OR'. Or, WRw 4 and WR" taken together form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, 0, or S, wherein said ring is optionally substituted with up to three WRw substituents. [0951 In one embodiment, compounds of formula VA-1 have y occurrences of X-Rx, wherein y is 0-4. In one embodiment, y is 0. [0961 In one embodiment, the present invention provides compounds of formula VA 1, wherein X is a bond and Rx is hydrogen. [097] In one embodiment, the present invention provides compounds of formula VA 1, wherein: each of WRW 2 and WRw 4 is independently selected from hydrogen, CN, CF 3 , halo, Cl-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, or phenyl, wherein said WR'2 and WRw 4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , -SCF 3 , halo, -COOR', -COR', -O(CH 2

)

2 N(R')(R'), O(CH 2 )N(R')(R'), -CON(R')(R'), -(CH 2

)

2 OR', -(CHz)OR', optionally substituted phenyl, N(R')(R'), -NC(O)OR', -NC(O)R', -(CH 2

)

2 N(R')(R'), or -(CH 2 )N(R')(R'); and WReW is selected from hydrogen, -OH, NH 2 , CN, NHR', N(R') 2 , -NHC(O)R', NHC(O)OR', NHSO 2 R', -OR', CH 2 OH, C(O)OR', SO 2 NHR', or CH 2 NHC(O)O-(R'), [0981 In one embodiment, the present invention provides compounds of formula VA 1, wherein: WRw is a pheny ring optionally substituted with up to three substituents selected from OR', -CF 3 , -OCF 3 , SR', S(O)R', SO 2 R', -SCF 3 , halo, CN, -COOR', -COR', O(CH2) 2 N(R')(R'), -O(CH 2 )N(R')(R'), -CON(R')(R'), -(CH 2

)

2 0R', -(CH 2 )OR', CH 2 CN, optionally substituted phenyl or phenoxy, -N(R')(R'), -NR'C(O)OR', -NR'C(O)R', (CH 2 )2N(R')(R'), or -(CH2)N(R')(R'); WR4 is Cl-C6 straight or branched alkyl; and WRW is OH. [0991 In one embodiment, each of WRw 2 and WRw 4 is independently selected from

CF

3 or halo. In one embodiment, each of WRw and WRW 4 is independently selected from optionally substituted hydrogen, C1-C6 straight or branched alkyl. In certain embodiments, each of of WRw 2 and WRw 4 is independently selected from optionally substituted n-propyl, - 34 isopropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2 (ethoxycarbonyl)-ethyl, 1,1 -dimethyl-3 -(t-butoxycarbonyl-amino) propyl, or n-pentyl. [01001 In one embodiment, each of WRW 2 and WRW 4 is independently selected from optionally substituted 3-12 membered cycloaliphatic. Exemplary embodiments of such cycloaliphatic include cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, [2.2.2.]bicyclo-octyl, [2.3.1.] bicyclo-octyl, or [3.3.1 ]bicyclo-nonyl. [0101] In certain embodiments WRW 2 is hydrogen and WRw 4 is Cl -C6 straight or branched alkyl. In certain embodiments, WRW 4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, or t-butyl. [01021 In certain embodiments WRW 4 is hydrogen and WRw2 is C1-C6 straight or branched alkyl. In certain embodiments, WRw 2 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, or n-pentyl. [01031 In certain embodiments each of WRW 2 and WRW 4 is Cl-C6 straight or branched alkyl. In certain embodiments, each of WRw 2 and WRw 4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, or pentyl. [0104] In one embodiment, WRWS is selected from hydrogen, CHF 2 , NH 2 , CN, NHR',

N(R')

2 , CH 2

N(R')

2 , -NHC(O)R', -NHC(O)OR', -OR', C(O)OR', or SO 2 NHR'. Or, WRw' is OR', e.g., OH. [0105] In certain embodiments, WRW5 is selected from hydrogen, NH 2 , CN, CHI 2 , NH(C1-C6 alkyl), N(C1-C6 alkyl) 2 , -NHC(O)(C1-C6 alkyl), -CH 2 NHC(O)O(CI-C6 alkyl), NHC(O)O(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), C(0)0(C1-C6 alkyl), CH 2 O(C1-C6 alkyl), or S0 2

NH

2 . In another embodiment, WRws is selected from -OH, OMe, NH2, -NHMe, -N(Me) 2 ,

-CH

2

NH

2 , CH 2 OH, NHC(O)OMe, NHC(O)OEt, CN, CHF 2 , -CH 2 NHC(O)O(t-butyl), -0 (ethoxyethyl), -O-(hydroxyethyl), -C(O)OMe, or -SO 2

NH

2 . [01061 In one embodiment, compound of formula VA-1 has one, preferably more, or more preferably all, of the following features: i) WRw2 is hydrogen; ii) WRw 4 is Cl-C6 straight or branched alkyl or monocyclic or bicyclic aliphatic; and iii) WRw 5 is selected from hydrogen, CN, CHF 2 , NH 2 , NH(C1-C6 alkyl), N(C1-C6 alkyl) 2 , -NHC(O)(CI-C6 alkyl), -NHC(O)O(Cl-C6 alkyl), -CH 2 C(O)O(CI-C6 alkyl), -OH, -O(C1-C6 alkyl), C(O)O(Cl-C6 alkyl), or SO 2 NH2. -35- [01071 In one embodiment, compound of formula VA-1 has one, preferably more, or more preferably all, of the following features: i) WRw 2 is halo, Cl-C6 alkyl, CF 3 , CN, or phenyl optionally substituted with up to 3 substituents selected from Cl -C4 alkyl, -O(C 1 -C4 alkyl), or halo; ii) WRW 4 is CF 3 , halo, Cl-C6 alkyl, or C6-CIO cycloaliphatic; and iii) WRws is OH, NH 2 , NH(CI-C6 alkyl), or N(Cl-C6 alkyl). [01081 In one embodiment, X-RX is at the 6-position of the quinolinyl ring. In certain embodiments, X-RX taken together is Ct-C6 alkyl, -O-(C 1-C6 alkyl), or halo. [01091 In one embodiment, X-Rx is at the 5-position of the quinolinyl ring. In certain embodiments, X-RX taken together is -OH. [01101 In another embodiment, the present invention provides compounds of formula VA-1, wherein WRw 4 and WRw 5 taken together form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, 0, or S, wherein said ring is optionally substituted with up to three WR substituents. [0111] In certain embodiments, WRw 4 and WRws taken together form an optionally substituted 5-7 membered saturated, unsaturated, or aromatic ring containing 0 heteroatoms. In other embodiments, WRw 4 and WRW5 taken together form an optionally substituted 5-7 membered ring containing 1-3 heteroatoms selected from N, 0, or S. In certain other embodiments, WRW 4 and WRws taken together form an optionally substituted saturated, unsaturated, or aromatic 5-7 membered ring containing 1 nitrogen heteroatom. In certain other. embodiments, WRW 4 and WRY5 taken together form an optionally substituted 5-7 membered ring containing 1 oxygen heteroatom. [01121 In another embodiment, the present invention provides compounds of formula V-A-2: (WR)m RXXN Y--RY H V-A-2 wherein: Y is CH 2 , C(O)O, C(O), or S(0)2; -36m is 0-4; and X, Rx, W, and Rw are as defined above. [01131 In one embodiment, compounds of formula VA-2 have y occurrences of X-RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01141 In one embodiment, Y is C(O). In another embodiment, Y is C(O)O. Or, Y is

S(O)

2 . Or, Y is CH 2 . [01151 In one embodiment, m is 1 or 2. Or, m is 1. Or, m is 0. [01161 In one embodiment, W is a bond. [01171 In another embodiment, Rw is CI-C6 aliphatic, halo, CF 3 , or phenyl optionally substituted with CI-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or CI-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C0 2 -, -OCO-,

-NR'CO

2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or NR'SO 2 NR'-. In another embodiment, R' above is CI-C4 alkyl. Exemplary embodiments of WRW include methyl, ethyl, propyl, tert-butyl, or 2-ethoxyphenyl. 10118] In another embodiment, RW in Y-Rw is C1-C6 aliphatic optionally substituted with N(R") 2 , wherein R" is hydrogen, C1 -C6 alkyl, or two R" taken together form a 5-7 membered heterocyclic ring with up to 2 additional heteroatoms selected from 0, S, or NR'. Exemplary such heterocyclic rings include pyrrolidinyl, piperidyl, morpholinyl, or thiomorpholinyl. [0119] In another embodiment, the present invention provides compounds of formula V-A-3: (WR)m 0 o N N RX-X-1 NN (QRQ). V-A-3 wherein: Q is W; RQ is RW; m is 0-4; -37n is 0-4; and X, Rx, W, and Rw are as defined above. [01201 In one embodiment, compounds of formula VA-3 have y occurrences of X-RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2, [01211 In one embodiment, n is 0-2. [01221 In another embodiment, in is 0-2. In one embodiment, m is 0. In one embodiment, m is 1. Or, m -is 2. 101231 In one embodiment, QRQ taken together is halo, CF 3 , OCF 3 , CN, C1-C6 aliphatic, 0-C l-C6 aliphatic, O-phenyl, NH(CI-C6 aliphatic), or N(CI-C6 aliphatic) 2 , wherein said aliphatic and phenyl are optionally substituted with up to three substituents selected from CI-C6 alkyl, O-CI-C6 alkyl, halo, cyano, OH, or CF 3 , wherein up to two methylene units of said CI-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C02-, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, SOR', SO 2 R',

-SO

2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is Cl-C4 alkyl. [01241 Exemplary QRQ include methyl, isopropyl, sec-butyl, hydroxymethyl, CF 3 , NMe 2 , CN, CH 2 CN, fluoro, chloro, OEt, OMe, SMe, OCF 3 , OPh, C(O)OMe, C(O)O-iPr, S(O)Me, NHC(O)Me, or S(O) 2 Me. 10125] In another embodiment, the present invention provides compounds of formula V-A-4: Rw 0 0 RX-X Rw N H V-A-4 wherein X, Re, and Rw are as defined above. [01261 In one embodiment, compounds of formula VA-4 have y occurrences of X-Re, wherein y is 04. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01271 In one embodiment, Rw is Cl-C12 aliphatic, C5-C10 cycloaliphatic, or C5-C7 heterocyclic ring, wherein said aliphatic, cycloaliphatic, or heterocyclic ring is optionally substituted with up to three substituents selected from C1-C6 alkyl, halo, cyano, oxo, OH, or

CF

3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally -38replaced with -CO-, -CONR'-, -C0 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is CI-C4 alkyl. 101281 Exemplary Rw includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t butyl, n-pentyl, vinyl, cyanomethyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl, or -C(CH3) 2 -NHC(O)O-T, wherein T is Cl-C4 alkyl, methoxyethyl, or tetrahydrofuranylmethyl. 101291 In another embodiment, the present invention provides compounds of formula V-A-5: (WRw)m 0 0 RxX_ N N(R')2 H N H V-A-5 wherein: m is 0-4; and X, Rx, W, Rw, and R' are as defined above. 101301 In one embodiment, compounds of formula VA-5 have y occurrences of X-Rx, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. 101311 In one embodiment, m is 0-2. Or, m is 1. Or, m is 2. [0132] In another embodiment, both R' are hydrogen. Or, one R' is hydrogen and the other R' is C1-C4 alkyl, e.g., methyl. Or, both R' are C1-C4 alkyl, e.g., methyl. [01331 In another embodiment, m is I or 2, and RW is halo, CF 3 , CN, C1-C6 aliphatic, 0-C1 -C6 aliphatic, or phenyl, wherein said aliphatic and phenyl are optionally substituted with up to three substituents selected from C1-C6 alkyl, O-C1-C6 alkyl, halo, cyano, OI, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or CI-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is C1 -C4 alkyl. [01341 Exemplary embodiments of RW include chloro, CF 3 , OCF 3 , methyl, ethyl, n propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, propyloxy, or 2-ethoxyphenyl. -39- [01351 In another embodiment, the present invention provides compounds of formula V-A-6: (WRw)m 0 0 RX-X H H B V-A-6 wherein: ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of -Q-RQ, wherein n is 0-4, and Q and RQ are as defined above; and Q, R?, X, RX, W, and Rw are as defined above. [01361 In one embodiment, compounds of formula VA-6 have y occurrences of X-Rx, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01371 In one embodiment, m is 0-2. Or, m is 0. Or m is 1. [01381 In one embodiment, n is 0-2. Or, n is 0. Or, n is 1. [01391 In another embodiment, ring B is a 5-7 membered monocyclic, heterocyclic ring having up to 2 beteroatoms selected from 0, S, or N, optionally substituted with up to n occurrences of -Q-R. Exemplary heterocyclic rings include N-morpholinyl, N-piperidinyl, 4 benzoyl-piperazin-l-yL, pyrrolidin-1-yl, or 4-methyl-piperidin-1-yl. [01401 In another embodiment, ring B is a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroatoms selected from 0, S, or N, optionally substituted with up to n occurrences of -Q-RQ. Exemplary such rings include benzimidazol-2-yl, 5-methyl-furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridine-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxy-pyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-y1, 5-cyano thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl. [0141] In another embodiment, the present invention provides compounds of formula V-B-1: -40 - (RWW)m Ra-X H V-B-1 wherein: one of Qi and Q3 is N(WRw) and the other of Qi and Q3 is selected from 0, S, or N(WRW); Q2 is C(O), CH 2 -C(O), C(O)-CH 2 , CH 2 , CH 2

-CH

2 , CF 2 , or CF 2

-CF

2 ; m is 0-3; and X, W, RX, and RW are as defined above. [01421 In one embodiment, compounds of formula V-B-1 have y occurrences of X-RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01431 In one embodiment, Q3 is N(WRw); exemplary WRW include hydrogen, C1-C6 aliphatic, C(O)CI-C6 aliphatic, or C(O)OC1-C6 aliphatic. [01441 In another embodiment, Q3 is N(WRw), Q2 is C(O), CH 2 , CH 2

-CH

2 , and Qt is 0. [0145] In another embodiment, the present invention provides compounds of formula V-B-2: (RW)m RW 3 RWs 0 0 1-3 RX -X N 'RWl H V-B-2 wherein: R is hydrogen or CI -C6 aliphatic; each of R"3 is hydrogen or Cl -C6 aliphatic; or both RW 3 taken together form a C3-C6 cycloalkyl or heterocyclic ring having up to two heteroatoms selected from 0, S, or NR', wherein said ring is optionally substituted with up to two WRw substituents; -41m is 0-4; and X, Rx, W, and Rw are as defined above. [01461 In one embodiment, compounds of formula V-B-2 have y occurrences of X-RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01471 In one embodiment, WRwi is hydrogen, Cl-C6 aliphatic, C(O)Cl-C6 aliphatic, or C(O)OCl-C6 aliphatic. (01481 In another embodiment, each RW 3 is hydrogen, C1-C4 alkyl. Or, both RW 3 taken together form a C3-C6 cycloaliphatic ring or 5-7 membered heterocyclic ring having up to two heteroatoms selected from 0, S, or N, wherein said cycloaliphatic or heterocyclic ring is optionally substituted with up to three substitutents selected from WRwL. Exemplary such rings include cyclopropyl, cyclopentyl, optionally substituted piperidyl, etc. [01491 In another embodiment, the present invention provides compounds of formula V-B-3: (RWW)m 0 0RW RX-X- R H V-B-3 wherein: Q4 is a bond, C(O), C(O)O, or S(0) 2 ; R is hydrogen or C1-C6 aliphatic; n is 0-4; and X, W, RW, and RX are as defined above. [01501 In one embodiment, compounds of formula V-B-3 have y occurrences of X-Re, wherein y is 0-4. In one embodiment, y is 0. [0151] In one embodiment, Q4 is C(O). Or Q4 is C(O)O. In another embodiment, Ru is CI-C6 alkyl. Exemplary Rl include methyl, ethyl, or t-butyl. (0152] In another embodiment, the present invention provides compounds of formula V-B-4: oX-X(WRW)m H V-B-4 wherein: m is 0-4; and X, RX, W, and Rw are as defined above. [0153] In one embodiment, compounds of formula V-B-4 have y occurrences of X-RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01541 In one embodiment, m is 0-2. Or, m is 0. Or, m is 1. [0155] In another embodiment, said cycloaliphatic ring is a 5-membered ring. Or, said ring is a six-membered ring. [01561 In another embodiment, the present invention provides compounds of formula V-B-5: (WRw)m 0 0 RX-X_ H H V-B-5 wherein: ring A 2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A 2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRW; m is 0-4; and X, W, R and RX are as defined above. [01571 In one embodiment, compounds of formula V-B-5 have y occurrences of X-Rx, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [01581 In one embodiment, ring A 2 is an optionally substituted 5-membered ring selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. -43- 101591 In one embodiment, ring A 2 is an optionally substituted 5-membered ring selected from pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl, or triazolyl. Exemplary such rings include: NN S aa bb cc dd 0 N ee ff gg; wherein said ring is optionally substituted as set forth above. [01601 In another embodiment, ring A 2 is an optionally substituted 6-membered ring. Exemplary such rings include pyridyl, pyrazinyl, or triazinyl. In another embodiment, said ring is an optionally pyridyl. [01611 In one embodiment, ring A 2 is phenyl. [0162] In another embodiment, ring A 2 is pyrrolyl, pyrazolyl, pyridyl, or thiadiazolyl. 101631 Examplary W in formula V-B-5 includes a bond, C(O), C(0)0 or CI-C6 alkylene. [01641 Exemplary Rw in formula V-B-5 include cyano, halo, C1-C6 aliphatic, C3-C6 cycloaliphatic, aryl, 5-7 membered heterocyclic ring having up to two heteroatoms selected from 0, S, or N, wherein said aliphatic, phenyl, and heterocyclic are independently and optionally substituted with up to three substituents selected from Cl-C6 alkyl, 0-C 1-C6 alkyl, halo, cyano, OH, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO 2 -, -OCO-, -NR'CO 2 -, -0-, NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is C1-C4 alkyl. [0165] In one embodiment, the present invention provides compounds of formula V-B 5-a: -44-

G

5 0 0

G

4 N) N RX-X H H N H V-B-5-a wherein:

G

4 is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted Cl -C6 aliphatic, aryl-Cl-C6 alkyl, or a phenyl, wherein G 4 is optionally substituted with up to 4 WRw substituents; wherein up to two methylene units of said C1-C6 aliphatic or CI-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-.; Gs is hydrogen or an optionally substituted Cl-C6 aliphatic; wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRe. [0166 In one embodiment, compounds of formula V-B-5-a have y occurrences of X RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2. [0167] In one embodiment, G 4 is hydrogen. Or, G 5 is hydrogen. [01681 In another embodiment, G 4 is hydrogen, and G 5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo, cyano, or CF 3 , and wherein up to two methylene units of said Cl-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, CONR'-, -CO 2 -, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is Cl-C4 alkyl. [01691 In another embodiment, G 4 is hydrogen, and G 5 is cyano, methyl, ethyl, propyl; isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH 2 C(O)OMe, (CH 2

)

2 NHC(O)O-tert-butyl, or cyclopentyl. [0170] In another embodiment, Gs is hydrogen, and G4 is halo, Cl-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with Cl-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said Cl-C6 aliphatic or CI-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SOr, or -NR'SO 2 NR'-. In another embodiment, R' above is C1 -C4 alkyl. -45 - 101711 In another embodiment, G 5 is hydrogen, and G 4 is halo, CF 3 , ethoxycarbonyl, t butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CHz)2-NMe 2 )-phenyl, 2-methoxy-4 chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec butylaminocarbonyl, ethyl, t-butyl, or piperidin- 1 -ylcarbonyl. [01721 In another embodiment, G 4 and G 5 are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with CI-C6 aliphatic, C(O)(CI-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl is optionally substituted with CI-C6 alkyl, halo, cyano, or

CF

3 , wherein up to two methylene units of said CI-C6 aliphatic or Cl-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C0 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is Cl-C4 alkyl. [01731 In another embodiment, G 4 and G 5 are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with acyl, benzyl, C(O)CH 2 N(Me)C(O)CH 2 NHMe, or ethoxycarbonyl. [0174] In another embodiment, the present invention provides compounds of formula I': RI OR-' O R2 Ar' R N R6 R R4 or pharmaceutically acceptable salts thereof, wherein RI, R 2 , R, R 4 , RW, R', R', and Ar' is as defined above for compounds of formula P,. [0175] In one embodiment, each of R', R2, R , R , R , R, and Ar' in compounds of formula P is independently as defined above for any of the embodiments of compounds of formula I. [0176] Representative compounds of the present invention are set forth below in Table 1 below.. [01771 Table 1 -46- Cmpd Name No. I N-[5-(5-chloro-2-methoxy-phenyl)-1 H-indot-6-ylJ-4-oxo-1 H-quinoline-3-carboxamide 2 N-(3-methoxy-4-tert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 3 N-[2-(2-methoxyphenoxy-5-(trifluoromethyl)phenyl]-4-oxo-1 H-quinoline-3-carboxam ide 4 N-(2-morpholinophenyl)-4-oxo-1 H-quinotine-3-carboxamide 5 N-[4-(2-hydroxy-1 I1 -dimelhyl-ethyl)phenyl)-4-oxo-I H-quinoline-3-carboxamide 6 N-(3-(hydroxymethyl)-4-te-t-butyl-phenyl]-4-oxo-1 H-quinoline-3-carboxamide 7 N-(4-benzoylamino-2,5-diethoxy-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 8 N-(3-amlno-4-ethyl-phenyl)-4-oxo-1 H-qulnoline-3-carboxam ide 9 4-oxo-N-(3-sulfamoylphenyl)-1 H-quinoline-3-carboxamide 10 1 ,4-dihydro-N-(2,3,4,5-tetrahydro-1 H-berizo[b]azepin-8-y)--4-oxoquinoline-3-carboxamlde 11 4-oxo-N-[2-[2-(trifluoromethyl)phenyllphenyl]-l H-quinoline-3-carboxamide 12 N-[2-(4-iimethylaminopheny)phenyl]-4-oxo-1 H-quinoline-3-carboxamlde 13 N-(3-cyano-4-tert-butyl-pheny)-4-oxo-1 H-quinoline-3-carboxamide 14 (54(4-oxo-1 -quinotin-3-y ~carbonylamino]-2-tert-butyl-phenyl]aminoformlc acid metl ester 15 N-(2-methoxy-3-pyridy--4-oxo-1 H-qulnoline-3-carboxamlde 16 4-oxa-N-(2-propylphenyl)-1 H-quinoline-3-carboxamide 17 N-(5-amlno-2-propoxy-phenyl)-4-oxo-1 H-quinollne-3-carboxamlde 18 N-(9H-fluoren-l -yI)-4-oxo-1 H-quinoline -3-carboxamide 19 4-oxo-N-(2-quinoly4)-1 H-quinoline-3-carboxamide 20 N-[2-(2-methylpherioxy)phenyl]-4-oxo-I H-qulnollne-3-carboxamide 21 4-oxo-N=[4--(2-pyridylsulfamoyl)pheny,4J-I H-qulnoline-3-carboxamlde 22 4-Oxo-1 ,4-dihydro-quinoline-3-carboxylic acid N-(1 ,2'-dihydrospirofcyclopropane-1 ,3'-[3H-]ildoI W-yQ)-amide 23 N-12-(2-ethoxypheny-5-hydroxy4-tert-butyl-phenyl-4-oxo-1 H-qulnoline-3-carboxamlde F24 14-oxo-N-(3-pyrrolidln-i -ylsulfonytphenyl)-1 H-quinoline-3-carboxamide -47- 25 N-[2-(3-acetylaminopheny~phenyl]-4-oxo-1 H-quinoline-3-carboxamide 26 4-oxo-N-[2-(l -piperidyl)pheny[]-1 H-quinoline-3-carboxamide 27 N-[l1 -[2-[methyl-(2-methylamn inoacetyl)-aminolacetyl]l- H-indol-6-yl-4-xo-l H-quinoline-3 carboxamide 28 [2-methyi-2-[4-[(4-oxo-1 H-quinolin-3-yl)carbonylamlinojphenyl]-propyllamlnoformic acid 2 mnethoxyethyl ester 29 1 -isopropyl-4-oxo-N-pheny-1 H-quinoline-3-carboxamnido 30 [.2-isopropyl-5-[(4-oxo-1 H-quinolin-3-yI)carbonylamino]phenyl]aminoformic acid methyl ester 31 4-oxo-N-(p-tolyl)-1 H-quinotine-3-carboxamide 32 N-(5-chloro-1 H-indoI-6-yl--4-oxo-1 H-quinoline-3-carboxamlde 33 N-(1 H-indol-6-yl)-4-oxo-1 H-quinoflne-3-carboxamlde 34 N4[4-(I, I -dlethylpropyl)-2-fluoro-5-hydroxy-phenyi]-4-hydroxy-qulnolfne-3-carboxamde 35 1 ,4-dihydro-N-(2.3,4,5--tetrahydro-5,5-dimethyl-1 H-benzo[b]azepin-8-y)-4-oxoquinoline-3 carboxamide 36 N-(2-isopropylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 37 N-(l H-indol-7-yi)-4-oxo-1 H-quinoline-3-carboxamide 38 N-{2-(l H-indol-2-yl)phenylj-4-oxo-1 H-quinollne-3-carboxamide 39 [3-[(2,4-dimethoxy-3-quinolyl)carbonylamino]-4-tert-butyl-phenyl]aminoformio acid tert-butyl ester 40 N-[2-(2-hydroxyethyt)phenyl]-4-xo-1 H-quinoline-3--carboxamlIda 41 N-(5-amino-2-propyl-phenyt)-4--ox-1 H-quinoline-3-carboxamlde 42 N-[2-f3-choro-5-trffluoomethyl)-2-pyridyt]oxy]pheny4J-4-oxo-1 H-qulnollne-3-carboxamldo 43 N-[2-(3-ethoxyphenyl)-5-hydroxy-4-terf-buty-phenyl]-4-xo-1 H-quinoline-3-carboxamide 44 N-(2-methylbenzothiazol-5-yl)-4-oxo-I 14-quinoline-3-carboxamide 45 N-(2-cyano-3--fluoro-phenyl)-4-oxo-1 H-quinotine-3-carboxamide 46 N-[3-chloro-5-(2-morpholinoethylsulfonylamino)pheny]-4-xo-1 H-quinoline-3-carboxamide 47 N-[4-isopropyf-2-(trifluoromethyl)phenyl]-4-xo-1 H-quinoline-3-carboxamide 48 N-(5-chloro-2-fluoro-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 49 N-[2-(2,6-dlmethoxyphenyl)phenyl]-4-oxo-1 H-qulnollne-3-carboxamide -48- 50 4-oxo-N-(2,4,6-trimethylphenyl)-I H-quinoline-3-carboxamide 51 6-[(4-methyl-i -piperidyl)sulfonylj-4-oxo-N-(5-tert-butyl-1 H--indol-6-yi)-1 H-qulnoline-3 carboxamide 52 N-[2-(m-tolyl)phenyl]-4-oxo-1 H-quinoline-3-carboxam ide 53 4-oxo-N-(4-pyridyl)-1 H-quinoline-3-carboxamide 54 4-oxo-N-(8-thia-7,9-diazabicyclo[4.3.0Jnona-2,4,6,9-tetraen-5-y)-I H-quinoline-3-carboxamide 55 N-(3-amino-2-methoxy-5-tert-butyl-pheny)-4-oxo-1 H-quinoline-3-carboxarnide 56 1 ,4-dlhydro-N-(1 ,2,3,4-tetrahydro-6-hydroxynaphthalen-77y)-4-oxoquinoline-3-carboxamide 57 N-[4-(3-ethyI-2,6-dioxo-3-piperidyI)phenylJ-4-oxo-I H-quinoline-3-carboxarnide 58 N-p-amino-4-(trifluoromethoxy)pheny]-4-oxo-1 H-quinoline-3-carboxamide 59 N-f2-(5-isopropyl-2-methoxy-pheny )phenylj-4-oxo-1 H-quinoline--3-crarboxamide 60 [4-isopropyt-3-[(4-oxo-I H-q ulna in-3-yI)carbonylamninolphenyllaminoformic acid tert-butyl ester 61 N-(2,3-dimethylphenyl)-4-oxo-I H-quinoline-3--carboxamide 62 4-oxo-N-[3-(trifluorom ethoxy)phenyl]-1 H-quinoline-3-carboxamide 63 N-[2-(2,4-difluorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 64 4-oxo-N-(2-oxo-1 .3-dihydrobenzoimidazol-5-y)-1 H-quinoline-3-carboxamide 65 4-oxo-N-[S-(3-pyridy)-1 H-indol-6-y}-1 H-quinoline-3-carboxamide 66 N-(2,2-difluorobenzo[1 ,3Idioxol-5-yI)-4-oxa-I H-quinollne-3-carboxamide 67 6-ethy-4-hydroxy-N-(1 H-lndol..6-y)quinoline-3-carbaxamide 68 3-f 2-[(4-oxo-1 H-qulnolln-3-yl)carbonylamlno]phenyljbenzolc acid methyl ester 69 N-(3-amlno-4-lsopropyl-phenyl)-4-oxo-I H-quinoline-.3--carboxamide 70 4-oxo-N-f2-(4-pyridyl)phenyj--1 H-uinollne-3-carboxamide 71 3-[2-[(4-oxo-1 H-quinollr-3-yI)carbonylaminojphenylqbenzoic acid isopropyl ester 72 N-(2-ethylphenyl)-4-xo-i H-quinoline-3-carboxamide 73 4-oxo-N-(2-phenyl-3H-benzomidazol-5-ylI)- H-quinollne-3-carboxarnide 74 4-oxo-N-[5-(triftuoromethy$)-2-pyridIH-quinoline-3-carboxamide -49-.

75 4-oxo-N-(3-quinolyl)-1 H-quinoline-3-carboxamide 76 N-[2-(3,4-difluorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 77 N-(5-fluoro-1 H-indol-6-yi)-4-oxo-1 H-quinoline-3-carboxamide 78 4-oxo-N-(2-sulfamoylphenyl)-1 H-quinoline-3-carboxamide 79 N-[2-(4-fluoro-3-methyl-phenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 80 N-(2-methoxyphenyl)-4-oxo-1 H-quinoline-3-carboxamide 81 4-oxo-N-(3-propionylaminophenyl)-1 H-quinoline-3-carboxamide 82 N-(4-diethylamino-2-methyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 83 N-[2-(3-cyanophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 84 N-(4-methyl-2-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 85 N-[2-(3,4-dichlorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 86 N-[4-[2-(aminomethyl)pheny]phenyl]-4-oxo-1 H-quinoline-3-carboxamide 87 4-oxo-N-(3-phenoxyphenyl)-1 H-quinotine-3-carboxamide 88 [2-methyl-2-[4-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformic acid tert-buty ester 89 N-(2-cyano-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 90 4-oxo-N-(2-tert-butylphenyl)-1 H-quinoline-3-carboxamide 91 N-(3-chloro-2,6-diethyl-pheny)-4-oxo-1 H-quinoline-3-carboxamide 92 N-[2-fluoro--ydroxy-4-(1-methylycohexyl)-phenyl]-4-oxo-1 H-quinoline-3-carboxamide 93 N-[2-(6-cyano-2-thlenyl)pheny]-4-oxo-1 H-quinoline-3-carboxamide 94 N-(5-amino-2-methyl-pheny)-4-oxo-1 H-quinoline-3-carboxamide 95 N-(2-cyanophenyl)-4-oxo-1 H-quinoline-3-carboxamide 96 N-[3-(cyanornethyl)-1 H-Indol-6-yl]-4-oxo-1 H-quinoline-3-carboxamide 97 N-J2-(2,4-dimethoxypyrimidin-5-yl)phenyl]-4-oxo-1 H-quinoline-3-carboxamlde 98 N-(5-dimethylamino-2-propyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 99 4-oxo-N-(4-pentylphenyl)-1 H-quinoline-3-carboxamide -50- 103 6-fluoro-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 104 N-(2-methyl-1 H-lndo-6-y}-4-oxo-1 H-quinoline-3-carboxamide 105 1 ,4-dihydro-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yI)-4-oxoquinoline-3-carboxamide 106 N-(2-cyano-4,5-dlmethoxy-phenyl)-4-oxo-I H-quinoline-3-carboxamide 107 7-[4-oxo-1 H-quinolin-3-yI)carbonyIamino-1 ,2,3,4-tetrahydroisoquiioline-2-carboxyic acid tert butyl ester 184 ,4-dimethyl-7-[(4-oxo-1 H-quinolin-a-yI)carbonytamino]-1 ,2,3,4-tetrahydroquinoline-1 -carboxylic 108 acid tert-butyl ester 109 N-(1 -acetyl-2,3,4,5-tetrahydro-5,5-dimethyl-1 H-benzo[blazepn-8-yI)-1 ,4-dihydro-4-oxoqiioline 3-carboxamide 110 N-[4-(cyanomethyl)phenyfl-4-oxo-1 H-quinoline-3-carboxamide ill 4--oxo-N-[2-(trifluoromethyl)phenytl-I H-quinoline-3-carboxamide 112 6-ethoxy-4-hydroxy-N-(l H-indol-6-yI)quinoline-3-carboxamide 113 N-(3-methyl-1 H-indol-6-yi)-4-oxo-1 H-quinoline-3-carboxam ide 114 [4-(2-ethoxyphenyt)-3-[(4-oxo-1 H-quinolin-3-yi)carbanylaminolphenyl]aminoformic acid tert-hutyl ester 115 N-f 2-(2-furyl)phenytj-4-oxo-1 H-quinoline-3-carboxamide 116 5-hydroxy-N-(1 H-indoW -- yI)-4-.oxo-1 H-.qunoline-3-carboxamide 117 N-(3-dlmethylamlno-44-sopropyl-pheny)-4-oxo-1 H-qulnoflnre-3-carboxanhlde 118 N-[2-(1 H-indol-5-yI)phenyl]-4-oxo-1 H-qulnoline-3-carbaxamide 119 [2-methyI-2-[4-[(4-oxo-1 H-qulnolin-3-yl)carbonyamnolphenyl]-propylaminoformc acid ethyl ester 120 N-(2-methoxy-5-methyl-phenyl)-4-oxo-I H-quinoline-3-carboxamide 121 N-(3,4-dlchlorophenyl)-4-axo-1 H -qulnollne--3-carboxamide 122 N-(3,4-drmethoxyphenyI)-4-oxo-I H-quinoine-3-carboxamide 123 N-[2-(3-fury)phenyl]-4-oxo-1 H-qulnolimn-3-carboxamide 124 6-lluoro-4-oxo-N-(5-tert-butyl-1 H-indol-6-yI)-1 H-quinollne-3-carboxamide -51- 125 N-(6-ethyl-2-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 126 N-f 3-hydroxy-4-[2-(2-methoxyethoxy)-, .1 -dim ethyl-ethyl]-pheriyl]-4-oxo- 1 1-i-qul noline-3 _______carboxam ide 127 [5-[(4-oxo-1 H-quinolln-3-yl )carbonylaminoj-2-tert-butyl-phenytjaminoformic acid ethyl ester 128 1 ,6-dimethyl-4-oxo-N-(2-phenylphenyl)-1 l--quinoline-3-carboxamide 129 [2-ethyl-5-[(4-oxo-1 H-quinolin-3-yl)carbonylaminolphenyljaminoformic acid methyl ester 130 4-hydroxy-N-( 1 H-indol-6-yI)-5,7-bis(trifluoromethyl)quinoline-3-carboxam ide 131 N-(3-arrino-5-chloro-phenyl)-4-oxo-I H-quinoline-3-carboxamide 132 N-(5-acetylamirio-2-ethoxy-phenyl)-4-oxo-1 H-quinoline-3-carboxamlde 133 N-[3-chloro-5-[2-(1 -piperldyl)ethylsulfonylamino]phenyl-4-oxo-1 H-quinoline-3-carboxamide 134 N-(2-{4-rnethylsulfinylphenyl)pheny]--4-oxo-1 H-quinoline-3--carboxamide 135 N-(2-benzofl ,3]dloxol-5-ylphenyl)-4-oxo-1 H-cpiinoline-3-carboxamide 136 N-{2-hydroxy -3,5-ditert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 137 6-[(4-fluorophenyl)-methyl-sulfamoyl]-N-(5-hydroxy-2,4-ditert-butyl-pheny)-4-oxo-1 H-quinoline 3-carboxamid e 138 N-[2-(3,5-difluorophenyi)pheny]-4-oxo-I H-quinoline-3-carboxamide 139 N-12-(24-dichlorophenyl)pheny]-4-oxo-1 H-quinoline-3-carboxamide 140 N-(4-oyclohexylphenyl)4-oxo-1 H-quinolne-3-carboxamide 141 [2-methyl-5-[(4-oxo-1 H-qulnolln-3-yl)carbonylamlno]phenyl~aminoformic acid ethyl ester 142 4-oxo-N-(2-e-butylpheyl)-1 H-qulnaflrie-3-oarboxamide 143 N-2-fluora-5-.hydroxy-4-tert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 144 N-(3-hydroxypheriyl)-4-oxo-i H-quinoflne-3-carboxamide 145 6-[(4-oxo-1 H-quinolin-3-yI)oarbonylamino-1 H-indole-4-carboxylc acid ethyl ester 146 4-oxo-N-(1 ,7,9-triazablcyclol4.3.O]nona-2,4,6,8-tetraen-5-yiI)- H-quinoline-3-carboxamlde 147 N-E2-(4-fluorophenoxy)-3-pyridyl-4-oxo-I H-qunoline--3-carboxamide 148 4-oxo-N-[5-(1 -piperidylcarbonyt)-1 H-indol-6-yJ-1 H-qulnoline-3-carboxamide 149 N-(3-acetyamino-4-ethyf-pheny)-4-oxo-1 H-quinaline-3-carboxamide - 52 - 150 4-oxo-N-[4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]phenyl]-1 H-quinoline-3 carboxamide 151 N-12-(4-methyl-2-thienyl)phenyl}-4-oxo-1 H-quinoline-3-carboxamide 152 4-oxo-N-(2-oxo-3H-benzooxazol-6-y)-1 H-quinoline-3-carboxamide 153 N-[4-(1,1-diethyl-2,2-dimethyl-propyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3 carboxamide 154 N-[3,5-bis(trifluoromethy)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 155 4-oxo-N-(2-pyridyl)-1 H-quinoline-3-carboxamide 156 4-oxo-N-[2-[2-(trifluoromethoxy)phenyl]phenyl]-1 H-quinoline-3-carboxamide 157 N-(2-ethyl-5-methylamino-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 158 4-oxo-N-(5-phenyl-1 H-indol-6-y)-1 H-quinoline-3-carboxamide 159 [7-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]tetralin-1 -yl]aminoformic acid methyl ester 160 N-(3-amino-4-propyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 161 N-[3-(2-ethoxyethoxy)-4-tert-butyl-phenyl]-4-oxo-1 H-quinoline-3-carboxamide 162 N-(6-methoxy-3-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 163 N-[5-(aminomethyl)-2-(2-ethoxyphenyl)-phenyl]-4-oxo-1 H-quinoline-3-carboxamide 164 4-oxo-N-[3-(trifluoromethyl)phenyl]-1 H-quinoline-3-carboxamide 165 4-oxo-N-(4-sulfamoylphenyl)-1H-quinoline-3-carboxamide 166 4-[2-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid methyl ester 167 N-(3-amino-4-methyl-phenyl)4-oxo-1 H-quinoline-3-carboxamide 168 4-oxo-N-(3-pyrdyl)-1 H-quinoline-3-carboxamide 169 N-(1-rnethyl-1H-indol-o-yl)-4-oxo-1 H-quinoline-3-carboxamide 170 N-(5-chloro-2-pyridy)4-oxo-1 H-quinoline-3-carboxamide 171 N-[2-(2,3-dichlorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 172 N-(2-(benzo[b]thlophen-2-yl)phenyl)-1,4-dihydro-4-oxoqulnoline-3-carboxamide 173 N-(6-methyi-2-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 174 N-[2-(5-acetyl-2-thienyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide -53 - 175 4-Oxo-1 ,4-dihydro-quinoline-3-carboxylic acid N-(1 '-Acetyl-l1',2'-dihydrospiro[cyclopropane-1,3' _______3H-indolj-6'-yl)-am ide 176 4-oxo-N-[4-(trifluoromethoxy)pheny]-1 H-quinoline-3-carbaxamide 177 N-(2-butoxyphenyl)-4-oxo-1 H-quinoline-3-carboxamide 178 4-oxo-N-[2-(2-tert-butylphenoxy)phenl]-1 H-quinoline-3-carboxamide 179 N-(3-carbamoylphenyl)-4-oxo-l H-quinoline-3-carboxamide 180 N-(2-ethyl-6-meihyl-phenyf)-4-oxo-1 H-quinoline-3-carboxamide 181 4-axo-N-t2-(p-tolyl)phenyl-1 H-quinoiine-3-carboxamide 182 N-[2-(4-fluorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 183 7-f(4-ox-l1H-qu inolin-3-yI)carbonylamino]-1 ,2,3,4-tetrahydroquinoline-1 -carboxylic'acid tert butyl ester 184 N-(1 H-Indol-6-yi)-4-oxo-2-<trifluoromethyt)-1 H-quinoline-3-carboxamide 185 N-(3-morpholinosulfonylphenyl)-4-oxo -1 H-quinollne-3-carboxamide 186 N-(3-cyolopentyl-1 H-indol-6-y)-4-oxo-1 H-quinoline-3-carboxamide 187 N-(1 -acetyl-1 H-indol--6-yi)-4-oxo-1 H-qulnoline-3-carboxamide 188 6-f(4-oxo-1 H-quinolln-3-y )carbonylamlno]-1 H-lndole-5-carboxylic acid ethyl ester 189 N-(4-benzyloxyphenyl)-4-oxo-1 H-qulnollne-3-carboxamide 190 N-12-(3-chloro-4-fluoro-phenyl)phenyll-4-oxo-1 H-qulnollne-3-carboxamide 191 4-oxo-N-(5-qunolyl)-1 --- ulnoline-3-carboxamide 192 N-(3-methyl-2-pyrldyI)-4-oxo-1 H-quinoline-3-carboxamlde 193 N-(2,6-dlmethoxy-3-pyridyl)-4-oxo-1 H-quinollnev-3-carboxamide 194 N-(4-cyanophenyl)-4-oxo-I H-quinollne-3-carboxamide 195 N-(5-methyl-2-pyrldyI)-4-oxo-1 H-qulnollne-3-carboxamide 196 N-I5-(3,3-dimethlbutanoylamino)-2-tert-butyl-phenylN-oxo-1 H-quinollne-3-carboxamide 197 4-oxo.-N-[6-<trifluoromethyl)-3-pyridyl]-1 H-quinoline-3-oarboxamide 198 N-(4-fluorophenyIl-4-oxo-I H-quinoline-3-carboxamide 199 N-[2-(o-tolyl)phenyll-4-oxo-1 H-qulnollne-3-carboxamlde, 200 1 ,4-dihydro-N-(1 ,2,3,4-tetrahydro-1 -hydroxynaphthalen-7-y)-4-oxoquinoline-3-Carboxamide 201 N-(2-cyano-3-methyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 202 N-[2-(5-chloro-2-methoxy-pheny)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 203 N-(1 -benzyl-l H-indol-6-yl )-4-oxo-1 H-quinoline--3-carboxamide 204 N-(4,4-dlmethytchroman-7-yl)-4-oxo-1 H-quinoline-3-carboxamlde 205 N-[2-(4-methoxyphenoxy)-5-(trifluoromethy)phenyl-4-oxo- H-quinoline-3--carboxam ide 2G6 N-[2-(2,3-dimethylphenoxy)-3-pyridyl]-4-oxo-1 H-quinoline-3-carboxamide 207 2-[6-[(4-oxo-1 H-quinolin-3-yI)carbonylamno]-H-indol-3-yl]acetIC acid ethyl ester 208 N-{4-(2-adamantyl)-5-hydroxy-2-m ethyl-phenyl-4-oxo-1 H--qulnollne-3-carboxamide 209 N-[4-{hydroxymethyl)phenyl-4-oxo-I H-quinolirie-3-carboxamide 210 2,4-dimethoxy-N-(2-phenylpheny)-quinoline-3-carboxamide 211 N.-2-methoxy-5-tert-butyl-pheny)-4-oxo-1 H-quinoline-3-carboxam Ida 212 N-13-(3-methyl-5-oxo-1 ,4-dihydropyrazoi-I -yi)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 213 N-[2-(2,5-dichlorophenyl)phenyl]-4-oxo-I H-quinoline-3-carboxamide 214 N-(3-methylsulfonylaminophenyI)-4-oxo-1 H-quinoline-3-carboxamide 215 4-oxo--phenyl-1 H-.quinollne-3-carboxamide 216 N-(3H-benzoidazol-2-y)-4-oxo-I H-quinoline-3-carboxamidft 217 N-(1 H-ijndazoI-5-yI)-4-oxo-1 H--qulnoline-.3-carboxamlde 218 6-4uoro-N-[2-fluoro-5-hydroxy-4-(I -methylcyclohexyl)-phenyl-4-oxo-1I H-quinoline-3 carboxamide 219 4-oxo-N--pyrazin-2-yl-1 H-quinollne-3-carboxamide 220 N-(2,3-dihydroxy-4,6-dltert-butyl-phenyl)-4-oxo-I H-quinollne-3-carboxamlde 221 f5-j(4-oxo-1 H-quinolin-3-yl)carbonylamino]-2-propy-pheny41aminoformG acid methyl ester 222 N-(3-chloro-2-cyano-phenyl)-4-oxo-1 H-qulnoline-3-carboxamtde 223 N-2-4-methylsulfanylphenyl)phenyll-4-oxo-1 H-quinoline-3-carboxamide 224 4-oxo-N-(44[2-[(2,2,2-trifluoroacetyiaminomethyl]phenylphenfl-1 H-qulnollne-3-carboxamide - 55 - 225 [2-isopropyl-5-[4-oxo-1 H-quinolin-3-yl)carbonylaminojpheny]aminoformic acid ethyl ester 226 4-oxo-N-(4-propylpheny)-1 H-quinoline-3-carboxamide 227 N-[2-(3H-benzoimidazol-2-yl )phenyll-4-oxo-1 H-quinoline-3-carboxamide 228 N-[2 -(hydroxy-phenyl-methyl)phenyl]-4-oxo-1 H-quinoline-3--carboxamide 229 N-(2-methylsulfanylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 230 N-(2-methy--1 H-indof-5-yi)-4-oxo-1 H-quinoline-3-carboxam ide 231 3-[4-hydroxy-2-[(4-oxo-1 H-quinolin-3-yI)carbonylarninoj-5-tert-butyl-phenyllbenzoic acid methyl ester 232 N-(5-acetyiamino-2-propyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 233 N-(1 -acetylindolin-6-yi)-4-oxo-1 H-quinoline-3-carboxamide 234 4-axo-N-[5-(trifluoromethyl)-l H-indol-6-yl]-i H-guinoline-3-carboxamide 235 N-(6-isopropy-3-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 236 4-.oxo-N-[4-(trifluoromethyl)phenyl]-I H-quinoline-3-carboxamlde 237 N-[5-(2-methoxyphenyl)-l H-indol-6-yi]-4-oxo-1 H-quinoline-3-carboxamide 238 T-I(4-oxo-1 H-quinolin-3-ylcarbonyl)amino]-spiro piperidine-4,4(l H)-quinoline]. 2'.3-dihydro ________carboxylic acid tert-butyl ester 239 [4-isopropyl-3+{4-oxo-1 H-quinolin-3-yI)carbonylaniino]phenyqaminoformic acid methyl ester 240 N-(2-benzyloxyphenyt)-4-oxo-1 H-quinoline-3-carboxamlde 241 4-oxo-N-(8-quinoyl)-1 H-quinoline-3--carboxamide 242 N-(5-amino-2,4-dichloro-phenyl)-4-oxo-I H-qulnollne-3-carboxamide 243 N-(5-acetylamlno-2-isopropyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 244 4-axo-N-(6,7,8,9-tetrahydro-6Hf-carbazol-2-y)-1 H-cluinolin-3-carbaxamide 245 N-[2-(2,4--dichlorophenoxy)phenyl]-4-oxo-1 H-quinollne-3-carboxamide 246 N-(3,4-dimethylphenyI)-4-oxo-1 H-quiriotine-3-carboxam ids 247 4-oxo-N-[2-(2-phenoxyphenyl)pheny(I-1 H-quinoline-3-carboxamide 248 N-(3-acetylamino-4-methyl-phenyl)-xo-1 H-quinoline-3-carboxamlde 249 [4-ethyl-3-((4-oxo-1 H-quinolin-3-yl)carbonylaminolphenylamlnofonhic acid methyl ester -56 - 250 N-(5-acetylamino-2-methoxy-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 251 [2-methy-2-[4-[(4-oxo-1 H-quinol in-3-yl)carbonylamino~pheny]-propyl]aminoformic acid isobutyl ________ester 252 N-(2-benzoylphenyl)-4-oxo-1 H-quinoline-3--carboxarnide 253 4-oxo-N-[2-[3-(trifluoromethoxy)phenyllphenyl-1 H-quinoline-3-carboxamide 254 6-fluoro- N-5-fluoro-1 H-indol-6-yi)-4-oxo-1 H-quinoline-3-carboxamide 255 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-6-pyrro lid in-i -ysulfonyl- I H-qulnoline-3-carboxamide 256 N-(I H-benzotriazol-5-yl)-4-oxo-1 H-quinoline-3-carboxamide 257 N-(4--fluoro-3-methyl-phenyl)-4-oxo-I H-quinoline-3--carboxamide 258 N-lndolin-63-yl-4-oxo-1 H-quinoline-3-carboxamide 259 4-oxo-N-(3-sec-butyl-I H-indol-6-yl)-1 H-quinoline-3--crboxarnide 260 N-(5-amino-2-tert-butyl-phenyl)-4-oxo-I H-quinolirie-3-carboxamlde 261 N-[2-(3,4-dimethylphenyl)pheny[J-4-oxo-I H-quinoline-3-carboxamide 262 1 .4-dlhydro-N-(3,4-dhydro-3-oxo-2H-benzo[b] 1,4]thiazin-6-yI)-4-oxoquinoline-3-carboxamide 263 N-(4--bromo-2- ethyl-phenyl)-4-oxo-I H-quinoline-3--carboxam ide 264 N-(2,5-diethoxyphenyl)-4-oxo-1 H-quinoline-3-carboxamide 265 N-(2-benzylpheny)--oxo-1 H-quinoline-3-carboxamide 266 N-[5-hydroxy-4.tert-butyl-2-(trlfluoromethyl)phenylj-4-oxo-I H-quinine-3-carboxamide 267 4-oxo-N-(4-phenoxyphenyl)-1 H-quinollne-3--carboxamlde 268 4-oxo-N-sufamoy-4-tert-uy-pheny)-I H-quinoline-3-carboxamlde 269 [4-isopropyl-3-f(4-oxo-1 H-qulnolln-3- yl)carbonylamno]phenyl]aminnoformic acid ethyl ester 270 N-(2-cyano-1 H-iJndol4)-yl)-4-oxo-1 H-quinoline-3--carboxamide 271 N-(3-amino4-tert-butyl-phenyl)-4-oxo-I H-quinoline-3-carboxamide 272 N-[3-(2-morphollnoethylsulfonylamlno)-5-(trifluoromethyl)phenyl]A-oxo-I H-qulnollne-3 crboxamide 273 [7-(4-axo-1 H-quinolin-3-yl)carbonylarnInoltetral In-I -ylaminoformlc acid tert-butytl ester 274 4-oxo-6-yn-olidln-1 -ylsulfonyl-N-(5-tert-butyl-1 H-Indo[:6-yl)-1 H-quinollne-3-carboxamlde - 57 - 275 4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide 276 N-(4-morpholinosulfonylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 277 N-[2-(3-fluorophenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 278 4-oxo-N-[2-[3-(trifluoromethyl)phenylphenyl]-1 H-quinoline-3-carboxamide 279 N-[2-(2-methylsulfanylphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 280 4-oxo-N-(6-quinoly)-1 H-quinoline-3-carboxamide 281 N-(2,4-dimethyphenyl)-4-oxo-1 H-quinotine-3-carboxamide 282 N-(5-amino-2-ethyl-pheny)-4-oxo-1 H-quinoline-3-carboxamide 283 N-{2-(3-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 284 N-(i H-indazol-6-yl)-4-oxo-1 H-quinoline-3-carboxamide 285 N-[2-(2,3-difluorophenyl)pheny]-4-oxo-1 H-quinoline-3-carboxamide 286 1,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-5-yl)-4-oxoquinoline-3-carboxamide 287 N-[2-fluoro-5-hydroxy-4-(1 -methylcyclohexyl)-phenyl]-5-hydroxy-4-oxo-1 H-quinoline-3 carboxamide 288 N-(5-fluoro-2-methoxycarbonyloxy-3-tert-butyl-pheny)-4-oxo-1 H-quinoline-3-carboxamide 289 N-(2-fluoro-4-methyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 290 N-[2-(3-isopropylphenyl)phenylj-4-oxo-1 H-quinoline-3-carboxamlde 291 N-(2-chloro-5-hydroxy-4-tert-butyl-phenyY4-oxo-1 H-quinoline-3-carboxamide 292 N-(5-chloro-2-phenoxy-pheny)-4-oxo-1 H-quinoline-3-carboxamide 293 4-oxo-N-[2-(1H-pyrrol-1-yl)phenyQ-1 H-quinoline-3-carboxamide 294 N-(1 H-indol-5-y)-4-oxo-1 H-quinoline-3-carboxamide 295 4-oxo-N-(2-pyrrolidin-1-ylphenyl)-1 H-quinoline-3-carboxamide 296 2,4-dimethoxy-N-(2-tert-butylphenyl)-quinoline-3-carboxamide 297 N-[2-(2,5-dimethyl-1 H-pyrrol-1-yl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 298 [2-ethyl-5-[(4-oxo-1 H-quinolin-3-yI)carbonylamino]phenylaminoformic acid ethyl ester 299 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-y)-1 H-quinoline-3-carboxamide -58- 300 N-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yt)-4-oxo-1 H-quinoline-3-carboxamide 301 N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 302 N-[2-[4-(hydroxymethyi)phenyl]phenyl]-4-oxo-1 H-quinoline-3-carboxamide 303 N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-y)-4-oxo-1 H-quinoline-3-carboxamide 304 [4-(2-ethoxyphenyl)-3-[(4-oxo-iH-quinolin-3-yl)carbonylamino]phenylmethy]aminoformic acid tert-butyl ester 305 N-[2-(4-methoxyphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 306 N-[2-(3-ethoxyphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 307 N-[2-(3-chlorophenyi)phenyl]-4-oxo-I H-quinoline-3-carboxamide 308 N-[2-(cyanomethyl)phenyl)-4-oxo-I H-quinoline-3-carboxamide 309 N-(3-isoquinolyl)-4-oxo-I H-quinoline-3-carboxarnide 310 4-oxo-N-(4-sec-butylpheny)-1 H-quinoine-3-carboxamide 311 N-[2-(5-methyl-2-furyl)pheny]-4-oxo-1 H-quinoline-3-carboxamide 312 N-[2-(2,4-dimethoxypheny)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 313 N-[2-(2-fluorophenyl)pheny}]4-oxo-1 H-quinoline-3-carboxamide 314 N-(2-ethyl-6-isopropyl-phenyi)-4-oxo-1 H-quinoline-3-carboxamide 315 N-(2,6-dimethylphenyl)-4-oxo-iH-quinoline-3-carboxamide 316 N-(5-acetylamino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 317 N-(2,6-dichloropheny)-4-oxo-1H-quinoline-3-carboxamide 318 4-oxo-N-[3-[2-(1 -piperidyl)ethylsulfonylamino]-5-(trifluoromethy)pheny]-1H -quinoline-3 carboxamide 319 6-fluoro-N-(2-fluoro-5-hydroxy-4-tertyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 320 4-oxo-N-(2-tert-butyl-1 H-indol-6-yl)-1 H-quinoline-3-carboxamide 321 N-[2-(4-benzoylplperazn-1 -yl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 322 N-(2-ethyl-6-sec-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 323 [2-methyl-2-[4-[(4-oxo-iH-quinolin-3-yl)carbonylaminolphenyl]-propyl]aminoformic acid methy ester 324 N-(4-butyiphenyl)-4-oxo-1 H-quinoline-3-carboxamide -59- 325 N-(2,6-diethylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 326 N-[2-(4-methylsulfonylphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 327 N-[5-(2-ethoxypheny)-1 H-indol-6-yl]-4-oxo-1 H-quinoline-3-carboxamide 328 N-(3-acetylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 329 N-f2-(o-tolyl)benzooxazol-5-ylJ-4-oxo-1 H-quinoline-3-carboxamide 330 N-(2-chlorophenyl)-4-oxo-1 H-quinoline-3-carboxamide 331 N-(2-carbamoylphenyi)-4-oxo-1 H-quinoline-3-carboxamide 332 N-(4-ethynylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 333 N-[2-[4-(cyanomethyl)phenyl]phenyl]-4-oxo-1 H-quinoline-3-carboxamide 334 7'-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4'(1'H)-1-acetyl-quinoline], 2',3' dihydro- carboxylic acid tert-butyl ester 335 N-(2-carbamoyl-5-methyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 336 N-(2-butylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 337 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1 H-quinoline-3-carboxamide 338 N-(3-methyl-1 H-indol-4-yI)-4-oxo-1 H-quinoline-3-carboxamide 339 N-(3-cyano-1 H-indol-6-yi)-4-oxo-1 H-quinoline-3-carboxamide 340 N-(3-methyIsulfonylamino-4-propyl-pheny)4-oxo-1 H-quinoline-3-carboxamide [2-methyl-2-[4-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]phenyl]-propylaminofornic acid neopentyl ester 342 N-[5-(4-isopropylphenyl)-1H-indol-6-y]-4-oxo-1 H-quinoline-3-carboxamide 343 N-[5-(Isobutyicarbamoyl)- H-Indol-6-yl]-4-oxo-1 H-quinoline-3-carboxamide 344 N-[2-(2-ethoxyphenyl)pheny]-4-oxo-1 H-quinoline-3-carboxamlde 345 6-fluoro-4-hydroxy-N-(1 H-indol-6-yl)quinoline-3-carboxamide 346 4-oxo-N-phenyl-7-(trifluoromethyl)-1 H-quinoline-3-carboxamide 347 N-[5-[4-(2-dimethylaminoethylcarbamoyl)phenyl]-1 H-indol-6-yI]-4-oxo-1 H-quinoline-3 carboxamide 348 N-[2-(4-ethoxyphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 349 4-oxo-N-(2-phenysufonylphenyl)-1H-quinoline-3-carboxamide - 60 - 350 N-(1 -naphthyl)-4-oxo-1 H-quinoline-3-carboxamide 351 N-(5-ethyi-1 H-indol-6-yl)-4-oxo-1 H-quinoline-3-carboxamide 352 2-(6-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]-1 H-indol-3-y]ethylaminoformic acid tert-buty ester 353 [3-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-buty ester 354 N-[2-[(cyclohexyl-methyl-amino)methyl]phenyll-4-oxo-1 H-quinoline-3-carboxamide 355 N-[2-(2-methoxyphenyl)phenyl-4-oxo-1 H-quinoline-3-carboxamide 356 N-(5-methylamino-2-propyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 357 N-(3-isopropyl-1 H-indol-6-yl)-4-oxo-1 H-quinoline-3-carboxamide 358 6-chloro-4-hydroxy-N-(1 H-indol-6-yl)quinoline-3-carboxamlde 359 N-[3-(2-dimethylaminoethylsulfonylamino)-5-(trifluoromethyl)phenyl]4-oxo-l H-quinoline-3 carboxamide 360 N-[4-(difluoromethoxy)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 361 N-{2-(2,5-dimethoxyphenyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 362 N-(2-chloro-4-tert-butyl-phenyl)-4-oxo-I H-quinoline-3-carboxamide 363 N-[2-(2-fluoro-3-methoxy-phenyt)phenyq-4-oxo-1 H-quinoline-3-carboxamide 364 N-(2-methyl-8-quinolyl)-4-oxo-1 H-quinoline-3-carboxamlde 365 N-(2-acetylpheny)-4-oxo-1 H-quinoline-3-carboxamlde 366 4-oxo-N-[2-[4-(trifluoromethyl)pheny1]pheny]-1 H-quinoline-3-carboxamide 367 N-[2-(3,5-dichlorophenyl)phenyt]-4-oxo-1 H-quinoline-3-carboxamide 368 N-(3-amino-4-propoxy-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 369 N-(2,4-dichloro-6-cyano-pheny)-4-oxo-1H-quinoline-3-carboxamide 370 N-(3-chlorophenyl)-4-oxo-1 H-quinoline-3-carboxamide 371 4-oxo-N-[2-(trifluoromethylsulfanyl)phenyl]-1 H-quinoline-3-carboxamide 372 N-[2-(4-methyl-1 -piperidyl)phenyll-4-oxo-1 H-quinoline-3-carboxamide 373 N-indan-4-yi-4-oxo-1 H-quinoline-3-carboxamide 374 4-hydroxy-N-(1 H-indol-6-yl)-2-methylsulfanyl-qulnoline-3-carboxamide -61- 375 1 ,4-dihydro-N-(i 2,3,4-tetrahydronaphthalen-6-yl)-4-oxoquinoline-3-carboxamide 376 4-oxo-N-(2-phenylbenzooxazol-5-y)-1 H-quinoline-3--carboxamide 377 6,8-difluoro-4-hydroxy-N-( 1 H-indol-6-y)quinoline-3-carboxamide 378 N-(3-amino-4-methoxy-phenyt)-4-oxo-I H-quinoline-3-carboxamide 379 N-[3-acetytam ino-5-(trifluoromethyl)phenyj-4-oxo-i H-quinoline-3-carboxamide 380 N-(2-ethoxyphenyl)-4-oxo-1 H-quinoline-3-carboxamlde 381 4-oxo-N-(5-tert-buty-1 H--indot-6-yl)-l H-quinoline-3-carboxamide 382 [5-{(4-oxo-1 H-qulnolIn-3-y.)carbonyamlno-2-propyl-phenyl]aminoformic acid ethyl ester 383 N-(3-ethyl-1 H-indol-6-yl)-4-oxo-1 H-quinoline-3-carboxamide 384 N'-f2-(2,5-difluorophenyl)phenyl-4-oxo-1 H-quinolirie-3-carboxarnlde 385 N-{2-(2,4-difluorophenoxy)-3-pyridyl]-4-oxo-I H-quinoline-3-carboxamide 386 N-(3,3-dtmethyindolin-r6-y)-4-oxo-1 H-quinoline-3-carboxamide 387 N-f2-methyl-3-(trifluoromethyl)phenyJ-4-oxo-1 H-quinollne-3-carboxamide 388 4-oxo-N-12-[4-(trifluoromethoxy)phenyl]phenyll-I H-quinoline-3-Garboxamide 389 N-(3-benzylphenyl)-4-oxo-1 H-quinoire-3-carboxamide 390 N-[3-(amInomethyl)--tert-butyl-pheny.1]-4-oxo-1 H-quinoline-3-carboxamide 391 N-t2-(4-isobutylphenyl)phenyUl-4-oxo-1 H-qulnoline-3-carboxam ide 392 N-(6-chloro-3-pyrldyl)-4-oxo-I H-quinoflne-3-carboxamide 393 N-[6-amino-2-(2-ethoxypheny)-phenl-4-oxo-1 H-quinollne-3-carboxamide 394 1 ,6-dimethyl-4-oxo-N-phenyl-1 H-quinoline-3-carboxamide 395 N-[4-(l-adamantyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-qunatine-3-Crarboxamide 396 [2-rneth'yl-2-[4-[(4-oxo-1 H-quinolin-3-yl)carbonylaminophenyl]-prpy]amifomic acid tetrahydrofuran-3-ylmethyl ester 397 4-oxo-N-(4-phenylphenyl)-1 H-qulnoline-3-carboxamide 398 4-oxo-N-[2-(p-tolylsulfonylanino)phenyl-IH-quinoie-3-arboxamide 399 N-{2-isopropyl-5-methylamino-phenyl)-4-oxo-1 H-quinoline-3-carboxamide - 62 - 400 N-(6-morphoiino-3-pyridyi)-4-oxo-1 H-quinoiine-3-carboxamide 401 N-[2-(2,3-dimethylphenyt)phenyl-4-oxo-I H-quinoline-3-carboxamide 402 4-oxo-N-{5-phenyl-2-pyridyl)-1 H-quinoline-3-carboxamide 403 N-[2-fluoro-5-hydroxy-4-(l 1 methyicycioocty)-pheny]-4-hydroxy-quinoie-3-carboxal1ide 404 N-f 5-(2,6-dimethoxypheny)-1 H-indol-6-yAj-4-oxo-1 H-quinoiine-3-carboxamide 405 N-(4-chiorophenyi)-4-oxo-1 H-quinoline-3-carboxamide 406 6-[(4-fluorophenyl)-methy-sufamoylj-4-oxo-N-(5-tert-butyi-1 H-indol-6-yi)-1 H-quinoline-2.

carboxamide 407 N-(2-fiuoro-5-hydroxy-4-trt-butl-pheny)-5-hydroxy-4-oxo-1 H-quinoline-3-carboxamide 408 N-(3-methoxyphenyl)-4-oxo-1 H-quinoline-3-carboxamide 409 N-(5-dimethylamino-2-ethyt-pheny)-4-oxo-1 H-quinoiine-3-carboxamide 410 4-oxo-N-[2-(4-phenoxyphenyi)phenyll-1 H-quinoline-3-carboxamide 411 7-chloro-4-oxo-N-phenyl-l H-quinoiine-3-carboxamide 412 6-[(4-oxo-1 H-qulnolin-3-yI )carbonylaminol-1 H-indole-7-oarboxyic acid ethyl ester 413 4-oxo-N-(2-phenoxypheny)-l H-quinoiine-3-carboxamide 414 N-(3H-benzoimidazol-5-yl)-4-oxo-1 H-.quinoline-3-carboxamide 415 N4-yrx--etbtlpey)4mtoyqloie3cro~md 416 12-methyi-2-[4-[(4-oxo-I H-quinolin-3-yI)carbonyaminophenI1-propyi]amiloforrmIC acid propyl ester 417 N-(2-(benzofblthlophen-3-y)pheny)-1 ,4-dihydro-4-axoquinoline-3-carboxarnide 418 N-(3-dimethylaminophenyl)-4-axo-1 H-quinoline-3--carboxamlde 419 N-(3-acetylaminophenyl)-4-oxo-1 H-quinoline-3-carboxamide 420 2-methyl-2-[4-(4-oxo-1 H-quinolin-3-yl)carbonyaminolphenyll-propaloic acid ethyl ester 421 N-[5-methoxy-4-tert-buty-2-(trifluoromethyl)phnl]-4-oxo-I i--quinoline-3-carboxamide 422 N-(5,6-dimethy-3H-benzomidazo-2-yi)-4-oxo-1 H-quinoiine-3-carboxamlde 423 N-[3-(2-ethoxyethyl)-1 H-indoi-6-yI]-4-oxo-1 H-.quinoine-3-carboxamid0e 424 N-f2-(4-chlorophenyl)phenyl-4-oxo-1 H--quinoine-3-carboxamide - 63 - 425 N-(4-isopropylphenyl)-4-oxo-1 H-quinoline-3-carboxamlde 426 N-(4-chloro-5-hydroxy-2-tert-butyl-pheny)-4-oxo-1 H-quinoline-3-carboxamie 427 5-[(4-oxo-1 H-quinolin-3-yt)carbonylamino-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert butyl ester 428 N-(3-hydroxy-4-tert-butyl-phenyt)-4-oxo-I H-quinoline-3-carboxamide 429 N-[3-amino-5-(trlfluoromethyl)phenylq-4-oxo-1 H-quinotine-3-carboxamide 430 N-(2-isopropyl-6-methyl-phenyl )-4-oxo-I H-quinoline-3-carboxarnide 431 N-(3-aminophenyl)-4-oxo-I H-quinoline-3-carboxamide 432 N-[2-(4-isopropylphenyl)phenyl]-4-oxo-1 H-.quirioline-3-carboxamide 433 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-I H-quinoline-3-carboxa mide 434 N-(2,5-dimethyiphenyl)-4-oxo-1 H-quinoline-3-carboxamide 435 N-j[2-(2-fluorophenoxy)-3-pyridyi]-4-oxo-I H-quinoline-3-carboxanucte 436 N-[2-(3,4-dimethoxyphenyl)phenyI]A4-ox& 1 H-quinoline-3-carboxamlde 437 N-.benzo[1 ,3ldioxol--y-4-oxo-1 H-quinotine-3-carboxamide 438 N-[5-(difluoromethyl)-2,4-ditert-butyl-phenyl]-4-oxo-I H-quinoline-3-carboxamide 439 N-(4-methoxyphenyl)-4-oxo-1 H-quinoline-3-Garboxamlde 440 N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]ti ,4]dioxin-6-yi)-1 ,4-dihydro-4-oxoquinoline-3 carboxamide 441 N-[3-methylsulfonylamino-5-(trifluoromethyt)phenyll-4-oxo-I H-quinollne-3-carboxamide 442 4-oxo-N-[3-(1 -plperldyisutfonyl)phenylj-1 H-qulnoline-3-carboxamlde 443 4-oxo-N-uinoxalin-6-y-1 H-quiriollne-3-carboxamide 444 5-[(4-axo-1 H-quinolin-3-yl)carbonylamino]-2-tert-butyl-benzoic acid methyl ester 445 N-(2-Isopropenylphenyl)-4-oxo-I H-quinoline-3-varboxamide 446 N4(1, 1 -dloxobenzothlophen-6-yI)-4-oxo-1 H-quinoline-3-carboxam ide 447 N-(3-cyanophenyl)-4-oxo-1 H-quinollne-3-carboxamide 448 4-oxo-N-(4-tert-butylpheiyl)-1 H-qulnollne-3-carboxamide 449 N-{m-tolyl)-4-oxo-1 H-quinoline-3-carboxamide -64- 450 N-(4-(1 -hydroxyethyl)phenyl]-4-oxo-1 H-quinoline-3-carboxamide 451 N-(4-cyano-2-ethyl-phenyl)-4-oxo-i H-quinoline-3-carboxamide 452 4-oxo-N-(4-vinylphenyi)-l H-quinoline-3-carboxamide 453 N-(3-amino-4-chlaro-pheny)-4-oxo-1 H-quinoline-3-carboxamide 454 N-(2-methyl-5-phenyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 455 N-[4-(1 -adamantyi)phenyl]-4-oxo-I H-quinoline--3-carboxamide 456 4-oxo-N-f3-(trifluoromethylsuifanyl)phenytj-1 H-quinoline-3-carboxam ide 457 N-{4-mot-pholinophenyl)-4-oxo-1 H-qulnollne-3-carboxamide 458 N-{3-(2-hydroxyethoxy)-4-tort-butyl-phenyl]-4-oxo-1 H-quinoline-3-carboxamide 459 N-(o-tolyl)-.4-oxo-1 H-quinoline-3--carboxamide 460 f2-methyl-2-[44(4-oxo-1 H-qulnolin-3-yt)carbonylaminojphenyl]-prop .yl]aminoformic acid butyl ester 461 4-oxo-N-(2-phenylphenyl)-i H-quinoline-3-carboxamide 462 N-(3-dimethylamino-4-propyt-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 463 N-(4-ethyIphenyl)A4-oxo-1 H-quinoline-3-carboxamide 464 5-hydroxy--N-(5-hydroxy-2,4-ditert-butyi-pheny)-4-oxo-I H--quinolne-3-carboxamide 465 [5-[4-oxoA- H-qulnolin-3-yI)carbonylamino]-2-tet-utyl-henylrnethyl]aminoformic acid tert-butyt ester 466 N-(2,6-iisopropylphenyl)-4-oxo-1 H-quinoline-3-carboxamide 467 N-(2,3-dlhydrobenzofuran-5--yi)-4-oxo-1 H-quinoline-3-carboxamlde 468 1 -methyt4.axo-N-phenyl-1 H-quinollne-3-carboxamide 469 4-oxo-N-(2-pheny lphenyl)-7-(trfluoromethyl)-l H-quinoline-3-carboxamide 470 4-oxo-N-(4-phenylsufanylphenyl)-I H-quinoline-3-carboxamide 471 13-[(4-oxo-I H-quinolin-3-yl)carbonylaminoj-4-propyl-phenyllaminoformic acid methyl ester 472 [4-ethyl-3-[(4-oxo-1 H-quinolln-3-yt)oarboriyiaminojphenyl]aminoformc acid ethyl ester 473 14-sopropyl-4-oxo-N-(2-tert-butylphenQ-1 H-quinollne-3-carboxamide 474 N-(3-methyl-2-oxo-3H-benzcoxazol.-5-yiH--oxo-1 H-quinoline-3-carboxamide -. 65 - 475 N-(2,5-dichloro-3-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 476 N-(2-cyano-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 477 N-(5-fluoro-2-pyridyl)-4-oxo-1 H-quinoline-3-carboxamide 478 4-oxo-N-(3-tert-buty-1 H-indol-6-y)-1 H-quinoline-3-carboxamide 479 N-(1 H-indol-6-yi)-5-methoxy-4-oxo-1 H-quinoline-3-carboxamide 480 1 -ethyl-6-methoxy-4-oxo-N-phenyl-1 H-quinoline-3-carboxamide 481 N-(2-naphthyl)4-oxo-1 H-quinoline-3-carboxam ide 482 [7-[(4-oxo-1 H-quinolin-3-yl)carbonylaminoltetralin-1-yl]aminoformic acid ethyl ester 483 N-[2-fluoro-5-hydroxy-4-(I-methylcycloheptyl)-phenyl]-4-hydroxy-quinoline-3-carboxamide 484 N-(3-methylamino-4-tert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide 485 N-(3-dimethyfamino-4-tert-butyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide [0178] In another embodiment, the present invention provides compounds useful as intermediates in the synthesis of compounds of formula I. In one embodiment, such compounds have formula A-I:

NH

2

G

2 ' ."G1 G3 A-I; or a salt thereof; wherein: G, is hydrogen, R', C(O)R', C(S)R', S(O)R', S(O) 2 R', Si(CH 3

)

2 R', P(O)(OR') 3 ,

P(S)(OR')

3 , or B(OR')2; G2 is halo, CN, CF 3 , isopropyl, or phenyl wherein said isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WRw, wherein W and RW are as defined above for formula I and embodiments thereof; -66- G3 is an isopropyl or a C3-CIO cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from WRw, wherein W and Rw are as defined above for formula I and embodiments thereof; provided that when G, is methoxy, G 3 is tert-butyl, then 02 is not 2-amino-4-methoxy-5-tert butyl-phenyl. [0179] In one embodiment, the present invention provides compounds of formula A-I, provided that when G2 and G 3 each is t-butyl, then G is not hydrogen. [0180] In another embodiment:

G

1 is hydrogen; G2 is halo or isopropyl, wherein said isopropyl is optionally substituted with up to 3 substituents independently selected from R'; and G3 is an isopropyl or a C3-C 10 cycloaliphatic ring, wherein said G 3 is optionally substituted with up to 3 substituents independently selected from R'. [01811 In another embodiment: G, is hydrogen;

G

2 is halo, preferably fluoro; and

G

3 is a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from methyl, ethyl, propyl, or butyl. [01821 In another embodiment:

G

1 is hydrogen; 02 is CN, halo, or CF 3 ; and

G

3 is an isopropyl or a C3-CIO cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R'. [01831 In another embodiment: G, is hydrogen;

G

2 is phenyl is optionally substituted with up to 3 substituents independently selected from -OC1-C4 alkyl, CF 3 , halo, or CN; and

G

3 is an isopropyl or a C3-C1O cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R'. - 67 - [01841 Exemplary G 3 include optionally substituted cyclopentyl, cyclobexyl, cycloheptyl, or adamantyl. Or, G3 is C3-C8 branched aliphatic chain. Exemplary G3 include isopropyl, t-butyl, 3,3-diethyl-prop-3-yl, or 3,3-diethyl-2,2-dimethyl-prop-3-yl. [01851 In another embodiment: Gi is hydrogen;

G

2 is t-butyl; and

G

3 is a t-butyl. [0 1861 In another embodiment, the present invention provides a compound of formula A-Il: G,5

H

2 N) N H A-II; or a salt thereof, wherein: G4 is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted Cl-C6 aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4 WRW substituents;

G

5 is hydrogen or an optionally substituted Cl-C6 aliphatic; provided that both, 04 and G 5 , are not simultaneously hydrogen; wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRw. [01871 In one embodiment, G 4 is hydrogen. Or, Gs is hydrogen. [01881 In another embodiment, G4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with CI-C6 alkyl, halo, cyano, or CF 3 , and wherein up to two methylene units of said C-C6 aliphatic or CI-C6 alkyl is optionally replaced with -CO-, CONR'-, -C02-, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-,

-SO

2 NR'-, NR'SO 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is Cl-C4 alkyl. [0189] In another embodiment, G4 is hydrogen, and Gs is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH 2 C(O)OMe, (CH2)2 NHC(O)O-tert-But, or cyclopentyl. [01901 In another embodiment, G5 is hydrogen, and G4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 alkyl, halo, - 68 cyano, or CF 3 , wherein up to two methylene units of said CI-C6 aliphatic or C I-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-. In another embodiment, R' above is C-C4 alkyl. [01911 In another embodiment, G 5 is hydrogen, and G4 is halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH 2

)

2 -NMe 2 , 2-inethoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyt, sec-butylaminocarbonyl, ethyl, t butyl, or piperidin- 1 -ylcarbonyl. [0192] In a related embodiment of formula A-II, the nitrogen ring atom of said indole ring is substituted with Cl-C6 aliphatic, C(O)(CI-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said CI-C6 aliphatic or C I-C6 alkyl is optionally replaced with CO-, -CONR'-, -C02-, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, NR'-, -SO 2 NP'-, NR'S0 2 -, or-NR'SO 2 NR'-. In another embodiment, R' above is C1-C4 alkyl. [01931 In another embodiment the nitrogen ring atom of said indole ring is substituted with acyl, benzyl, C(O)CH 2 N(Me)C(O)CH 2 NHMe, or ethoxycarbonyl. [01941 4. General Synthetic Schemes [01951 Compounds of the present invention are readily prepared by methods known in the art. Illustrated below are exemplary methods for the preparation of compounds of the present invention. [01961 The scheme below illustrates the synthesis of acid precursors of the compounds of the present invention. [0197] Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C: - 69 - R6=SMe R6=H R6=CF3 00O 2 C COPE d Et0 2 CjC0 2 Et b cI N SNa N R6 3 H H O 0 R aN) R6 H O 0 H a) (CQ 2 Et) 2

CH

2 ; b) (CO 2 Et)2CH=CH(OEt); C) CF 3

CO,

2 H, PPh 3 , CCL 1 , Et 3 N; d) Mel; e) PPA or diphenylether, f) NaOH. 101981 Synthesis of Acid Precusors P-IV-A, P-IN-B or P-TV-C: 0 0 R6 b RA H, C

CO

2 Et

NH

2

CO

2 Et RI COPE d COPE e 02H HNI - 70 a) AcONH 4 ; b) EtOCHC(CO 2 Et) 2 , 130*C; c) Ph 2 O, AT; d) 12, EtOH; e) NaOH. [01991 Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C OH R - ~ *-~ a '-b C N R - ~ R ----- 0 R N OH N Cl b R' OR' J CO 2 Et COOH R d R OR' OR' [02001 POCl 3 ; b) R'ONa; c) n-BuLi, CICO 2 Et; d) NaOH [02011 Synthesis of Amine Precursor P-III-A: b c NN N 0 CHaSO4 2 N - $, N 0 2 O N H 2 N -, N N N R N .R

(CH

3

)

2

SO

4 ; b) K 3 Fe(CN) 6 , NaOH, H 2 0; c) HNO 3 , H 2

SO

4 ; d) RCOCH 3 , MeOH, NH 3 ; e) H 2 , RaneyNi [0202] Synthesis of Amine Precursor P-IV-A: R1 R2 RI R2 RI R2 O a O 1 Ob 02NO ON ON OH 0 0 OH R1 R2

H

2 N OH

OH

[02031 HNO 3 , HOAc; b) Na 2

S

2

O

4 , THF/H 2 0; c) H 2 , Pd/C. [0204] Synthesis of Amine Precursor P-V-A-1: b R R R R a b R c NH, OzN NH 2 OzN OH HzN OH dI R R

O

2 N OR' H 2 N OR' [0205] KNO3, H 2

SO

4 ; b) NaNO 2 , H 2 S0 4 - H20; c) NH 4

CO

2 H, Pd-C; d) R'X; e)

NH

4 CO2H, Pd-C [0206] Synthesis of Amine Precursor P-V-A-1: -72 - RI RI ~R R1 OH OH OH Rb R2 OH d R1 R2 0 RO 0 Ar R2 R ON OH Br R2 02N OR' hi

H

2 N OH H 2 N'-"OO)KOR CF R2

H

2 N OR' -73a) S0 2 Cl 2 , R2= Cl; b) R2OH, R2=alkyl; c) NBS, RI=Br; d) ClCO 2 R, TEA; e)

HNO

3 , H 2 S0 4 ; f) base; g) ArB(OH) 2 , R1=Br; h) [H]; I) R'X, Rl= Br; j) ClCF 2

CO

2 Me; k) [H]; 1) [H]. [0207] Synthesis of Amine Precursor P-V-A-1: R aR bR CR

R

2 N H 2 N H 2 N NO 2 RR d 0 e f Na NO 2 N NH2 H H2 0R g - _ R N OH H OH H [02081 KNO 3 ; b) [H]; c) KNO 3 ; d) AcCl; e) [H]; f) i) NaNO 2 ; ii) H 2 0; g) HCI [0209] Synthesis of Amine Precursor P-V-A-1: -74- R R

H

2 NNRP NHR' d R R R b c OzN NO, H 2 N NH 2 PG NH 2 R 9\fIR C NH, h -0 2 NA NH2 R R et j

O

2 N NHBoc H 2 N NHBoc 02N NBoc H 2 N NBoc R R [02101 HNO 3 , H 2

SO

4 ; b) [H]; c) protection; d) R'CHO; e) deprotection; f) {H]; g) Na 2 S, S, H20; h) nitration; i) (BOC) 2 0; j) [H]; k) RX; 1) [H]; PG= protecting group [0211] Synthesis of Amine Precursors P-V-A-i or P-V-A-2: - 75 - RR R a b R c 0 2 N) 0 2 N Sr 0 2 NM CN H 2 N RR 0 2 NM H 0 2 N 0O h RR R- OR H2 NHBoc 0 2 NOR 0 RR K- OH

H

2 NJ( [02121 a) Br 2 ; b) Zn(CN) 2 , Pd(PPh) 3 ; c) [H]l; d) BH 3 ; e) (BOC) 2 0; f) [H]; g) H 2 S0 4 ,

H

2 0; h) R'X; i) [H]; j) LiAIH 4 102131 Synthesis of Amine Precursors P-V-A-i or P-V-A-2: R R R - NH 2 N ''0 2 N H 2 2 S 2 1 (i)iNaNO 2 , HC1; ii) Na 2

SO

3 , CuSO 4 , HCI; b) NH 4 Cl; C) [H] - 76 - [0214] Synthesis of Amine Precursors P-V-A-1: R R a [f- b c K'CHO 0 2 N CHO R R d 0 2 N~'a'CHF,

H

2 N

CHF

2 a) CHC1 2 OMe; b) KNO 3 , H 2 S0 4 ; c) Deoxo-Fluor; d) Fe [02151 Synthesis of Amine Precursors P-V-A-3: Br Br Ar CN 0CN 2 N CN Ar Ar N d H S H 2 N

NH

2 H2 _ NHBoc Ar Aryl or Heteroaryl a) Nitration; b) ArB(OH) 2 , Pd; c) BH 3 ; d) (BOC)20 [0216] Synthesis of Amine Precursors P-V-B-1: N a b0 H2N OH ND O R C Nl d 1 cd

H

2 N 0 H -77 a) AcCI; b) DEAD; c) AtCl 3 ; d) NaOH [02171 Synthesis of Amine Precursors P-V-B-1: R YH Y a b ~ ON NH, bN 0 0 2 N Y=O, S O2 d H2 N PG PG a) CICH 2 COCI; b) [H]; c) protection; d) (H] PG= protecting group [02181 Synthesis of Amine Precursors P-V-B-1: R xR 0 R a " OH b 0 2 N NO 2 0 2 N NOH H2N O X=F, CI a) HSCH 2

CO

2 H; b) [H] - 78 - 102191 Synthesis of Amine Precursors P-V-B-2: RRl R12 RI k R2 NR2 oH O o Alkylation a NH 2 0H(A~ N o -N N H H Rlb HO R2 RI R2 R2 RI R2I

NH

2 c n=or2 mO or2 H o~ r2 fl OH R1 R2 0 2 N i 9 Ri R2

O

2 N N PG h Ri R2 PG a) AICl 3 ; b) [H]; d) i) RIR2CHCOCH 2

CH

2 CI; ii) NaBH 4 ; d) NH 2 OH; e) DIBAL-H; f) nitration; g) protection; b) [H] PG= protecting group [02201 Synthesis of Amine Precursors P-V-B-3: Ri R2 RI R2 Rl ~R2 RI R2

H

2 02 O2N ) b Ol PG H2N PG -79a) Nitration; b) Protection; c) (H] PG= protecting group [02211 Synthesis of Amine Precursors P-V-B-5: 2Na O2N b H2N H RR a) when X=Cl, Br, I: RX, K 2 C0 3 , DMF or CH 3 CN; when X=OH: RX, TFFH, DIEA, THF b) H 2 , Pd-C, EtOH or SnCI 2 .2H 2 0, EtOH or SnCl 2 .2H 2 0, DIEA, EtOH. [0222] Synthesis of Amine Precursors P-V-B-5:

NH

2 a N R b N H H C -R d 2 N oRN R NN H 2H h 02N NN 2 N HN NNH, O,N NH, - 2N 1 O a) RCOCL, Et 3 N, CH 2 C1 2 ; b) n-BuLi, THF; c) NaBH4, AcOH; d) KNO 3 , H 2 S0 4 ; e) DDQ, 1,4 dioxane; f) NaNO 2 , HCI, SnCI 2 .2H 2 0, H20; g) MeCOR, EtOH; h) PPA; i) LiAllt, THE or H2, Raney Ni, EtOH or MeOH - 80 - 102231 Synthesis of Amine Precursors V-B-5: NH _ b R O2N NH 0 2 N NH2 0 2 N N R 2N 2 H H R R jo R R dR

H

2 N R d O2N N H 2H a) NaNO 2 , HCI, SnCI 2 .2H 2 0, H 2 0; b) RCH 2 COR, AcOH, EtOH; c) H 3 PO4, toluene; d) H 2 , Pd-C, EtOH [02241 Synthesis of Amine Precursors P-V-B-5: 2 b 2R NH 0 2 N N 0 2 N N 2 HH d \ ON N

H

2 N~f) 02ND H a) NaNO 2 , HCI, SnC1 2 .2H 2 0, H 2 0; b) RCH 2 COH, AcOH, EtOH; c) H 3

PO

4 , toluene; d) H 2 , Pd-C, EtOH - 81 - [02251 Synthesis of Amine Precursors P-V-B-5: R R N2N b HNJ 0 2 N H H2N H ON ON c ~ b ONN HN N 02H QN)D H HH d / Nu Nu \ f b O2N - N N N 2 NN N H2N :Nu a) RX (X=Br, I), zinc triflate, TBAI, DIEA, toluene; b) H2, Raney Ni, EtOH or H 2 , Pd-C, EtOH or SnC1 2 .21 2 0, EtOH; c) CISO 2 NCO, DMF, CH 3 CN; d) Me 2 NH, H 2 CO, AcOH; e) MeI, DMF, THF, H 2 0; f) MNu (M= Na, K, Li; Nu= nucleophile) [0226] Synthesis of Amine Precursors P-V-B-5: R R R NN-. a~ C 0 2 N NO 2 O o N NNc H 2NO I N NN H a) HNO 3 , H 2

SO

4 ; b) Me 2 NCH(OMe) 2 , DMF; c) H 2 , Raney Ni, EtOH -82- [02271 Synthesis of Amine Precursors P-V-B-5: b Rc R N NN PG PG R f R e R

H

2 N 02 N 02 N O H 2H2H a) When PG= SO 2 Ph: PhSO 2 CI, Et 3 N, DMAP, CH 2

CI

2 ; When PG= Ac: AcCl, NaHCO 3 , CH 2 Cl 2 ; b) When R= RCO: (RCO) 2 0, AiCl 3 , CH 2

C

2 ; When R=Br: Br 2 , AcOH; c) HBr or HCt; d) KNO 3 ,

H

2 S0 4 ; e) MnO 2 , CH 2

C

2 or DDQ, 1,4-dioxane; f) H 2 , Raney Ni, EtOH [0228] Synthesis of Amine Precursors P-V-B-5: R R R rR

NH

2 NH 2 0 2 N

H

2 c 2 N

NH

2 - d R R ON H2N a) NBS, DMF; b) KNO 3 , H 2 S0 4 ; c) HC=CSiMe 3 , Pd(PPh 3

)

2 Cl 2 , CuI, Et 3 N, Toluene, H20; d) CuI, DMF; e) H 2 , Raney Ni, MeOH - 83 - [0229] Synthesis of Amine Precursors P-V-A-3 and P-V-A-6: Ar= Aryl or heteroaryl

H

2 N H 2 N Br Ar a) ArB(OH) 2 , Pd(PPh 3

)

4 , K 2 C0 3 , H 2 0, THF or ArB(OH) 2 , Pd 2 (dba) 3 , P(tBu) 3 , KF, THF [02301 Synthesis of Amine Precursors P-V-A-4: R a R b R 0 2 N" ONJH 2 R= CN, CO 2 Et; a) Mel, NaOtBu, DMF; b) HCO 2 K, Pd-C, EtOH or HCO 2

NH

4 , Pd-C, EtOH [0231] Synthesis of Amine Precursors P-V-A-4: 0 H 2Wa a ___H,, Ar

H

2 N BO a H 2 N A a) ArBr, Pd(OAc) 2 , PS-PPhs, K 2 C0 3 , DMF [02321 Synthesis of Amine Precursors P-V-B-4: -84 - 0 2 N

H

2 N R R a) H 2 , Pd-C, MeOH [02331 Synthesis of Amine Precursors P-V-B-4: a J ) b - I 0 2 N 0 2 N

H

2 N 0 OH OH 0 2 N d 2 N

H

2 N N OH NH 2 NHPG a) NaBH 4 , MeOH.; b) H 2 , Pd-C, MeOH; c) NH 2 OH, Pyridine; d) H 2 , Pd-C, MeOH; e) Boc 2 O, Et 3 N, MeOH [02341 Synthesis of Compounds of Formula I: R1 0 0 RI 0 0 R2 R2A OH a N R3 I N. R7 N R6 R3 N R6 R4 R5 R4 R5 a) AriR7NH, coupling reagent, base, solvent. Examples of conditions used: HATU, DIEA; BOP, DIEA, DMF; HBTU, Et 3 N, CH 2

CI

2 ; PFPTFA, pyridine. -85- [0235] Synthesis of Compounds of Formula ': ~R5 Ri o o Ri 0 0 R2 N "Ar, a R2 N Ar R3 N R6 R7 R3 N R6 H R4 R4

R

5 = aliphatic: a) RsX (X= Br, I), Cs 2

CO

3 , DMF [02361 Syntheis of Compounds of formula V-B-5: 00 0 EtO HO R\N R7a) RN RI 0 N R7 I 1 R R 7 1N 14N R1 R0s R1 O R N R2 0R R2 R3 N R6 R N R N31R6 R) N R6 R4 R5 R4 R5 R4 a) NaOH, THF; b) HNR 2 , HATU, DIHA, DMF -02371 Syntheis of Compounds of formula V-B-5: Br WRw R1 N:W

R

7 '- NI RIN- H Ri 0 N U N R2 R2 N 06 RI R3 NR6 R4# R6 R4 R5 WIRW = aryl or heteroaryl: a) ArB(OH) 2 , (dppfoPdC 2 , K 2 C0 3 , DMF -86- [0238] Synthesis of Compounds of Formula V-A-2 & V-A-5: (WRw)m RNO I I 'HNO, R3 N R6 R4 RS (Rw)mn (WRw)m RI 0 0 RI 0 0 w R2 N PG b R2 N NH H (R= H, Me) H R3 N R6 R3 N R6 R4 R6 R4 R5 c d 0(WRw)m ('= H) (R' = H) R1 O OWRw)m HRR N N Ri 0 R R3 N R6 H H R4 R5 R3 N R6 (X = CO, Co2, So2) R4 R5 (X = So2, R = CHCH 2 ) (WRw)m Ri 0 0 RI\, 00 R2 .NR H R3 N R6 R4 R5 a) SnCl 2 .2H 2 0, EtOH; b) PG= BOC: TFA, CH 2 Cl 2 ; c) CH 2 O, NaBH 3 CN,. CH 2

CL

2 , MeOH; d) RXCI, DIEA, THF or RXCI, NMM, 1,4-dioxane or RXCI, CH 2

CI

2 , DMF; e) R'R"NH, LiC1O 4 ,

CH

2 C1 2 , iPrOH - 87 - [0239] Synthesis of compounds of formula V-B-2: Rw 3 Rw awR Rw 3 [2RI 0 SynthesisRo RIn o f V N a R 1 N K 7PG I R7( H R3 N R6 -P R3 N R6 R4 R R4 a) When PG = BOC: TFA, CH 2

CI

2 ; When PG Ac: NaOH or HCl, EtOH or THF [02401 Synthesis of compounds of formula V-A-2: (WR) (WRw). Ri aRi 0 R PG R3 R2 NH2 R22H ON R3N RR43 R H R4 R4 R a) When PG BOC: TFA, CH 2

CI

2 2 R i 0 0 Ri 0 0 R2~ HNPG2 H II I~ R4 RO R4 R5 RI 0 0 R2 HN 0,N R3 N R6 a) When PG BOC: TFA, CH 2 C0z; b) ROCOCO, Et 3 N, DMF -88- [02411 Synthesis of compounds of formula V-A-4: Ri O O R1 0 0O R2 N a R2 N II N HP H R3 N R6 HPG R3 N R6 NH 2 R4 R5 R4 R5 lb R2 N':Z H N H R1R 6 R3 N R6 NR R4 R5 a)When PG = BOC: TFA, CH 2

C

2 ; b) When R'= CO 2 R: ROCOCL, DIEA, MeOH . 102421 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. 102431 5. Ues, Formulation and Administration 10244] Pharmaceutically acceptable compositions [0245] As discussed above, the present invention provides compounds that are useful as modulators of ABC transporters and thus are useful in the treatment of disease, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type I chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, - 89 - Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type 1, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease. [02461 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 comprise one or more additional therapeutic agents. [02471 It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable derivative or a 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 thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. [02481 As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt"imeans 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. [0249] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of -90 an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pirate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N*(Ci.4alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such 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. [0250] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable -91composition, 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 com 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. [02511 Uses of Compounds and Pharmaceutically Acceptable Compositions [02521 In yet another aspect, the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity, e.g., CFTR. In certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of the ABC transporter activity, the method comprising administering a composition comprising a compound of formula (I) to a subject, preferably a mammal, in need thereof. [0253 In certain embodiments, the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type I hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type I chylomicronemia, -92 abetalipoproteinemia, lysosomal storage diseases, such as 1-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention. [0254] According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention. [0255] 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 I hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type I chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, 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, -93 - Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebuliar ataxia type 1, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease. [02561 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 I chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease. 102571 In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in a patient. t0258] In certain embodiments, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or -94histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cf concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, AF508. [0259] In another embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods or gene therapy.. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient. [02601 In one embodiment, the compounds and compositions of-the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cysticfibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521 - 529, 2000). Other patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification. [0261] In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease. 102621 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 -95formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. [02631 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 [02641 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. -96- [02651 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. [02661 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. [0267] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [02681 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 -97 solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [02691 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [02701 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. [02711 The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as -98sucrose, 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. . [0272] 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. [0273] As described generally above, the compounds of the invention are useful as modulators of ABC transporters. Thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder. When hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "ABC transporter-mediated disease, condition or disorder". Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state. -99- [02741 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. [02751 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". [0276] In one embodiment, the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent. [0277] 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. [0278] 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 - 100another 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. [0279] 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. [02801 Modulation of ABC transporter activity, e.g., CFTR, 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. 102811 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 formula (I). 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. [02821 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 formula (I). 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. 101- [0283] 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. [02841 The optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (L Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Toda 4(9): 431-439). [02851 These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC 2 (3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPRTm II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. [02861 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 formula (1) 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 -102in the presence of a composition of formula (I). In preferred embodiments, the kit is used to measure the density of CFTR. [02871 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. EXAMPLES [00286] Example 1: [002871 General scheme to prepare Acid Moities: o0 0 0 R I N H E tO C c O 2 Et R 2C 2 R ROH N N H H H a) 140-150 'C; b) PPA, POCl 3 , 70 0C or diphenyl ether, 220 *C; c) i) 2N NaOH ii) 2N HUl [002881 Specific example: 2-Phenylaminomethylene-malonic acid diethyl ester EtO c CO Et EtO C COZEt 0 0 0 140-150 zC ~ PPA 0 i) 2N NaOH OH (INH. EtO 1 0 POCI .NH 2 C HH A-1 A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.29 mol) was heated at 140-150 *C for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 'H NMR (d-DMSO) 8 11.00 (d, 111), 8.54 (d, J= 13.6 Hz, 1H), 7.36-7.39 (in, 2H), 7.13-7.17 (m, 3 H), 4.17-4.33 (m, 4H), 1.18 1.40 (m, 6H). {002891 4-Hydroxyquinoline-3-carboxylic acid ethyl ester A I L three-necked flask fitted with a mechanical stirrer was charged with 2 phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to about 70 "C and stirred for 4 h. The -103mixture was cooled to room temperature, and filtered. The residue was treated with aqueous Na 2

CO

3 solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a pale brown solid (15.2 g, 70 %). The crude product was used in next step without further purification. [002901 A-1; 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCL. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4 dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 92 %). 'H NMR (d DMSO) 8 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J= 8.0 Hz, IH), 7.88 (in, 111), 7.81 (d, J= 8.4 Hz, I H), 7.60 (m, 1H). [002911 Specific Example: A-2; 6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid F OH 6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid (A-2) was synthesized following the general scheme above starting from 4-fluoro-phenylamine. Overall yield (53 %). tH NMR (DMSO-d 6 ) S 15.2 (br s, 1 H), 8.89 (s, 1 H), 7.93-7.85 (in, 2 H), 7.80-7.74 (m, I H);. ESI-MS 207.9 m/z (NiH 4 ). [002921 Example 2: -104- OMe OMe E C OMe N. H 2 , Raney Ni Lt''- P

NO

2 EtOH NH 2 H N CO 2 Et Br Br CO 2 EI Me0 MeO Me Go 2 Et Pd-C CO2Et NHHH CO2H A-4 [00293] 2-Bromo-5-methoxy-phenylamine A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H 2 (I atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylanine (7.5 g, 86 %). 1002941 2-[(2-Bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2 (ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100 *C for-2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81 %). [00295] 8-Bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester 2

-[(

2 -Bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester (9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120 "C. The mixture was stirred at this temperature for additional 30 min and then cooled to room temperature. Absolute ethanol (30 mL) was added and the resulting mixture was refluxed for 30 min. The mixture was basified with aqueous sodium bicarbonate at 25 *C and extracted with EtOAc (4 x 100 mL). The organic layers were combined, dried and the solvent evaporated to give 8-bromo-5-methoxy-4-oxo-1,4 dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 30 %). -105- [00296j 5-Methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester A mixture of 8 -bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10 % Pd/C (100 mg) in glacial acetic acid (50 ml) was stirred under H2 (2.5 atm) overnight. The catalyst was removed via filtration, and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in

CH

2 Cl 2 (100 mL) and washed with aqueous sodium bicarbonate solution and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to afford 5-methoxy-4-oxo- 1,4-dihydro-quinoline-3 -carboxylic acid ethyl ester as a yellow solid (1 g, 57 %). [002971 A-4; 5-Methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid A mixture of 5-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (1 g, 7.1 mmol) in 10% NaOH solution (50 rniL) was heated to reflux overnight and then cooled to room temperature. The mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCI solution to pH 1-2. The resulting precipitate was collected by filtration to give 5-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (A-4) (530 mg, 52 %). 111 NMR (DMSO) 8: 15.9 (s, 1 H), 13.2 (br, 1 H), 8.71 (s, I H), 7.71 (t, J= 8.1 Hz, I H), 7.18 (d, J = 8.4 Hz, 1 H), 6.82 (d, J= 8.4 Hz, 1 H), 3.86 (s, 3 H); ESI-MS 219.9 m/z (MH*). [00298] Example 3:

CH

2

(CO

2 Et) 2 > Na . N ~ Me NH ECO 2 Et e DMF 2 Et H H 1,2-dichlorobenzene CO 2 Et I) NaOH .CO 2 N SMe SMe A-1 6 [0288] Sodium 2-(mercapto-phenylanino-methylene)-malonic acid diethyl ester - 106- To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in Et 2 O at room temperature was added dropwise, over a 30 minutes period, ethyl malonate (24 g, 0.15 mol). Phenyl isothiocyanate (20.3 g, 0.15 moI) was then added dropwise with stirring over 30 min. The mixture was refluxed for I h and then stirred overnight at room temperature. The solid was separated, washed with anhydrous ether (200 mL), and dried under vacuum to yield sodium 2 (mercapto-phenylamino-methylene)-malonic acid diethyl ester as a pale yellow powder (46 g, 97 [00299] 2 -(Methylsulfanyl-phenylamino-methylene)-malonic acid diethyl ester Over a 30 min period, methyl iodide (17.7 g, 125 mmol) was added dropwise to a solution of sodium 2 -(nercapto-phenylamino-methylene)-malonic acid diethyl ester (33 g, 104 mmol) in DMF (100 mL) cooled in an ice bath. The mixture was stirred at room temperature for I h, and then poured into ice water (300 mL). The resulting solid was collected via filtration, washed with water and dried to give 2 -(methylsulfany-phenylamino-methylene)-.malonic acid diethyl ester as a pale yellow solid (27 g, 84 %). [003001 4 -Hydroxy-2-nethylsulfanyl-quinoline-3-carboxylic acid ethyl ester A mixture of 2 -(methylsulfanyl-phenylamino-methylene)-malonic acid diethyl ester (27 g, 87 mmol) in 1,2-dichlorobenzene (100 mL) was heated to reflux for 1.5 h. The solvent was removed under reduced pressure and the oily residue was triturated with hexane to afford a pale yellow solid that was purified by preparative HPLC to yield 4-hydroxy-2-methylsulfanyl quinoline-3-carboxylic acid ethyl ester (8 g, 35 %). [00301] A-16; 2 -Methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 4 -Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1.5 h. After cooling, the mixture was acidified with concentrated HCI to pH 4. The resulting solid was collected via filtration, washed with water (100 mL) and MeOH (100 mL) to give 2-methylsulfanyl-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85 %). 'H NMR (CDC 3 ) S 16.4 (br s, I H), 11.1 (br s, I H), 8.19 (d, J= 8 Hz, IH), 8.05 (d, J= 8 Hz, IH), 7.84 (t, J= 8, 8 Hz, IH), 7.52 (t, J= 8 Hz, IH), 2.74 (s, 3H); ESI-MS 235.9 m/z (MH*). - 107 - [003021 Example 4: OH OH Nr 1 Cj NH(cFEt) 2 c r < COEt d CO 2 N NCF, ."N'.KCF3 N CF, N CF, A-15 a) PPh 3 , Et 3 N, CCl4, CF 3

CO

2 H; b) diethyl malonate; c) T- 200*C; d) 10% NaOH [003031 2,2,2-Trifluoro-N-phenyl-acetimidoyI chloride A mixture of Ph 3 P (138.0 g, 526 mmol), Et 3 N (21.3 g, 211 mmol), CC1 4 (170 mL) and TFA (20 g, 175 mmol) was stirred for 10 min in an ice-bath. Aniline (19.6 g, 211 mmol) was dissolved in CC1 4 (20 mL) was added. The mixture was stirred at reflux for 3 h. The solvent was removed under vacuum and hexane was added. The precipitates (Ph 3 PO and Ph 3 P) were filtered off and washed with hexane. The filtrate was distilled under reduced pressure to yield 2,2,2-trifluoro-NT phenyl-acetimidoyl chloride (19 g), which was used in the next step without further purification. [003041 2

-(

2

,

2

,

2 -Trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester To a suspension of NaH (3.47 g, 145 mmol, 60 % in mineral oil) in THF (200 mL) was added diethyl malonate (18.5 g, 116 mmol) at 0 *C. The mixture was stirred for 30 min at this temperature and 2,2,2-trifluoro-N-phenyl-acetimjidoyl chloride (19 g, 92 mmol) was added at 0 *C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH 2 C1 2 , washed with saturated sodium bicarbonate solution and brine. The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated to provide 2

(

2

,

2

,

2 -trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester, which was used directly in the next step without further purification. [00305] 4 -Hydroxy-2-trifluoromethyl-quoline-3-carboxylic acid ethyl ester 2

-(

2 ,2,2-Trifluoro-I-phenyimino-ethyl)-malonic acid diethyl ester was heated at 210 *C for I h with continuous stirring. The mixture was purified by column chromatography (petroleum ether) to yield 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (12 g, 24 % over 3 steps). - 108 - [003061 A-15; 4 -Hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid A suspension of 4 -hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 h. After cooling, dichloromethane was added and the aqueous phase was separated and acidified with concentrated HCL to pH 4. The resulting precipitate was collected via filtration, washed with water and Et 2 O to provide 4 -hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80 %). 'H NMR (DMSO-d 6 ) 3 8.18-8.21 (d, J= 7.8 Hz, 1 H), 7.92-7.94 (d, J = 8.4 Hz, 1 H), 7.79-7.83 (t, J = 14.4 Hz, I H), 7.50-7.53 (t, J= 15 Hz, 1 H); ESI-MS 257.0 m/z (MH+). [003071 Example 5: 00 a N2 b N, COEt c 0NH 2 2

CO

2 Et 0 0 H

CO

2 Et d

CO

2 Et

CO

2 H &N: H X3 a) CH 3 C(O)ONH4, toluene; b) EtOCHC(CO 2 Et) 2 , 130 *C; c) Ph 2 O; d) 12, EtOH; e) NaOH [003081 3-Amino-cyclohex-2-enone A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) -and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90 %), which was used directly in the next step without further purification. [00309] 2

-[(

3 -Oxo-cyclohex-1-enylamino)-methylene]-malonic acid diethyl ester -109- A mixture of 3 -amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2 (ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130 *C for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give 2 -[(3-oxo-cyclohex-l-enylamino)-methylene] malonic acid diethyl ester (7.5 g, 90 %). [00310) 4

,

5 -Dioxo-1,4,5,6,7,8-hexahydro-quinoline-3--carboxylic acid ethyl ester A mixture of 2-[(3-oxo-cyclohex-l-enylamino)-methylene]-malonic acid diethyl ester (2.8 g, 1 mmol) and diphenylether (20 mL) was refluxed for 15 min. After cooling, n-hexane (80 mL) was added. The resulting solid was isolated via filtration and recrystallized from methanol to give 4 ,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3 -carboxylic acid ethyl ester (1.7 g 72 %). [00311] 5-Hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester To a solution of 4,5-dioxo-1, 4 ,5, 6 ,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.6 g, 6.8 mmol) in ethanol (100 mL) was added iodine (4.8 g, 19 mmol). The mixture was refluxed for 19 h and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, water and acetone, and then recrystallized from DMF to give 5-hydroxy-4-oxo-1,4 dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 43 %). [003121 A-3; 5-Hydroxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated at reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCI to pH 1-2. The resulting precipitate was collected via filtration to give 5-hydroxy-4-oxo-1, 4-dihydro quinoline-3-carboxylic acid (A-3) (540 mg, 87 %). 'H NMR (DMSO-d) 8 13.7 (br, 1 H), 13.5 (br, 1 H), 12.6 (s, 1 H), 8.82 (s, 1 H), 7.68 (t, J= 8.1 Hz, 1 H), 7.18 (d, J= 8.4 Hz, I H), 6.82 (d, J= 8.4 Hz, 1 H); ESI-MS 205.9 m/z (MH*). [003131 Example 6: - 110 - HC 1 M e OH N C1 N OMe Me Me C CO 2 Et d N COOH N OMe N OMe A-17 a) POCl 3 ; b) MeONa; c) n-BuLi, CICO 2 Et; d) NaOH 2, 4 -Dichloroquinoline A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl 3 was heated at reflux for 2 h. After cooling, the solvent was removed under reduced pressure to yield 2

,

4 -dichloroquinoline, which was used without further purification. [00314] 2

,

4 -Dimethoxyquinoline To a suspension of 2

,

4 -dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH 2 C1 2 . The combined organic layers were dried over Na 2

SO

4 and concentrated to give 2

,

4 -dimethoxyquinoline as a white solid (13 g, 74 % over 2 steps). [00315] Ethyl 2,4-dimethoxyquinoline-3-carboxylate To a solution of 2

,

4 -dimethoxyquinoline (11.5 g, 60.8 mmol) in anhydrous THF was added dropwise n-BuLi (2.5 M in hexane, 48.6 mL, 122 mnol) at 0 "C. After stirring for 1.5 h at 0 *C, the mixture was added to a solution of ethyl chloroformate in anhydrous THF and stirred at 0 "C for additional 30 min and then at room temperature overnight. The reaction mixture was poured into water and extracted with CH 2 Cl 2 . The organic layer was dried over Na 2

SO

4 and concentrated under vacuum. The resulting residue was purified by column chromatography (petroleum ether / EtOAc = 56 / 1) to give ethyl 2, 4 -dimethoxyquinoline-3-carboxylate (9.6 g, 60 %). - 111 - [003161 A-17; 2,4-Dimethoxyquinoline-3-carboxylic acid Ethyl 2,4-dimethoxyquinoline-3-carboxylate (1.5 g, 5.7 mmol) was heated at reflux in NaOH solution (10 %, 100 mL) for I h. After cooling, the mixture was acidified with concentrated HCI to pH 4. The resulting precipitate was collected via filtration and washed with water and ether to give 2,4-dimethoxyquinoline-3-carboxylic acid (A-17) as a white solid (670 mg, 50 %). 'H NMR (CDC 3 ) 6 8.01-8.04 (d, J=12 Hz, 1 H), 7.66-7.76 (m, 2 H), 7.42-7.47 (t, J= 22 Hz, 2 H), 4.09 (s, 3 H). 3.97 (s, 3 H); ESI-MS 234.1 m/z (MH*). [00317] Commercially available acids Acid Name A-5 6,8-Difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-6 6-[(4-Fluoro-phenyl)-methyl-sulfamoyl]-4-oxo-1,4-dihydro-quinoline-3 carboxylic acid A-7 6-(4-Methyl-piperidine-1-sulfonyl)-4-oxo-1,4-dihydro-quinoline-3 carboxylic acid A-8 4-Oxo-6-(pyrrolidine-1-sulfonyl)-1,4-dihydro-quinoline-3-carboxylic acid A-10 6-Ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-11 6-Ethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-12 4-Oxo-7-trifluoromethyl-1,4-dihydro-quinoline-3-carboxylic acid A-13 7-Cbloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-14 4-Oxo-5,7-bis-trifluoromethyl-1,4-dihydro-quinoline-3-carboxylic acid A-20 1-Methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-21 1-Isopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-22 1,6-Dimethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-23 1-Ethyl-6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-24 6-Chloro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid -112- (003181 Amine Moieties [003191 N-I Substituted 6-aminoindoles [00320] Example 1: [00321] General Scheme: a b 02N a O2N b H 2 N R R a) RX (X = Cl, Br, 1), K 2 C0 3 , DMF or CH 3 CN; b) H 2 , Pd-C, EtOH or SnC12-2H 2 0, EtOH. [003221 Specific example: Me 1-121 Pd-C 0 2 N M 2N N EtH H 2N B-I [003231 1-Methyl-6-nitro-1H-indole To a solution of 6-nitroindole (4.05g 25 mmol) in DMF (50 mL) was added K 2 C0 3 (8.63 g, 62.5 mmol) and MeI (5.33 g, 37.5 mmol). After stirring at room temperature overnight, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na 2

SO

4 and concentrated under vacuum to give the product 1-methyl-6-nitro-1H-indole (4.3 g, 98 %). [003241 B-1; 1-Methyl-iH-indol-6-ylamine A suspension of 1-methyl-6-nitro-1H-indole (4.3 g, 24.4 mmol) and 10% Pd-C (0.43 g) in EtOH (50 mL) was stirred under H 2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and acidified with HCl-MeOH (4 mol/L) to give 1-methyl-lH-indol-6-ylamine hydrochloride salt (B-1) (1.74 g, 49 %) as a grey powder. 'H NMR (DMSO-d): 8 9.10-(s, 2 H), - 113 - 7.49(d,J= 8.4 Hz, I H), 7.28 (d,J=2.0 Hz, I H), 7.15(s, I H), 6.84 (d,J-=8.4 Hz, 1 H),6.38 (d, J= 2.8 Hz, 1H), 3.72 (s, 3 H); ESI-MS 146.08 m/z (MH*). 100325] Other examples:

H

2 N N [00326] B-2; 1-Benzyl-1H-indol-6-ylamine 1-Benzyl-IH-indol-6-ylamine (B-2) was synthesized following the general scheme above starting from 6-nitroindole and benzyl bromide. Overall yield (- 40 %). HPLC ret. time 2.19 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 223.3 m/z (MH*).

H

2 N N 0 [00327] B-3; 1-(6-Amino-indol-1-yl)-ethanone 1-(6-Amino-indol-1-yl)-ethanone (B.-3) was synthesized following the general scheme above starting from 6-nitroindole and acetyl chloride. Overall yield (- 40 %). HPLC ret. time 0.54 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 175.1 m/z (MH+). [003281 Example 2: - 114 - A.oc y *'boo N uoH Ioc OH + EtaN, CHcI HI T 2 , rHF 014JCXH 0 -4SnvCI.H20HO oa 901-- 0 H2 TFFH, DIEA NJ DIEA, EtOH THF 0OO B-26 [00329] {[ 2 -(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester To a stirred solution of (tert-butoxycarbonyl-methyl-amino)-acetic acid (37 g, 0.2 mol) and Et 3 N (60.6 g, 0.6 mol) in CH 2 Cl 2 (300 mL) was added isobutyl chloroformate (27.3 g, 0.2 mmol) dropwise at -20 *C under argon. After stirring for 0.5 h, methylamino-acetic acid ethyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at -20 'C. The mixture was allowed to warm to room temperature (c.a. I h) and quenched with water (500 mL). The organic layer was separated, washed with 10 % citric acid solution, dried over Na 2

SO

4 , filtered and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc 1:1) to give ([2 (tert-butoxycarbonyl-methyl-amino)-acetyl-methyl-amino)- acetic acid ethyl ester (12.5 g, 22 [00330] {12-(tert-Butoxycarbonyl-methyl-amino)-acetyll-methyl-amino}-acetic acid A suspension of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]- methyl-amino) -acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H 2 0 (20 mL) and THF (100 mL) was stirred overnight. Volatile solvent was removed utider vacuum and the residue was extracted with ether (2 x 100 mL). The aqueous phase was acidified to pH 3 with dilute HCl solution, and then extracted with CH 2

CI

2 (2 x 300 mL). The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated under vacuum to give ([2-(tert-butoxycarbonyl-methyl amino)-acetyl]-methyl-amino}-acetic acid as a colorless oil (10 g, 90 %). 'H NMR (CDC 3 ) 8 - 115- 7.17 (br s, I H), 4.14-4.04 (m, 4 H), 3.04-2.88 (m, 6 H), 1.45-1.41 (m, 9 H); ESI-MS 282.9 m/z (M+Na*). [003311 Methy-({metbyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl} methyl)-carbamic acid tert-butyl ester To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (13.8g, 53 mmol) and TFFH (21.0g, 79.5 mmol) in anhydrous THF (125 mL) was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60 *C for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (x 3), dried over Na 2

SO

4 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (6.42 g, 30 %). 'H NMR (400 MHz, DMSO-d6) 8 1.37 (mn, 9H), 2.78 (m, 3H), 2.95 (d, J = 1.5 Hz, IH), 3.12 (d, J= 2.1 Hz, 2H), 4.01 (d, J= 13.8 Hz, 0.6H), 4.18 (d, J = 12.0 Hz, 1.4H), 4.92 (d, J= 3.4 Hz, 1.4H), 5.08 (d, J = 11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d, J = 3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 405.5 mIz (MH). [00332] B-26; ({[2-(6-Amino-indol-1-yl)-2-oxo-ethyll-methyl-carbamoyl} methyl)-methyl-carbamic acid tert-butyl ester A mixture of methyl-({methyl-[2-(6-nitro-indol-1-y1)-2-oxo-ethyl]-carbamoyl}-methyl) carbamic acid tert-butyl ester (12.4 g, 30.6 mmol), SnCl 2 -2H 2 0 (34.5g, 153.2 mmol) and DIBA (74.8 mL, 429 mmol) in ethanol (112 mL) was heated to 70 *C for 3 h. Water and EtOAc were added and the mixture was filtered through a short plug of Celite. The organic layer was separated, dried over Na 2

SO

4 and concentrated to yield ({[2-(6-Amino-indol-1-yl)-2-oxo-ethyl] methyl-carbamoyl}-methyl)-methyl-carbamic acid tert-butyl ester (B-26) (11.4 g, quant.). HPLC ret. time 2.11 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 375.3 m/z (MH*). [00333] 2-Substituted 6-aminoindoles -116- [003341 Example 1: 0 NaNO,, HCI COEt -NH2.HC SnCI H20 O2N EtOH 0 2 N NH 2 2 2 2 H EtOH B-4-a 0N CO2 O 2 N NCO 2 Et LiAIH, O 2NEN NO, + H THF H 2 N H

CO

2 EtB B-4-b [00335] B-4-a; (3-Nitro-phenyl)-hydrazine hydrochloride salt 3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H 2 0 (40 mL) and 37% HCl (40 mL). A solution of NaNO 2 (13.8 g, 0.2 mol) in H 2 0 (60 mL) was added at 0 *C, followed by the addition of SnCl 2

-H

2 0 (135.5 g, 0.6 mol) in 37% HCl (100 mL) at that temperature. After stirring at 0 *C for 0.5 h, the solid was isolated via filtration and washed with water to give (3 nitro-phenyl)-hydrazine hydrochloride salt (B4-a) (27.6 g, 73 %). [003361 2-[(3-Nitro-phenyl)-hydrazono]-propionic acid ethyl ester (3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3 nitro-phenyl)--hydrazono]-propionic acid ethyl ester, which was used directly in the next step.. [003371 B-4-b; 4-Nitro-IH-indole-2-carboxylic acid ethyl ester and 6-Nitro 1H-indole -2-carboxylic acid ethyl ester 2

-[(

3 -Nitro-phenyl)-hydrazono]-propionic acid ethyl ester from the preceding step was dissolved in toluene (300 mL). PPA (30 g) was added. The mixture was heated at reflux overnight and then cooled to room temperature. The solvent was removed to give a mixture of 4-nitro-IH -117indole-2-carboxylic acid ethyl ester and 6-nitro-I H-indole -2-carboxylic acid ethyl ester (B-4-b) (15 g, 40 %). [003381 B-4; 2-Methyl-1H-indol-6-ylamine To a suspension of LiAIH 4 (7.8 g, 0.21 mol) in THF (300 mL) was added dropwise a mixture of 4-nitro- 1 H-indole-2-carboxylic acid ethyl ester and 6-nitro- I H-indole -2-carboxylic acid ethyl ester (B-4-b) (6g, 25.7 tnmol) in THF (50 mL) at 0 *C under N 2 . The mixture was heated at reflux overnight and then cooled to 0 *C. H 2 0 (7.8 mL) and 10 % NaOH (7.8 mL) were added to the mixture at 0 'C. The insoluble solid was removed via filtration. The filtrate was dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford 2-methyl-1H-indol-6-ylamine (B-4) (0.3 g, 8 %). 'H NMR

(CDCI

3 ) 5 7.57 (br s; 1 H), 7.27 (d, J=8.8 Hz, I H), 6.62 (s, I H), 6.51-6.53 (m, I H), 6.07 (s, I H), 3.59-3.25 (br s, 2 H), 2.37 (s, 3H); ESI-MS 147.2 m/z (MI). [003391 Example 2: 0 2 N N CO 2 Et O2N N CO 2 H H H 1 SOCl 2 O 10% NaOH 2 + a NO 2 + 2. NH,.H 2 0 N CO 2 Et N COH H H B-4-b 02N N CONH2 20N 1 CN (CFaCO)2 H H 2 . Raney Ni

NO

2 EtaN, CH2CI

N

2 + EtOH H2N CN II B-5 N CONH 2 N CN H H [00340] 6-Nitro-1H-indole-2-carboxylic acid and 4-Nitro-1HI- indole-2 carboxylic acid - 118- A mixture of 4 -nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-I H-indole -2-carboxylic acid ethyl ester (B-4-b) (0.5 g, 2.13 mmol) in 10 % NaOH (20 mL) was heated at reflux overnight and then cooled to room temperature. The mixture was extracted with ether. The aqueous phase was separated and acidified with HCl to pH 1-2. The resulting solid was isolated via filtration to give a mixture of 6-ritro- 1H-indole-2-carboxylic acid and 4-nitro-IH- indole-2 carboxylic acid (0.3 g, 68 %). [003411 6 -Nitro-1H-indole-2-carboxylic acid amide and 4-Nitro-1H- indole-2 carboxylic acid aide A mixture of 6 -nitro-IH-indole-2-carboxylic acid and 4-nitro-1H- indole-2-carboxylic acid (12 g, 58 mmol) and SOC1 2 (50 mL, 64 mmol) in benzene (150 mL) was refluxed for 2 h. The benzene and excessive SOCl 2 was removed under reduced pressure. The residue was dissolved in CH 2

C

2 (250 mL). NH40H (21.76 g, 0.32 mol) was added dropwise at 0 *C. The mixture was stirred at room temperature for 1 h. The resulting solid was isolated via filtration to give a crude m.nixture of 6 -nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H- indole-2-carboxylic acid amide (9 g, 68 %), which was used directly in the next step. [003421 6 -Nitro-1H-indole-2-carbonitrile and 4-Nitro-1H- indole-2 carbonitrile A mixture of 6 -nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H- indole-2-carboxylic acid aide (5 g, 24 mmol) was dissolved in CH 2

C

2 (200 nL). Et 3 N (24.24 g, 0.24 mol) was added, followed by the addition of (CF 3

CO)

2 0 (51.24 g, 0.24 mol) at room temperature. The mixture was stirred for 1 h and poured into water (100 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na 2 SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to. give a mixture of 6-nitro-1H-indole-2-carbonitrile and 4 nitro-1H- indole-2-carbonitrile (2.5 g, 55 %). [00343] B-5; 6-Andno-1H-indole-2-carbonitrile A mixture of 6 -nitro-1H-indole-2-carbonitrile and 4-nitro-1H- indole-2-carbonitrile (2.5 g, 13.4 mmol) and Raney Ni (500 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 - 119 atm) for I h. Raney Ni was filtered off. The filtrate was evaporated under reduced pressure and purified by column chromatography to give 6-amino-IH-indole-2-carbonitrile (B-5) (1 g, 49 %). H NMR (DMSO-d) 8 12.75 (br s, I H), 7.82 (d, J= 8 Hz, 1 H), 7.57 (s, I H), 7.42 (s, I H), 7.15 (d, J= 8 Hz, I H); ESI-MS 158.2 m/z (MH). [00344] Example 3:

NH

2 N n-BuLi Et 3 N, CH 2

C

2 THF N H NaBH 4

KNO

3 , N C N AcOH N H2SO4H H DDQ H 2 ,Raney Ni H N. N 2 1,4-dioxane 0 2 N MeOH H MeOH B-6 [003451 2,2-Dimethyl-N-o-tolyl-propionamide To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et 3 N (22.3 g, 0.22 mol) in CH 2 C1 2 was added 2,2-dimethyl-propionyl chloride (25.3 g, 0.21 mol) at 10 "C. The mixture was stirred overnight at room temperature, washed with aq. HCL (5%, 80 mL), saturated NaHCO 3 solution and brine, dried over Na 2

SO

4 and concentrated under vacuum to give 2,2--dimethyl-N-o-tolyl propionamide (35.0 g, 92 %). [00346] 2-tert-Butyl-1[H-indole To a solution of 2,2-dimethyl-N-o-tolyl- propionamide (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. The mixture was stirred - 120overnight at 15 *C, cooled in an ice-water bath and treated with saturated NH 4 CI solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated in vacuum. The residue was purified by column chromatography to give 2-tert-butyl- 1 H-indole (23.8 g, 88 %). [00347] 2-tert-Butyl-2,3-dihydro-1 H-indole To a solution of 2-tert-butyl-IH-indole (5.0 g, 29 mrnol) in AcOH (20 mL) was added NaBH 4 at 10 *C. The mixture was stirred for 20 min at 10 *C, treated dropwise with H 2 0 under ice cooling, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2

SO

4 , filtered, and concentrated under vacuum to give a mixture of starting material and 2 tert-butyl-2,3-dihydro- 1 H-indole (4.9 g), which was used directly in the next step. [003481 2-tert-Butyl-6-nitro-2,3-dihydro-1I-indole To a solution of the mixture of 2-tert-butyl-2,3-dihydro-l H-indole and 2-tert-butyl-1H-indole (9.7 g) in HzS0 4 (98%, 80 mL) was slowly added KNO 3 (5.6 g, 55.7 mnol) at 0 *C. The reaction mixture was stirred at room temperature for 1 h, carefully poured into cracked ice, basified with Na 2

CO

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

SO

4 and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0 g, 32 % over 2 steps). [003491 2-tert-Butyl-6-nitro-1H-indole To a solution of 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ at room temperature. After refluxing for 2.5 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro- 1 H-indole (1.6 g, 80 %). [00350] B-6; 2-tert-Butyl-1l-indol-6-ylamine To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Ni (0.2 g). The mixture was stirred at room temperature under H 2 (1 atm) for 3 h. The - 121 reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-I H-indol-6-yiamine (B-6) (1.0 g, 89 %). 'H NMR (DMSO d 6 ) 10.19 (s, 1 H), 6.99 (d, J= 8.1 Hz, I H), 6.46 (s, 1 H), 6.25 (dd, J= 1.8, 8.1 Hz, 1 H), 5.79 (d, J= 1.8 Hz, I H), 4.52 (s, 2 H), 1.24 (s, 9 H); ESI-MS 189.1 m/z (MH*). 1003511 3-Substituted 6-aninoindoles [003521 Example 1: H3PO4 0 2 N N'.-NH 2 .HCi 02NN N toluene H H B-4-a 0 2 N N H H 2 , Pd-C

NO

2 EtOH H 2 N N N H B-7 N H [003531 N-(3-Nitro-phenyl)-N'-propylidene-hydrazine Sodium hydroxide solution (10 %, 15 mL) was added slowly to a stirred suspension of (3-nitro phenyl)-hydrazine hydrochloride salt (B-4-a) (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 vas isolated via filtration, washed with water and dried in air to obtain N-(3 nitro-phenyl)-N'-propylidene-hydrazine, which was used directly in the next step. [003541 3-Methyl-4-nitro-1H-indole and 3-Methyl-6-nitro-1H-indole A mixture of N-(3-nitro-phenyl)-N'-propylidene-hydrazine dissolved in 85 % H 3

PO

4 (20 mL) and toluene (20 mL) was heated at 90-100 *C for 2 h. After cooling, toluene was removed under reduced pressure. The resultant oil was basified with 10 % NaOH to pH 8. The aqueous layer -122was extracted with EtOAc (100 mL x 3). The combined organic layers were dried, filtered and concentrated under reduced pressure to afford a mixture of 3-methyl-4-nitro--1H-indole and 3 methyl-6-nitro-1 H-indole (1.5 g, 86 % over two steps), which was used directly in the next step. [00355] B-7; 3-Methyl-1H-indol-6-ylamine A mixture of 3-methyl-4--nitro-1H-indole and 3-methyl-6-nitro-1H-indole (3 g, 17 mol) and 10 % Pd-C (0.5 g) in ethanol (30 mL) was stirred overnight under H 2 (1 atm) at room temperature. Pd C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 3-methyl- 1 H-indol-6-ylamine (B-7) (0.6 g, 24 %). H NMR (CDCl 3 ) 8 7.59 (br s, I H), 7.34 (d, J= 8.0 Hz, I H), 6.77 (s, 1fH), 6.64 (s, l H), 6.57 (m, I H), 3.57 (br s, 2 H), 2.28 (s, 3H); ESI-MS 147.2 m/z (MH*). [00356] Example 2: CN CISO2NCO CN H 2 , Pd-C N 0 2 N N DMF, CH 3 CN 0 2 N N EtOH H 2 N H B-8 [003571 6-Nitro-1H-indole-3-carbonitrile To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) and CH 3 CN (243 mL) was added dropwise a solution of CISO 2 NCO (5 mL, 57 mmol) in CH 3 CN (39 mL) at 0 *C . After addition, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into ice-water, basified with sat NaHCO 3 solution to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated to give 6-nitro-IH-indole-3-carbonitrile (4.6 g, 82 %). [00358] B-8; 6-Amino-1H-indole-3-carbonitrile A suspension of 6-nitro -lH-indole-3-carbonitrile (4.6 g, 24.6 mmol) and 10% Pd-C (0.46 g) in EtOH (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 (Pet. Ether / EtOAc = 3 / 1) to give 6-amino-IH-indole-3-carbonitrile (B-8) (I g, 99 %) as a pink powder. 1 H -123- NMR (DMSO-d 6 ) 5 11.51 (s, 1 H), 7.84 (d, J= 2.4 Hz, I H), 7.22 (d, J= 8.4 Hz, I H), 6.62 (s, I H), 6.56 (d, J 8.4 Hz, I H), 5.0 (s, 2H); ESI-MS 157.1 m/z (MH*). [003591 Example 3: 1. Mel Me 2 NH, HCHO 1. Mel 0 2 N N AcOH 0 2 N N 2. KCN H H N CN N H 2 , Pd-C CN 0 2 N "N EtOH H 2 N N H H B-9-a B-9 [00360] Dimethyl-(6-nitro-1l-indol-3-ylmethyl)-amine A solution of dimethylamine (25 g, 0.17 mol) and formaldehyde (14.4 mL, 0.15 mol) in acetic acid (100 mL) was stirred at 0 *C for 30 min. To this solution was added 6-nitro-1H-indole (20 g, 0.12 mol). After stirring for 3 days at room temperature, the mixture was poured into 15% aq. NaOH solution (500 mL) at 0 *C. The precipitate was collected via filtration and washed with water to give dimethyl-(6-nitro- I H-indol-3-ylmethyl)-amine (23 g, 87 %). [00361] B-9-a; (6-Nitro-1H-indol-3-yl)-acetonitrile To a mixture of DMF (35 mL) and Mel (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL x 3), dried over Na 2

SO

4 , filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-IH-indol-3 yl)-acetonitrile (B-9-a) (7.5 g, 36 %). (003621 B-9; (6-Amino-1H-indol-3-yl)-acetonitrile A mixture of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74.5 mml) and 10 % Pd-C (300 mg) in EtOH (50 mL) was stirred at room temperature under H 2 (1 atm) for 5 h. Pd-C was -124removed via filtration and the filtrate was evaporated to give (6-amino-I H-indol-3-yl) acetonitrile (B-9) (1.1 g, 90 %). 'H NMR (DMSO-d 6 ) S 10.4 (br s, I H), 7.18 (d, J= 8.4 Hz, I H), 6.94 (s, I H), 6.52 (s, I H), 6.42 (dd, J= 8.4, 1.8 Hz, I H), 4.76(s, 2 H), 3.88 (s, 2 H); ESI MS 172.1 m/z (MH+). [003631 Example 4: NHBoc NHBoc CN 1. 8H 3 .SMe 2

H

2 , Raney Ni 0 2 N N 2. Boc 2 O 2 N EtOH H 2 N N H H H B-9-a B-I 0 [00364] [2-(6-Nitro-IH- indol-3-yl)-ethyl]-carbamic acid tert-butyl ester To a solution of(6-nitro-IH-indol-3-yl)-acetonitrile (B-9-a) (8.6 g, 42.8 mmol) in dry THF (200 mL) was added a solution of 2 M borane-dimethyl sulfide complex in THF (214 mL. 0.43 mol) at 0 *C. The mixture was heated at reflux overnight under nitrogen. The mixture was then cooled to room temperature and a solution of (Boc) 2 0 (14 g, 64.2 mmol) and Et 3 N (89.0 mL, 0.64 mol) in THF was added. The reaction mixture was kept stirring overnight and then poured into ice-water, The organic layer was separated and the aqueous phase was extracted with EtOAc (200 x 3 mL). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude was purified by column chromatography to give [2-(6-nitro-1H- indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (5 g, 38 %). [00365] B-10; [2-(6-Amino-IH-indol-3-yi)-ethyl]-carbamic acid tert-butyl ester A mixture of [2-(6-nitro-1H- indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (5 g, 16.4 mmol) and Raney Ni (1 g) in EtOH (100 mL) was stirred at room temperature under H 2 (1 atm) for 5 h. Raney Ni was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give [2-(6-amino-IH-indol-3-yl)-ethyl] carbamic acid tert-butyl ester (B-10) (3 g, 67 %). 'H NMR (DMSO-d 6 ) 8 10.1 (br s, 1 H), 7.11 (d, J= 8.4 Hz, I H), 6.77-6.73 (m, 2 H), 6.46 (d, J= 1.5 Hz, 1 H), 6.32 (dd, J= 8.4, 2.1 Hz, 1 H), 4.62 (s, 2 H), 3.14-3.08 (m, 2 H), 2.67-2.62 (m, 2 H), 1.35 (s, 9H); ESI-MS 275.8 m/z (MH*). -125- [003661 Example 5: [00367] General Scheme: R Q\ b 0ON N"'l:0J N JC N 2H 0 2 N H

H

2 N H a) RX (X=Br,I), zinc triflate, TBAI, DIEA, toluene; b) H2, Raney Ni, EtOH or SnCl 2 -2H 2 0, EtOH. [003681 Specific example: Br H2, Raney Ni O2N N zinc triflate 0 EtOH TBAI, DIEA 2 H H 2 N ) NH - . B-11 [00369] 3-tert-Butyl-6-nitro-1H-indole To a mixture of 6-nitroindole (1 g, 6.2 mmol), zinc triflate (2.06 g, 5.7 mmol) and TBAI (1.7 g, 5.16 rmnol) in anhydrous toluene (11 mL) was added DIEA (1.47 g, 11.4 mmol) at room temperature under nitrogen The reaction mixture was stirred for 10 min at 120 *C, followed by addition of t-butyl bromide (0.707 g, 5.16 mmol). The resulting mixture was stirred for 45 min at 120 *C. The solid was filtered off and the filtrate was concentrated to dryness and purified by column chromatography on silica gel (Pet.EtherJItOAc 20:1) to give 3-tert-butyl-6-nitro-I H indole as a yellow solid (0.25 g, 19 %). 'H NMR (CDCl 3 ) 8 8.32 (d, J= 2.1 Hz, 1H), 8.00 (dd, J -2.1, 14.4 Hz, 1H), 7.85 (d, J= 8.7 Hz, 111), 7.25 (s, IH), 1.46 (s, 9H). [00370] B-11; 3-tert-Butyl-IH-indol-6-ylamine A suspension of 3-tert-butyl-6-nitro-IH-indole (3:0 g, 13.7mmol) and Raney Ni (0.5g) in ethanol was stirred at room temperature under H2(1 atm) for 3 h. The catalyst was filtered off and the -126filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (Pet.Ether. / EtOAc 4 : 1) to give 3-tert-butyl-IH-indol-6-ylamine (B-11) (2.0 g, 77.3%) as a gray solid. 'H NMR (CDCI): 6 7.58 (m, 2H), 6.73 (d, J= 1.2 Hz, IH), 6.66 (s, 1H), 6.57(dd, J= 0.8, 8.6 Hz, I H), 3.60 (br s, 2H), 1.42 (s, 9H). [00371] Other examples: H 2N' L H [00372] B-12; 3 -Ethyl-1H-indol-6-ylamine 3-Ethyl-1H-indol-6-ylamine (B-12) was synthesized following the general scheme above starting from 6-nitroindole and ethyl bromide. Overall yield (42 %). HPLC ret. time 1.95 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 161.3 m/z (MH*).

H

2 N N H [003731 B-13; 3 -Isopropyl-1H--indol-6-yamine 3 -Isopropyl-1H-indol-6-ylamine (B-1-3) was synthesized following the general scheme above starting from 6-nitroindole and isopropyl iodide. Overall yield (17 %). HPLC ret. time 2.06 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 175.2 m/z (MU).

H

2 N N H [003741 B-14; 3 -sec-Butyl-1H-indol-6-ylamine -127- 3 -sec-Butyl-1H-indol-6-yyamine (B-14) was synthesized following the general scheme above starting from 6-nitroindole and 2-bromobutane. Overall yield (20 %). HPLC ret. time 2.32 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 189.5 m/z (MH*).

H

2 N N [00375) B-15; 3 -Cyclopentyl-lH-indol-6-ylaniine 3- Cyclopentyl -IH-indol-6-ylamine (B-15) was synthesized following the general scheme above starting from 6-nitroindole and iodo-cyclopentane. Overall yield (16 %). HPLC ret. time 2.39 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 201.5 m/z (MH*).. 0i

H

2 N N [00376] B-16; 3 -(2-Ethoxy-ethyl)-H-indol-6-ylamine 3

-(

2 -Ethoxy-ethyl)-1H-indol-6-ylamine (B-16) was synthesized following the general scheme above starting from 6-nitroindole and 1-bromo-2-ethoxy-ethane. Overall yield (15 %). HPLC ret. time 1.56 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 205.1 m/z (MH*). .0I 0 0 N. H H [003771 B-17; ( 6 -Amino-1H-indol-3-y)-acetic acid ethyl ester - 128- (6-Amino-IH-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesized following the general scheme above starting from 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24 %). HPLC ret. time 0.95 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 219.2 m/z (MH+). {00378] 4-Substituted 6-aminoindole 0 2 N COOH 0 2 N CO 2 Et COOH

HNO

3 1. SOC1 2

H

2

SO

4 2. EtOH

NO

2

NO

2

NO

2 / CO 2 Et

N

2 SnCI DMF 02N EtOH H 2 N N

CO

2 Et H B-18 [00379] 2-Methyl-3,5-dinitro-benzoic acid To a mixture of HN0 3 (95%, 80 mL) and H 2 S0 4 (98%, 80 mL) was slowly added 2 methylbenzoic acid (50 g, 0.37 mol) at 0 *C. After addition, the reaction mixture was stirred for 1.5 h while keeping the temperature below 30 *C, poured into ice-water and stirred for 15 min. The resulting precipitate was collected via filtration and washed with water to give 2-methyl-3,5 dinitro-benzoic acid (70 g, 84 %). [00380] 2-Methyl-3,5-dinitro-benzoic acid ethyl ester A mixture of 2-methyl-3,5-dinitro-benzoic acid (50 g, 0.22 mol) in SOC 2 (80 mL) was heated at reflux for 4 h and then was concentrated to dryness. CH2C12 (50 mL) and EtOH (80 mL) were added. The mixture was stirred at room temperature for 1 h, poured into ice-water and extracted with EtOAc (3 x 100 mL). The combined extracts were washed with sat. Na 2 C0 3 (80 mL), water (2 x 100 mL) and brine (100 mL), dried over Na 2

SO

4 and concentrated to dryness to give 2 -methyl-3,5-dinitro-benzoic acid ethyl ester (50 g, 88 %), -129 - [003811 2

-(

2 -Dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethyl-amine (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 precipitate was collected via filtration and washed with water to give 2

-(

2 -dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 48 %). 100382] B-18; 6 -Amino-1H-indole-4-carboxylic acid ethyl ester A mixture of 2-(2-dimethylamino-vinyl)-3,5-dinitro- benzoic acid ethyl ester (11.3 g, 0.037 mol) and SnC 2 (83 g. 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified with sat. Na 2

CO

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

SO

4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6 -amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, 40 %). 1 H NMR (DMSO-d 6 ) 5 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), 4.324.25 (q, J= 7.2 Hz, 2 H), 1.35-1.31 (t, J= 7.2, 3 H). ESI-MS 205.0 mlz (MH). [00383] 5-Substituted 6-aminoindoles [003841 Example 1: [00385] General Scheme: H2SO 0 2 N NO2

H

2 , Raney-Ni H2N)] [003861 Specific example: -130- F 2NO2 M _2 HI2 Raney-Ni H2N

-

2

S

4 2 0N 2 DMF 0N N0 2 EtOH

H

2 B-20 1-Fluoro-5-methyl-2,4-dinitro-benzene To a stirred solution of HNO 3 (60 mL) and H 2

SO

4 (80 mL), cooled in an ice bath, was added 1 fluoro-3-methyl-benzene (27.5g, 25 mmol) at such a rate that the temperature did not rise over 35 *C. The mixture was allowed to stir for 30 min at room temperature and poured into ice water (500 mL). The resulting precipitate (a mixture of the desired product and I -fluoro-3-methyl-2,4 dinitro-benzene, approx. 7:3) was collected via filtration and purified by recrystallization from 50 mL isopropyl ether to give I -fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36 [00387] [ 2 -(5-Fluoro- 2 ,4-dinitro-phenyl)-vinyl]-dimethyl-amine A mixture of 1 -fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), dimethoxymethyl dimethylamine (11.9 g, 100 mmol) and DMF (50 mL) was heated at 100 "C for 4 h. The solution was cooled and poured into water. The red precipitate was collected via filtration, washed with water adequately and dried to give [2-(5-fluoro-2,4-dinitro-phenyl)-viny] dimethyl-amine (8 g, 63 %). [003881 B-20; 5 -Fluoro-1I-indol-6-ylanine A suspension of [ 2 -(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-anine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (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 chromatography (Pet.Ether/ EtOAc = 5 / 1) to give 5-fluoro-IH-indol-6-ylamine (B-20) as a brown solid (1 g, 16 %). 'H NMR (DMSO-d) S 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, 111), 3.91 (br s, 2H); ESI-MS 150.1 m/z (MH). [003891 Other examples: C

H

2 N 2N H - 131 - [003901 B-21; 5-Chloro-1Hf-indol-6-ylamine 5-Chloro-1H-indol-6-ylamine (B-21) was synthesized following the general scheme above starting from i-chloro-3-methyl-benzene. Overall yield (7 %). 'H NMR (CDCl 3 ) 6.7.85 (br s, I H), 7.52 (s, I H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, 2H); ESI-MS 166.0 rm/z (MH).

F

3 C ~

H

2 N N H [003911 B-22; 5-Trifluoromethyl-1H-indol-6-ylamine 5-Trifluoromethyl- I H-indol-6-ylamine (B-22) was synthesized following the general scheme above starting from I -methyl-3-trifluoromethyl-benzene. Overall yield (2 %). 'H NMR (DMSO-d 6 ) 10.79 (br s, 1 H), 7.55 (s, I H), 7.12 (s, I H), 6.78 (s, I H), 6.27(s, I H), 4.92 (s, 2 H); ESI-MS 200.8 mn/z (MH"). [00392] Example 2: 0 N Aczo, AICt NaBH 4 48%HBr Hc 0, OC H4

CH

2 Cl CH 2 1 2 mdw (1 1 mol)i MnON

H

2 , Raney N ice-water bath. After addition, the mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4 and concentrated to dryness under reduced pressure to provide I benzenesulfonyl-2,3 -dihydro-IH-indole (30.9 g, 96%) - 132 - [003941 1-(1-Benzenesulfonyl-2,3-dihydro-lH-indol-5-yl)-ethanone To a stirring suspension of AIC1 3 (144 g, 1.08 mol) in CH 2 C1 2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes. A solution of l-benzenesulfonyl 2,3-dihydro-lH-indole (46.9 g, 0.18 mol) in CH 2

CI

2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH 2 C1 2 . The combined organic layers were washed with saturated aqueous NaHC0 3 and brine, dried over Na 2

SO

4 and concentrated under vacuum to yield 1-(1-benzenesulfonyl-2,3-dihydro-H-indol-5-yl)-ethanone (42.6 g, 79 [003951 1-Benzenesulfonyl-S-ethyl-2,3-diliydro-1H-indole To magnetically stirred TFA (1600 mL) was added at 0 *C sodium borohydride (64 g, 1.69 mol) over I h. To this mixture was added dropwise a solution of 1-(1-benzenesulfonyl-2,3-dihydro IH-indol-5-yl)-ethanone (40 g, 0.13 mol) in TFA (700 mL) over 1 h. The mixture was stirred overnight at 25 'C, diluted with H 2 0 (1600 ml), and basified with sodium hydroxide pellets at 0 C. The organic layer was separated and the aqueous layer was extracted with CH 2

CI

2 . The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica get to give I benzenesulfony-5-ethyl-2,3-dihydro-1H-indole (16.2 g, 43 %). 1003961 5-Ethyl-2,3-dihydro-1H-indole A mixture of I-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH solution to pH 9 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-ethyl-2,3-dihydro- I H-indole (2.5 g, 32 %). [00397] 5-Ethyl-6-nitro-2,3-dihydro-1H-indole To a solution of 5-ethyl-2,3-dihydro-IH-indole (2.5 g, 17 mmol) in H 2

SO

4 (98%, 20 mL) was slowly added KNO 3 (1.7 g, 17 mmol) at 0 *C. After addition, the mixture was stirred at 0 - 10 - 133 - *C for 10 min, carefully poured into ice, basified with NaOH solution to pH 9 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na 2

SO

4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-6-nitro-2,3--dihydro-H-indole (1.9 g, 58 %). [00398] 5-Ethyl-6-nitro-1I-indole To a solution of 5-ethyl-6-nitro-2,3-dihydro--I H-indole (1.9 g, 9.9 mmol) in CH 2 Cl 2 (30 mL) was added MnO 2 (4 g, 46 mmol). The mixture was stirred at room temperature for 8 h. The solid was filtered off and the filtrate was concentrated to dryness to give crude 5-ethyl-6-nitro- 1 H indole (1.9 g, quant.). [003991 B-23; 5-Ethyl-1H-indol-6-ylamine A suspension of 5-ethyl-6-nitro-l H-indole (1.9 g, 10 mmol) and Raney Ni (1 g) was stirred 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 column chromatography on silica gel to give 5-ethyl-lH-indol-6-ylamine (B-23) (760 mg, 48 %). 'H NMR (CDC1 3 ) 8 7.90 (br s, IH), 7.41 (s, 111), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (br s, 2H), 2.63 (q, J= 7.2 Hz, 2H), 1.29 (t, J= 6.9 Hz, 3H); ESI-MS 161.1 m/z (MH). [00400] Example 3: BrBr P(M)C NBS, DMF NHKNO3 H 2 SOA rH NIhe --- N2NH 2 -5- -10 0C 0 2 N NH 2 Cut, Et 3 N Tot, H 2 0 ~ Si Cul, DMF H 2 , Raney Ni

O

2 N NH 2 0 2 N N MeOH H 2 N N H H B-24 [00401] 2-Bromo-4-tert-butyl-phenylamine -134- To a solution of 4 -tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2

SO

4 and concentrated. The crude product was directly used in the next step without further purification. 100402] 2 -Bromo-4-tert-butyl-5-nitro-phenylam-ine 2 -Bromo-4-tert-butyl-phenylamine (162 g, 0.71 mol) was added dropwise to H 2

SO

4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to -5 to -10 *C. A solution of KNO 3 (82.5 g, 0.82 mol) in H 2 S0 4 (410 mL) was added dropwise while the temperature was maintained between -5 to -10 *C. Upon completion, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na 2

CO

3 and brine, dried over Na 2

SO

4 and concentrated. The residue was purified by a column chromatography (EtOAc / petroleum ether I / 10) to give 2 -bromo-4-tert-butyl-5-nitro phenylamine as a yellow solid (152 g, 78 %). [00403] 4-tert-Butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine To a mixture of 2 -bromo-4-tert-butyl-5-nitro-phenyam'ine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et 3 N (27.9 mL, 200 mmol), Pd(PPh 3

)

2

C

2 (2.11 g, 3 mmol), CuI (950 mg, 0.5 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 *C in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH 4 0H solution and water, dried over Na 2

SO

4 and concentrated. The crude product was purified by column chromatography (0 - 10 % EtOAc / petroleum ether) to provide 4-tert-butyl-5-nitro-2 trimethylsilanylethynyl-phenylarnine as a brown viscous liquid (25 g, 81 %). [004041 5-tert-Butyl-6-nitro-1H-indole To a solution of 4 -tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added Cul (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 - 135 filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na 2

SO

4 and concentrated. The crude product was purified by column chromatography (10 - 20 % EtOAc / Hexane) to provide 5-tert-butyl-6-nitro IH-indole as a yellow solid (12.9 g, 69%). [004051 B-24; 5-tert-Butyl-1H-indol-6-ylamine Raney Ni (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30 "C for 3 h. The catalyst was filtered off. The filtrate was dried over Na 2

SO

4 and concentrated. The crude dark brown viscous oil was purified by column chromatography (10 -20 % EtOAc / petroleum ether) to give 5-tert-butyl 1H-indol-6-ylamine (B-24) as a gray solid (11 g, 87 %). 'H NMR (300 MHz, DMSO-d6) 8 10.3 (br s, 1H), 7.2 (s, IH), 6.9 (m, IH), 6.6 (s, IH), 6.1 (in, IH), 4.4 (br s, 2H), 1.3 (s, 9H). [00406] Example 4: c2H 1. HN03y HzSO4 CO 2 Et -N EtO C H, E02C O, Raneyi NI H2N 2. SoC, EtOH O2N NO 2 DMF 0 2 N NO2 B-25 H [004071 5-Methyl-2,4-dinitro-benzoic acid To a mixture of HNO 3 (95 %, 80 mL) and H 2 S0 4 (98 %, 80 mL) was slowly added 3 methylbenzoic acid (50 g, 0.37 mol) at 0 "C. After addition, the mixture was stirred for 1.5 h while maintaining the temperature below 30 *C. The mixture was poured into ice-water and stirred for 15 mi. The precipitate was collected via filtration and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84 %). To a solution of this mixture in EtOH (150 mL) was added dropwise SOC 2 (53.5 g, 0.45 mol). The mixture was heated at reflux for 2 h and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 10% Na 2

CO

3 solution (120 mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester while the aqueous layer contained 3-methyl-2,6-dinitro-benzoic acid. The organic layer was washed with brine (50 mL), dried over Na 2

SO

4 and concentrated to dryness to provide 5-methyl-2,4 dinitro-benzoic acid ethyl ester (20 g, 20 %). -136- [00408] 5-( 2 -Dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester A mixture of 5-methyl-2,4-dinitro-benzoic acid ethyl ester (39 g, 0.15 mol) and dimethoxymethyl-dimethylamine (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 precipitate was collected via filtration and washed with water to afford 5-( 2 -dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 28 %). [00409] B-25; 6 -Amino-1H-indole-5-carboxylic acid ethyl ester A mixture of 5-( 2 -dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 0.05 mol) and Raney Ni (5 g) in EtOH (500 mL) was stirred under H 2 (50 psi) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-I H-indole-5-carboxylic acid ethyl ester (B-25) (3 g, 30 %). 'H NMR (DMSO-d 6 8 10.68 (s, I 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). [00410] Example 5: 0 C Br Br HCJ Br III\C ION qqAc Ac

KNO

3 Br D Br OH 2 , Raney Ni Sr01 S1.4-doxane o EN EtOH B-27 1-(2, 3 -Dihydro-indol-1-yl)-ethanone To a suspension of NaHCO 3 (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 mol) in

CH

2 Cl 2 (600 mL) cooled in an ice-water bath, was added dropwise acetyl chloride (78.5 g, 1.0 -137mol). The mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated to give 1-(2,3-dihydro-indol- 1-yl)-ethanone (82 g, 100 %). [004111 1-(5-Bromo-2,3-dihydro-indol--1-yI)-ethanone To a solution of 1-(2,3-dihydro-indol-I-yl)-ethanone (58.0 g, 0.36 mol) in acetic acid (3000 mL) was added Br 2 (87.0 g, 0.54 mol) at 10 *C. The mixture was stirred at room temperature for 4 h. The precipitate was collected via filtration to give crude ]-(5-bromo-2,3 -dihydro-indol- 1-yl) ethanone (100 g, 96 %), which was used directly in the next step. [004121 5-Bromo-2,3-dihydro-1H-indole A mixture of crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 0.34 mol) in HCI (20 %, 1200 mL) was heated at reflux for 6 h. The mixture was basified with Na 2

CO

3 to pH 8.5-10 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-bromo-2,3-dihydro-1H-indole (37 g, 55 %). [004131 5-Bromo-6-nitro-2,3-dihydro-1H-indole To a solution of 5-bromo-2,3-dihydro-1H-indole (45 g, 0.227 mol) in H 2

SO

4 (98 %, 200 mL) was slowly added KNO 3 (23.5 g, 0.23 mol) at 0 *C. After addition, the mixture was stirred at 0 10 *C for 4 h, carefully poured into ice, basified with Na 2

CO

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

SO

4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-6-nitro-2,3-dihydro-IH-indole (42 g, 76 %). [004141 5-Bromo-6-nitro-1H-indole To a solution of 5-bromo-6-nitro-2,3-dihydro-1H-indole (20 g, 82.3 mmol) in 1,4-dioxane (400 mL) was added DDQ (30 g, 0.13 mol). The mixture was stirred at 80 *C for 2 h. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford 5-bromo-6-nitro-1H-indole (7.5 g, 38 %). [004151 B-27; 5-Bromo-1H-indol-6-ylamine -138- A mixture of 5-bromo-6-nitro-1 H-indole (7.5 g, 31.1 mmol) and Raney Ni (I g) in ethanol was stirred under H 2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-IH-indol-6-ylamine (B-27) (2 g, 30 %). 'H NMR (DMSO-d) 8 1 0.6 (s, 1 H), 7.49 (s, I H), 6.79-7.02 (m, 1 H), 6.79 (s, I H), 6.14-6.16 (m, I H), 4.81 (s, 2 H). [00416] 7-Substituted 6-aminoindole

NO

2 NO 2

CO

2 H 1. HNO 3 , H 2

SO

4

CO

2 H SOC1 2

CO

2 Et 2. SOCN2, EtOH

NO

2 EtOH

NO

2 C -W N 2N H2

H

2 N DMF EtO 2 C NO 2 Raney Ni CO 2 EtH B-19 100417] 3 -Methyl-2,6-dinitro-benzoic acid To a mixture of HNO 3 (95 %, 80 mL) and H 2 S0 4 (98 %, 80 mL) was slowly added 3 methylbenzoic acid (50 g, 0.37 mol) at 0 *C. After addition, the mixture was stirred for 1.5 h while maintaining the temperature. below 30 *C. The mixture was poured into ice-water and stirred for 15 min. The precipitate was collected via filtration and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84 %). To a solution of this mixture in EtOH (150 mL) was added dropwise SOC 2 (53.5 g, 0.45 mol). The mixture was heated to reflux for 2 h and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 10% Na 2

CO

3 solution (120 mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester. The aqueous layer was acidified with HC1 to pH 2 - 3 and the resulting precipitate was collected via filtration, washed with water and dried in air to give 3-methyl-2,6-dinitro-benzoic acid (39 g, 47 -139- [004181 3-Methyl-2,6-dinitro-benzoic acid ethyl ester A mixture of 3-methyl-2,6-dinitro-benzoic acid (39 g, 0.15 mol) and SOC1 2 (80 mL) was heated at reflux for 4 h. The excess SOCl 2 was removed under reduced pressure and the residue was added dropwise to a solution of EtOH (100 mL) and Et 3 N (50 mL). The inixture was stirred at 20 *C for I h and concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with Na 2

CO

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

SO

4 and concentrated to give 3-methyl-2,6-dinitro-benzoic acid ethyl ester (20 g, 53 %). [00419] 3

-(

2 -Dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester A mixture of 3-methyl-2,6-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethylamine (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 precipitate was collected via filtration and washed with water to give 3

-(

2 -dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (25 g, 58%). [00420] B-19; 6-Amino-1H-indole-7-carboxylic acid ethyl ester A mixture of 3-(2-dimethylamino-vinyl)-2, 6-dinitro-benzoic acid ethyl ester (30 g, 0.097 mol) and Raney Ni (10 g) in EtOH (1000 mL) was stirred under H 2 (50 psi) for 2 h. The catalyst was filtered pff and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-7-carboxylic acid ethyl ester (B-19) as an off-white solid (3.2 g, 16 %). 'H NMR (DMSO-d) 6 10.38 (s, 1 H), 7.44-7.41 (d, J= 8.7 Hz, 1 H), 6.98 (t, 1 H), 6.65 (s, 2 H), 6.50-6,46 (m, 1 H), 6.27-6.26 (m, 1 H), 4.43-4.36 (q, J= 7.2 Hz, 2 H), 1.35 (t, J= 7.2 Hz, 3 H). [004211 Phenols [00422] Example 1: KNO,. HS , NNO

NH

4 COOH N -S4 V OH P C-1-a C-1 - 140 - [004231 2 -tert-Butyl-5-nitroaniline To a cooled solution of sulfuric acid (90 %, 50 mL) was added dropwise 2-tert-butyl phenylamine (4.5 g, 30 mmol) at 0 *C. Potassium nitrate (4.5 g, 45 mmol) was added in portions at 0 *C. The reaction mixture was stirred at 0-5 *C for 5 min, poured into ice-water and then extracted with EtOAc three times. The combined organic layers were washed with brine and dried over Na 2

SO

4 . After removal of solvent, the residue was purified by recrystallization using 70 % EtOH - H20 to give 2 -tert-butyl-5-nitroaniline (3.7 g, 64 %). 'H NMR (400 MHz, CDCl3) 6 7.56 (dd, J= 8.7, 2.4 Hz, 1 H), 7.48 (d, J= 2.4 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.17 (s, 2H), 1.46 (s, 9H); HPLC ret. time 3.27 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 195.3 m/z (MH). [00424] C-1-a; 2-tert-Butyl-5-nitrophenol To a mixture of 2 -tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mL of 15 % H 2 S0 4 was added dropwise a solution of NaNO 2 (763 mg, 11.0 mmol) in water (3 mL) at 0 *C. The resulting mixture was stirred at 0-5 *C for 5 min. Excess NaNO 2 was neutralized with urea, then 5 mL of H 2

SO

4

-H

2 0 (v/v 1:2) was added and the mixture was refluxed for 5 min. Three additional 5 mL aliquots of H2SO4-H20 (v/v 1:2) were added while heating at reflux. The reaction mixture was cooled to room temperature and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO 4 . After removal of solvent, the residue was purified by column chromatography (0-10 % EtOAc - Hexane) to give 2 -tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62 %). 'H NMR (400 MHz, CDCl 3 ) 5 7.76 (dd, I= 8.6,2.2 Hz, 1H), 7.58 (d, J= 2.1 Hz, 1H), -7.43 (d, J = 8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99 % CH 3 CN, 5 min run. [004251 C-1; 2 -tert-Butyl-5-aminophenoL To a refluxing solution of 2-tert-butyl 5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd-C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2 -tert-butyl-5-aminophenol (C-1) (144 mg, 87 %). 'H NMR (400 MHz, DMSO-ds) 6 8.76 (s, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.04 (d, J= 2.3 Hz, 1H), 5.93 (dd, J = 8.2, 2.3 Hz, IH), - 141 - 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99 % CH3CN, 5 min run; ES I-MS 166.1 m/z (MH*). [004261 Example 2: [00427] General scheme: R RN 0 2 N OH 0 2 N R H2N C-1-a a) RX (X = Br, 1), K 2

CO

3 or Cs 2

CO

3 , DMF; b) HCO2NH 4 or HCO 2 K, Pd-C, EtOH [00428] Specific example: CH)1, K 2 C0 HCOOK 0 2 N OH DMF, RT 0 2 N Pd-C H 2 N 0 C-1-a C-2 [00429] 1-tert-Butyl-2-methoxy-4-nitrobenzene To a mixture of 2 -tert-butyl-5-nitrophenol (C-1-a) (100 mg, 0.52 mmol) and K 2 C0 3 (86 mg, 0.62 mmol) in DMF (2 mL) was added CH3 (40 uL, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4 . After filtration, the filtrate was evaporated to dryness to give 1-tert-butyl-2-methoxy4-nitrobenzene (82 mg, 76 %) that was used without further purification. 'H NMR (400 MHz, CDC 3 ) 5 7.77 (t, J 4.3 Hz, IH), 7.70 (d, J= 2.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, IH), 3.94 (s, 3H), 1.39 (s, 9H). [004301 C-2; 4 -tert-Butyl-3-methoxyaniline To a refluxing solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (2 mL) was added potassium formate (300 mg, 3.6 mmol) in water (1 mL), followed by 10% Pd-C (15 mg). The reaction mixture was refluxed for additional 60 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to dryness to give 4-tert-butyl-3 - 142 methoxyaniline (C-2) (52 mg, 72 %) that was used without further purification. HPLC ret. time 2.29 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 180.0 m/z (MH*). [00431] Other examples:

H

2 N O [00432] C-3; 3

-(

2 -Ethoxyethoxy)-4-tert-bitylbenzenamine 3-( 2 -Ethoxyethoxy)-4-tert-butylbenzenamine (C-3) was synthesized following the general scheme above starting from 2 -tert-butyl-5-nitrophenol (C-1-a) and 1 -bromo-2-ethoxyethane. 'H NMR (400 MHz, CDC1 3 ) 6 6.97 (d, J = 7.9 Hz, IH), 6.17 (s, IH), 6.14 (d, J = 2.3 Hz, 1H), 4.00 (t, J= 5.2 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J 7.0 Hz, 3H); HPLC ret. time 2.55 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 238.3 m/z (MH*).

H

2 N O OH [004331 C4; 2

-(

2 -tert-Butyl-5-aminophenoxy)ethanoI 2

-(

2 -tert-Butyl-5-aminophenoxy)ethano (C4) was synthesized following the general scheme above starting from 2 -tert-butyl-5-nitrophenol (C-I-a) and 2-bromoethanol. HPLC ret. time 2.08 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 210.3 m/z (MH*). -143- [004341 Example 3: AcCI + O H2N OH c H o DEAD H AC3 0 NaO

H

2 N C-5 [004351 N-( 3 -Hydroxy-phenyl)-acetamide and acetic acid 3 -formylamino-phenyl ester To a well stirred suspension of 3-amino-phenol (50 g, 0.46 mol) and NaHCO 3 (193.2 g, 2.3 mol) in chloroform (1 L) was added dropwise chloroacetyl chloride (46.9 g, 0.6 mol) over a period of 30 min at 0 "C. After the addition was complete, the reaction mixture was refluxed overnight and then cooled to room temperature. The excess NaHCO 3 was removed via filtration. The filtrate was poured into water and extracted with EtOAc (300 x 3 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to give a mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3 formylamino-phenyl ester (35 g, 4:1 by NMR analysis). The mixture was used directly in the next step. [004361

N-[

3

-(

3 -Methyl-but-3-enyloxy)-phenyl]-acetamide A suspension of the mixture of N-( 3 -hydroxy-phenyl)-acetaide and acetic acid 3-formylamino phenyl ester (18.12 g, 0.12 mol), 3 -methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph 3 P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated.- The -144residue was purified by column chromatography to give N-[ 3 -(3-methyl-but-3-enyloxy)-phenyl) acetamide (11 g, 52 %). [004371 N-(4,4-Dimethyl-chroman-7-y1)-acetamide A mixture of N-[ 3

-(

3 -methyl-but-3-enyloxy)-phenylJ-acetamide (2.5 g, 11.4 mmol) and AIC1 3 (4.52 g, 34.3 mmol) in fluoro-benzene (50 mL) was heated at reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted with EtOAc (40 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated under vacuum. The residue was purified by column chromatography to give N-(4,4-dimethyl-chroan-7-yl)-acetamide (1.35 g, 54 %). [004381 C-5; 3

,

4 -Dihydro-4,4-dimethyl-2H-chromen--7-amine A mixture of N-( 4

,

4 -dimethyl-chroman-7-y1)-acetamide (1.35 g, 6.2 mmol) in 20 % HCI solution (30 mL) was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was basified with 10 % aq. NaOH to pH 8 and extracted with EtOAc (30 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated to give 3

,

4 -dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, 92 %). 'H NMR (DMSO-d 6 ) 5 6.87 (d, J = 8.4 Hz, 1 H), 6.07 (dd, J= 8.4, 2.4 Hz, 1 H), 5.87 (d, J= 2.4 Hz, 1 H), 4.75 (s, 2 H), 3.99 (t, J= 5.4 Hz, 2 H), 1.64 (t, J= 5.1 Hz, 2 H), 1.15 (s, 6 H); ESI-MS 178.1 m/z (MH). [004391 Example 4: [00440] General scheme: - 145- - OH aOH0 ON o X R -,a c d X R X R RO O2NOH H2N OH X = F, Cl; a) ROH, H 2

SO

4 or MeSO 3 H, CHf 2

C

2 ; b) R'CO 2 CI, Et 3 N, 1,4-dioxane or CHC1 3 ; c)

HNO

3 , H 2

SO

4 or KNO 3 , H 2

SO

4 or HNO 3 , AcOH; d) piperidine, CH 2 Cl 2 ; e) HCO 2

NH

4 , Pd-C, EtOH or SnC1 2 .2H 2 0, EtOH or H 2 , Pd-C, MeOH. [004411 Specific example F OH F ECC2 F HSO OH H 2 S04, CHA0 Et3N NFC2HS~ OH

-

C

2 I

HS

4 0 0 F I__________ HC0 2 NH, C-7N

CH

2

C;

2 0 2 O PdIC, EtOH O1N OH + C-7 F

NO

2 0 C-6-a [00442] 2 -tert-Butyl-4-fluorophenol 4-Fluorophenol (5g, 45 mmol) and tert-butanol (5.9 mL, 63 mmol) were dissolved in C11 2 Cl 2 (80 mL) and treated with concentrated sulfuric acid (98 %, 3 mL). The mixture wiias stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHCO 3 , -146dried over MgSO 4 and concentrated. The residue was purified by column chromatography (5-15 % EtOAc - Hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42 %). 'H NMR (400 MHz, DMSO-d 6 ) 8 9.32 (s, 1H), 6.89 (dd, J= 11.1, 3.1 Hz, IH), 6.84-6.79 (m, I H), 6.74 (dd, J= 8.7, 5.3 Hz, IH), 1.33 (s, 9H). [004431 2-tert-Butyl-4-fluorophenyl methyl carbonate To a solution of 2-tert-butyl-4-fluorophenol (2.63g, 15.7 mmol) and NEt 3 (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methyl chloroformate (1.27 mL, 16.5 mmol). The mixture was stirred at room temperature for 1 h. The precipitate was removed via filtration. The filtrate was then diluted with water and extracted with ether. The ether extract was washed with water and dried over MgSO 4 . After removal of solvent, the residue was purified by column chromatography to give 2-tert-butyl-4-fluorophenyl methyl carbonate (2.08g, 59 %). 'H NMR (400 MHz, DMSO-d 6 ) 6 7.24 (dd, J = 8.8, 5.4 Hz, IH), 7.17-7.10 (m, 2H), 3.86 (s, 3H), 1.29 (s, 9H). [00444] 2-tert-Butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) and 2 tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (C-6-a) To a solution of 2-tert-butyl-4-fluorophenyl methyl carbonate (1.81g, 8 mmol) in H 2

SO

4 (98 %, I mL) was added slowly a cooled mixture of H 2

SO

4 (1 mL) and HNO 3 (1 mL) at 0 *C. The mixture was stirred for 2 h while warming to room temperature, poured into ice and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by column chromatography (0-10 % EtOAc - Hexane) to give 2-tert butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) (1.2 g, 55 %) and 2-tert-butyl-4-fluoro-6 nitrophenyl methyl carbonate (C-6-a) (270 mg, 12 %). 2-tert-Butyl-4-fluoro-5-nitropheny methyl carbonate (C-7-a): 'H NMR (400 MHz, DMSO-ds) 8 8.24 (d, J = 7.1 Hz, 1 H), 7.55 (d, J = 13.4 Hz, 1H), 3.90 (s, 3H), 1.32 (s, 9H). 2-tert-butyl-4-fluoro-6-nitropheny methyl carbonate (C-6-a): '11 NMR. (400 MHz, DMSO-d) 5 8.04 (dd, J = 7.6, 3.1 Hz, 111), 7.69 (dd, J= 10.1, 3.1 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 9H). [004451 2-tert-Butyl-4-fluoro-5-nitrophenol -147- To a solution of 2 -tert-butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) (1.08 g, 4 mmol) in CH 2 Cl 2 (40 mL) was added piperidine (3.94 mL, 10 mmol). The mixture was stirred at room temperature for 1 h and extracted with IN NaOH (3x). The aqueous layer was acidified with IN HCI and extracted with diethyl ether. The ether extract was washed with brine, dried (MgSO4) and concentrated to give 2 -tert-butyl-4-fluoro-5-nitrophenol (530 ng, 62 %). 'H NMR (400 MHz, DMSO-d 6 ) 8 10.40 (s, IlH), 7.49 (d, J = 6.8 Hz, 1H), 7.25 (d, J = 13.7 Hz, 1H), 1.36 (s, 9H). [004461 C-7; 2 -tert-Butyl-5-anino-4-fluorophenol To a refluxing solution of 2 -tert-butyl-4-fluoro-5-nitrophenol (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) was added 5 % Pd-C (260 mg). The mixture was refluxed for additional I h, cooled and filtered through Celite. The solvent was removed by evaporation to give 2 -tert-butyl-5-amino-4-fluorophenol (C-7) (550 mg, 83 %). 'H NMR (400 MHz, DMSO-d) 5 8.83 (br s, I H), 6.66 (d, J = 13.7 Hz, IH), 6.22 (d, J = 8.5 Hz, 111), 4.74 (br s, 2H), 1.26 (s, 9H); HPLC ret. time 2.58 min, 10-99 % CH 3 CN, 5 min run; ESI MS 184.0 m/z (MH 4 ). [004471 Other examples: CI

H

2 N OH [004481 C-10; 2-tert-Butyl-5-amino-4-chlorophenol 2 -tert-Butyl-5-amino-4-chlorophenol (C-10) was synthesized following the general scheme above starting from 4-chlorophenol and tert-butanol. Overall yield (6 %). HPLC ret. time 3.07 min, 10-99 % CH 3 CN, 5 min rn; ESI-MS 200.2 m/z (MH). - 148 - F

H

2 N OH [004491 C-13; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol S-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3 %). HPLC ret. time 3.00 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 224.2 m/z (MH+). F

H

2 N OH [004501 C-19; 5-Amino-2-(3-ethylpentan-3-yl)-4-fluoro-phenol 5-Amino-2-(3-ethylpentan-3-yl)-4-fluoro-phenol (C-19) was synthesized following the general scheme above starting from 4-fluorophenol and 3-ethyl-3-pentanol. Overall yield (1 %). F

H

2 N OH [004511 C-20; 2-Admantyl-5-amino-4-fluoro-phenol 2-Admantyl-5-amino-4-fluoro-phenol (C-20) was synthesized following the general scheme above starting from 4-fluorophenol and adamantan-I-ol. F

H

2 N OH -149- 1004521 C-21; 5-Amino-4-fluoro-2-(1-methylcycloheptyl)phenol 5-Amino-4-fluoro-2-(I-methylcycloheptyl)phenol (C-21) was synthesized following the general scheme above starting from 4-fluorophenol and I -methyl-cycloheptanol. F

H

2 N OH [00453] C-22; 5-Amino-4-fluoro-2-(1-methylcyclooctyl) phenol 5 -Amino-4-fluoro-2-(1-methylcyclooctyl)phenol (C-22) was synthesized following the general scheme above starting from 4-fluorophenol and I -methyl-cyclooctanol. F

H

2 N OH [004541 C-23; 5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol 5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol (C-23) was synthesized following the general scheme above starting from 4-fluorophenol and 3-ethyl-2,2-dimethyl-pentan-3-ol. [00455] Example 5: F F

HCO

2

NH

4 O O Pd-C, EtOH O O

NO

2 Y

NH

2 C-6-a C-6 [00456] C-6; 2-tert-Butyl-4-fluoro-6-aminophenyl methyl carbonate - 150 - To a refluxing solution of 2 -tert-butyl-4-fluoro-6-nitropheny methyl carbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 mL) was added 5 % Pd-C (170 mg). The mixture was refluxed for additional I h, cooled and filtered through Celite. The solvent was removed by evaporation and the residue was purified by column chromatography (0-15 %, EtOAc - Hexane) to give 2-tert-butyl-4-fluoro-6-aminophenyl methyl carbonate (C-6) (60 mg, 27 %). HPLC ret. time 3.35 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 242.0 m/z (MH*). (004571 Example 6: CICO2Me HNO%, HrSO' NEtDMAP OH C2CI,

HCO

2

NH

4 ON 2NH Pd-C, EtOH HzN OH ON a OHc O O KOH.MeOH SnC6.2H 2 0 OI EtOH OH NOOH NO- NO, NH, 0 C-8 [00458] Carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butyl phenol (103.2g, 500 mmol), Et 3 N (139 mL, 1000 mmol) and DMAP (3.05g, 25 mmol) in dichiloromethane (400 mL) cooled in an ice-water bath to 0 *C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1 L) using 10% ethyl acetate - hexanes (- 4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.). 'H NMR (400 MHz, DMSO-d 6 ) 8 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H). -151 - [004591 Carbonic acid 2

,

4 -di-tert-butyl-5-nitro-phenyl ester methyl ester and Carbonic acid 2

,

4 -di-tert-butyl-6-nitro-phenyl ester methyl ester To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 18 mmol) in conc. sulfuric acid (2 mL), cooled in an ice-water bath, was added a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL). The addition was done slowly so that the reaction temperature did not exceed 50 *C. The reaction was allowed to stir for 2 h while warming to room temperature. The reaction mixture was then added to ice-water and extracted into diethyl ether. The ether layer was dried (MgSO 4 ), concentrated and purified by column chromatography (0 - 10% ethyl acetate - hexanes) to yield a mixture of carbonic acid 2,4-di-tert-butyl-5-nitro phenyl ester methyl ester and carbonic acid 2

,

4 -di-tert-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step. 1004601 2, 4 -Di-tert-butyl-5-nitro-phenol and 2 ,4-Di-tert-butyl-6-nitro-phenol The mixture of carbonic acid 2 ,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2

,

4 -di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 12.9 mmol) was dissolved in MeOH (65 mL) and KOH (2.0g, 36 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by adding conc. HCI and partitioned between water and diethyl ether. The ether layer was dried (MgSO 4 ), concentrated and purified by column chromatography (0 - 5 % ethyl acetate - hexanes) to provide 2

,

4 -di-tert-butyl-5-nitro-phenol (1.31 g, 29 % over 2 steps) and 2,4-di-tert-butyl-6-nitro phenol. 2 ,4-Di-tert-butyl-5-nitro-phenol: 'H NMR (400 MHz, DMSO-d) 5 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2

,

4 -Di-tert-butyl-6-nitro-phenol: 'H NMR (400 MHz, CDCl 3 ) 6 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J 2.4 Hz, I H), 1.47 (s, 9H), 1.34 (s, 9H). [00461] C-9; 5-Amino-2,4-di-tert-butyl-phenol To a reluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.4 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to yield 5-amino-2,4-di-tert-butyl-phenoI as a grey solid (1.66 g, quant.). 'H NMR (400 MHz, -152- DMSO-d 6 ) 8 8.64 (s, I H, OH), 6.84 (s, I H), 6.08 (s, I H), 4.39 (s, 2H, NH 2 ), 1.27 (m, 18H); HPLC ret. time 2.72 min, 10-99 % CH3CN, 5 min run; ESI-MS 222.4 m/z (MH*I). 1004621 C-8; 6 -Amino-2,4-di-tert-butyl-phenoI A solution.of 2

,

4 -di-tert-butyl--6-nitro-phenol (27 mg, 0.11 mmol) and SnC1 2 .2H 2 0 (121 mg, 0.54 mnmol) in EtOH (1.0 mL) was heated in microwave oven at 100 *C for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO 3 and filtered through Celite. The organic layer was separated and dried over Na 2

SO

4 . Solvent was removed by evaporation to provide 6 -amino-2,4-di-tert-butyl-phenol (C-8), which was used without further purification. HPLC ret. time 2.74 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 222.5 m/z (MH 4 ). [004631 Example 7: sO2. . Cl C _ NC IC Q M K N O , H 2 S O 4 OH . OOH Et 3 N, DMAP CH2C C' CI C 1 KOHMeOH H- Ni ON oMecM 02N OH MeOH OH O O C-11 [004641 4 -tert-butyl-2-chloro-phenol To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and S0 2

C

2 (37.5 g, 0.28 mol) in CH 2

C

2 was added MeOH (9.0 g, 0.28 mol) at 0 *C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether / EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95 %). [00465] 4 -tert-Butyl-2-chlorophenyl methyl carbonate - 153 - To a solution of 4 -tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 mL) was added Et 3 N (50.5 g, 0.50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at 0 *C. The reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction mixture was washed with H 2 0 and the organic layer was dried over Na 2

SO

4 and concentrated to give 4 -tert-butyl-2-chlorophenyl methyl carbonate (56.6 g, 92 %), which was used directly in the next step. [004661 4 -tert-Butyl-2-chloro-5-nitrophenyI methyl carbonate 4 -tert-Butyl-2-chlorophenyl methyl carbonate (36.0 g, 0.15 mol) was dissolved in conc. H 2 SO4 (100 mL) at 0 *C. KNO 3 (0.53 g, 5.2 mmol) was added in portions over 25 min. The reaction was stirred for 1.5 h and poured into ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aq. NaHCO 3 , dried over Na 2

SO

4 and concentrated under vacuum to give 4-tert-butyl-2-chloro-5-nitropheny methyl carbonate (41.0 g), which was used without further purification. [00467] 4 -tert-Butyl-2-chloro-5-nitro-phenol Potassium hydroxide (10.1 g, 181 mmol) was added to 4 -tert-butyl-2-chloro-5-nitrophenyt methyl carbonate (40.0 g, 139 mmol) in MeOH (100 mL). After 30 min, the reaction was acidified with IN HCI and extracted with dichloromethane. The combined organic layers were combined, dried over Na 2

SO

4 and concentrated under vacuum. The crude residue was purified by column chromatography (Pet. Ether / EtOAc, 30:1) to give 4-tert-butyl-2-chloro-5-nitro phenol (23.0 g, 68 % over 2 steps). [00468] C-11; 4 -tert-Butyl-2-chloro-5-amino-phenol To a solution of 4-tert-butyl-2-chloro-5-nitro-phenol (12.6 g, 54.9 mmol) in MeOH (50 mL) was added Ni (1.2 g). The reaction was shaken under H 2 (1 atm) for 4 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (P.E. / EtOAc, 20:1) to give 4 -tert-butyl-2-chloro-5-amino-phenol (C-11) (8.5 g, 78 %). 1 H NMR (DMSO-d) 5 9.33 (s, 1 H), 6.80 (s, 1 H), 6.22 (s, I H), 4.76 (s, I H), 1.23 (s, 9 H); ESI MS 200.1 m/z (MH). -154- 1004691 Example 8: Admanty Admanty Admantyf CICO 2Et

KNO

3 . H 2 S0 4 I OH *CH-ICl 2 - OO Ad atNEt, MAP OaoN 0 Piperidine Admantyl Admantyl H2Cl20 EtOH ON OH HN OH C-12 2 -Admantyl-4-methyl-phenyl ethyl carbonate Ethyl chloroformate (0.64 mL, 6.7 mmol) was added dropwise to a solution of 2-admantyl-4 methylphenol (1.09 g, 4.5 mmol), Et 3 N (1.25 mL, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 mL) cooled in an ice-water bath to 0 *C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered and the filtrate was concentrated. The residue was purified by column chromatography (10-20 % ethyl acetate -hexanes) to yield 2 admantyl-4-methyl-phenyl ethyl carbonate as a yellow oil (1.32 g, 94 %). [00470] 2 -Admantyl-4-methyl-5-nitrophenyl ethyl carbonate To a cooled solution of 2 -adrnantyl-4-methyl-phenyl ethyl carbonate (1.32 g, 4.2 mmol) in

H

2

SO

4 (98 %, 10 mL) was added KNO 3 (510 mg, 5.0 mmol) in small portions at 0 "C. The mixture was stirred for 3 h while warming to room temperature, poured into ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO 3 and brine, dried over MgSO 4 and concentrated to dryness. The residue was purified by column chromatography (0-10 % EtOAc - Hexane) to yield 2 -admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 25 %). [004711 2-Admantyl-4-methyl-5-nitrophenoI - 155- To a solution of 2-admantyl-4-methyl-5-nitropheny ethyl carbonate (378 mg, 1.05 mmol) in

CH

2 C1 2 (5 mL) was added piperidine (1.0 mL). The solution was stirred at room temperature for I h, adsorbed onto silica gel under reduced pressure and purified by flash chromatography on silica gel (0-15 %, EtOAc - Hexanes) to provide 2-admantyl-4-methyl-5-nitrophenol (231 mg, 77 [004721 C-12; 2-Admantyl-4-methyl-5-aminophenol To a solution of 2-admantyl-4-methyl-5-nitrophenol (231 mg, 1.6 mmol) in EtOH (2 mL) was added Pd- 5% wt on carbon (10 mg). The mixture was stirred under H 2 (1 atm) overnight and then filtered through Celite. The filtrate was evaporated to dryness to provide 2-admantyl-4 methyl-5-aminophenol (C-12), which was used without further purification. HPLC ret. time 2.52 min, 10-99 % CH3CN, 5 min run; ESI-MS 258.3 m/z (MH*). [00473] Example 9: N Br EaCO 2 Me HNQ, H 2

SO

4 a OH CH 3 CN I.Et 3 N, CHCI, 0 OHO O KOH,MeOH Br BnBr Cs 2 CO Br 0 2 N 0 I MF ON OH O 2 N OBn C-14-a KF, KBr, CuEtOH DMF 0 2 N OBn H 2 N OH C-14 24ert-Butyl-4-bromophenol To a solution of 2-tert-butylphenol (250g, 1.67 mol) in CH 3 CN (1500 mL) was added NBS (300 g, 1.67 mol) at room temperature. After addition, the mixture was stirred at room temperature - 156overnight and then the solvent was removed. Petroleum ether (1000 mL) was added, and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give the crude 2-tert-butyl-4-bromophenol (380 g), which was used without further purification. [00474] Methyl (2-tert-butyl-4-bromophenyl) carbonate To a solution of 2-t-butyl-4-bromophenol (380 g, 1.67 mol) in dichloromethane (1000 mL) was added Et 3 N (202 g, 2 mol) at room temperature. Methyl chloroformate (155 mL) was added dropwise to the above solution at 0 *C. After addition, the mixture was stirred at 0 *C for 2 h., quenched with saturated ammonium chloride solution and diluted with water. The organic layer was separated and washed with water and brine, dried over Na 2

SO

4 , and concentrated to provide the crude methyl (2-tert-butyl-4-bromopheny) carbonate (470 g), which was used without further purification. 1004751 Methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate Methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g, 1.67 mol) was dissolved in conc. H 2 SO4 (1000 ml) at 0 *C. KNO 3 (253 g, 2.5 mol) was added in portions over 90 min. The reaction mixture was stirred at 0 *C for 2 h and poured into ice-water (20 L). The resulting precipitate was collected via filtration and washed with water thoroughly, dried and recrystallized from ether to give methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (332 g, 60 % over 3 steps). [004761 C-14-a; 2-tert-Butyl-4-bromo-5-nitro-phenol To a solution of methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (121.5 g, 0.366 mol) in methanol (1000 mL) was added potassium hydroxide (30.75 g, 0.549 mol ) in portions. After addition, the mixture was stirred at room temperature for 3 h and acidified with 1N HCI to pH 7. Methanol was removed and water was added. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na 2

SO

4 and concentrated to give 2-tert-butyl-4 bromo-5-nitro-phenol (C-14-a) (100 g, 99 %). [00477] 1-tert-Butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene -157- To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.1 g, 4 mmol) and Cs 2

CO

3 (1.56 g, 4.8 mmol) in DMF (8 mL) was added benzyl bromide (500 pL, 4.2 mmol). The mixture was stirred at room temperature for 4 h, diluted with H 2 0 and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgS04. After removal of solvent, the residue was purified by column chloromatography (0-5 % EtOAc - Hexane) to yield 1-tert-butyl-2-(benzyloxy)-5-bromo4-nitrobenzene (1.37 g, 94 %). 'H NMR (400 MHz, CDCl 3 ) 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, SH), 5.22 (s, 2H), 1.42 (s, 9H). (00478] 1-tert-Butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene A mixture of 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (913 mg, 2.5 mmol), KF (291 mg, 5 mmol), KBr (595 mg, 5 mmol), Cui (570 mg, 3 mmol), methyl chlorodifluoroacetate (1.6 mL, 15 mmol) and DMF (5 mL) was stirred at 125 *C in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgS04. After removal of the solvent, the residue was purified by column chromatography (0-5 % EtOAc - Hexane) to yield 1-tert butyl- 2 -(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (591 mg, 67 %). 'H NMR (400 MHz,

CDC

3 ) 7.66 (s, 1H), 7.37 (m, 5H), 7.19 (s, 1H), 5.21 (s, 2H), 1.32 (s, 9H). [00479] C-14; 5-Amino-2-tert-butyl-4-trifluoromethyl-phenol To a refluxing solution of 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 mL) was added 10% Pd-C (245 mg). The mixture was refluxed for additional 2 h, cooled to room temperature and filtered through Celite. After removal of solvent, the residue was purified by column chromatography to give 5-Amino-2-tert-butyl-4-trifluoromethyl-phenol (C-14) (120 mg, 52 %). 'H NMR (400 MHz, CDCl1) 8 7.21 (s, 1H), 6.05 (s, 1H), 1.28 (s, 9H); HPLC ret, time 3.46 mi, 10-99 % CH 3 CN, 5 min run; ESI-MS 234.1 m/z (MH*). [004801 Example 10: [004811 General scheme: - 158 - Br Ar b Ar 0 2 N OH Ol 2 OH H2N OH C-14-a a) ArB(OH) 2 , K 2 C0 3 , Pd(PPh 3

)

4 , H 2 0, DMF or ArB(OH)2, (dppf)PdC 2 , K 2 C0 3 , EtOH; b) H 2 , Raney Ni, MeOH or HCO 2

NH

4 , Pd-C, EtOH or SnC1 2 .2H 2 0. [00482] Specific example: B(OH)2 H, ay Ni O2 OH Pd(PPh),, K2CO, MeOH C-14-a H,0, DMF ON OH OH C-15 [004831 2-tert-Butyl-4-(2-ethoxyphenyl)-5-nitrophenol To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmnol) in DMF (90 mL) was'added 2-ethoxyphenyl boronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 ml) and Pd(PPh) 4 (1.73 g, 1.5 mmol). The mixture was heated at 90 'C for 3 h under nitrogen. -The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether - ethyl acetate, 10:1) to afford 2-tert-butyl4-(2-ethoxyphenyl)-5-nitrophenol (9.2 g, 92 %). 'HNMR (DMSO.-d 6 ) 8 10.38 (s, 1 H), 7.36 (s, I H), 7.28 (in, 2 H), 7.08 (s, I H), 6.99 (t, I H, J= 7.35 Hz), 6.92 (d, I H, J= 8.1 Hz), 3.84 (q, 2 H, J= 6.6 Hz), 1.35 (s, 9 H), 1.09 (t, 3 H, J= 6.6 Hz); ESI-MS 314.3 m/z (MI-). [004841 C-15; 2-tert-Butyl-4-(2-ethoxyphenyl)-5-aminophenol To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 ml) was added Raney Ni (300 mg). The mixture was stirred under H 2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - ethyl acetate, 6:1) to afford 2-tert -159butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g, 92 %). 'HNMR (DMSO-d) 5 8.89 (s, I H), 7.19 (t, IH, J= 4.2 Hz), 7.10 (d, IH, J= 1.8 Hz), 7.08 (d, I H, J= 1.8 Hz), 6.94 (t, IH, J= 3.6 Hz), 6 .67 (s, I H), 6.16 (s, I H), 4.25 (s, I H), 4.00 (q, 2H, J= 6.9 Hz), 1.26 (s, 9H), 1.21 (t, 3 H, J= 6.9 Hz); ESI-MS 286.0 m/z (MH*). [004851 Other examples:

H

2 N OH 1004861 C-16; 2 -tert-Butyl-4-(3-ethoxyphenyl)-5-aninophenol 2 -tert-Butyl-4-(3-ethoxyphenyl)-S-aminophenol (C-16) was synthesized following the general scheme above starting from 2 -tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-ethoxyphenyl boronic acid. HPLC ret. time 2.77 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 286.1 m/z (MH*). 0

H

2 N OH [00487] C-17; 2 -tert-Butyl-4-(3-methoxycarbonylphenyl)-5-aminopheno

(C

17) 2-tert-Butyl-4-(3-methoxycarbonylphenyl)-5-aminophenol (C-17) was synthesized following the general scheme above starting from 2 -tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3 (methoxycarbonyl)phenylboronic acid. HPLC ret. time 2.70 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 300.5 m/z (MWH). [004881 Example 11; -160- Br Br CF , Cs 2

CO

3 r CICF 2

CO

2 Me

O

2 N OH DMF 2 N O KF, KBr, Cul C-14-a

CF

3 HCO 2

NH

4

CF

3 Pd-C, EtOH 02N O - H 2 N C-18 [004891 1-tert-Butyl-2-methoxy-5-bromo4-nitrobenzene To a mixture of 2 -tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.5 g, 5.5 mmol) and Cs 2

CO

3 (2.2 g, 6.6 mmol) in DMF (6 mL) was added methyl iodide (5150 pL, 8.3 mmol). The mixture was stirred at room temperature for 4 h, diluted with H20 and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4 . After removal of solvent, the residue was washed with hexane to yield 1-tert-butyl-2-methoxy-5-bromo-4 nitrobenzene (1.1 g, 69 %). " H NMR (400 MHz, CDCl 3 ) 3 7.58 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 1.39 (s, 9H). [00490] 1-tert-Butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene A mixture of 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg, 3.6 mmol), methyl chlorodifluoroacetate (2.2 mL, 21.0 mmol) in DMF (5 mL) was stirred at 125 *C in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography (0-5 % EtOAc - Hexane) to yield 1-tert butyl- 2 -methoxy-5-(trifluoromethyl)-4-nitrobenzene (512 mg, 61 %). 'H NMR (400 MHz, CDC1 3 ) 3 7.60 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 1.33 (s, 9H). [00491] C-18; 1-tert-Butyl-2-methoxy-5-(trifluoromethyl)4-aminobenzene - 161 - To a refluxing solution of I -tert-butyl- 2 -methoxy-5-(trifluoromethyl)-4-nitrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 mL) was added 10% Pd-C (200 mg). The mixture was refluxed for I h, cooled and filtered through Celite. The solvent was .removed by evaporation to give 1 -tert-butyl-2-methoxy-5-(tnfluoromethyl)-4-taminobenzene (C 18) (403 mg, 95 %). 'H NMR (400 MHz, CDCla) 5 7.19 (s, 1H), 6.14 (s, 1H), 4.02 (bs, 2H), 3.74 (s, 3H), 1.24 (s, 9H). [004921 Example 12: Br H2, Ni Br 0 2 N OH OMeOH 0,N) j OHH 2N) OH C-14-a C-27 [004931 C-27; 2 -tert-Butyl-4-broino-5-amino-phenol To a solution of 2 -tert-butyl-4-bromo-5-nitrophenol (C-14-a) (12 g, 43.8 mmol) in MeOH (90 mL) was added Ni (2.4 g). The reaction mixture was stirred under H 2 (1 atm) for 4 h. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70 %). 'H NMR (DMSO-d) 6 9.15 (s, 1 H), 6.91 (s, I H), 6.24 (s, 1 H), 4.90 (br s, 2 H), 1.22 (s, 9 H); ESI-MS 244.0 m/z (MH*). [004941 Example 13: HCHO HNaBH CN, MeOH HN OH C-9 OC-24 [004951 C-24; 2,4-Di-tert-butyl-6-(N-methylamino)pheno - 162 - A mixture of 2

,

4 -di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol), NaBH3CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 mL) was stirred at reflux for 3 h. After removal of the solvent, the residue was purified by column chromatography (petroleum ether - EtOAc, 30:1) to give 2

,

4 -di-tert-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 15 %). HNMR (DMSO-d>) S 8.67 (s, I H), 6.84 (s, I H), 5.99 (s, 1 H), 4.36 (q, J= 4.8 Hz, I H), 2.65 (d, J= 4.8 Hz, 3 H), 1.23 (s, 18 H); ESI-MS 236.2 m/z (MH). [004961 Example 14: OH O BO 2N MeOH NaH, 2 HF KNO,TMSCI " .' 0 ~ H', Raney Ni 0-"' KNO 3 , A1CI, CHOL, . ,S0 0,N): "MO

H

2 N OAcCOO H., Raney Ni HzN NO 2 NaHC03 CH22 NO2 MeOH O 1. NaNO 2 , H 2

SO

4 0 H.N 0.H HcI HzN OH C-25 [004971 2 -Methyl-2-phenyl-propan-1-ol To a solution of 2-methyl-2-phenyl- propionic acid (82 g, 0.5 mol) in THF (200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 m.L) at 0-5 *C. The mixture was stirred at this temperature for 30 min and then heated at reflux for I h. After cooling, methanol (150 mL) and - 163 water (50 mL) were added. The mixture was extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water and brine, dried over Na 2

SO

4 and concentrated to give 2 -methyl-2-phenyl-propan- 1-ol as an oil (70 g, 77 %). [00498] 2 -(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene To a suspension of NaH (29 g, 0.75 mol) in THF (200 mL) was added dropwise a solution of 2 methyl-2-phenyl-propan-1-ol (75 g, 0.5 mol) in THF (50 mL) at 0 *C. The mixture was stirred at 20 "C for 30 min and then a solution of I-bromo-2-methoxy-ethane (104 g, 0.75 mol) in THF (100 mL) was added dropwise at 0 'C. The mixture was stirred at 20 *C overnight, poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 2-(2-Methoxy-ethoxy)-1,1 dimethyl-ethyl]-benzene as an oil (28 g, 27 %). [00499] 1-[ 2 -(2-Methoxy-ethoxy)-1,1-dimethyl-ethylj-4-nitro-benzene To a solution of 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene (52 g, 0.25 mol) in CHCl 3 (200 mL) was added KNO 3 (50.5 g, 0.5 mot) and TMSCI (54 g, 0.5 mol). The mixture was stirred at 20 "C for 30 min and then AlC1 3 (95 g, 0.7 mol) was added. The reaction mixture was stirred at 20 *C for I h and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with CHCl 3 (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2 SO4, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to obtain 1-[2-(2-methoxy-ethoxy)-1,1 dimethyl-ethyl]-4-nitro-benzene (6 g, 10 %). 1005001 4

-[

2

-(

2 -Methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine A suspension of 1-[ 2

-(

2 -methoxy-ethoxy)-1,1-dimethy-ethyl]-4-nitro-benzene (8.1 g, 32 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H 2 (1 atm) at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated to obtain 4 -[2-(2-methoxy-ethoxy) 1,1-dimethyl-ethyl]-phenylamine (5.5 g, 77 %). [005011 4

-[

2

-(

2 -Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-itro-phenylamine -164- To a solution of 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylanine (5.8 g, 26 mmol) in

H

2

SO

4 (20 mL) was added KNO 3 (2.63 g, 26 mmol) at 0 *C. After addition was complete, the mixture was stirred at this temperature for 20 min and then poured into ice-water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , and concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 100:1) to give 4-[2-(2-methoxy-ethoxy)-1,1 dimethyl-ethyll-3-nitro-phenylamine (5 g, 71 %). [00502] N-{4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl} acetamide To a suspension of NaHCO 3 (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4-[2-(2 methoxy-ethoxy)-1, I -dimethyl-ethylj-3-nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5 *C. The mixture was stirred overnight at 15 *C and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , and concentrated to dryness to give N- {4-[2-(2-methoxy-ethoxy)-1, 1 dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5.0 g, 87 %). [005031 N-{ 3 -Ano-4-2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl} acetamide A mixture ofN-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H 2 (1 atm) at room temperature 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 100:1) to give N-{3-amino-4-[2 (2-methoxy-ethoxy)-1,I-dimethyl-ethyl]-phenyl}-acetamide (1.6 g, 35 %). 100504] N-{3-Hydroxy4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-pheny1} acetanide To a solution of N-{3-amino-4-[2- (2-methoxy- ethoxy)-1,1 -dimethyl-ethylJ-phenyl}- acetamide (1.6 g, 5.7 mmol) in H 2 S0 4 (15 %, 6 mL) was added NaNO 2 at 0-5 *C. The mixture was stirred at this temperature for 20 min and then poured into ice water. The mixture was extracted with - 165- EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 and concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 100:1) to give N- { 3 -hydroxy-4-[2-(2-methoxy-ethoxy)- 1,1 -dimethyl-ethyl] phenyl}- acetamide (0.7 g, 38 %). [00505] C-25; 2 -(l-( 2 -Methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol A mixture of N-( 3 -hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-- acetamide (1 g, 3.5 mmol) and HCI (5 mL) was heated at reflux for I b. The mixture was basified with Na 2

CO

3 solution to pH 9 and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 and concentrated to dryness.: The residue was purified by column chromatography (petroleum ether - EtOAc, 100:1) to obtain 2 (1-( 2 -methoxyethoxy)-2-methylpropan-2-yl)-5-aminopeno (C-25) (61 mg, 6 %). 'H4NMR (CDCl 3 ) 8 9.11 (br s, I H), 6.96-6.98 (d, J= 8 Hz, 1 H), 6.26-6.27 (d, J= 4 Hz, I H), 6.17-6.19 (m, 1 H), 3.68-3.69 (m, 2 H), 3.56-3.59 (m, 4 H), 3.39 (s, 3 H), 1.37 (s, 6 H); ESI-MS 239.9 m/z (MH*). [005061 Example 15: HNO, Na 2

S

2

O

4 O AcOH 0 2 N O THF, H 2 0 0 o H., Pd-C EIOH ' ? O 0 2 N OH H2N OH OH OH [005071 C-26 100508] 4,6-di-tert-Butyl-3-nitrocyclohexa-3,5-diene-1,2-dione To a solution of 3 ,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 mL) was slowly added HN0 3 (15 mL). The mixture was heated at 60 "C for 40 min before it was poured into H 2 0 (50 mL). The mixture was allowed to stand at room temperature -166for 2 h, then was placed in an ice bath for I h. The solid was collected and washed with water to provide 4

,

6 -di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24 %). 'H NMR (400 MHz, DMSO-d 6 ) 5 6.89 (s, I H), 1.27 (s, 9H), 1.24 (s, 9H). [00011 4,6-Di-tert-butyl-3-nitrobenzene-1,2-dioI In a separatory funnel was placed THF/H 2 0 (1:1, 400 mL), 4

,

6 -di-tert-butyl-3-nitrocyclohexa 3 ,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na 2

S

2 0 4 (3 g, 17.3 mmol). The separatory funnel was stoppered and was shaken for 2 min. The mixture was diluted with EtOAc (20 rnL). The layers were separated and the organic layer was washed with brine, dried over MgSO 4 and concentrated to provide 4

,

6 -di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74 %), which was used without further purification. 'H NMR (400 MHz, DMSO-d 6 ) 5 9.24 (s, 1H), 8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H), 1.25 (s, 9H). [0002 C-26; 4

,

6 -Di-tert-butyl-3-aminobenzene-1,2-diol To a solution of 4

,

6 -di-tert-butyl-3-nitrobenzene- 1,2-diol (1.92 g, 7.2 mmol) in EtOH (70 mL) was added Pd-5% wt. on carbon (200 mg). The mixture was stirred under H2 (1 atm) for 2 h. The reaction was recharged with Pd-5% wt. on carbon (200 mg) and stirred under H 2 (1 atm) for another 2 h. The mixture was filtered through Celite and the filtrate was concentrated and purified by column chromatography (10-40 % ethyl acetate - hexanes) to give 4,6-di-tert-butyl 3 -arninobenzene-1,2-diol (C-26) (560 mg, 33 %). 'H NMR (400 MHz, CDCl 3 ) 8 7.28 (s, 1H), 1.42 (s, 9H), 1.38 (s, 9H). [00031 Anilines [0004] Example 1: [00051 General scheme SnC6.2H 2 0 0 2 N X EtOH H2N I NH2 X=N0 orNH 167- [005091 Specific example: Cl SnC2.2H 2 0 Cl O2N

NO

2 EtH

H

2 N NH2 D-1 [005101 D-1; 4 -Chloro-benzene-1,3-diamine A mixture of 1-chloro-2,4-dinitro-benzene (100 mg, 0.5 mmol) and SnC 2 2H 2 0 (1.12 g, 5 ru-nol) in ethanol (2.5 mL) was stirred at room temperature overnight. Water was added and then the mixture was basified to pH 7-8 with saturated NaHCO 3 solution. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2

SO

4 , filtered and concentrated to yield 4-chloro-benzene-1,3-diamine (D-1) (79 mg, quant.). HPLC ret. time 0.38 min,'10-99 % CH 3 CN, 5 min run; ESI-MS 143.1 m/z (MH*) [005111 Other examples: CI CI C1

H

2 N NH2 [005121 D-2; 4

,

6 -Diehloro-benzene-1,3-dianine 4

,

6 -Dichloro-benzene-1,3-diamine (D-2) was synthesized following the general scheme above starting from 1,5-dichloro-2,4-dinitro-benzene. Yield (95 %). HPLC ret. time 1.88 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 177.1 m/z (MH*). N O N

H

2 N NH 2 [005131 D-3; 4 -Methoxy-benzene-1,3-diamine - 168 - 4 -Methoxy-benzene-1,3-diamine (D-3) was synthesized following the general scheme above starting from 1-methoxy-2,4-dinitro-benzene. Yield (quant.). HPLC ret. time 0.31 min, 10-99 %

CH

3 CN, 5 min run. O 1CF3

H

2 N

NH

2 [005141 D-4; 4 -Trifluorometlioxy-benzene-1,3-diamine 4 -Trifluoromethoxy-benzene-1,3-diamine (D-4) was synthesized following the general scheme above starting from 2

,

4 -dinitro-l-trifluoromethoxy-benzene. Yield (89 %). HPLC ret. time 0.91 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 193.3 m/z (MH). 0

H

2 N

NH

2 [00515] D-5; 4 -Propoxybenzene-1,3-diamine 4-Propoxybenzene-1,3-diamine (D-5) was synthesized following the general scheme above starting from 5-nitro-2-propoxy-phenylamine. Yield (79 %). HPLC ret. time 0.54 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 167.5 ni/z (MH*). [005161 Example 2: [00517] General scheme 0 R a R b R R 0 2 N NO2

H

2 N

NH

2 a) HN0 3 , H 2 S0 4 ; b) SnCl 2 2H2 0 , EtOH or H 2 , Pd-C, MeOH [00518] Specific example: -169-

HNO

3 SnCI 2 .2H 2 0

H

2

SO

4 EtOH 0 2 N

NO

2 H 2 N

NH

2 D-6 [00519] 2,4-Dinitro-propylbenzene A solution of propylbenzene (10 g, 83 mmol) in conc. H 2

SO

4 (50 mL) was cooled at 0 *C for 30 min, and a solution of conc. H 2

SO

4 (50 mL) and fuming HNO 3 (25 mL), previously cooled to 0 *C, was added in portions over 15 min. The mixture was stirred at 0 'C for additional 30 min, and then allowed to warm to room temperature. The mixture was poured into ice (200 g) - water (100 mL) and extracted with ether (2 x 100 mL). The combined extracts were washed with H2O (100 mL) and brine (100 m.L), dried over MgSO 4 , filtered and concentrated to afford 2,4-dinitro; propylbenzene (15.6 g, 89 %). 'H NMR (CDCl 3 , 300 MHz) 5 8.73 (d, J= 2.2 Hz, 1H), 8.38 (dd, J= 8.3, J= 2.2, 1H), 7.6 (d, J= 8.5 Hz, 1H), 2.96 (dd, 2H), 1.73 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). [005201 D-6; 4-Propyl-benzene-1,3-diamine To a solution of 2,4-dinitro-propylbenzene (2.02 g, 9.6 mmol) in ethanol (100 mL) was added SnC 2 (9.9 g, 52 mmol) followed by conc. HC (10 mL). The mixture was refluxed for 2 h, poured into ice-water (100 mL), and neutralized with solid sodium bicarbonate. The solution was further basified with 10% NaOH solution to pH - 10 and extracted with ether (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to provide 4-propyl-benzene-1,3-diamine (D-6) (1.2 g, 83 %). No further purification was necessary for use in the next step; however, the product was not stable for an extended period of time. 'H NMR (CDC1 3 , 300 MHz) 5 6.82 (d, J= 7.9 Hz, 1H), 6.11 (dd, J= 7.5, J- 2.2 Hz, 1H), 6.06 (d, J= 2.2 Hz, 1H), 3.49 (br s, 4H, NH 2 ), 2.38 (t, J= 7.4 Hz, 2H), 1.58 (m, 2H), 0.98 (t, J= 7.2 Hz, 3H); ESI-MS 151.5 m/z (MH). [005211 Other examples: - 170-

H

2 N NH 2 [005221 D-7; 4-Ethylbenzene-1,3-diamine 4-Ethylbenzene-1,3-diamine (D-7) was synthesized following the general scheme above starting from ethylbenezene. Overall yield (76 %).

H

2 N

NH

2 [005231 D-8; 4 -Isopropylbenzene-1,3-diamine 4 -Isopropylbenzene-1,3-diamine (D-8) was synthesized following the general scheme above starting from isopropylbenezene. Overall yield (78 %).

H

2 N NH2 [00524] D-9; 4-tert-Butylbenzene-1,3-diamine 4 -tert-Butylbenzene-1,3-diamine (D-9) was synthesized following the general scheme above starting from tert-butylbenzene. Overall yield (48 %). 'H NMR (400 MHz, CDCl 3 ) i 7.01.(d, J =8.3 Hz, 1H), 6.10 (dd, J= 2.4, 8.3 Hz, 1H), 6.01 (d, J= 2.4 Hz, 11), 3.59 (br, 41), 1.37 (s, 9H); C NMR (100 MHz, CDC1 3 ) S 145.5, 145.3, 127.6, 124.9, 105.9, 104.5, 33.6, 30.1; ESI-MS 164.9 m/z (MH). 100525] Example 3: [00526] General scheme -171 - KR

H

2 N orR R H2N NO, BoCHN NO 2 BocHN NH 2 C R a) KNO 3 , H 2 S0 4 ; b) (i) HNO 3 , H 2

SO

4 ; (ii) Na 2 S, S, H 2 0; c) Boc 2 0, NaOH, THF; d) H 2 , Pd-C, MeOH [005271 Specific example: NaO THF HPN RO RP NO Bocf-tl NO 2 MOHBdJ D-10 [005281 4 -tert-Butyl-3-nitro-phenylamine To a mixture of 4 -tert-butyl-phenylamine (10.0 g, 67.01 mmol) dissolved in H 2

SO

4 (98 %, 60 mL) was slowly added KNO 3 (8.1 g, 80.41 mmol) at 0 *C. After addition, the reaction was allowed to warm to room temperature and stirred overnight. The mixture was then poured into ice-water and basified with sat. NaHCO 3 solution to pH 8. The mixture was extracted several times with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether EtOAc, 10:1) to give 4 -tert-butyl-3-nitro-phenylamine (10 g, 77 %). [005291 ( 4 -tert-Butyl-3-nitro-phenyl)-carbanic acid tert-butyl ester A mixture of 4 -tert-butyl-3-nitro-phenylanine (4.0 g, 20.6 mmol) and Boc 2 O (4.72 g, 21.6 mmol) in NaOH (2N, 20 mL) and THF (20 mL) was stirred at room temperature overnight. THF was removed under reduced pressure. The residue was dissolved in water and extracted with

CH

2 C1 2 . The organic layer was washed with NaHCO 3 and brine, dried over Na 2

SO

4 and concentrated to afford ( 4 -tert-butyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (4.5 g, 74 %). -172- [005301 D-10; ( 3 -Amino-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester A suspension of (4-tert-butyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (3.0 g, 10.19 mol) and 10% Pd-C (1 g) in MeOH (40 mL) was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether - EtOAc, 5:1) to give (3-anino-4-tert-butyl-pheny)-carbamic acid tert-butyl ester (D-10) as a brown oil (2.5 g, 93 %). 'H NMR (CDCl 3 ) 5 7.10 (d, J= 8.4 Hz, I H), 6.92 (s, 1 H), 6.50-6.53 (m, I H), 6.36 (s, I H), 3.62 (br s, 2 H), 1.50 (s, 9 H), 1.38 (s, 9 H); ESI-MS 528.9 m/z (2M+H*). [00531] Other examples: BocHN

NH

2 [00532] D-11; ( 3 -Anino-4-isopropyl-phenyl)-carbamic acid tert-butyl ester

(

3 -Amino-4-isopropyl-phenyl)-carbamic acid tert-butyl ester (D-11) was synthesized following the general scheme above starting from isopropylbenezene. Overall yield (56 %). BocHN

NH

2 [00533] D-12; (3-Amino-4-ethyl-phenyl)-carbamic acid tert-butyl ester

(

3 -Amino-4-ethyl-phenyl)-carbamic acid tert-butyl ester (D-12) was synthesized following the general scheme above starting from ethylbenezene. Overall yield (64 %). 'H NMR (CD 3 OD, 300 MHz) 8 6.87 (d, J= 8.0 Hz, lH), 6.81 (d, J= 2.2 Hz, 1H), 6.63 (dd, J= 8.1, J= 2.2, 1H), 2.47 (q, J= 7.4 Hz, 2H), 1.50 (s, 9H), 1.19 (t, J= 7.4 Hz, 3H); ESI-MS 237.1 m/z (MH*). -173- BocHN

NH

2 [005341 D-13; (3-Amino4-propyl-phenyl)-carbamic acid tert-butyl ester

(

3 -Amino-4-propyl-phenyl)-carbainic acid tert-butyl ester (D-13) was synthesized following the general scheme above starting from propylbenezene. Overall yield (48 %). [00535] Example 4:

NH

2 CbZ-CI NH, Ac2,0. HCO2H H py ridine 0 I

NH

2 CH, N 0 pyridine, CH2C2 ' N O H H,. Pd-c H

UAIH

4 , THF H H eHd-C&

NH

2 rlT

NH

2 0-14 [005361 (3-Amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester A solution of 4 -tert-butylbenzene-1,3-diamine (D-9) (657 mg, 4 mmol) and pyridine (0.39 mL, 4.8 mmol) in CH 2

CI

2 / MeOH (12 / 1, 8 mL) was cooled to 0 *C, and a solution of benzyl chloroformate (0.51 mL, 3.6 mmol) in.CH 2

C

2 (8 mL) was added dropwise over 10 min. The mixture was stirred at 0 "C for 15 min, then warmed to room temperature. After 1 h, the mixture was washed with IM citric acid (2 x 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the crude ( 3 -amino-4-tert-butyl phenyl)-carbamic acid benzyl ester as a brown viscous gum (0.97 g), which was used without further purification. 'HNMR (400 MHz, CDCl 3 ) 8 7.41-7.32 (m, 6H,), 7.12 (dJ= 8.5 Hz, 1H), 6.89 (br s, 1H), 6.57 (dd, J= 2.3, 8.5 Hz, IH), 5.17 (s, 2H), 3.85 (br s, 211), 1.38 (s, 9H); 1 3 C NMR (100 MHz, CDC 3 , rotameric) 5 153.3 (br), 145.3, 136.56, 136.18, 129.2, 128.73, 128.59, 128.29, 128.25, 127.14, 108.63 (br), 107.61 (br), 66.86, 33.9, 29.7; ESI-MS 299.1 m/z (MH*). - 174- 1005371 ( 4 -tert-Butyl-3-formylamino-phenyl)-carbamic acid benzyl ester A solution of ( 3 -amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester (0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) in CH2Cl 2 (7.5 mL) was cooled to 0 *C, and a solution of formic acetic anhydride (3.5 mmol, prepared by mixing formic acid (158 pL, 4.2 mmol, 1.3 equiv) and acetic anhydride (0.32 mL, 3.5 mmol, 1.1 eq.) neat and ageing for 1 hour) in CH 2 C1 2 (2.5 mL) was added dropwise over 2 min. After the addition was complete, the mixture was allowed to warm to room temperature, whereupon it deposited a precipitate, and the resulting slurry was stirred overnight. The mixture was washed with 1 M citric acid (2 x 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na 2

SO

4 ), and filtered. The cloudy mixture deposited a thin bed of solid above the drying agent, HPLC analysis showed this to be the desired formamide. The filtrate was concentrated to approximately 5 mL, and diluted with hexane (15 mL) to precipitate further formamide. The drying agent (Na 2

SO

4 ) was slurried with methanol (50 mL), filtered, and the filtrate combined with material from the CH 2

CI

2 / hexane recrystallisation. The resultant mixture was concentrated to afford (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester as an off-white solid (650 mg, 50 % over 2 steps). 1 H and 1 3 C NMIR (CD 3 0D) show the product as a rotameric mixture. 1H NMR (400 MHz, CD 3 0D, rotameric) S 8.27 (s, I H-a), 8.17 (s, 1H-b), 7.42-7.26 (in, 8H), 5.17 (s, IH-a), 5.15 (s, 1H-b), 4.86 (s, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H-b); 3 C NMR (100 MHz, CD 3 0D, rotaneric) E 1636.9, 163.5, 155.8, 141.40, 141.32, 139.37, 138.88, 138.22, 138.14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24, 129.19, 129.13, 128.94, 128.50, 121.4 (br), 118.7 (br), 67.80, 67.67, 35.78, 35.52, 31.65, 31.34; ESI-MS 327.5 m/z(MH*). [00538] N-(5-Anino-2-tert-butyl-phenyl)-formamide A 100 mL flask was charged with (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd-C (50 mg), and stirred under H 2 (1 atm) for 20 h. CH 2

CI

2 (5 mL) was added to quench the catalyst, and the mixture then filtered through Celite, and concentrated to afford N-(5-amino-2-tert-butyl-phenyl)-formamide as an off white solid (366 mg, 96 %). Rotameric by 'H and ' 3 C NMR (DMSO-dQ). 'H NMR (400 MHz, DMSO-d 6 , rotameric) S 9.24 (d, J= 10.4 Hz, 1H), 9.15 (s, IH), 8.23 (d, J= 1.5 Hz, IH), 8.06 (d, J= 10.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, IH), 6.51 (d, J= 2.5 Hz, 1H), 6.46 (dd, J= 2.5, 8.5 Hz, 1H), 6.39 (dd, J=2.5, 8.5 Hz, 1H), 6.29 (d, J=2.5Hz, 1H), 5.05 (s, -175 - 2H), 4.93 (s, 2H), 1.27 (s, 9H); "C NMR (100 MHz, DMSO-d 6 , rotameric) 5 164.0, 160.4, 147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15, 115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 m/z (MH*). [00539] D-14; 4-tert-butyl-M-methyl-benzene-1,3-diamine A 100 mL flask was charged with N-(5-amino-2-tert-butyl-phenyl)-fornamide (340 mg, 1.77 mmol) and purged with nitrogen. THF (10 mL) was added, and the solution was cooled to 0 "C. A solution of lithium aluminum hydride in THF (4.4 mL, IM solution) was added over 2 min. The mixture was then allowed to warm to room temperature. After refluxing for 15 h, the yellow suspension was cooled to 0 C, quenched with water (170 gL), 15 % aqueous NaOH (170 pL), and water (510 IL) which were added sequentially and stirred at room temperature for 30 min. The mixture was filtered through Celite, and the filter cake washed with methanol (50 mL). The combined filtrates were concentrated in vacuo to give a gray-brown solid, which was partitioned between chloroform (75 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL), dried (Na 2

SO

4 ), filtered, and concentrated to afford 4-tert-butyl-N 3 -methyl benzene--1,3-diamine (D-14) as a brown oil which solidified on standing (313 mg, 98 %). 'H NMR (400 MHz, CDC1 3 ) & 7.01 (d, J= 8.1 Hz, 1H), 6.05 (dd, J= 2.4, 8.1 Hz, 1H), 6.03 (d, J= 2.4 Hz, IH), 3.91 (br s, 1H), 3.52 (br s,2H), 2.86 (s, 3H), 1.36 (s, 9H); 'CNMR (100 MHz, CDC1 3 ). 148.4,145.7, 127.0, 124.3,103.6,98.9,33.5,31.15,30.31; ESI-MS 179.1 ml/z(MH*-). [005401 Example 5: [00541] General scheme: RR

HNO

3 R BocO 1-0S.4 I N4 HO H-aO Pyridine H 2 s 4 0 2 N NO 2 Nag 2 0 H 2 N NO 2 R MR R Mel, AgO H, Id BOcH-N NO 2 DMF BocW'a NO 2 EtOAc BocN NH 2 [00542] Specific example: - 176 - HNO Na 2 .SS -. Boc 2 O H 4 02N NO 2 Pyridine Mel, AgO H 2 , Pd-C BocHN NO DMF BocHN NO 2 EtOAc BocN NH 2 SN 20-15 [005431 2,4-Dinitro-propylbenzene A solution of propylbenzene (10 g, 83 mmol) in conc. H 2 S0 4 (50 mL) was cooled at 0 *C for 30 mins, and a solution of conc. H 2

SO

4 (50 mL) and fuming HNO 3 (25 mL), previously cooled to 0 *C, was added in portions over 15 min. The mixture was stirred at 0 *C for additional 30 min. and then allowed to warm to room temperature. The mixture was poured into ice (200 g) -water (100 mL) and extracted with ether (2 x 100 mL). The combined extracts were washed with H 2 0 (100 mL) and brine (100 mL), dried over MgSOg, filtered and concentrated to afford 2,4-dinitro propylbenzene (15.6 g, 89 %). 'H NMR (CDCI,, 300 MHz) S 8.73 (d, J= 2.2 Hz, 1H), 8.38 (dd, J= 8.3, 2.2 Hz, 1H), 7.6 (d, J= 8.5 Hz, IH), 2.96 (m, 2H), 1.73 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). [005441 4-Propyl-3-nitroaniline A suspension of 2,4-dinitro-propylbenzene (2 g, 9.5 mmol) in H 2 0 (100 mL) was heated near reflux and stirred vigorously. A clear orange-red solution of polysulfide (300 mL (10 eq.), previously prepared by heating sodiuri sulfide nanohydrate (10.0 g), sulfur powder (2.60 g) and H20 (400 mL), was added dropwise over 45 mins. The red-brown solution was heated at reflux for 1.5 h. The mixture was cooled to 0 *C and then extracted with ether (2 x 200 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford 4-propyl-3-nitroaniline (1.6 g, 93 %), which was used without further purification. [00545] (3-Nitro-4-propyl-phenyl)-carbaniic acid tert-butyl ester -177- 4-Propyl-3-nitroaniline (1.69 g, 9.4 mmol) was dissolved in pyridine (30 mL) with stirring. Boc anhydride (2.05 g, 9.4 mmol) was added. The mixture was stirred and heated at reflux for 1 h before the solvent was removed in vacuo. The oil obtained was re-dissolved in CH 2 C1 2 (300 mL) and washed with water (300 mL) and brine (300 mL), dried over Na 2

SO

4 , filtered, and concentrated. The crude oil that contained both mono- and bis-acylated nitro products was purified by column chromatography (0-10 % CH 2

CI

2 - MeOH) to afford (3-nitro-4-propyl phenyl)-carbamic acid tert-butyl ester (2.3 g, 87 %). [00546] Methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester To a solution of (3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (200 mg, 0.71 mmol) in DMF (5 mL) was added Ag 2 O (1.0 g, 6.0 mmol) followed by methyl iodide (0.20 mL, 3.2 mmol). The resulting suspension was stirred at room temperature for 18 h and filtered through a pad of Celite. The filter cake was washed with CH 2 Cl 2 (10 mL). The filtrate was concentrated in vacuo. The crude oil was purified by column chromatography (0-10 % CH 2

C

2 - MeOH) to afford methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester as a yellow oil (110 mg, 52 %). 'H NMR (CDCI,, 300 MHz) 8 7.78 (d, J= 2.2 Hz, 1H), 7.42 (dd, J= 8.2, 2.2 Hz, 1H), 7.26 (d, J= 8.2 Hz, 1H), 3.27 (s, 3H), 2.81 (t, J= 7.7 Hz, 2H), 1.66 (m, 2H), 1.61 (s, 9H), 0.97 (t, J= 7.4 Hz, 3H). [00547] D-15; ( 3 -Amino-4-propyl-phenyl)-methyl-carbamic acid tert-butyl ester To a solution of methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 ml) was added 10% Pd-C (100 mg). The resulting suspension was stirred at room temperature under H 2 (1 atm) for 2 days. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford (3-Amino-4-propyl-phenyl)-methy-carbamic acid tert-butyl ester (D-15) as a colorless crystalline compound (80 mg, 81 %). ESI-MS 265.3 m/z (MH). [00548] Other examples: - 178 - BocN

NH

2 [00549] D-16; ( 3 -Amino-4-ethyl-phenyl)-methyl-carbamic acid tert-butyl ester

(

3 -Amino-4-ethyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-16) was synthesized following the general scheme above starting from ethylbenezene. Overall yield (57 %). BocN

NH

2 [00550] D-17; ( 3 -Amino-4-isopropyl-phenyl)-methyl-carbamic acid tert-butyl ester

(

3 -Arnino- 4 -isopropyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-17) was synthesized following the general scheme above starting from isopropylbenezene. Overall yield (38 %). [00551] Example 6:

NO

2

N

2 5(OH) 2 ' + O Pd 2 (dba 2

)

3 , KF 02N Na 2 S, 8 2N Br P(tBu) 3 , THF O H20

NH

2 NHBoc NHBoc 02N Boc2 0 2 N NiCI 2 .6H 2 0 H N NaBHz, EtOH 2 D-18 [005521 2'-Ethoxy-2,4-dinitro-biphenyl - 179- A pressure flask was charged with 2-ethoxyphenylboronic acid (0.66 g, 4.0 mmol), KF (0.77 g, 13 mmol), Pd 2 (dba) 3 (16 mg, 0.02 mmol), and 2,4-dinitro-bromobenzene (0.99 g, 4.0 mmol) in THF (5 mL). The vessel was purged with argon for I min followed by the addition of tri-tert butylphosphine (0.15 ml, 0.48 mmol, 10 % solution in hexanes). The reaction vessel was purged with argon for additional I min., sealed and heated at 80 *C overnight. After cooling to room temperature, the solution was filtered through a plug of Celite. The filter cake was rinsed with

CH

2 Cl 2 (10 mL), and the combined organic extracts were concentrated under reduced pressure to provide the crude product 2'-ethoxy-2,4-dinitro-biphenyl (0.95 g, 82%). No further purification was performed. 'H NMR (300 MHz, CDC 3 ) 8 8.75 (s, 1H), 8.43 (d, J= 8.7 Hz, IH), 7.60 (d, J =8.4 Hz, IH), 7.40 (t, J= 7.8 Hz, IH), 7.31 (d, J= 7.5 Hz, IH), 7.08 (t, J= 7.5 Hz, lH), 6.88 (d, J= 8.4 Hz, 1H), 3.44 (q, J= 6.6 Hz, 2H), 1.24 (t, J= 6.6 Hz, 3H); HPLC ret. time 3.14 min, 10 100 % CH 3 CN, 5 min gradient. [005531 2'-Ethoxy-2-nitrobiphenyl-4-yI amine A clear orange-red solution of polysulfide (120 ml, 7.5 eq.), previously prepared by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 ml), was added dropwise at 90 *C over 45 minutes to a suspension of 2'-ethoxy-2,4-dinitro-biphenyl (1.2 g, 4.0 mmol) in water (40 ml). The red-brown solution was heated at reflux for 1.5 h. The mixture was cooled to room temperature, and solid NaC1 (5 g) was added. The solution was extracted with CH 2

C

2 (3 x 50 nL), and the combined organic extracts was concentrated to provide 2'-ethoxy-2 nitrobiphenyl-4-yl amine (0.98 g, 95 %) that was used in the next step without further purification. 'H NMR (300 MHz, CDC1 3 ) 8 7.26 (m, 2H), 7.17 (d, J= 2.7 Hz, 1H), 7.11 (d, J 7.8 Hz, 1H), 7.00 (t, J= 6.9 Hz, 1H), 6.83 (m, 2H), 3.91 (q, J= 6.9 Hz, 2H), 1.23 (t, J= 7.2 Hz, 3H); HPLC ret. time 2.81 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 259.1 m/z (M). [00554] (2'-Ethoxy-2-nitrobiphenyl-4-yI)-carbamic acid tert-butyl ester A mixture of 2'-ethoxy-2-nitrobipenyl-4-yl amine (0.98 g, 4.0 mmol) and Boc 2 O (2.6g, 12 mmol) was heated with a heat gun. Upon the consumption of the starting material as indicated by TLC, the crude mixture was purified by flash chromatography (silica gel, CH 2 Cl 2 ) to provide (2'-ethoxy-2-nitrobiphenyl-4-yl)-carbamic acid tert-butyl ester (1.5 g, 83 %). 'H NMR (300 MHz, CDCI 3 ) 5 7.99 (s, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.25 (in, 3H), 6.99 (t, J= 7.5 Hz, 1H), - 180- 6.82 (m, 2H), 3.88 (q, J= 6.9 Hz, 2H), 1.50 (s, 9 H), 1.18 (t, J= 6.9 Hz, 3H); HPLC ret. time 3.30 min, 10-100 % CH 3 CN, 5 min gradient. [005551 D-18; (2'-ethoxy-2-aminobiphenyl-4-yI)-carbanic acid tert-butyl ester To a soloution of NiC1 2 .6H 2 0 (0.26 g, 1.1 mmol) in EtOH (5 mL) was added NaBH 4 (40 mg, 1.1 mmol) at -10 *C. Gas evolution was observed and a black precipitate was formed. After stirring for 5 min, a solution of 2 '-ethoxy-2-nitrobiphenyl-4-y)carbamic acid tert-butyl ester (0.50 g, 1.1 mmol) in EtOH (2 mL) was added. Additional NaBH 4 (80 mg, 60 mmol) was added in 3 portions over 20 min. The reaction was stirred at 0 "C for 20 min followed by the addition of NH 4 0H (4 mL, 25% aq. solution). The resulting solution was stirred for 20 min. The crude mixture was filtered through a short plug of silica. The silica cake was flushed with 5% MeOH in CH 2 C1 2 (10 mL), and the combined organic extracts was concentrated under reduced pressure to provide (2' ethoxy-2-aminobiphenyl-4-yl)-carbamic acid tert-butyl ester (D-18) (0.36 g, quant.), which was used without further purification. HPLC ret, time 2.41 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 329.3 m/z (MH*). [005561 Example 7: CF-

F

3 MeSO 2 CI Pyr, CH 2

C

2 / S

H

2 N NH 2

H

2 N N H D-19 1005571 D-19; N-( 3 -Amino-5-trifluoromethyl-phenyl)-methanesulfonamide A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 nmmol) in pyridine (0.52 mL) and CH 2

CI

2 (6.5 mL) was cooled to 0 *C. Methanesulfonyl chloride (171 mg,* 1.49 mmol) was slowly added at such a rate that the temperature of the solution remained below 10 *C. The mixture was stirred at ~8 *C and then allowed to warm to room temperature after 30 min. After stiring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH 4 CI (10 mL) solution, extracted - 181 with CH 2

CI

2 (4'x 10 mL), dried over Na 2

SO

4 , filtered, and concentrated to yield N-(3-amino-5 trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97 %), which was used without further purification. 'H-NMR (CDCl 3 , 300 MHz) 5 6.76 (m, 1H), 6.70 (m, I H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/dz (MH*). [00558] Cyclic amines [005591 Example 1: KNO Boc20, DMAP H2SO4 0 2 N N CH 2 Cl 2 H H

H

2 , Pd-C 02N NBoc MeOH H2 NBoc DC-1 [005601 7-Nitro-1,2,3,4-tetrahydro-quinoline To a mixture of 1,2,3,4-tetrahydro-quinoline (20.0 g, 0.15 mol) dissolved in H 2

SO

4 (98 %, 150 mL), KNO 3 (18.2 g, 0.18 mol) was slowly added at 0 *C. The reaction was allowed to warm to room temperature and stirred over night. The mixture was then poured into ice-water and basified with sat. NaHCO 3 solution to pH 8. After extraction with CH 2 C12, the combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 10:1) to give 7-nitro-1,2,3,4-tetrahydro quinoline (6.6 g, 25 %). [005611 7-Nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester A mixture of 7-nitro-1,2,3,4-tetrahydro-quinoline (4.0 g, 5.61 mmol), Boc 2 O (1.29 g, 5.89 mmol) and DMAP (0.4 g) in CH 2

CI

2 was stirred at room temperature overnight. After diluted with water, the mixture was extracted with CH 2

C

2 . The combined organic layers were washed with NaHCO 3 and brine, dried over Na 2

SO

4 and concentrated to provide crude 7-nitro-3,4-dihydro -182- 2H-quinoline- 1 -carboxylic acid tert-butyl ester that was used in the next step without further purification. [00562] DC-1; tert-Butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate A suspension of the crude 7-nitro-3,4-diiydro-2H-quinoline- 1-carboxylic acid tert-butyl ester (4.5 g, 16.2 mol) and 10% Pd-C (0.45 g) in MeOH (40 mL) was stirred under H 2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether - EtOAc, 5:1) to give tert-butyl 7-amino-3,4 dihydroquinoline-1(2H)-carboxylate (DC-1) as a brown solid (1.2 g, 22 % over 2 steps). 'H NMR (CDC 3 ) 5 7.15 (d, J= 2 Hz, 1 H), 6.84 (d, J= 8 Hz, 1 H), 6.36-6.38 (m, 1 H), 3.65-3.68 (m, 2 H), 3.10 (br s, 2 H), 2.66 (t, J= 6.4 Hz, 2 H), 1.84-1.90 (m, 2 H), 1.52 (s, 9 H); ESI-MS 496.8 m/z (2M+H). [005631 Example 2: OH CHH LiA H 4 NaN2 3 11W

H

2 S0 4 2N' AcCI

H-

2 , Pd-C NaHO 3 e, N 0 2 N N EtOH H 2 N DC-2 [005641 3-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one A stirring mixture of oxindole (5.7 g, 43 mmol) and Raney nickel (10 g) in ethane-1,2-diol (100 mL) was heated in an autoclave. After the reaction was complete, the mixture was filtered and - 183the excess of diol was removed under vacuum. The residual oil was triturated with hexane to give 3

-(

2 -hydroxy-ethyl)-1,3-dihydro-indol-2-one as a colorless crystalline solid (4.6 g, 70 %). [00565] 1,2-Dihydro-3-spiro-1'-cyclopropyl-lff-indole-2-one To a solution of 3

-(

2 -hydroxy-ethyl)-1,3-dihydro-indol-2-one (4.6 g, 26 mmol) and triethylamine (10 mL) in CH 2 Cl 2 (100 mL) was added MsCI (3.4 g, 30 mmol) dropwise at -20 *C. The mixture was then allowed to warm up to room temperature and stirred overnight. The mixture was filtered and the filtrate was concentrated under vacumn. The residue was purified by column chromatography to give crude 1,2-dihydro-3-spiro-l'-cyclopropyl-H-indole-2-one as a yellow solid (2.5 g), which was used directly in the next step. [00566] 1, 2 -Dihydro-3-spiro-1'-cyclopropyl-1H-indole To a solution of 1,2-dihydro-3-spiro-l'-cyclopropyl-IH-indole-2-one (2.5 g crude) in THF (50 mL) was added LiAlH 4 (2 g, 52 mmol) portionwise. After heating the mixture to reflux, it was poured into crushed ice, basified with aqueous ammonia to pH 8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2

SO

4 and. concentrated to give the crude 1,2-dihydro-3-spiro-l'-cyclopropyl-IH-indole as a yellow solid (about 2 g), which was used directly in the next step. [00567] 6 -Nitro-1,2-dihydro-3-spiro-1'-cyclopropyl-IH-indole To a cooled solution (-5 *C to -10 "C) of NaNO 3 (1.3 g, 15.3 mmol) in H 2

SO

4 (98 %, 30 mL) was added 1,2-dihydro- 3-spiro-1'-cyclopropyl-IH-indole (2 g, crude) dropwise over a period of 20 min. After addition, the reaction mixture was stirred for another 40 min and poured over crushed ice (20 g). The cooled mixture was then basified with NH 4 0H and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO4, and concentrated under reduced pressure to yield 6-nitro-1,2-dihydro-3-spiro- '-cyclopropyl- IH-indole as a dark gray solid (1.3 g) [005681 1-Acetyl-6-nitro-1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indole NaHCO 3 (5 g) was suspended in a solution of 6 -nitro-1,2-dihydro-3-spiro-l'-cyclopropyl-lH indole (1.3 g, crude) in CH 2

CI

2 (50 mL). While stirring vigorously, acetyl chloride (720 mg) was - 184 added dropwise. The mixture was stirred for I h and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to give 1 acetyl-6-nitro-1,2-dihydro-3-spiro- I'-cyclopropyl-IH-indole (0.9 g, 15 % over 4 steps). [00569] DC-2; 1-Acetyl-6-amino-1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indole A mixture of -1-acetyl-6-nitro-1,2-dihydro-3-spiro-l'-cyclopropyl- IH-indole (383 mg, 2 mnol) and Pd-C (10 %, 100 mg) in EtOH (50 mL) was stirred at room temperature under H 2 (1 atm) for 1.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with HCI / MeOH to give 1-acetyl-6-amino-1,2-dihydro-3-spiro-1' cyclopropyl-LH-indole (DC-2) (300 mg, 90 %) as a hydrochloride salt. [00570] Example 3: 01.SOC 2 0

AICI

3 OH 2. PhNH 2 , CH 2

CI

2 C 6

H

6 LiAIH 4 KNO 3 N O THF H 2

S

4 o H Boc2O Pd-C 0 2 N NBoc H 2 N NBoc DC-3 [005711 3-Methyl-but-2-enoic acid phenylamide A mixture of 3-methyl-but-2- enoic acid (100 g, 1 mol) and SOC 2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOC1 2 was removed under reduced pressure. CH 2 Cl 2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et 3 N (101 g, 1 mol) at 0 *C. The mixture was stirred at room temperature for 1 h and quenched with HCI (5%, 150 mL). The aqueous layer was separated and extracted with CH 2 C12. The combined organic layers were -185washed with water (2x1 00 mL) and brine (100 mL), dried over Na 2

SO

4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80 %). [005721 4,4-Dimethyl-3,4-dihydro- IH-quinolin-2-one

AIC

3 (500 g, 3.8 mol) was carefully added to a suspension of 3-methyl-but-2-enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000 mL). The reaction mixture was stirred at 80 "C overnight and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over Na 2

SO

4 and concentrated to give 4,4-dimethyl-3,4 dihydro-1H-quinolin-2-one (90 g, 86 %). [005731 4,4-Dimethyl-1,2,3,4-tetrahydro-quinoline A solution of 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (35 g, 0.2 mol) in THF (100 mL) was added dropwise to a suspension of LiAlH 4 (18 g, 0.47 mol) in THF (200 mL) at 0 *C. After addition, the mixture was stirred at room temperature for 30 min and then slowly heated to reflux for 1 h. The mixture was then cooled to 0 *C. Water (18 nL) and NaOH solution (10 %, 100 mL) were carefully added to quench the reaction. The solid was filtered off and the filtrate was concentrated to give 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline. [005741 4,4-Dinethyl-7-nitro-1,2,3,4-tetrahydro-quinoline To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (33 g, 0.2 mol) in H 2

SO

4 (120 mL) was slowly added KNO 3 (20.7 g, 0.2 mol) at 0 *C. After addition, -the mixture was stirred at room temperature for 2 h, carefully poured into ice water and basified with Na 2

CO

3 to pH 8. The mixture was extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water and brine, dried over Na 2

SO

4 and concentrated to give 4, 4-dimethyl-7-nitro-1, 2, 3, 4 tetrahydro-quinoline (21 g, 50 %). [005751 4,4-Dimethyl-7-nitro-3,4-dihydro-2H-quinoline--carboxylic acid tert butyl ester A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (25 g, 0.12 mol) and Boc 2 O (55 g, 0.25 mol) was stirred at 80 "C for 2 days. The mixture was purified by silica gel -186chromatography to give 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert butyl ester(8 g, 22 %). [005761 DC-3; tert-Butyl 7-aiino-3,4-dihydro-4,4-dimethylquinoline-1(2H) carboxylate A mixture of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1 carboxylic acid tert-butyl ester (8.3 g, 0.03 mol) and Pd-C (0.5 g) in methanol (100 mL) was stirred under H 2 (1 atm) at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was washed with petroleum ether to give tert-butyl 7-amino-3,4-dihydro-4,4 dimethylquinoline-I(2H)-carboxylate (DC-3) (7.2 g, 95 %)- 'H NMR (CDC 3 ) 8 7.11-7.04 (m, 2 H), 6.45-6.38 (m, 1 H), 3.71-3.67 (m, 2 H), 3.50-3.28 (m, 2 H), 1.71-1.67 (m, 2 H), 1.51 (s, 9 H), 1.24 (s, 6 H). [00577] Example 4: CH, AJC4 CI PhNH, NaHCO -T 1CHC6 CHCN NaBH 4 H 2 S0 4 '.KNO, MeOH H H2 04 O 2 N AcC, NaHCO

H

2 , Pd-C

CHA

2 C 02 MeOH H 2 N DC-4 [00578] 1-Chloro-4-methylpentan-3-one Ethylene was passed through a solution of isobutyryl chloride (50 g, 0.5 mol) and ALC 3 (68.8 g, 0.52 mol) in anhydrous CH 2 Cl 2 (700 mL) at 5 *C. After 4 h, the absorption of ethylene ceased, and the mixture was stirred at room temperature overnight. The mixture was poured into cold diluted HCl solution and extracted with CH 2

C

2 . The combined organic phases were washed - 187with brine, dried over Na 2

SO

4 , filtered and concentrated to give the crude 1-chloro-4 methylpentan-3-one, which was used directly in the next step without further purification. [005791 4 -Methyl-1-(phenylamino)-pentan-3-one A suspension of the crude I-chloro-4-methy[pentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHCO 3 (210 g, 2.5 mol) in CH 3 CN (1000 mL) was heated at reflux overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with CH 2

CI

2 , washed with 10% HCI solution (100 mL) and brine, dried over Na 2

SO

4 , filtered and concentrated to give the crude 4-methyl-I -(phenylamino)-pentan-3 -one. [005801 4-Methyl-1-(phenylamino)-pentan-3-ol At -10 -C, NaBH 4 (56.7 g, 1.5 mol) was gradually added to a mixture of the crude 4-methyl-I (phenylamino)-pentan-3-one (about 80 g) in MeOH (500 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for 20 min. The solvent was removed and the residue was repartitioned between water and CH 2

CI

2 . The organic phase was separated, washed with brine, dried over Na 2

SO

4 , filtered and concentrated. The resulting gum was triturated with ether to give 4-methyl-I -(phenylamino)-pentan-3-ol as a white solid (22 g, 23 %)0. [00581] 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[bjazepine A mixture of 4-methyl-1-(phenylamino)-pentan-3-ol (22 g, 0.11 mol) in 98% H 2 S0 4 (250 mL) was stirred-at 50 0C for 30 min. The reaction mixture was poured into ice-water basified with sat. NaOH solution to pH 8 and extracted with CH 2

CI

2 .The combined organic phases were washed with brine, dried over Na 2 SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 5,5-dimethyl- 2,3,4,5-tetrahydro-1 H benzo[b]azepine as a brown oil (1.5 g, 8 %). [00582] 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine At 0 0C, KNO 3 (0.76 g, 7.54 mmol) was added portionwise to a solution of 5,5-dimethyl-2,3,4,5 tetrahydro-1H-benzo[b]azepine (1.1 g, 6.28 nmol) in H 2

SO

4 (15 mL). After stirring 15 min at this temperature, the mixture was poured into ice water, basified with sat. NaHCO 3 to pH 8 and - 188extracted with EtOAc. The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated to give crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-[ H-benzo[b]azepine (1.2 g), which was used directly in the next step without further purification. [005831 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b azepin-1 yl)ethanone Acetyl chloride (0.77 mL, 11 mmol) was added to a suspension of crude 5,5-dimethyl-8-nitro 2 ,3,4,5-tetrahydro-l H-benzo[b]azepine (1.2 g, 5.45 mmol) and NaHCO 3 (1.37 g, 16.3 mmol) in

CH

2

CI

2 (20 mL). The mixture was heated at reflux for 1 h. After cooling, the mixture was poured into water and extracted with CH 2

CI

2 . The organic layer was washed with brine, dried over Na 2

SO

4 and concentrated. The residue was purified by column chromatography to afford 1 (5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[bjazepin--yl)ethanone (1.05 g, 64 % over two steps). [005841 DC-4; 1-( 8 -Amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[biazepin-1 yl)ethanone A suspension of 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 40 mmol) and 10% Pd-C (0.2 g) in MeOH (20 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated to give 1-(8-amino-2,3,4,5 tetrahydro-5,5-dimethy1benzo[b]azepin-1-yl)ethanone as a White solid (DC-4) (880 mg, 94 %). 'H NMR (CDC1 3 ) 8 7.06 (d, J= 8.0 Hz, 1 H), 6.59 (dd, J= 8.4, 2.4 Hz, 1 H), 6.50 (br s, 111), 4.18-4.05 (m, 1H), 3.46-3.36'(m, 1H), 2.23 (s, 3H), 1.92-1.85 (m, 1H), 1.61-1.51 (m, 3H), 1.21 (s, 3H), 0.73 (t, J= 7.2 Hz, 3 H); ESI-MS 233.0 m/z (MJf). [005851 Example 5: - 189 - Noc Bn N n 1. HCI, MeOH NH2OH.HCI 2. BnBr, K2CO 3 , CH 3 CN NaOAc, EtOH 0 0 N NBn H HO N DIBAL-H H 2 , Pd(OH) 2 -C 1. KNO 3 , H 2

SO

4

CH

2 C1 2 MeOH 2. Boc 2 O NN H H H NBoc NBoc NBoc AcCI, NaHCO 3

H

2 Raney NI

CH

3 CN MeOH O2N N 02N N H2N N H O O DC-5 100586] Spiro[1H-indene-1,4'-piperidin-3(2H)-one, 1'-benzyl A mixture of spiro[1H-indene-1,4'-piperidine]-l'-carboxylic acid, 2,3-dihydro-3-oxo-, 1,1 dimethylethyl ester (9.50 g, 31.50 nnol) in saturated HCI/MeOH (50 mL) was stirred at 25 *C overnight. The solvent was removed under reduced pressure to yield an off-white solid (7.50 g). To a solution of this solid in dry CH 3 CN (30 mL) was added anhydrous K 2 CO3 (7.85 g, 56.80 mmol). The suspension was stirred for 5 min, and benzyl bromide (5.93 g, 34.65 mmol) was added dropwise at room temperature. The mixture was stirred for 2 h, poured into cracked ice and extracted with CH 2

CI

2 . The combined organic layers were dried over Na 2

SO

4 and concentrated under vacuum to give crude spiro[1H-indene-1,4'-piperidin]-3(2H)-one, l'-benzyl (7.93 g, 87 %), which was used without further purification. [00587] Spiro[1H-indene-1,4'-piperidin]-3(2U)-one, l'-benzyl, oxime To a solution of spiro[1H-indene-1,4'-piperidin]-3(2H)-one, l'-benzyl (7.93 g, 27.25 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (3.79 g, 54.50 mmol) and anhydrous sodium acetate (4.02 g, 49.01 mmol) in one portion. The mixture was refluxed for 1 h, and then cooled to room temperature. The solvent was removed under reduced pressure and 200 mL of -190water was added. The mixture was extracted with CH 2 Cl 2 . The combined organic layers were dried over Na 2

SO

4 and concentrated to yield spiro[1H-indene-1,4'-piperidin]-3(2H)-one,

'

benzyl, oxime (7.57 g, 91 %), which was used without further purification. 100588] 1, 2

,

3

,

4 -Tetrahydroquinolin4-spiro-4'-(N'-benzyl-piperidine) To a solution of spiro[ IH-indene-1,4'-piperidinl-3(2H)-one, '-benzyl, oxime (7.57 g, 24.74 mmol) in dry CH 2

CI

2 (150 mL) was added dropwise DIBAL-H (135.7 mL, IM in toluene) at 0 "C. The mixture was stirred at 0 'C for 3 h, diluted with CH 2

CI

2 (100 mL), and quenched with NaF (20.78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension was stirred vigorously at 0 *C for 30 min. After filtration, the residue was washed with CH 2

CI

2 . The combined filtrates were concentrated under vacuum to give an off-brown oil that was purified by column chromatography on silica gel (CH 2

C

2 - MeOH, 30:1) to afford 1,2,3,4 tetrahydroquinolin-4-spiro-4'-(N'-benzyl-piperidine) (2.72 g, 38 %). [00589] 1, 2

,

3

,

4 -Tetrahydroquinolin-4-spiro-4'-piperidine A suspension of 1, 2

,

3

,

4 -Tetrahydroquinolin-4-spiro-4'-(N'-benzyl-piperidine) (300 mg, 1.03 mmol) and Pd(OH) 2 -C (30 mg) in MeOH (3 mL) was stirred under H 2 (55 psi) at 50 *C over night. After cooling, the catalyst was filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure to yield 1,2,3,4-tetrahydroquinolin-4-spiro-4' piperidine as a white solid (176 mg, 85 %), which was used without further purification. [00590] 7 '-Nitro-spiro[piperidine-4,4'(1'H)-quinoline], 2',3'-dihydro carboxylic acid tert-butyl ester

KNO

3 (69.97 mg, 0.69 -mmol) was added portion-wise to a suspension of 1,2,3,4 tetrahydroquinolin-4-spiro-4'-piperidine (133 mg, 0.66 mmol) in 98% H 2 S0 4 (2 mL) at 0 *C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. The mixture was then poured into cracked ice and basified with 10% NaOH to pH- 8. Boc 2 O (172 mg, 0.79 mmol) was added dropwise and the mixture was stirred at room temperature for I h. The mixture was then extracted with EtOAc and the combined organic layers were dried over Na 2 SO4, filtered and concentrated to yield crude 7' - 191 nitro-spiro[piperidine-4,4'(I'H)-quinoline), 2',3'-dihydro- carboxylic acid tert-butyl ester (230 mg), which was used in the next step without further purification. [005911 7'-nitro-spiro[piperidine-4,4'(I IH)-1-acetyl-quinolinel, 2',3'-dihydro carboxylic acid tert-butyl ester Acetyl chloride (260 mg, 3.30 mmol) was added dropwise to a suspension of 7'-nitro spiro[piperidine-4,4'('H)-quinoline], 2',3'-dihydro- carboxylic acid tert-butyl ester (230 mg) and NaHCO 3 (1.11 g, 13.17 mnol) in MeCN (5 mL) at room temperature. The reaction mixture was refluxed for 4 h. After cooling, the suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 10:1) to provide 7'-nitro-spiro[piperidine-4,4'(1'H)- I -acetyl-quinoline), 2',3'-dihydro- carboxylic acid tert-butyl ester (150 mg, 58 % over 2 steps) 1005921 DC-5; 7'-Anino-spiro[piperidine-4,4'(1'H)-1-acetyl-quinolinel, 2',3' dihydro- carboxylic acid tert-butyl ester A suspension of 7'-nitro-spiro[piperidine-4,4'(i')-1-acetyl-quinoline], 2',3'-dihydro- carboxylic acid tert-butyl ester (150 mg, 0.39 mnnol) and Raney Ni (15 mg) in MeOH (2 mL) was stirred under H 2 (1 atm) at 25 *C overnight. The catalyst was removed via filtration and washed with MeOH. The combined filtrates were dried over Na 2

SO

4 , filtered, and concentrated to yield 7' amino-spiro[piperidine-4,4'(1'H)-1 -acetyl-quinoline], 2',3'-dihydro- carboxylic acid tert-butyl ester (DC-5) (133 mg, 96 %). [005931 Example 7: C1 HS C 2 H 2 H SnC 2 .2H 2 0 H O2 NO2 Et 3 N, 1,4-dioxane 0 2 N NO 2 EtOH H2N O DC-7 1005941 2-(2,4-Dinitrophenylthio)-acetic acid Et 3 N (1.5 g, 15 mmol) and mercapto-acetic acid (1 g, 11 mmol) were added to a solution of 1 chloro-2,4-dinitrobenzene (2.26 g, 10 mmol) in 1,4-dioxane (50 mL) at room temperature. After -192stirring at room temperature for 5 h, H20 (100 mL) was added. The resulting suspension was extracted with ethyl acetate (100 mL x 3). The ethyl acetate extract was washed with water and brine, dried over Na 2

SO

4 and concentrated to give 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 74 %), which was used without further purification. [005951 DC-7; 6-Amino-2H-benzo[b][1,4]thiazin-3(4H)-one A solution of 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 9 mmol) and tin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) was refluxed overnight. After removal of the solvent under reduced pressure, the residual slurry was diluted with water (100 mL) and basified with 10 % Na 2

CO

3 solution 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 Na 2

SO

4 , and concentrated. The residue was washed with CH 2

CI

2 to yield 6-amino-2H-benzo[b][1,4]thiazin 3(4H)-one (DC-7) as a yellow powder (1 g, 52 %). 'H NMR (DMSO-d 6 ) 5 10.24 (s. 1 H), 6.88 (d, 1 H, J = 6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2 H), 3.28 (s, 2 H); ESI-MS 181.1 m/z (MH 4 ). [00596] Example 7: Br Br Br Ac 2 O jBr

O

2 N NH, HOAc 0 2 N

K

2 CO, DMF N NEt 4 CI, HCOPa H 2 , Pd-C NaOAc, Pd(OAc) 2 0 2 N N'MeOH DMF 2 DC-8 [00597] N-(2-Bromo-5-nitrophenyl)acetamide Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirring solution of 2-bromo-5 nitroaniline (3 g, 13.8 mmol) in glacial acetic acid (30 mL) at 25 "C. The reaction mixture was stirred at room temperature overnight, and then poured into water. The precipitate was collected -193via filtration, washed with water and dried under vacuum to provide N-(2-bromo-5 nitrophenyl)acetamide as an off white solid (3.6 g, 90 %). [005981 N-(2-Bromo-5-nitrophenyl)-N-(2-niethylprop-2-enyl)acetamide At 25 "C, a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitropheny)acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reaction mixture was stirred at 25 *C overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na 2

CO

3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and concentrated under vacuum to provide N-(2-bromo-5 nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85 %). ESI-MS 313 m/z (MH). [005991 1-(3,3-Dimethyl-6-nitroindolin-1-yl)ethanon e A solution of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (3.1 g, 10.2 mmol), tetraethylammonium chloride hydrate (2.4 g, 149 mmol), sodium formate (1.08 g, 18mmol), sodium acetate (2.76 g, 34.2 mmol) and palladium acetate (0.32 g, 13.2 mmol) in anhydrous DMF (50 mL) was stirred at 80 *C for 15 h under N 2 atmosphere. After cooling, the mixture was filtered through Celite. The Celite was washed with EtOAc and the combined filtrates were washed with sat. NaHCO 3 . The separated organic layer was washed with water and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to provide 1-(3,3-dimethyl-6 nitroindolin-1-yl)ethanone as a brown solid (2.1 g, 88%). [00600] DC-8; 1-( 6 -Amino-3,3-dimethyl-2,3-dihydro-indol-1-y)-ethanone 10% Pd-C (0.2 g) was added to a suspension of 1-(3,3-diinethyl-6-nitroindolin-1-yl)ethanone (2.lg, 9 mmol) in MeOH (20 mL). The reaction was stirred under H2(40 psi) at room temperature overnight. Pd-C was filtered off and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography to yield 1-(6-amino-3,3 dinethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g, 61 %). -194- [006011 Example 8: ,OH DIBAL-H KNO 3

CH

2

CI

2 H 2 S0 4

CI

2 N n H AcCI, NaHCO 3 H2, Pd-C

CH

2

C

2 0 2 N N EtOH H 2 N N 0 O DC-9 . [006021 2,3,4,5-Tetrahydro-1H-benzo[blazepine DIBAL (90 mL, 90 mmol) was added dropwise to a solution of 4-dihydro-2H-naphthalen-I-one oxime (3 g, 18 mmol) in dichloromethane (50 mL) at 0 "C. The mixture was stirred at this temperature for 2 h. The reaction was quenched with dichloromethane (30 mL), followed by treatment with NaF (2 g. 0.36 mol) and H20 (5 mL, 0.27 mol). Vigorous stirring of the resulting suspension was continued at 0 "C for 30 min. After filtration, the filtrate was concentrated. The residue was purified by flash column chromatography to give 2,3,4,5-tetrahydro-1H benzo[b]azepine as a colorless oil (1.9 g, 70 %). [00603] 8-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine At -10 *C, 2,3,4,5-tetrahydro-IH-benzo[b]azepine (1.9 g, 13 mmol) was added dropwise to a solution of KNO 3 (3 g, 30 mmol) in H 2

SO

4 (50 mL). The mixture was stirred for 40 min, poured over crushed ice, basified with aq. ammonia to pH 13, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na 2

SO

4 and concentrated to give 8 nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a black solid (1.3 g, 51 %), which was used without further purification. [00604] 1-(8-Nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone Acetyl chloride (1 g, 13 mmol) was added dropwise to a mixture of 8-nitro-2,3,4,5-tetrahydro 1H-benzo[b]azepine (1.3 g, 6.8 mmol) and NaHCO 3 (I g, 12 mmol) in CH202 (50 mL). After - 195 stirring for I h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH 2

CI

2 , washed with brine, dried over Na 2

SO

4 and concentrated. The residue was purified by column chromatography to give 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl) ethanone as a yellow solid (1.3 g, 80 %). [006051 DC-9; 1-(8-Aniino-2,3,4,5-tetrahydro-benzo[bjazepin-1-yl)-ethanone A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[bjazepin-1-yl)- ethanone (1.3 g, 5.4 mmol) and Pd-C (10 %, 100 mg) in EtOH (200 mL) was stirred under H2 (1 atm) at room temperature for 1.5 h. The mixture was filtered through a layer of Celite and the filtrate was concentrated to give 1-( 8 -amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as a white-solid (1 g, 90 %). 'H NMR (CDC1 3 ) 6 7.01 (d, J= 6.0 Hz, 1 H), 6.56 (dd, J= 6.0, 1.8 Hz, 1 H), 6.50 (d, J= 1.8 Hz, I H), 4.66-4.61 (in, 1 H), 3.50 (br s, 2 H), 2.64-2.55 (m, 3 H), 1.94-1.91 (in, 5 H), 1.77 1.72 (m, 1 H), 1.32-1.30 (in, 1 H); ESI-MS 204.1 m/z (MH*). 1006061 Example 9: y OH00 OH ___ I "- O BH,.SMe 2 ON NH 2 BnMe 3 NQ 0 2 N O THF 0 2 N NaHCO,,

CH

2 Ci 2 AcC H, Pd-C NaHCO 3 , CHCla 0 2 N N EtOH HN DC-10 [00607] 6-Nitro-4H-benzo[1,4]oxazin-3-one At 0 *C, chloroacetyl chloride (8.75 mL, 0.11 mol) was added dropwise to a mixture of 4-nitro 2-aminophenol (15.4 g, 0.1 mol), benzyltrimethylanmonium chloride (18.6 g, 0.1 mol) and NaHCO 3 (42 g, 0.5 mol) in chloroform (350 ml) over a period of 30 min. After addition, the reaction mixture was stirred at 0 *C for 1 h, then at 50 0C overnight The solvent was removed under reduced pressure and the residue was treated with water (50 ml). The solid was collected - 196 via filtration, washed with water and recrystallized from ethanol to provide 6-nitro-4H benzo[ ,4]oxazin-3-one as a pale yellow solid (8 g, 41 %). [006081 6-Nitro-3,4-dihydro-2H-benzo[1,4]oxazine A solution of BHrMe 2 S in THF (2 M, 7.75 mL, 15.5 mmol) was added dropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.1 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight, The reaction was quenched with MeOH (5 mL) at 0 *C and then water (20 mL) was added. The mixture was extracted with Et 2 O and the combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated to give 6-nitro-3,4 dihydro-2H-benzo[1,4]oxazine as a red solid (0.5 g, 89 %), which was used without further purification. [006091 4-Acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO 3 (7.14 g, 85 mmol) in CH 2

C

2 (50 mL). After addition, the reaction was stirred for 1 h at this temperature. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with Et20: hexane (1:2, 50 mL) under stirring for 30 min and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a pale yellow solid (2 g, 90 [006101 DC-10; 4-Acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazine A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g, 67.6 mmol) and Pd-C (10 %, 100 mg) in EtOH (30 mL) was stirred under H 2 (1 atm) overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was treated with HCI / MeOH to give 4-acetyl-6-amino-3,4-dihydro-2H-bezo[1 ,4]oxazine hydrochloride (DC-10) as an off-white solid (1.1 g, 85 %). 'H NMR (DMSO-d) 10.12 (brs, 2H), 8.08 (br s, IH), 6.90-7.03 (m, 2 H), 4.24 (t, J= 4.8 Hz, 2 H), 3.83 (t, J= 4.8 Hz, 2H), 2.23 (s, 3 H); ESI-MS 192.1 m/z (MH). - 197- [006111 Example 10: 1. KNO 3 , H 2

SO

4 Boc 2 O, NaOH KK NH 2. HCI ON NHHCI 1,4-dioxane, H I H2 Pd(OH)2-CI I 2' 2 . NBoc 0 2 N -) NBoc MeOH

H

2 N No DC-6 [006121 1,2,3,4-Tetrahydro-7-nitroisoquinoline hydrochloride 1,2,3,4-Tetrahydroisoquinoline (6.3 mL, 50.0 mmol) was added dropwise to a stirred ice-cold solution of concentrated H 2 S0 4 (25 mL). KNO 3 (5.6 g, 55.0 mmol) was added portionwise while maintaining the temperature below 5 *C. The mixture was stirred at room temperature overnight, carefully poured into an ice-cold solution of concentrated NH 4 0H, and then extracted three times with CHC1 3 . The combined organic layers were washed with brine, dried over Na 2

SO

4 and concentrated. The resulting dark brown oil was taken up into EtOH, cooled in an ice bath and treated with concentrated HCL. The yellow precipitate was collected via filtration and recrystallized from methanol to give 1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as yellow solid (2.5 g, 23 %). 'H NMR (400 MHz, DMSO-d6) 8 9.86 (s, 2H), 8.22 (d, J= 1.6 Hz, 1H), 8.11 (dd, J= 8.5, 2.2 Hz, 1 H), 7.53 (d, J= 8.5 Hz,1H), 4.38 (s, 2H), 3.38 (s, 2H), 3.17-3.14 (in, 2H); HPLC ret. time 0.51 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 179.0 m/z (MH). [00613] tert-Butyl 3,4-dihydro-7-nitroisoquinoline-2(1IH)-carboxylate A mixture of 1,2,3,4-Tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol), 1,4-dioxane (24 mL), H20 (12 mL) and IN NaOH (12 mL) was cooled in an ice-bath, and Boc 2 O (2.8 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 2.5 h, acidified with a 5% KHSO 4 solution to pH 2-3, and then extracted with EtOAc. The organic layer was dried over MgSO 4 and concentrated to give tert-butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quant.), which was used without further purification. 'H NMR (400 MHz, DMSO-d6) S 8.13 (d, J= 2.3 Hz, 1H), 8.03 (dd, J= 8.4, 2.5 Hz, 1H), 7.45 (d, J= 8.5 Hz, 111), 4.63 (s, 2H), 3.60-3.57 (m, 2H), -198- 2.90 (t, J= 5.9 Hz, 2H), 1.44 (s, 9H); HPLC ret. time 3.51 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 279.2 m/z (MH*). [006141 DC-6; tert-Butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate Pd(OH) 2 (330.0 mg) was added to a stirring solution of tert-butyl 3,4-dihydro-7 nitroisoquinoline-2(IH)-carboxylate (3.3 g, 12.0 mmol) in MeOH (56 mL) under N 2 atmosphere. The reaction mixture was stirred under H2 (1 atm) at room temerpature for 72 h. The solid was removed by filtration through Celite. The filtrate was concentrated and purified by column chromatography (15-35 % EtOAc - Hexanes) to provide tert-butyl 7-amino-3,4 dihydroisoquinoline-2(1 H)-carboxylate (DC-6) as a pink oil (2.0 g, 69 %). 'H -NMR (400 MHz, DMSO-d6) 5 6.79 (d, J= 8.1 Hz, IH), 6.40 (dd, J= 8.1, 2.3 Hz, IH), 6.31 (s, IH), 4.88 (s, 2H), 4.33 (s, 2H), 3.48 (t, J= 5.9 Hz, 2H), 2.58 (t, J= 5.9 Hz, 2H), 1.42 (s, 9H); HPLC ret. time 2.13 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 249.0 m/z (MH*). [00615] Other amines (006161 Example 1: N HNO ON

H

2

SO

4 0 2 N KF, Pd(dbaA O Br r P(t-Bu THF

NH

2 NHBoc BHa.THF BoonO H H 2 N H2N THF 1,4-<Noxane' E-1 - 199 - [006171 4-Bromo-3-nitrobenzonitrile To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H 2

SO

4 (10 mL) was added dropwise at 0 *C nitric acid (6 mL). The reaction mixture was stirred at 0 "C for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4 bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56 %). 'H NMR (300 MHz, DMSO d 6 ) 8 8.54 (s, IH), 8.06 (d, J= 8.4 Hz, 1H), 7.99 (d, J= 8.4 Hz, 1H); I'C NMR (75 MHz, DMSO-d 6 ) S 150.4,137.4,136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100 %

CH

3 CN, 5 min gradient; ESI-MS 227.1 m/z (MH*). [00618] 2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile A 50 mL round-bottom flask was charged with 4-bromo-3-nitrobenzonitrile (1.0 g 4.4 mmol), 2 ethoxyphenylboronic acid (731 mg, 4.4 mmol), Pd 2 (dba) 3 (18 mg, 0.022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel was evacuated and filled with argon. Dry THF (300 mL) was added followed by the addition of P(t-Bu) 3 (0.11 mL, 10% wt. in hexane). The reaction mixture was stirred at room temperature for 30 min., and then heated at 80 *C for 16 h. After cooling to room temperature, the resulting mixture was filtered through a Celite pad and concentrated. 2'-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as a yellow solid (1.12 g 95%). 1 H NMR (300 MHz, DMSO-d 6 ) 8 8.51 (s, 114), 8.20 (d, J= 8.1 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.41 (t, J= 8.4 Hz, lH), 7.37 (d, J= 7.5 Hz, IH), 7.08 (t, J= 7.5 Hz, 1H), 7.03 (d, J= 8.1 Hz, 1H), 3.91 (q, J= 7.2 Hz, 2H), 1.12 (t, J= 7.2 Hz, 3H); 1 3 C NMR (75 MHz, DMSO-d 6 ) 8 154.9, 149.7, 137.3, 137.2, 134.4, 131.5, 130.4, 128.4, 125.4, 121.8, 117.6, 112.3, 111.9,64.1, 14.7; HPLC ret. time 2.43 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 269.3 m/z (MH*). [00619] 4-Aminomethyl-2'-ethoxy-biphenyl-2-ylamine To a solution of 2'-ethoxy-2-nitrobipheny-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 mL) was added a solution of BH 3 .THF (5.6 mL, 10% wt. in THF, 5.6 mmol) at 0 *C over 30 min. The reaction mixture was stirred at 0 "C for 3 h and then at room temperature for 15 h. The reaction solution was chilled to 0 *C, and a H 2 0/THF mixture (3 mL) was added. After being agitated at room temperature for 6 h, the volatiles were removed under reduced pressure. The residue was - 200 dissolved iin EtOAc (100 mL) and extracted with IN HCI (2 x 100 mL). The aqueous phase was basified with IN NaOH solution to pH land extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried over Na 2

SO

4 , filtered, and evaporated. After drying under vacuum, 4-aminomethyl-2'-ethoxy-biphenyl-2-ylamine was isolated as a brown oil (370 mg, 82 %). 'H NMR (300 MHz, DMSO-d) 6 7.28 (dt, J= 7.2 Hz, J= 1.8 Hz, 1H), 7.09 (dd, J= 7.2 Hz, J= 1.8 Hz, IH), 7.05 (d, J= 7.5 Hz, IH), 6.96 (dt, J= 7.2 Hz, J= 0.9 Hz, 1H), 6.83 (d, J= 7.5 Hz, 1H), 6.66 (d, J= 1.2 Hz, 1H), 6.57 (dd, J= 7.5 Hz, J= 1.5 Hz, 1H), 4.29 (s, 2H), 4.02 (q, J= 6.9 Hz, 2H), 3.60 (s, 2H), 1.21 (t, J= 6.9 Hz, 3H); HPLC ret. time 1.54 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 243.3 m/z (MH*). [00620] E-1; (2-Anino-2'-ethoxy-biphenyl-4-yimethyl)carbamic acid tert-butyl ester A solution of Boc20 (123 mg, 0.565 mmol) in 1,4-dioxane (10 mL) was added over a period of 30 min. to a solution of 4-aminomethyl-2'-ethoxy-biphenyl-2-ylamine (274 mg, 1.13 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The volatiles were removed on a rotary evaporator. The residue was purified by flash chromatography (silica gel, EtOAc - CH 2 Cl 2 , 1:4) to afford ( 2 -Amino-2'-ethoxy-biphenyl4 ylmethyl)carbamic acid tert-butyl ester (E-1) as a pale yellow oil (119 mg, 31 %). 'H NMR (300 MHz, DMSO-d 6 ) 8 7.27 (m, 2H), 7.07 (dd, J= 7.2 Hz, J= 1.8 Hz, 111), 7.03 (d, J= 7.8 Hz, 1H), 6.95 (dt, J= 7.2 Hz, J= 0.9 Hz, 1H1), 6,81 (d, J= 7.5 Hz, 1H), 6.55 (s, 1H), 6.45 (dd, J= 7.8 Hz, J= 1.5 Hz, 1H), 4.47 (s, 2Hf), 4.00 (q, J= 7.2 Hz, 2H), 1.38 (s, 9H), 1.20 (t, J= 7.2 Hz, 3H); HPLC ret. time 2.34 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 343.1 m/z (MH+). [00621] Example 2: - B r . Z n ( C N ) 2 P d ( P f h ) 2 N H 4 0 0 Hj 2 N Ag 2

SO

4 B H2S0 4 OzN DMF. 200C N CHHa 2N:" 2a r0 2 NC .

d- 2 NC O2N CN E-2 [00622] 2 -Bromo-l-tert-butyl-4-nitrobenzene -201- To a solution of 1-tert-butyl-4-nitrobenzene (8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 mL of 90% sulfuric acid was added dropwise bromine (7.95 g, 50 mmol). Stiring was continued at room temperature overnight, and then the mixture was poured into dilute sodium hydrogen sulfite solution and was extracted with EtOAc three times. The combined organic layers were washed with brine and dried over MgSO 4 . After filtration, the filtrate was concentrated to give 2-bromo-l-tert-butyl-4-nitrobenzene (12.7 g, 98 %), which was used without further purification. 'H NMR (400 MHz, CDCI) 6 8.47 (d, J= 2.5 Hz, 1H), 8.11 (dd, J = 8.8, 2.5 Hz, lH), 7.63 (d, J = 8.8 Hz, IH), 1.57 (s, 9H); HPLC ret. time 4.05 min, 10-100 %

CH

3 CN, 5 min gradient. [006231 2-tert-Butyl-5-nitrobenzonitrile To a solution of 2-bromo- 1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 nmmol) and Zn(CN) 2 (770 mg, 6.56 mmol) in DMF (10 mL) was added Pd(PPh 3

)

4 (474 mg, 0.41 mmol) under a nitrogen atmosphere. The mixture was heated in a sealed vessel at 205 "C for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgS04. After removal of solvent, the residue was purified by column chromatography (0-10 % EtOAc-Hexane) to give 2-tert-butyl-5 nitrobenzonitrile (1,33 g, 80 %). 'H NMR (400 MHz, CDCl 3 ) 8 8.55 (d, J= 2.3 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 7.73 (d, I = 8.9 Hz, 1H), 1.60 (s, 9H); HPLC ret. time 3.42 min, 10-100 % CH 3 CN, 5 min gradient. [00624] E-2; 2-tert-Butyl-5-aminobenzonitrile To a refluxing solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 mL) was added ammonium formate (816 mg, 12.6 mmol), followed by 10% Pd-C (570 mg). The reaction mixture was refluxed for additional 90 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give 2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, 91 %), which was used without further purification. HPLC ret. time 2.66 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 175.2 m/z (MH*). [006251 Example 3: -202- WNH F,.Pd-C H w e TH F- O ,N 0 O WMO H E-4 [006261 ( 2 -tert-Butyl-5-nitrophenyl)methanamine To a solution of 2 -tert-butyl-5-nitrobenzonitrile (612 ing, 3.0 mmol) in THF (10 mL) was added a solution of BH 3 -THF (12 mL, IM in THF, 12.0 mmol) under nitrogen. The reaction mixture was stirred at 70 'C overnight and cooled to 0

*

C. Methanol (2 mL) was added followed by the addition of IN HCl (2 mL). After refluxing for 30 min, the solution was diluted with water and extracted with EtOAc. The aqueous layer was basified with IN NaOH and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over Mg 2

SO

4 . After removal of solvent, the residue was purified by column chromatography (0-10 % MeOH CH 2 C1 2 ) to give ( 2 -tert-butyl-5-nitrophenyl)methanamine (268 mg, 43 %). 'H NMR (400 MHz, DMSO-d) S 8.54 (d, J = 2.7 Hz, 1H), 7.99 (dd, J= 8.8, 2.8 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1H), 4.03 (s, 2H), 2.00 (t, J = 2.1 Hz, 2H), 1.40 (s, 9H); HPLC ret. time 2.05 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 209.3 m/z (MIH). [006271 tert-Butyl 2 -tert-butyl-5-nitrobenzylcarbamate A solution of ( 2 -tert-butyl-5-nitrophenyl)methanamine (208 mg, 1 mmol) and Boc 2 O (229 mg, 1.05 mmol) in THF (5mL) was refluxed for 30 min. After cooling to room temperature, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4 . After filtration, the filtrate was concentrated to give tert-butyl 2 -tert-butyl-5-nitrobenzylcarbamate (240 mg, 78 %), which was used without further purification. 'H NMR (400 MHz, DMSO-d) 8 8.26 (d, J= 2.3 Hz, 1H), 8.09 (dd, J =8.8, 2.5 Hz, 1H), 7.79 (t, J = 5.9 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 1.48 (s, 18H); HPLC ret. time 3.72 min, 10-100 % CH 3 CN, 5 min gradient. [006281 E-4; tert-Butyl 2-tert-butyl-5-aniinobenzylcarbamate To a solution of tert-butyl 2 -tert-butyl-5-nitrobenzylcarbamate (20 mg, 0.065 mmol) in 5% AcOH-MeOH (I mL) was added 10% Pd-C (14 mg) under nitrogen atmosphere. The mixture -203 was stirred under H 2 (1 atm) at room temperature for I h. The catalyst was removed via filtration through Celite, and the filtrate was concentrated to give tert-butyl 2-tert-butyl-5 aminobenzylcarbamate (E-4), which was used without further purification. 'H NMR (400 MHz, CDCl 3 ) S 7.09 (d, J = 8.5 Hz, IH), 6.62 (d, J = 2.6 Hz, I H), 6.47 (dd, J= 8.5, 2.6 Hz, I H), 4.61 (br s, IH), 4.40 (d, J = 5.1 Hz, 2H), 4.15 (br s, 2H), 1.39 (s, 9H), 1.29 (s, 9H); HPLC ret. time 2.47 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 279.3 m/z (MH). [006291 Example 4: N. tiSO~ Met N* -HCOK Pd N. 4 KCO, DMF O OO 0 1 ON C ,-tO E-6 100630] 2-tert-Butyl-5-nitrobenzoic acid A solution of 2-tert-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 mL of 75% H 2 S0 4 was microwaved at 200 *C for 30 min. The reaction mixture was poured into ice, extracted with EtOAc, washed with brine and dried over MgS04. After filtration, the filtrate was concentrated to give 2-tert-butyl-5-nitrobenzoic acid (200 mg, 90 %), which was used without further purification. 'H NMR (400 MHz, CDC1 3 ) 6 8.36 (d, I = 2.6 Hz, 1H), 8.24 (dd, J = 8.9, 2.6 Hz, IH), 7.72 (d, J =8.9 Hz, 1H) 1.51 (s, 9H); HPLC ret. time 2.97 min, 10-100 % CH 3 CN, 5 min gradient. [00631) Methyl 2-tert-butyl-5-nitrobenzoate To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K 2 C0 3 (147 mg, 1.1 mmol) in DMF (5.0 mL) was added CH 3 I (40 p.L, 0.64 mmol). The reaction mixture was stirred at room temperature for 10 min, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4 .After filtration, the filtrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate, which was used without further purification. IHNMR(400 MHz, CDCl 3 ) 6 8.20(d, J=2.6 Hz, 1H), 8.17 (t, J=1.8Hz, 1H), 7.66 (d, J = 8.6 Hz, IH), 4.11 (s, 3H), 1.43 (s, 9H). - 204 - [00632] E-6; Methyl 2-tert-butyl-5-aminobenzoate To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL),' followed by the addition of 20 mg of 10% Pd-C. The reaction mixture was refluxed for additional 40 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give methyl 2-tert butyl-5-aminobenzoate (E-6) (76 mg, 95 %), which was used without further purification. 'H NMR (400 MHz, CDC 3 ) S 7.24 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 8.6, 2.7 Hz, 1H), 6.60 (d, J 2.7 Hz, lH), 3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 208.2 m/z (MH*). [006331 Example 5: 1. NaNO, HCI O2N NH2 2. Na 2 SO, CuSO 4 , HCI O2N SOCI

NH

4 OH SnC2.2HO Et 2 0 02N ONH j: S 2 H 2 N

SO

2

NH

2 E-7 [006341 2-tert-Butyl-5-nitrobenzene-1-sulfonyl chloride A suspension of 2-tert-butyl-5-nitrobenzenamine (0.971 g, 5 mmol) in conc. HCl (5 mL) was cooled to 5-10 "C and a solution of NaNO 2 (0.433g, 6.3 nunol) in H20 (0.83 mL) was added dropwise. Stirring was continued for 0.5 h, after which the mixture was vacuum filtered. The filtrate was added, simultaneously with a solution ofNa 2

SO

3 (1.57 g, 12.4 mmol) in H20 (2.7 mL), to a stirred solution of CuSO 4 (0.190 g, 0.76 mmol) and Na 2

SO

3 (1.57 g, 12.4 mmol) in HCl (11.7 mL) and H 2 0 (2.7 mL) at 3-5 "C. Stirring was continued for 0.5 h and the resulting precipitate was filtered off, washed with water and dried to give 2-tert-butyl-5-nitrobenzene-1 -205 sulfonyl chloride (0.235 g, 17%). 'H NMR (400 MHz, DMSO-d) S 9.13 (d, J = 2.5 Hz, 1I), 8.36 (dd, J= 8.9, 2.5 Hz, IH), 7.88 (d, J = 8.9 Hz, IH), 1.59 (s, 9H). [006351 2-tert-Butyl-5-nitrobenzene-1-sulfonamide To a solution of 2-tert-butyl-5-nitrobenzene-1-sulfony chloride (100 mg, 0.36 mmol) in ether (2 mL) was added aqueous NH 4 0H (128 piL, 3.6 mmol) at 0 *C. The mixture was stirred at room temperature overnight, diluted with water and extracted with ether. The combined ether extracts were washed with brine and dried over Na 2

SO

4 . After removal of solvent, the residue was purified by column chromatography (0-50 % EtOAc-Hexane) to give 2-tert-butyl-5 nitrobenzene-I-sulfonamide (31.6 mg, 34 %). {00636 E-7; 2-tert-Butyl-5-aminobenzene-1-sulfonamide A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamide (32 mg, 0.12 mmol) and SnCl 2 2H 2 0 (138 mg, 0.61 mmol) in EtOH (1.5 mL) was heated in microwave oven at 100 *C for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO 3 and filtered through Celite. The organic layer was separated from water and dried over Na 2

SO

4 . Solvent was removed by evaporation to provide 2-tert-butyl-5-aminobenzene-1 -sulfonamide (E-7) (28 mg, 100 %), which was used without further purification. HPLC ret. time 1.99 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 229.3 m/z (MH). [00637] Example 6:

UAJH

4

H

2 N O THF OH HNJC) C H2ND CH 0 E-8 [00638] E-8; (2-tert-Butyl-5-aminophenyl)iethanol To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 mL) was added dropwise LiAl 4 (1.4 mL, IM in THF, 1.4 mmol) at 0 *C. The reaction mixture was - 206 refluxed for 2 h, diluted with H20 and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4 . After filtration, the filtrate was concentrated to give (2-tert-butyl-5-aminophenyl)methanol (E-8) (25 mg, 20 %), which was used without further purification. H NMR (400 MHz, CDCl 3 ) S 7.17 (d, J= 8.5 Hz, IH), 6.87 (d, J =2.6 Hz, lH), 6.56 (dd, J = 8.4, 2.7 Hz, IH), 4.83 (s, 2H), 1.36 (s, 9H). [006391 Example 7: 0 Me 2

SO

4

K

3 Fe(CNj HNO N+ NaOH, H20 H2SO, MeSOO N MeSO 4 - N NOH0 N 0 O2N NO2 O H 2 N Hz, Raney Ni 2 N o MeOH, NH N MeOH N E-9 1006401 1-Methyl-pyridinium monomethyl sulfuric acid salt Methyl sulfate (30 mL, 39.8 g, 0.315 mol) was added dropwise to dry pyridine (25.0 g, 0.316 mol) added dropwise. The mixture was stirred at room temperature for 10 min, then at 100 *C for 2 h. The mixture was cooled to room temperature to give crude 1-methyl-pyridinium monomethyl sulfuric acid salt (64.7 g, quant.), which was used without further purification. [006411 1-Methyl-2-pyridone A solution of 1-methyl-pyridinium monomethyl sulfuric acid salt (50 g, 0.243 mol) in water (54 mL) was cooled to 0 *C. Separate solutions of potassium ferricyanide (160 g, 0.486 mol) in water (320 mL) and sodium hydroxide (40 g, 1.000 mol) in water (67 mL) were prepared and added dropwise from two separatory funnels to the well-stirred solution of 1 -methyl-pyridinium monomethyl sulfuric acid salt, at such a rate that the temperature of reaction mixture did not rise above 10 *C. The rate of addition of these two solutions was regulated so that all the sodium hydroxide solution had been introduced into the reaction mixture when one-half of the potassium - 207 - . Ferric Cyanide solution had been added. After addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Dry sodium carbonate (91.6 g) was added, and the mixture was stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted with CH 2

C

2 (100 mL x 3). The combined organic layers were dried and concentrated to yield I -methyl-2-pyridone (25.0 g, 94 %), which was used without further purification. [006421 1-Methyl-3,5-dinitro-2-pyridone 1-Methyl-2-pyridone (25.0 g, 0.229 mol) was added to sulfuric acid (500 mL) at 0 'C. After stirring for 5 min., nitric acid (200 nL) was added dropwise at 0 cC. After addition, the reaction temperature was slowly raised to 100 *C, and then maintained for 5 h. The reaction mixture was poured into ice, basified with potassium carbonate to pH 8 and extracted with CH 2

C

2 (100 mL x 3). The combined organic layers were dried over Na 2

SO

4 and concentrated to yield 1-methyl 3,5-dinitro-2-pyridone (12.5 g, 28 %), which was used without further purification. [00643] 2-Isopropyl-5-nitro-pyridine To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5.1 mL, 48 mmol), followed by ammonia solution in methyl alcohol (10.0 g, 17%, 100 mmol). The reaction mixture was heated at 70 *C for 2.5 h under atmospheric pressure. The solvent was removed under vacuum and the residual oil was dissolved in CH 2 C1 2 , and then filtered. The filtrate was dried over Na 2

SO

4 and concentrated to afford 2-isopropyl-5-nitro-pyridine (1.88 g, 28 %). [00644] E-9; 2-Isopropyl-5-amino-pyridine 2-Isopropyl-5-nitro-pyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 mL), and Raney Ni (0.25 g) was added. The mixture was stirred under H 2 (1 atm) at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated under vaccum to give 2 isopropyl-5-amino-pyridine (E-9) (0.55 g, 52 %). 'H NMR (CDCl 3 ) 8 8.05 (s, 1 H), 6.93-6.99 (ma, 2 H), 3.47 (br s, 2 H), 2.92-3.02 (n, I H), 1.24-1.26 (m, 6 H). ESI-MS 137.2 m/z (MH*). [006451 Example 8: - 208 - (EtaH____ Li, NH HO NaH, THF E 1 O=P-OEt OEt MeOCHCI2 CHO KNO 3

O

2 N CHO TiC 4 , CH 2 Cz + H 2 S0 4 + 0 2 N CHO Deoxo-Fluor Fe

O

2 N CHF 2 I + ~ AoOH- H2N

CHF

2 E-10 0 2 N

CHF

2 1006461 Phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 mL) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g, 169.6 mmol) in THF (150 mL) at 0 *C. The mixture was stirred at 0 *C for 15 min and then phosphorochloridic acid diethyl ester (30.15 g, 174.7 mmol) was added dropwise at 0 *C. After addition, the mixture was stirred at this temperature for 15 min. The reaction was quenched with sat. NH 4 CI (300 mL). The organic layer was separated and the aqueous phase was extracted with Et 2 O (350 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and concentrated under vacuum to give crude phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester as a yellow oil (51 g, contaminated with some mineral oil), which was used directly in the next step. -209- {00647] 1,3-Di-tert-butyl-benzene To NH 3 (liquid, 250 mL) was added a solution of phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester (51 g, crude from last step, about 0.2 mol) in Et 2 O (anhydrous, 150 mL) at -78 *C under N 2 atmosphere. Lithium metal was added to the solution in small pieces until a blue color persisted. The reaction mixture was stirred at -78 *C for 15 min and then quenched with sat.

NH

4 Cl solution until the mixture turned colorless. Liquid NH 3 was evaporated and the residue was dissolved in water, extracted with Et2O (300 mL x 2). The combined organic phases were dried over Na 2

SO

4 and concentrated to give crude 1,3-di-tert-butyl-benzene as a yellow oil (30.4 g, 94 % over 2 steps, contaminated with some mineral oil), which was used directly in next step. [00648] 2 ,4-Di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde To a stirred solution of 1,3-di-tert-butyl-benzene (30 g, 157.6 mmol) in dry CH 2 C1 2 (700 mL) was added TiC 4 (37.5 g, 197 mmol) at 0 *C, and followed by dropwise addition of MeOCHC 2 (27.3 g, 236.4 mmol). The reaction was allowed to warm to room temperature and stirred for I h. The mixture was poured into ice-water and extracted with CH 2 Cl 2 . The combined organic phases were washed with NaHCO 3 and brine, dried over Na 2

SO

4 and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl benzaldehyde and 3,5-di-tert-butyl-benzaldehyde (21 g, 61 %). 100649] 2

,

4 -Di-tert-butyl-5-nitro-benzaldehyde and 3,5-di-tert-butyl-2-nitro benzaldehyde To a mixture of 2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldebyde in H 2 S0 4 (250 mL) was added KNO 3 (7.64 g, 75.6 mmol) in portions at 0 *C. The reaction mixture was stirred at this temperature for 20 min and then poured into crushed ice. The mixture was basified with NaOH solution to pH 8 and extracted with Et 2 O (10 mL x 3). The combined organic layers were washed with water and brine and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl-5-nitro-benzaldehyde and 3

,

5 -di-tert-butyl-2-nitro-benzaldehyde (2:1 by NMR) as a yellow solid (14.7 g, 82 %). After further purification by column chromatography (petroleum ether), 2,4-di-tert-butyl-5-nitro benzaldehyde (2.5 g, contains 10% 3,5-di-tert-butyl-2-nitro-benzaldehyde) was isolated. -210- [006501 1,5-Di-tert-butyl-2-difluoromethyl-4-nitro-benzene and 1,5-Di-tert butyl-3-difluoromethyl-2-nitro-benzene 2,4-Di-tert-butyl-5-nitro-benzaldehyde (2.4 g, 9.11 mmol, contaminated with 10% 3,5-di-tert butyl-2-nitro-benzaldehyde) in neat deoxofluor solution was stirred at room temperature for 5 h. The reaction mixture was poured into cooled sat. NaHCO 3 solution and extracted with dichloromethane. The combined organics were dried over Na 2 S04, concentrated and purified by column chromatography (petroleum ether) to give 1,5-di-tert-butyl-2-difluoromethyl-4-nitro benzene (1.5 g) and a mixture of 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene and 1,5-di tert-butyl-3-difluoromethyl-2-nitro-benzene (0.75 g, contains 28 % 1,5-di-tert-butyl-3 difluoromethyl-2-nitro-benzene). [006511 E-10; 1,5-Di-tert-butyl-2-difluoromethyl-4-amino-benzene To a suspension of iron powder (5.1 g, 91.1 imnol) in 50% acetic acid (25 ml) was added 1,5-di tert-butyl-2-difluoromethyl-4-nitro-benzene (1.3 g, 4.56 mmol). The reaction mixture was heated at 115 "C for 15 min. Solid was filtered off was washed with acetic acid and CH 2 C1 2 . The combined filtrate was concentrated and treated with HCI/MeOH. The precipitate was collected via filtration, washed with MeOH and dried to give 1,5-Di-tert-butyl-2-difluoromethyl-4-amino benzene HCl salt (E-10) as a white solid (1.20 g, 90 %). 'H NMR (DMSO-d,) S 7.35-7.70 (t, J= 53.7 Hz, 1 H), 7.56 (s, 1 H), 7.41 (s, I H), 1.33-1.36 (d, J= 8.1 Hz, IH); ESI-MS 256.3 m/z (MH+). [006521 Example 9 [00653] General scheme: .. /OH AorB

H

2 N /-Q Ar-B H 2 N Br OH Ar A) Pd(PPh 3

)

4 , K 2 C0 3 , H 2 0, THF; B) Pd 2 (dba) 3 , P(tBu) 3 , KF, THF [00654] Method A -211 - In a 2-dram vial, 2-bromoaniline (100 mg, 0.58 mmol) and the corresponding aryl boronic acid (0.82 mmol) were dissolved in THF (1 mL). H 2 0 (500 gL) was added followed by K 2 C0 3 (200 mg, 1.0 mmol) and Pd(PPh 3

)

4 (100 mg, 0.1 mmol). The vial was purged with argon and sealed. The vial was then heated at 75 *C for 18 h. The crude sample was diluted in EtOAc and filtered through a silica gel plug. The organics were concentrated via Savant Speed-vac. The crude amine was used without further purification. [00655] Method B In a 2-dram vial, the corresponding aryl boronic acid (0.58 mmol) was added followed by KF (110 mg, 1.9 mmol). The solids were suspended in THF (2 mL), and then 2-bromoaniline (70 gL, 0.58 mmol) was added. The vial was purged with argon for I min. P(Bu) 3 (100 pL, 10% sol. in hexanes) was added followed by Pd 2 (dba) 3 (900 ptL, 0.005 M in THF). The vial was purged again with argon and sealed. The vial was agitated on an orbital shaker at room temperature for 30 min and heated in a heating block at 80 *C for 16 h. The vial was then cooled to 20 "C and the suspension was passed through a pad of Celite. The pad was washed with EtOAc (5 mL). The organics were combined and concentrated under vacuum to give a crude amine that was used without further purification. [006561 The table below includes the amines made following the general scheme above. F-1 4'-Methyl-biphenyl-2-ylamine A F-2 3'-Methyl-biphenyl-2-ylamine A F-3 2'-Methyl-biphenyl-2-ylamine A F-4 2',3'-Dimethyl-biphenyl-2-ylamine A F-5 (2'-Amino-biphenyl-4-yl)-methanol A F-6 N*4'*,N*4'*-Dimethyl-biphenyl-2,4'-diamine B F-7 - 2'-Trifluoromethyl-biphenyl-2-ylamine B F-8 (2'-Amino-biphenyl-4-yl)-acetonitrile A -212- F-9 4'-Isobutyl-biphenyl-2-ylainine A F-10 3 t -Trifluoromethyl-biphenyl-2-ylarnine B F-1l 2-Pyridin-4-yi-phenylamine B F-12 2-(l1 H-lndol-5-yl)-phenylamine B F-13 31,4'-Dimethyl-biphenyl-2-ylamine A F-14 4'-Isopropyl-biphenyl-2-ylar-nine A F-IS 3'-Isopropyl-biphenyl-2-ylamine A F- 16 4'-Trifluoromethyl-biphenyl-2-ylamine B F-l7 4'-Methoxy-biphenyl-2-ylamine B F-18 3'-Methoxy-biphenyl-2-ylamine B F-1 9 2-Benzo[1 ,3jdioxol-5-yI-phenylamine B F-201 3'-Ethoxy-biphenyt-2-yl amine B F-21 4'-Ethoxy-biphenyl-2-ylaniine B F-22 2'-Ethoxy-biphenyl -2-yl amine B F-23 4'-Methylsulfanyl-biphenyl-2-ylamnine B F-24 3 ,4'-Dimethoxy-biphenyl-2-ylamine B F-25 2',6'-Dimethoxy-bipheiiyl-2-ylamine B F-26 2',5'-Dimethoxy-biphenyl-2-ylamine B F-27 2',4'-Diiuethoxy-biphenyl-2-ylainine B F-28 5'-Chloi-o-2'-methoxy-biphenyl-2-ylamine B F-29 4'-Trifluoromethoxy-biphenyl-2-ylaminc B F-30 3'-Trifluoromethoxy-biphenyl-2-ylamine B F-31 4'-Phenoxy-biphenyl-2-ylaniine B F-32 2'-Fluoro-.3'-methoxy-biphenyl-2-ylamine B F-33 2'-Phenoxy-biphenyl-2-ylaxniine B F-34 2-(2,4-Dimethoxy-pyrimidin-5-yl)-phenylamine B F-35 5'-Isopropyl-2'-methoxy--biphenyl-2-ylamine B F-36 2'-Trifluoromethoxy-biphenyl-2-ylamine B F-37 4'-Fluoro-biphenyt-2-ylaniine B =F-38 3'-Fluoro-biphenyl-2-ylamine B -213- F-39 2'-Fluoro-biphenyl-2-ylamine B F-40 2'-Amino-biphenyl-3-carbonitrile B F-41 4'-Fluoro-3'-methyl-biphenyl-2-ylamine B F-42 4'-Chloro-biphenyl-2-ylanine B F-43 3'-Chloro-biphenyl-2-ylamine B F-44 3',5'-Difluoro-biphenyl-2-ylamine B F-45 2',3'-Difluoro-biphenyl-2-ylamine B F46 3',4'-Difluoro-biphenyl-2-ylamine B F-47 2',4'-Difluoro-biphenyl-2-ylamine B F-48 2',5'-Difluoro-biphenyl-2-ylainine B F-49 3'-Chloro-4'-fluoro-biphenyl-2-ylamine B F-50 3',5'-Dichloro-biphenyl-2-ylamine B F-51 2',5'-Dichloro-biphenyl-2-ylamine B F-52 2',3'-Dicbloro-biphenyl-2-ylamine B F-53 3',4'-Dichloro-biphenyl-2-ylamine B F-54 2'-Amino-biphenyl-4-carboxylic acid methyl ester B F-55 2'-Amino-biphenyl-3-carboxylic acid methyl ester B F-56 2'-Methylsulfanyl-biphenyl-2-ylamine B F-57 N-(2'-Anino-biphenyl-3-yl)-acetaniide B F-58 4'-Methanesulfinyl-biphenyl-2-ylamine B F-59 2',4'-Dichloro-biphenyl-2-ylamine B F-60 4'-Methanesulfonyl-biphenyl-2-ylamine B F-61 2'-Anino-biphenyl-2-carboxylic acid isopropyl ester B F-62 2-Fuian-2-yl-phenylanine B F-63 1-[5-(2-Amino-phenyl)-thiophen-2-yl]-etbanone B F-64 2-Benzo[b]thiophen-2-yl-phenylamine B F-65 2-Benzo[b]thiophen-3-yl-phenylamine B F-66 2-Furan-3-yl-phenylamine B F-67 2-(4-Methyl-thiophen-2-yl)-phenylamine B F-68 5-(2-Amino-phenyl)-thiophene-2-carbonitrile B -214- [006571 Example 10: OEt Me], NaO'Bu OEt HCOK, Pd-C OEt 0 DMF O EtOH O O2N 0 2 N H 2 N G-1 [00658] Ethyl 2-(4-nitrophenyl)-2-methylpropanoate Sodium t-butoxide (466 mg, 4.85 mmol) was added to DMF (20 mL) at 0 *C. The cloudy solution was re-cooled to 5 *C. Ethyl 4-nitrophenylacetate (1.0 g, 4.78 mmol) was added. The purple slurry was cooled to 5 *C and methyl iodide (0.688 mL, 4.85 mmol) was added over 40 min. The mixture was stirred at 5-10 *C for 20 min, and then re-charged with sodium t-butoxide (466 mg, 4.85 mmol) and methyl iodide (0.699 mL, 4.85 mmol). The mixture was stirred at 5-10 aC for 20 min and a third charge of sodium t-butoxide (47 mg, 0.48 mmol) was added followed by methyl iodide (0.057 mL, 0.9-mmol). Ethyl acetate (100 mL) and HCI (0.1 N, 50 mL) were added. The organic layer was separated, washed with brine and dried over Na 2

SO

4 , After filtration, the filtrate was concentrated to provide ethyl 2-(4-nitrophenyl)-2-inethylpropanoate (900 mg, 80 %), which was used without further purification. [00659] G-1; Ethyl 2-(4-aminophenyl)-2-methylpropanoate A solution of ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 mL) was treated with 10% Pd-C (80 mg) and heated to 45 *C. A solution of potassium formate (4.10 g, 48.8 mmol) in H 2 0 (II mL) was added over a period of 15 min. The reaction mixture was stirred at 65 *C for 2 h and then treated with additional 300 mg of Pd/C. The reaction was stirred for 1.5 h and then filtered through Celite. The solvent volume was reduced by approximately 50 % under reduced pressure and extracted with EtOAc. The organic layers were dried over Na 2

SO

4 and the solvent was removed under reduced pressure to yield ethyl 2-(4-aminophenyl)-2 methylpropanoate (G-1) (670 mg, 85 %). 'H NMR (400 MHz, CDCl 3 ) 8 7.14 (d, J =8.5 -Iz, 2H), 6.65 (d, J= 8.6 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J= 7.1 Hz, 3H). -215- [006601 Example 11: O LIPJH 4 NOH H2N O THF H2N G-1 G-2 [006611 G-2; 2 -(4-Aminophenyl)-2-methylpropan- 1-o A solution of ethyl 2

-(

4 -aninophenyl)-2-methylpropanoate (30 mg, 0.145 mmol) in THF (1 mL) was treated with LiAIH 4 (IM solution in THF, 0.226 mL, 0.226 mmol) at 0 "C and stirred for 15 min. The reaction was treated with 0. IN NaOH, extracted with EtOAc and the organic layers were dried over Na 2

SO

4 . The solvent was removed under reduced pressure to yield 2-(4 aminophenyl)-2-methylpropan-1-ol (G-2), which was used withoutfurther purification: 'H NMR (400 MHz, CDCl 3 ) 5 7.17 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 3.53 (s, 2H), 1.28 (s, 6H). [00662] Example 12: CN Mel, NaoBu OBH, NHz ONJ C DMF 0 e NTHF j BocoO, NaOH B. HCOCNH, Pd-C Y_ HBoc 1.4-doxane, H 1 o EtOH 0,ef HN G-3 [00663] 2 -methyl-2-(4-nitrophenyl)propanenitrle A suspension of sodium tert-butoxide (662 mg, 6.47 mmol) in DMF (20 mL) at 0 *C was treated with 4-nitrophenylacetonitrile (1000 mg, 6.18 mmol) and stirred for 10 min. Methyl iodide (400 [LL, 6.47 mmol) was added dropwise over 15 min. The solution was stirred at 0-10 *C for 15 ruin and then at room temperature for additional 15 min. To this purple solution was added sodium tert-butoxide (662 mg, 6.47 mmol) and the solution was stirred for 15 min. Methyl iodide (400 pL, 6.47 mmol) was added dropwise over 15 min and the solution was stirred -216overnight. Sodium tert-butoxide (192 mg, 1.94 mmol) was added and the reaction was stirred at 0 "C for 10 minutes. Methyl iodide (186 tL, 2.98 nunol) was added and the reaction was stirred for th. The reaction mixture was then partitioned between IN HCl (50 mL) and EtOAc (75 mL). The organic layer was washed with I N HCI and brine, dried over Na 2

SO

4 and concentrated to yield 2 -methyl-2-(4-nitrophenyl)propanenitrile as a green waxy solid (1.25 g, 99 %). 'H NMR (400 MHz, CDC 3 ) 3 8.24 (d, J = 8.9 Hz, 2H), 7.66 (d, J =8.9 Hz, 2H), 1.77 (s, 6H). [006641 2-Methyl-2-(4-nitrophenyl)propan-1-amine To a cooled solution of 2 -methyl-2-(4-nitrophenyl)propanenitrile (670 mg, 3.5 mmol) in THF (15 mL) was added BH 3 (1M in THF, 14 mL, 14 mmol) dropwise at 0 "C. The mixture was warmed to room temperature and heated at 70 *C for 2 h. IN HCI solution (2 mL) was added, followed by the addition of NaOH until pH > 7. The mixture was extracted with ether and ether extract was concentrated to give 2 -methyl-2-(4-nitrophenyl)propan- I-amine (610 mg, 90 %), which was used without further purification. IH NMR (400 MHz, CDC 3 ) S 8.20 (d, J= 9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 2.89 (s, 2H), 1.38 (s, 6H). [00665] tert-Butyl 2 -methyl-2-(4-nitrophenyl)propylcarbamate To a cooled solution of 2 -methyl-2-(4-nitrophenyl)propan-1-amine (600 mg, 3.1 mmol) and IN NaOH (3 mL, 3 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added Boc2O (742 mg, 3.4 mmol) at 0 *C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was made acidic with 5% KHSO 4 solution and then extracted with ethyl acetate. The organic layer was dried over MgSO 4 and concentrated to give tert-butyl 2.-methyl-2-(4 nitrophenyl)propylcarbamate (725 mg, 80 %), which was used without further purification. 'H NMR (400 MHz, CDCl 3 ) S 8.11 (d, J = 8.9 Hz, 2H), 7.46 (d, J= 8.8 Hz, 2H), 3.63 (s, 2H), 1.31 1.29 (m, 15H). [006661 G-3; tert-Butyl 2 -methyl-2-(4-aminophenyl)propylearbamate To a refluxing solution of tert-butyl 2 -methyl-2-(4-nitrophenyl)propylcarbamate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 nmmol) in EtOH (25 mL) was added Pd-5%wt on carbon (400 mg). The mixture was refluxed for 1 h, cooled and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-methyl-2-(4-aminophenyl)propylcarbamate (G-3) -217- (550 mg, 83 %), which was used without further purification. 'H NMR (400 MHz, DMSO-d) 8 6.99 (d, J = 8.5 Hz, 2H), 6.49 (d, I= 8.6 Hz, 2H), 4.85 (s, 2H), 3.01 (d, J= 6.3 Hz, 2H), 1.36 (s, 9H), 1.12 (s, 6H); HPLC ret. time 2.02 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 265.2 m/z (MH+). [00667] Example 13: NaBH 4 H 2 , Pd-C

O

2 N MeOH 0 2 N MeOH H 2 N O OH H-1 [006681 7-Nitro-1,2,3,4-tetrahydro-naphthalen-1-oI 7-Nitro-3,4-dihydro-2H-naphthalen-1-one (200 mg, 1.05 mmol) was dissolved in methanol (5 mL) and NaBH 4 ((78 mg, 2.05 mmol) was added in portions. The reaction was stirred at room temperature for 20 min and then concentrated and purified by column chromatography (10-50 % ethyl acetate - hexanes) to yield 7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol (163 mg, 80 %). 'H NMR (400 MHz, CD 3 CN) S 8.30 (d, J = 2.3 Hz, 1H), 8.02 (dd, J= 8.5, 2.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, IH), 4.76 (t, J= 5.5 Hz, 1H), 2.96-2.80 (m, 2H), 2.10-1.99 (m, 2H), 1.86-1.77 (m, 2H); HPLC ret. time 2.32 min, 10-99 % CH 3 CN, 5 min run. [006691 H-1; 7-Amino-1,2,3,4-tetrahydro-naphthalen-1-oI 7 -nitro-1,2,3,4-tetrahydro-naphthalen-1-ol (142 mg, 0.73 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N 2 (g). 10% Pd-C (10 mg) was added and the reaction was stirred under H2 (1 atm) at room temperature overnight. The reaction was filtered and the filtrate concentrated to yield 7-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (1-1) (113 mg, 95 %). HPLC ret. time 0.58 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 164.5 m/z (MH). [00670] Example14: -218-

NH

2 OH I H 2 , Pd-C 0 2 N Pyridine MeOH O N 2 N OH Boc20 H2N EtN, MeoH HNN

NH

2 H)

-

H-2 O [00671] 7-Nitro-3,4-dihydro-2H-naphthalen-1-one oxime To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62 mmol) in pyridine (2 mL) was added hydroxylamine solution (I mL, -50% solution in water). The reaction was stirred at room temperature for I h, then concentrated and purified by column chromatography (10-50 % ethyl acetate - hexanes) to yield 7-nitro-3,4-dihydro-2H-naphthalen-1 -one oxime (471 mg, 88 %). HPLC ret. time 2.67 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 207.1 m/z (MH*). [006721 1,2,3,4-Tetrahydro-naphthalene-1,7-diamine 7-Nitro-3,4-dihydro-2H-naphthalen-1-one oxime (274 mg, 1.33 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N 2 (g). 10 % Pd-C (50 mg) was added and the reaction was stirred under H 2 (1 atm) at room temperature overnight. The reaction was filtered and the filtrate was concentrated to yield 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (207 mg, 96 %). 'H NMR (400 MHz, DMSO-d) 8 6.61-6.57 (m, 2H), 6.28 (dd, J= 8.0,2.4 Hz, 1H), 4.62 (s, 2H), 3.58 (m, 1H), 2.48-2.44 (m, 2H), 1.78-1.70 (m, 211), 1.53-1.37 (m, 2H). [00673] H-2; (7-Anino-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbainc aeid tert-butyl ester To a solution of 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (154 mg, 0.95 mmol) and triethylamine (139 1 iL, 1.0 mmol) in methanol (2 mL) cooled to 0 *C was added di-tert-butyl dicarbonate (207 mg, 0.95 mmol). The reaction was stirred at 0 *C and then concentrated and purified by column chromatography (5-50 % methanol - dichloromethane) to yield (7-amino -219- 1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (H-2) (327 mg, quant.). HPLC ret. time 1.95 min, 10-99 % CH3CN, 5 min run; ESI-MS 263.1 m/z (MH+). [006741 Example 15: Br EtO CF, r 5 CF H N NH2 I N 3 EtN, MeOH Pd(OAc)r PS-PPh HNN CF,

K

2 C0, OMF H [006751 N-(2-Bromo-benzyl)-2,2,2-trifluoro-acetanide To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5 mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) and triethylamine (1.4 mL, 10.8 nmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under vacuum to yield N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (3.15g, quant.). HPLC ret. time 2.86 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 283.9 m/z (MH*). [006761 I-1; N-(4'-Amino-biphenyl-2-ylmethyl)-2,2,2-trifluoro-acetamide A mixture of N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (282 mg, 1.0 mmol), 4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (284 mg, 1.3 mmol), Pd(OAc) 2 (20 mg, 0.09 mmol) and PS-PPh 3 (40 mg, 3 mmol / g, 0.12 mmol) was dissolved in DMF (5 mL) and 4M K 2 CO3 solution (0.5 mL) was added. The reaction was heated at 80 *C overnight. The mixture was filtered, concentrated and purified by column chromatography (0-50 % ethyl acetate - hexanes) to yield N-(4'-amino-biphenyl-2-ylnethyl)-2,2,2-trifluoro-acetamide (1-1) (143 mg, 49 %). HPLC ret. time 1.90 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 295.5 m/z (MHE). [00677] Commercially available amines -220- Amine Name J-1 2-methoxy-5-methylbenzenamine J-2 2,6-diisopropylbenzenamitie J-3 pyridin-2-amine J-4 4-pentyibenzenatnine J-5 isoquinolin-3-amine J-6 aniline J-7 4-phenoxybenzenamrne J-8 2-(2,3 -dimethylphenoxy)pyridin-3-ainine J-9 4-ethynylbenzenamine J-1 0 2-sec-butylbenzenamine J-1 1 2-amino-4,5-dimethoxybenzonitrile J-12 2-teirt-butytbenzenamine J-13 1-(7-amino-3 ,4-dihydroisoquinolin-2(I H)-yl)ethanone J-14 4-(4-methyl-4H-1 ,2,4-triazol-3-yl)benzenamine J-15 2 t -Aminomethyl-biphenyl-4-ylamine J-16 1-nao--tmn J-17 2-(2-methoxyphenoxy)-5-(trifluoroniethyl)benzenamine J-18 2-tert-butylbenzenwmine J-19 2,4,6-trimethylbenzenamidne J-20 5,6-dimetiayl-1H-benzo[dlimidazol-2-aniine J-21 2,3-dibydro-IH-inden-4-amine J-22 2-see-butyl-6-ethylbenzenamine J-23 quinolin-5-ainine 3-24 4-{benzyloxy)benzenamine J-25 2'-Methoxy-biphenyt-2-ylanaine J-26 benzo[c][1,2,5]thiadiazol-4-amine J-27 3-benzylbenzenamine 5-28 4-isopropylbenzenamine J-29 2-(phenylsulfonyl)benzenaine -221- J-30 2-methoxybenzenamine J-31 4-amino-3-ethylbenzonitrile J-32 4-methylpyridin-2-amine 3-33 4-chlorobenzenamuine J-34 2-(benzyioxy)benzenamine 3-35 2-amino-6-chlorobenzonitrile 3-36 3 -methylpyridin-2-amine J-37 4-aminoberazonittnle J-38 3-chloro-2,6-diethylbenzenamine J-39 3-phenoxybetizenamine J-40 2-benzylbenzenaiinine J-41 2-(2-fluorophenoxy)pyridin-3-amine J-42 5-chloropyridin-2-aniine J-43 2-(trifluoromethyl)benzenarnine J-44 (4-(2-aminophenyl)piperazin-l -yl)(phenyL)methanone J-45 1 H-benzo~dj[ 1,2,3]triazol-5-amnine J-46 2-(1 H-indol-2-yl)benzenamine J-47 4-Methyl-biplienyl-3-ylamine 3-48 pyridin-3 -amine 3-49 3 ,4-dtimethoxybenzenanine 3-50 3H-benzo[d]imidazol-5-amine 3-51 3-aminobenzonitrile 3-52 6-chloropyridin-3-amine J-53 o-toluidine J-54 1H-indol-5-amine J-55 [1,2,4ltriazolo[ 1,S-a]pyridin-8-atnine J-56 2-methoxypyridin-3-amine J-57 2-butoxybenzenamine 3-58 2,6-diniethylbenzenamine J-59 2-(methylthio)benzenamine - 222 - J-60 2-(5-methylfiuran-2-y1)benzenamine J-61 3 -(4-aminophenyl)-3 -ethylpiperidine-2,6-dione 3-62 2,4-dimethylbenzenamine J-63 5-fluoropyridin-2-arnine J-64 4-cyclohexylbenzenamine 3-65 4-Amino-benzenesulfonamide J-66 2-ethiylbenzenamine J-67 4-fluoro-3-metbylbenzeiiarine J-68 2,6-dimnethoxypyridia-3-ainine 3m-69 4-tert-butylbenizenamine J-70 4-see-buitylbenzenamine J-71 5,6,7,8-tetrahydronaphthalen-2-amine J-72 3-(Pyrrolidine- 1 -sulfonyl)-phenyl amine J-73 4-Adamantan- 1 -yt-phenylamine J-74 3 -amnino-5,6,7,8-tetrahydronaphthalen-2-o J-75 benzo[d][1 ,3]dioxol-5-amine J-76 5-chloro-2-phenoxybenzenamine J-77 NI -tosylbenzene-I,2-diamine J-78 3,4-dimethylbenzenarnine J-79 2-(trifluoromethyltbio)benzenamine J-80 IH-indol-7-amine 3-81 3-niethoxybenzenaniine 3-82 quinolin-8 -amine J-83 2-(2,4-difluorophenoxy)pyridin-3-amine J-84 2-(4-aininophenyl)acetonitrile 3-85 2,6-dichlorobenzenamine J-86 2,3-dihydrobenzofuran-5-amnine J-87 p-tolxuidine J-88 2-methylquinotin-8-amine J-89 2-tert-butylbeazenamine - 223 - J-90 3-chlorobenzenamine J-91 4-tert-butyl-2-chlorobenzenamine J-92 2-Amino-benzenesulfonamide J-93 1-(2-aminophenyl)ethanone J-94 m-toluidine J-95 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)benzenamine J-96 2-amino-6-methylbenzonitrile J-97 2-(prop- I -en-2-yl)benzenamine J-98 4-Amino-N-pyridin-2-yl-benzenesulfonanide J-99 2-ethoxybenzenamine J-100 naphthalen-1-amine J-101 Biphenyl-2-ylamine J-102 2-(trifluoromethyl)4-isopropylbenzenaiine J-103 2,6-diethylbenzenamine J-104 5-(trifluoromethyl)pyridin-2-amine J-105 2-aminobenzamide J-106 3-(trifluoromethoxy)benzenamine J-107 3,5-bis(trifluoromethyl)benzenamine J-108 4-vinylbenzenamine J-109 4-(trifluoromethyl)benzenamine J-110 2-morpholinobenzenamine J-111 5-amino-1H-benzo[d]imidazol-2(3H)-one J-112 quinolin-2-amine J-113 3-methyl-1H-indol-4-amine J-114 pyrazin-2-amine J-115 1-(3-aminophenyl)ethanone J-116 2-ethyl-6-isopropylbenzenamine J-117 2-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yi)benzenamine J-118 N-(4-amino-2,5-diethoxyphenyl)benzamide J-119 5,6,7,8-tetrahydronaphthalen-1-amine -224- J-120 2-( 1 H-benzo[dlimidazol-2-yI)benzenaznine J£121 1, 1 -Dioxo- I H- I 1ambda*6*-benzo[b]thiophen-6-ylamine J-122 2,5-diethoxybenzenarnine J£123 2-isopropyl-6-methylbenzenamine J-1 24 tert-butyl 5-amino-3 ,4-clihydroisoquinotine-2(l H)-carboxylate J-125 2-(2-aminophenyl)ethanol J-126 (4- aminophenyl)methanol J-127 5-methylpyridin-2-ainine J-128 2-(pyrrolidin- I -yl)benzenarnine J-129 4-propylbenzenanline J-130 3 ,4-dichlorobenzenamine J-131 2-phenoxybenzenatnine J-132 Biphenyl-2-ylamine J£133 2.-chlorobenzenamine J£134 2-amino-4-methylbenzoitrile J-135 (2-amninophenyl)(phenyl)methanone J-136 aniline J-137 3-(tifluoromethylthio)benzenamine J-138 2-(2,5-dimethyl-1H-pyrrol-1-yl)benzenamine J-139 4-(Morpholine-4-sulfonyl)-phenylamine J-140 2-naethylbenzo[dlthiazol-5-amine J-141 2-amino-3,5-dichlorobenzonitrile J-142 2-fluoro-4-methyibenzenamine J-143 6-ethylpyridin-2-anhine J-144 2-(1H-pyrrol-1 -yI)benzenamine J-145 2-inetlayl-1H-indol-5-amine J-146 quinolin-6-amine J-147 lH-benzo[d]imnidazol-2-amine J-148 2-o-tolylbenzo[d]oxazol-S-arnine J-149 5-phenylpyridia-2-amine - 225 - J-150 Biphenyl-2-ylamine 3-151 4-(difluoromethoxy)benzenamine J-152 5-tert-butyl-2-methoxybenzenamine J-153 2-(2-ter-butylphenoxy)benzenan-ine J-154 3-aminobenzamide J-155 4-morpholinobenzenamine J-156 6-amninobenzo[d]oxazoI-2(3H)-one J-157 2-phenyl-3 H-benzo[d]imidazol-5-amine J-158 2,5-dichloropyridin-3-amine J-159 2,5-dimethylbenzenainine J-160 4-(phenylthio)benzenamine J-161 9H-fluoren-1 -amine J-162 2-(4-aminophenyl)-1 ,l,1 ,3,3,3-hexafluoropropan-2-ol J-163 4-bromo-2-ethylbenzenamine J-164 4-methoxybenzenamine J-165 3-(Piperidine- I -sulfonyl)-phenylamine J-166 quinoxatin-6-amine J-167 6-(trifluoromethyl)pyridin-3 -amino J-168 3 -(trifluoromethyl)-2-methylbenzenamine J-169 (2-aminopheny1)(pheny1)methanot J-170 anilibe J-171 6-rnethoxypyridiu-3-aniine J-172 4-biitylbenzenamnine J-173 3-(M~orpholine-4-sulfonyl)-phenylamine J-174 2,3-dimethylbenzenamine J-175, aniline J-176 Biphenyt-2-yaxnine J-177 2-(2,4-dichlorophenoxy)benzenatnine J-178 pyridin-4-ainine J-179 2-(4-methoxyphenoxy)-5-(trifluoromethyl)benzenamine -226- J-180 6-methylpyridin-2-amine J-1 81 5-chloro-2-.fluorobenzenamine J-182 1 H-indol-4-arnine J- 183 6-morpholinopyridin-3-amine J-184 aniline J-185 IH-indazol-5-amine J-186 2-[(Cyclohexyl-methyl-amino)-methyl]-phenylarnine J-1 87 2-pheiiylbenzo[d] oxazol-5-ami le J-188 naphthalen-2-amine J-1 89 2-arninobenzonitrile J-190 N I,N I -di ethyl-3 -methylbenzene- 1 ,4-disamine J-191 aniline J-192 2-butylbenzenamine J-193 I -(4--aminophenyl)ethanol J-194 2-amino-4-methylbenzamide J-195 quinolin-3-amine J-196 2-(piperidin- 1-yl)benzenamine J-197 3-Aniino-benzenesulfonamide J-198 2-ethyl-6-methyl-benzenamine J-199 Biphenyl-4-ylatmine J-200 2-(o-tolyloxy)benzenamine J-201 5-aniino-3-methylbenzo[d]oxazol-2(3H)-one J-202 4-ethylbenzenaniine J-203 2-isopropylbenzenamine J-204 3-(tiifluoromethyl)benzenamine 3-205 2-amino-6-fluorobenzonitrile J-206 2-(2-aminophenyl)acetonitrile J1-207 2-QI-fluorophenoxy)pyridin-3 -amine J-208 aniline J-209 2-(4-methylpiperidin- 1 -yl)benzenatnine - 227 - J-210 4-fluorobenzenamine J-211 2-propylbenzenamine J-212 4 -(trifluoromethoxy)benzenamine J-213 3-aminophenol J-214 2,2-difluorobenzo[d][1,3]dioxol-5-am-ine J-215 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine J-216 N-(3-aminophenyl)acetamide J-217 1-(3-aminophenyl)-3-methyl-iH-pyrazol-5(4H)-one J-218 5-(trifluoromethyl)benzene-1,3-diamine J-219 5-tert-butyl-2-methoxybenzene-1,3-diamine J-220 N-(3-amino-4-ethoxyphenyl)acetamide J-221 N-(3-Amino-phenyl)-methanesulfonanide J-222 N-(3-aminophenyl)propionamide J-223 NI,N1-dimethylbenzene-1,3-diamine J-224 N-(3-amino-4-methoxyphenyl)acetamide J-225 benzene-1,3-diamine J-226 4-methylbenzene-1,3-diamine J-227 IH-indol-6-amine J-228 6,7,8,9-tetrahydro-5H-carbazol-2-amine J-229 1H-indol-6-amine J-230 1H-indol-6-amine J-231 IH-indol-6-amine J-232 IH-indol-6-amine J-233 IH-indol-6-amine J-234 1H-indol-6-amine J-235 IH-indol-6-amine J-236 1H-indol-6-amine J-237 IH-indol-6-amine J-238 I H-indol-6-amine J-239 1-(6-Amino-2,3-dihydro-indol-1-yl)-ethanone - 228 - J-240 5-Chloro-benzene- 1,3-diamine [00678] Amides (Compounds of formula 1) [006791 General scheme: RI 0 0 R1 0 0 R2 OH a R2 N ' R6R7 R3 N R6 R3 N R6 R4 R5 R4 R5 a) ArIR7NH, coupling reagent, base, solvent. Examples of conditions used: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et 3 N, CH 2 C1 2 ; PFP-TFA, pyridine [006801 Specific example: H 0 0 OH J-136, HATU N r, DIEA, DMF N A-1 216 [00681] 215; 4-Oxo-N-phenyl-1H-quinoline-3-carboxamide To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1mmol) and DIEA (34.9 pL, 0.2mmol) in DMF (I mL) was added aniline (18.2 pL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99 % CH 3 CN / H 2 0) to yield 4-oxo-N-phenyt-lH quinoline-3-carboxamide (215) (12 mg, 45 %). 'H NMR (400 MHz, DMSO-d6) 8 12.97 (s, IH), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (in, 3H), - 229 - 7.55 (t, J= 8.1 Hz, 1H), 7.37 (t, J= 7.9 Hz, 2H), 7.10 (t, J= 6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 265.1 m/z (MH). [006821 The table below lists other examples synthesized by the general scheme above. Compound of fordla i Ad Amine 2 A-1 C-2 3 A-1 J-17 4 A-1 J-110 5 A-I G-2 6 A-1 E-8 7 A-1 J-118 8 A-1 D-7 9 A-1 J-197 11 A-1 F-7 12 A-1 F-6 13 A-1 E-2 15 A-1 J-56 16 A-1 J-211 18 A-I J-161 19 A-1 J-112 20 A-1 J-200 21 A-1 J-98 23 A-1 C-15 24 A-1 J-72 25 A-1 F-57 26 A-1 J-196 29 A-21 J-208 31 A-1 J-87 32 A-1 B-21 33 A-1 J-227 34 A-1 C-19 36 A-1 J-203 37 A-1 J-80 -230- 38 A-1 J-46 39 A-17 D-10 40 A-1 J-125 42 A-1 J-95 43 A-1 C-16 44 A-1 J-140 45 A-1 J-205 47 A-1 J-102 48 A-1 J-181 49 A-1 F-25 50 A-1 J-19 51 A-7 B-24 52 A-1 F-2 53 A-1 J-178 54 A-1 J-26 55 A-1 J-219 56 A-1 J-74 57 A-1 J-61 58 A-1 D-4 59 A-1 F-35 60 A-1 D-11 61 A-1 J-174 62 A-1 J-106 63 A-1 F-47 64 A-1 J-111 66 A-1 J-214 67 A-10 J-236 68 A-1 F-56 69 A-1 D-8 70 A-1 F-11 71 A-1 F-61 72 A-1 J-66 73 A-1 J-157 74 A-1 J-104 75 A-1 J-195 76 A-1 F-46 -231- 77 A-I B-20 78 A-1 J-92 79 A-1 F-41 80 A-1 J-30 81 A-1 J-222 82 A-1 J-190 83 A-1 F-40 84 A-1 J-32 85 A-1 F-53 86 A-1 J-15 87 A-1 J-39 88 A-1 G-3 89 A-1 J-134 90 A-1 J-18 91 A-1 J-38 92 A-1 C-13 93 A-1 F-68 95 A-1 J-189 96 A-1 B-9 97 A-1 F-34 99 A-1 J-4 100 A-1 J-182 102 A-1 J-117 103 A-2 C-9 104 A-1 B-4 106 A-. J-1 107 A-I DC-6 108 A-1 DC-3 109 A-1 DC-4 110 A-1 J-84 i1 A-1 J-43 112 A-1I J-235 113 A-1 B-7 114 A-1 D-18 115 A-1 F-62 116 A-3 J-229 -232- 118 A-1 F-12 120 A-1 J-1 121 A-1 J-130 122 A-1 J-49 123 A-1 F-66 124 A-2 B-24 125 A-1 J-143 126 A-1 C-25 128 A-22 J-176 130 A-14 J-233 131 A-1 J-240 132 A-1 J-220 134 A-1 F-58 135 A-1 F-19 136 A-1 C-8 137 A-6 C-9 138 A-1 F-44 139 A-I F-59 140 A-1 J-64 142 A-1 J-10 143 A-1 C-7 144 A-i J-213 145 A-1 B-1a 146 A-1 J-55 147 A-1 J-207 150 A-1 J-162 151 A-1 F-67 152 A-1 J-156 153 A-1 C-23 154 A-1 J-107 155 - A-1 J-3 166 A-1 F-36 160 A-1 D-6 161 A-1 C-3 162 A-1 J-171 164 A-1 J-204 - 233 - 165 A-1 J-65 166 A-1 F-54 167 A-1 J-226 168 A-1 J-48 169 A-1 B-i 170 A-1 J-42 171 A-1 F-52 172 A-1 F-64 173 A-1 J-180 174 A-i F-63 175 A-1 DC-2 176 A-1 J-212 177 A-1 J-57 178 A-1 J-153 179 A-1 J-154 180 A-1 J-198 181 A-1 F-1 182 A-I F-37 183 A-1 DC-1 184 A-15 J-231 185 A-1 J-173 186 A-1 B-15 187 A-1 B-3 188 A-1 B-25 189 A-1 J-24 190 A-1 F-49 191 A-1 J-23 192 A-1 J-36 193 A-1 J-68 194 A-1 J-37 195 A-1 J-127 197 A-1 J-167 198 A-1 J-210 199 A-1 F-3 200 A-1 H-1 201 A-1 J-96 - 234 - 202 A-1 F-28 203 A-1 B-2 204 A-1 C-5 205 A-1 J-179 206 A-1 J-8 207 A-1 B-17 208 A-1 C-12 209 A-1 J-126 210 A-17 J-101 211 A-1 J-1 52 212 A-1 J-217 213 A-1 F-51 214 A-1 J-221 215 A-1 J-136 216 A-1 J-147 217 A-1 J-185 218 A-2 C-13 219 A-1 J-114 220 A-1 C-26 222 A-1 J-35 223 A-1 F-23 224 A-1 1-1 226 A-1 J-129 227 A-1 J-120 228 A-1 J-169 229 A-1 J-59 230 A-I J-145 231 A-1 C-17 233 A-1 J-239 234 A-1 B-22 235 A-1 E-9 236 A-i J-109 240 A-1 J-34 241 A-1 J-82 242 A-1 D-2 244 A-1 J-228 -235- 245 A-1 J-177 246 A-1 J-78 247 A-1 F-33 250 A-1 J-224 252 A-1 J-135 253 A-1 F-30 254 A-2 B-20 255 A-B C-9 256 A-1 J-45 257 A-1 J-67 259 A-1 B-14 261 A-1 F-13 262 A-I DC-7 263 A-1 J-163 264 A-1 J-122 265 A-1 J-40 266 A-1 C-14 267 A-1 J-7 268 A-1 E-7 270 A-1 B-5 271 A-1 D-9 273 A-1 H-2 274 A-8 B-24 276 A-1 J-139 277 A-1 F-38 278 A-1 F-10 279 A-1 F-56 280 A-1 J-146 281 A-1 J-62 283 A-1 F-18 284 A-1 J-16 285 A-1 F-45 286 A-1 1-119 287 A-3 C-13 288 A-1 C-6 289 A-1 J-142 -236- 290 A-1 F-I5 291 A-1 C-10 292 A-1 J-76 293 A-1 J-144 294 A-1 J-54 295 A-1 J-1 28 296 A-17 J-12 297 A-1 J-138 301 A-1 J-14 302 A-1 F-5 303 A-1 J-13 304 A-1 E-1 305 A-1 F-17 306 A-1 F-20 307 A-1 F-43 308 A-1 J-206 309 A-1 J-5 310 A-1 J-70 311 A-1 J-60 312 A-1 F-27 313 A-1 F-39 314 A-1 J-116 315 A-1 J-58 317 A-1 J-85 319 A-2 C-7 320 A-1 B-6 321 A-1 J-44 322 A-1 J-22 324 A-1 J-172. 325 A-1 J-103 326 A-1 F-60 328 A-1 J-115 329 A1 J-148 330 A-1 J-133 331 A-1 J-105 332 A-1 J-9 -237- 333 A-1 F-8 334 A-1 DC-5 335 A-1 J-194 336 A-1 J-192 337 A-1 C-24 338 A-1 J-113 339 A-1 B-8 344 A-1 F-22 345 A-2 J-234 346 A-12 J-6 348 A-1 F-21. 349 A-1 J-29 350 A-1 J-100 351 A-1 B-23 352 A-1 B-10 353 A-1 D-10 354 A-1 J-186 355 A-I J-25 357 A-1 B-13 358 A-24 J-232 360 A-1 J-1 51 361 A-1 F-26 362 A-1 J-91 363 A-1 F-32 364 A-1 J-88 365 A-I J-93 366 A-1 F-I 6 367 A-1 F-50 368 A-1 D-5 369 A-i J-141 370 A-1 J-90 371 A-1 J-79 372 A-1 -J-209 373 A-1 J-21 374 A-16 J-238 375 A-1 J-71 - 238 - 376 A-1 J-187 377 A-5 J-237 378 A-1 D-3 380 A-1 J-99 381 A-1 B-24 383 A-1 B-12 384 A-1 F-48 385 A-1 J-83 387 A-1 J-1 68 388 A-1 F-29 389 A-1 J-27 391 A-1 F-9 392 A-1 J-52 394 A-22 J-170 395 A-1 C-20 397 A-1 J-199 398 A-1 J-77 400 A-1 J-183 401 A-1 F-4 402 A-1 J-149 403 A-1 C-22 405 A-1 J-33 406 A-6 B-24 407 A-3 C-7 408 A-1 J-81 410 A-1 F-31 411 A-13 J-191 412 A-1 B-19 413 A-1 J-131 414 A-1 J-50 417 A-1 F-65 418 A-1 J-223 419 A-1 J-216 420 A-1 G-1 421 A-1 C-18 422 A- J-20 -239- 423 A-1 B-16 424 A-1 F-42 425 A-1 J-28 426 A-1 C-11 427 A-1 J-124 428 A-1 C-1 429 A-1 J-21 8 430 A-1 J-123 431 A-1 J-225 432 A-1 F-14 433 A-1 G-9 434 A-1 J-159 435 A-1 J-41 436 A-1 F-24 437 A-1 J-75 438 A-1 E-10 439 A-1 J-164 440 A-1 J-215 441 A-1 D-19 442 A-1 J-1 65 443 A-1 J-1 66 444 A-1 E-6 445 A-1 J-97 446 A-1 J-121 447 A-1 J-51 448 A-1 J-69 449 A-1 J-94 450 A-1 J-193 451 A-1 J-31 452 A-1 J-108 453 A-1 D-1 454 A-1 J-47 455 A-I J-73 456 A-1 J-137 457 A-1 J-155 4568 A-1 C-4 -240- 459 A-1 J-53 461 A-I J-1 50 463 A-1 J-202 464 A-3 C-9 465 A-I E-4 466 A-1 J-2 467 A-1 J-86 468 A-20 J-184 469 A-12 J-132 470 A-1 J-160 473 A-21 J-89 474 A-1 J-201 475 A-1 J-158 477 A-1 J-63 478 A-1 B-11 479 A-4 J-230 480 A-23 J-175 481 A-1 J-188 483 A-1 C-21 484 A-1 D-14 B-26-I A-1 B-26 B-27-1 A-1 B-27 C-27-1 A-1 C-27 D-12-4 A-1 D-12 D-13-1 A-I D-13 D-15-1 A-1 D-15 D-16-1 A-1 D-16 D-17-1 A-1 D-17 DC-10-1 A-1 DC-10 DC-8-I A-1 DC-B DC-9-1 A-1 DC-9 [006831 Indoles [006841 Example 1: [00685] General Scheme: - 241

-

o HN 1 NNaOH H~IC NN R1R2NH, HATU N N THF a IEA, MF IN H C N I H NH 188 U8 [00686] Specific example: HON H~ ~ INNaCH H Ny-~0 THF DIDMF 188 1884 343 [006871 188-1; 6

-[(

4 -Oxo-H-quinolin-3-yl)carbonylamino]-1H-indole-5 carboxylic acid A mixture of 6 -[(4-oxo-1H-quinolin-3-yl)carbonylamino]-IH-indole-5-carboxylic acid ethyl ester (188) (450 mg, 1.2 mmol) and IN NaOH solution (5 mL) in THF (10 mL) was heated at 85 *C overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was acidified with IN HOI solution to pH 5, and the precipitate was filtered, washed with water and air dried to yield 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-lH-indole-5-carboxylic acid (188-1) (386 mg, 93 %). 'H-NMR (400 MHz, DMSO-d 6 ) & 12.92-12.75 (m, 2H), 11.33 (s, 11), 8.84 (s, 1 H), 8.71 (s, 1H), 8.30 (dd, J=8.1, 0.9 Hz, lH), 8.22 (s, 1H), 7.80-7.72 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 2.7 Hz, IH), 6.51 (m, IH); HPLC ret. time 2.95 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 376.2 m/z (MH 4 ). [00688] 343; N-[5-(Isobutylcarbamoy1)-1H-indol-6-yl]4-oxo-1H--quinoline-3 carboxamide To a solution of 6 -[(4-oxo- I H-quinolin-3-y)carbonylamino]-H-indole-5-carboxylic acid (188 I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 pL, 0.2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65 "C - 242 overnight. The resulting solution was filtered and purified by HP LC (10-99 % CH 3 CN / H 2 0) to yield the product, N-[5-(isobutylcarbamoyl)- I H-indol-6-yI]-4-oxo-1 H-quinoline-3-carboxamide (343) (20 mg, 66 %). 'H-NMR (400 MHz, DMSO-d) 8 12.66 (d, J = 7.4 Hz, 1H), 12.42 (s, IH), 11.21 (s, I H), 8.81 (d, J=6.6 Hz, I H), 8.47 (s, IH), 8.36 (t, J= 5.6 Hz, I H), 8.30 (d, J =8.4 Hz, 1H), 7.79 (t, J = 7.9 Hz, I H), 7.72-7.71 (in, 2H), 7.51 (t, J= 7.2 Hz, I H), 7.38 (m, I H), 6.48 (m, LH), 3.10 (t, J= 6.2 Hz, 2H), 1.88 (in, IH), 0.92 (d, J= 6.7 Hz, 6H); HPLC ret. time 2.73 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 403.3 m/z (MH). [006891 Another example: Q 0 H 1006901 148; 4 -Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3 carboxamide 4-Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]- 1H-quinoline-3-carboxamide (148) was synthesized following the general scheme above, coupling the acid (188-I) with piperidine. Overall yield (12 %). HPLC ret, time 2.79 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 415.5 m/z (MH'). [00691] Example 2: [00692] General scheme: Br A B 2QArB(OH (dppfPdC2 N H B-27-1 [006931 Specific example: -243- 0 Br Ph N PhB(OH), (dppf)PdCl 2 N N IH H "0,M |H H HH B-27-1 158 [00694] 158; 4-Oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide A mixture of N-(5-bromo-1H-indol-6-yl)-4-oxo-I H-quinoline-3-carboxamide (B-27-I) (38 mg, 0.1 mol), phenyl boronic acid (18 mg, 0.15 mmol), (dppf)PdC 2 (cat.), and K 2 C0 3 (100 ptL, 2M solution) in DMF (I mL) was heated in the microwave at 180 *C for 10 min. The reaction was filtered and purified by HPLC (10-99 % CH 3 CN / H 2 O) to yield the product, 4-oxo-N-(5-phenyl IH-indol-6-yl)-1H-quinoline-3-carboxamide (158) (5 mg, 13 %). HPLC ret. time 3.05 min, 10 99 % CH 3 CN, 5 min run; ESI-MS 380.2 m/z (MH*). [006951 The table below lists other examples synthesized following the general scheme above. 237 2-methoxyphenylboronic acid 327 2-ethoxyphenylboronic acid 404 2,6imethoxyphenylboronic acid 1 S-chloro-2-methoxy-phenylboronic acid 342 4-isopropylphenylboronic acid 347 4

-(

2 -Dimethylaminoethylcarbamoyl)phenylboronic acid 65 3-pyridinylboronic acid [006961 Example 3: - 244- HCL MeOH O H boc HCI B-26-1 27 [00697] 27; N-[1-[2-[Methyl-(2-methylaminoacetyl)-aminolacetyl]-1H-indol-6 yll- 4 -oxo-1H-quinoline-3-carboxamide To a solution of methyl-{[methyl-(2-oxo-2-{6-[(4-oxo-1,4-dihydro-quinoline-3-carbonyl) amino]-indol---yl}-ethyl)-carbamoyl]-methyl}-carbamic acid tert-butyl ester (B-26-I) (2.0 g, 3.7 mmol) dissolved in a mixture of CH 2 C1 2 (50 mL) and methanol (15 mL) was added HCI solution (60 mL, 1.25 M in methanol). The reaction was stirred at room temperature for 64 h. The precipitated product was collected via filtration, washed with diethyl ether and dried under high vacuum to provide the HCI salt of the product, N- 1-[2-[methyl-(2-methylaminoacetyl)~ aminolacetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (27) as a greyish white solid (1.25 g, 70 %). 'H-NMR (400 MHz, DMSO-d6) 8 13.20 (d, J = 6.7 Hz, 1H), 12.68 (s, IH), 8.96 8.85 (m, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.91-7.77 (m, 3H), 7.64-7.54 (m, 3H), 6.82 (n, lH), 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J = 5.6 Hz, 1.3H), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2H), 3.02 (s, 1H), 2.62 (t, J = 5.2 Hz, 2H), 2.54 (t, J = 5.4 Hz, lH); HPLC ret. time 2.36 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 446.5 m/z (MH*). [006981 Phenols [00699] Example 1: [00700] General scheme: - 245 - O HN OH HN O RX (X=Br.F I I CS 2

CO

3 , DMF N 428 [007011 Specific example: Ph O HN OH 0 HN OH O BnBr, Cs 2 COO DMF 428 275 [007021 275; 4-Benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3 carboxamide To a mixture of N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) (6.7 mg, 0.02 mmol) and Cs 2

CO

3 (13 mg, 0.04 mmol) in DMF (0.2 mL) was added BnBr (10 uL, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N-(3-hydroxy-4-tert-butyl phenyl)-quinoline-3-carboxamide (275). 'H NMR (400 MHz, DMSO--d,) 8 12.23 (s, 1H), 9.47 (s, IH), 9.20 (s, 1H), 8.43 (d, J= 7.9 Hz, IH), 7.79 (t, J= 2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (mi, 6H), 7.11 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4,2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H). HPLC ret time 3.93 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 427.1 m/z (MI). [007031 Another example: - 246 - HN OH N r [007041 415; N-(3-Hydroxy-4-tert-butyl-pheny)-4-methoxy-quinoline-3 carboxanide N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide (415) was synthesized following the general scheme above reacting N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo- I H quinoline-3-carboxamide (428) with methyl iodide. 'H NMR (400 MHz, DMSO-dt,) S 12.26 (s, IH), 9.46 (s, IH), 8.99 (s, IH), 8.42 (t, J = 4.2 Hz, I), 7.95-7.88 (in, 2H), 7.61-7.69 (in, IH), 7.38 (d, J= 2.1 Hz, IH), 7.10 (d, J = 8.4 Hz, IH), 6.96 (dd, J = 8.4, 2.1 Hz, I H), 4.08 (s, 3H), 1.35 (s, 9H); HPLC ret. time 3.46 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 351.5 m/z (MH). [00705] Example 2: Br NC 0 H OH 0 OH Zn(CNI. Pd(PPh) 4 I INMP 0 C-27-1 476 [007061 476; N-(4-tert-Butyl-2-cyano-5-hydroxyphenyl)-1,4-dihydro-4 oxoquinoline-3-carboxamide To a suspension of N-(4-tert-butyl-2-bromo-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3 carboxamide (C-27-I) (84 mg, 0.2 mmol), Zn(CN) 2 (14 mg, 0.12 mmol) in NMP (1 mL) was added Pd(PPh 3

)

4 (16 mg, 0.0 14 mmol) under nitrogen. The mixture was heated in a microwave oven at 200 *C for 1 i, filtered and purified using prepative HPLC to give N-(4-tert-butyl-2 -247cyano-5-hydroxypheny)--1,4-dihydro-4-oxoquinoline-3-carboxamide (476). 'HNMR (400 MHz, DMSO-d 6 ) 5 13.00 (d, J =6.4 Hz, IH), 12.91 (s, 1H), 10.72 (s, IH), 8.89 (d, J =6.8Hz, 1 H), 8.34 (d, J =8.2Hz, IH), 8.16 (s, IH), 7.85-7.75 (in, 2H), 7.56-7.54 (m, LH), 7.44 (s, 1H), 1.35 (s, 9H); HPLC ret. time 3.42 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 362.1 m/z (MH+). [007071 Anilines [007081 Example 1: 1007091 General scheme: H 0 I I HR2 N R2 CH 2

CI

2 N H H [007101 Specific example: 0 000 O N H 0kTFA iNNH 2 CH CI 2 H 353 260 [00711] 260; N-(5-Amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3 carboxamide A mixture of [3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformic acid tert-butyl ester (353) (33 mg, 0.08 mmol), TFA (1 mL) and CH 2 C1 2 (1 mL) was stirred at room temperature ovemight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99 % CH 3 CN / H20) to yield the product, N-(5-amino-2-tert butyl-phenyl)-4-oxo-1H-'quinoline-3-carboxamide (260) (15 mg, 56 %). 'H NMR (400 MHz, DMSO-d) 8 13.23 (d, J = 6.6 Hz, 1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J = 6.8 Hz, 1H), - 248 - 8.34 (d, J = 7.8 Hz, [H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J = 8.5,2.4 Hz, lH), 1.46 (s, 9H); HPLC ret. time 2.33 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 336.3 m/z (MH ). 1007121 The table below lists other examples synthesized following the general scheme above. Starting Product Intermediate 60 101 D-12-I 282 D-13-I 41 114 393 D-16-I 157 D-15-I 356 D-17-1 399 [00713] Example 2: 1007141 General Scheme: R - CH 2 O, AcOH 0 0 NaBH 3 CN N N NI H N 2

CH

2

CI

2 ,MeOH N N H H [00715] Specific example: - 249 - 0 CH20, AcOH 0 N NH 2 CHNC MeOH H 271 485 [007161 485; N-(3-Dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3 carboxamide To a suspension of N-(3-amino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3 -carboxarnide (271) (600 mg, 1.8 mmol) in CH 2

CI

2 (15 mL) and methanol (5 mL) were added acetic acid (250 iL) and formaldehyde (268 p±L, 3.6 mmol, 37 wt % in water). After 10 min, sodium cyanoborohydride (407 mg, 6.5 mmol) was added in one portion. Additional formaldehyde (135 pL, 1.8 mrnol, 37 wt% in water) was added at 1.5 and 4.2 h. After 4.7 h, the mixture was diluted with ether (40 mL), washed with water (25 mL) and brine (25 mL), dried (Na 2

SO

4 ), filtered, and concentrated. The resulting red-brown foam was purified by preparative HPLC to afford N-(3 dimethylamino-4-tert-butyl-phenyl)-4-oxo-IH-quinoline-3-carboxamide (485) (108 mg, 17 %). H NMR (300 MHz, CDCl 3 ) & 13.13 (br s, 1H), 12.78 (s, 1H), 8.91 (br s, 1H), 8.42 (br s, 1H), 8.37 (d, J= 8.1 Hz, IH), 7.72-7.58 (m, 2H), 7.47-7.31 (m, 3H), 3.34 (s, 6H), 1.46 (s, 9H); HPLC ret. time 2.15 min, 10-100 % CH 3 CN, 5 min run; ESI-MS 364.3 m/z (MH*). [00717] The table below lists other examples synthesized following the general scheme above. 69 117 160 462 282 409 41 98 -250- [007181 Example 3: [00719] General Scheme: 00 R OH R 1. HBTU, DIEA, THF N NH2 H O2N NH 2 2. SnC 2 .2H 2 0, EtOH N H 100720] Specific example: 0 00 OH 1. HBTU, DIEA, THF H 0 2 N N NH 2 2. SnCi.2H 2 0, EtOH A-I 94 [00721] 94; N-(5-Amino-2-methyl-phenyl)-4-oxo-1lH-quinoline-3-carboxamide To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (50 mg, 0.26 mmot), HBTU (99 mg, 0.26 mmol) and DIEA (138 pL, 0.79 nmol) in THF (2.6 mL) was added 2-methyl-5-nitro phenylamine (40 mg, 0.26 mmol). The mixture was heated at 150 'C in the microwave for 20 min and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) and SnC1 2 -2H 2 0 (293 mg, 1.3 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was basified with sat. NaHCO 3 solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2

SO

4 , filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99 %

CH

3 CN / H 2 0) to yield the product, N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3 carboxamide (94) (6 mg, 8 %). HPLC ret. time 2.06 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 294.2 m/z (MHI). [007221 Another example: -251- 0 0 OI-OL NH NI NH 2 H [007231 17; N-(5-Amino-2-propoxy-phenyl)-4-oxo-IH-quinoline-3-carboxanide N-(5-Amino-2-propoxy-phenyl)-4-oxo- I H-quinoline-3-carboxamide (17) was made following the general scheme above starting from 4-hydroxy-quinoline-3-carboxylic acid (A-1) and 5 nitro-2-propoxy-phenylamine. Yield (9 %). HPLC ret. time 3.74 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 338.3 m/z (MH). [007241 Example 4: [00725] General Scheme: R1 RI 0 0 1.J~N 0 Ni~XR 1NH2 N N',R2 Ix.. I H 2I I H H N N H H X= CO, CO 2 , SO 2 : a) R2XCl, DIEA, THF or R2XCl, NMM, 1,4-dioxane or R2XCI, Et 3 N,

CH

2 Cl 2 , DMF. [007261 Specific example: NHH N H 167 248 [007271 248; N-(3-Acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3 carboxamide To a solution of N-(3 -amino-4-methyl-phenyl)-4-oxo- 1 H-quinoline-3-carboxamide (167) (33mg, 0.11 mmol) and DIEA (49 tL, 0.28 mmol) in THF (1 mL) was added acetyl chloride (16 iL, -252- 0.22 mmol). The reaction was stirred at room temperature for 30 min. LCMS analysis indicated that diacylation had occurred. A solution of piperidine (81 pL, 0.82mmol) in CH 2

CI

2 (2 mL) was added and the reaction stirred for a further 30 min at which time only the desired product was detected by LCMS. The reaction solution was concentrated and the residue was dissolved in DMSO and purified by HPLC (10-99 % CH 3 CN / H 2 0) to yield the product, N-(3-acetylamino 4-methyl-phenyl)-4-oxo-IH-quinoline-3-carboxamide (248) (4 mg, 11 %). 'H NMR (400 MHz, DMSO-d 6 ) 5 12.95 (d, J = 6.6 Hz, I H), 12.42 (s, I H), 9.30 (s, lH), 8.86 (d, J= 6.8 Hz, I H), 8.33 (dd, J= 8.1, 1.3 Hz, IH), 7.85-7.81 (in, 2H), 7.76 (d, J = 7.8 Hz, lH), 7.55 (t, J = 8.1 Hz, IH), 7.49 (dd, I= 8.2, 2.2-Hz, I H), 7.18 (d, J = 8.3 Hz, I H), 2.18 (s, 3H), 2.08 (s, 3H); HPLC ret. time 2.46 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 336.3 m/z (MH*). [00728] The table below lists other examples synthesized following the general scheme above. 260 CO Me 316 260 CO neopentyl 196 429 CO Me 379 41 CO Me 232 101 CO Me 243 8 CO Me 149 271 CO 2 Et 127 271 CO 2 Me 14 167 CO 2 Et 141 69 CO 2 Me 30 160 CO 2 Me 221 160 CO 2 Et 382 69 CO 2 Et 225 282 CO 2 Me 249 282 CO 2 Et 472 -253- 41 CO 2 Me 471 101 CO 2 Me 239 101 CO 2 Et 269 8 CO 2 Me 129 8 CO2 Et 298 160 SO 2 Me 340 [007291 Example 5: [007301 General Scheme: RI 0 0 R1 RI OC l CI NO R ,R ,N H , U C IO , O NR i N 2 NMM 1,4dioxane | NH CHCzH R2 ~N> H H H [007311 Specific example: N, CF 429 318 [00732] 4--Oxo-N-[3-(trifluoromethyl)-5S-(vinylsulfonamido)pheny]-1,4~ dihydroquinoline-3-carboxamide To a suspension of N-[3-amnino-5-(trifluoromnethyl)pheny]-4-oxo-1lH-quinoline-3--carboxamiide (429) (500 mg 1.4 mmol) in 1,4-dioxane (4 mL) was added NMM (0.4 mL, 3.6 mmol). Chloroethylsulfonyl chloride (0.16 mL, 1.51 mmol) was added under an argon atmosphere. The mixture was stirred at room temperature for 6 /2 h, after which TLC (CH 2 C1 2 - EtOAc, 8:2) showed a new spot with a very similar Rr to the starting material. Another 0.5 eq. of NMM was added, and the mixture was stirred at room temperature overnight LCMS analysis of the crude -254 mixture showed >85% conversion to the desired product. The mixture was concentrated, treated with IM HCI (5 mL), and extracted with EtOAc (3 x 10 mL) and CH 2

CI

2 (3 x 10 mL). The combined organic extracts were dried over Na 2

SO

4 , filtered, and concentrated to yield 4-oxo-N [3-(trifluoromethyl)-5-(vinytsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide as an orange foam (0.495 g, 79 %), which was used in the next step without further purification. 'H NMR (d 6 -Acetone, 300 MHz) 8 8.92 (s, IH), 8.41-8.38 (m, I H), 7.94 (m, 2H), 7.78 (br s, 2H), 7.53-7.47 (m, 1H), 7.30 (s, 1H), 6.87-6.79 (dd, J= 9.9 Hz, 1H), 6.28 (d, J= 16.5 Hz, IH), 6.09 (d, J= 9.9 Hz, 1H); ESI-MS 436.4 m/z (MH-) [00733] 318; 4-Oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5 (trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]- 1,4-dihydroquinoline-3 carboxamide (50 mg, 0.11 mmol), piperidine (18 ptL, 1.6 eq) and LiClO 4 (20 mg, 1.7 eq) was suspended in a 1:1 solution of CH 2 Cl 2 : isopropanol (1.5 mL). The mixpre was refluxed at 75 *C for 18 h. After this time, LCMS analysis showed >95% conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-(l piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25 %). 'H-NMR (d 6 -Acetone, 300 MHz) S 8.92 (br s, 1H), 8.4 (d, J= 8.1 Hz, 1H), 8.05 (br s, IH), 7.94 (br s, 1H), 7.78 (br s, 2H), .7.53-751 (m, IH), 7.36 (br s, 1H), 3.97 (t, J=7.2 Hz, 211), 3.66 (t, J= 8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 489.1 m/z (MH*). [00734] The table below lists other examples synthesized following the general scheme above. 429 morpholine 272 429 dimethylamine 359 131 piperidine 133 -255- 131 morpholine 46 [00735] Example 6: [00736] General Scheme: O ONaOH H 0 0or IN HC N ( ND N N EtOH orTH- H IH ON N0 H H [007371 Specific example: IN NaOH t f N N Q Na--I H 0 /=0 EIOH )Nf XN H H 233 258 [007381 258; N-Indolin-6-yl-4-oxo-lH-quinoline.-3-carboxamide A mixture of N-(l -acetyliridolin-6-yl)-4-oxo- 1H-quinoline-3-carboxamide (233) (43mg, 0.12 mxnol), IN NaOH solution (0.5 niL) and ethanol (0.5 mL) was heated to reflux. for 48 h. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99 % CH 3 CN - H 2 0) to yield the product, N-indolin-6-yl-4-oxo-1H-quinoline-3 carboxamide (258) (10 mg, 20 %). HPLC ret. time 2.05 min, 10-99 % CH 3 CN, 5 min run; ESI MS 306.3 m/z (MIT). [007391 The table below lists other examples synthesized following the general scheme above. -256- Product Conditions Solvent Starting from DC-8-1 386 NaOH EtOH DC-9-I 10 HCI EtOH 175 22 HCI EtOH 109 35 HCI EtOH 334 238 NaOH EtOH DC-10-1 105 NaOH THF [007401 Example 2: [00741] General Scheme: ITFA 0 _____ N N No N N CH CI T IH ijj I H IL.2 N O H H 100742] Specific example: N C H P 2 183 299 [007431 299; 4 -Oxo-N-(1,2,3,4-tetrahydroquinoin-7-y)-1H-quinoline-3 carboxamide A mixture of 7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1 carboxylic acid tert-butyl ester (183) (23 mg, 0.05 mmol), TFA (1 mL) and CH 2 C1 2 (1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was -257dissolved in DMSO (1 mL) and purified by HPLC (10-99 % CH 3 CN - H 2 0) to yield the product, 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)- 1 H-qui noline-3 -carboxamide (299) (7 mg, 32 %). HPLC ret. time 2.18 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 320.3 m/z (MH*). [007441 Another example: 0 0 N ' N I I H H H [007451 300; N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H quinoline-3-carboxamide N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-IH-quinoline-3-carboxamide (300) was synthesized following the general scheme above starting from 4,4-dimethyl-7-[(4-oxo- 1 H quinolin-3-yl)carbonylamino]- 1,2,3,4-tetrahydroquinoline- I -carboxylic acid tert-butyl ester (108). Yield (33 %). 'H NMR (400 MHz, DMSO-d 6 ) 13.23 (d, J= 6.6 Hz, 1H), 12.59 (s, iH), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88 (m, 2H), 1.30 (s, 6H); HPLC ret. time 2.40 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 348.2 m/z (MH*). [00746] Other [00747] Example 1: [00748] General scheme: R 0 HN TFA O HN HN O CH2Cl NH2 HN - 25 08 -258- [007491 Specific example: 0 HN TFA HN I O HN O CH 2

C

2 O NH 2 304 163 [00750] 163; 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid (4-arinomethyl 2'-ethoxy-biphenyl-2-yl)-amide {2'-Ethoxy-2-[(4-oxo- 1,4-dihydroquinoline-3 -carbonyl)-amino]-biphenyl-4-ylmethyl) -carbamic acid tert-butyl ester (304) (40 mg, 0.078 mmol) was stirred in a CH 2

C

2 / TFA mixture (3:1, 20 mL) at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLC to afford 4-oxo-1,4-dihydroquinoline-3-carboxylix acid (4-aminomethyl-2'-ethoxybiphenyl-2-yl)amine (163) as a tan solid (14 mg. 43 %). 'H NMR (300 MHz, DMSO-d 6 ) 8 12.87 (d, J= 6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d, J= 6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.01 (dd, J=8.4 Hz, J= 1.5 Hz, 1H), 7.75 (dt, J= 8.1 Hz, J= 1.2 Hz, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, J= 7.5 Hz, J= 1.8 Hz, 1H), 7.10 (d, J= 8.1 Hz, 1H), 7.02 (dt, J= 7.5 Hz, J= 0.9 Hz, 1H), 4.09 (m, 2H), 4.04 (q, J= 6.9 Hz, 2H), 1.09 (t, J= 6.9 Hz, 3H); HPLC ret. time 1.71 min, 10-100 % CH 3 CN, 5 min gradient; ESI-MS 414.1 m/z (MH*). [007511 Another example: o HN O NH 2 H - 259 - [007521 390; N-[3-(Aminomethyl)-4-tert-butyl-phenyl-4-oxo-1H-quinoline-3 carboxamide N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo- I H-quinoline-3-carboxamide (390) was synthesized following the general scheme above starting from [5-[(4-oxo-l H-quinolin-3 yl)carbonylamino]-2-tert-butyl-phenyl]methylaminofonnic acid tert-butyl ester (465). H PLC ret. time 2.44 min, 10-99 % CH 3 CN, 5 min gradient; ESI-MS n/z 350.3 (M + H)*. [00753] Example 2: [007541 General scheme: H Ec0CO O, Hc [007551 Specific example: N NH~oc TFAO W H c0M K- H 2C-l- ' -H 88 323 [00756] 3

-(

2

-(

4 -(-Aino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H) one (2-Methyl-2-{4-[2-oxo-2-(4-oxo-1, 4 -dihydro-quinolin-3-yl)-ethyl]-phenyl)-propyl)-carbamic acid tert-butyl ester (88) (0.50 g, 1.15 nnol), TFA (5 nL) and CH 2

CI

2 (5 mL) were combined and stirred at room temerpature overnight. The reaction mixture was then neutralized with IN NaOH. The precipitate was collected via filtration to yield the product 3-(2-(4-(1-amino-2 methylpropan-2-yl)phenyl)acetyl)quinolin-4(IH)-one as a brown solid (651 mg, 91 %). HPLC ret. time 2.26 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 336.5 m/z (MH*). [00757] 323; [ 2 -Methyl-2-[ 4 -[(4-oxo-1H-quinolin-3-yl)earbonylaminolphenyl] propyl]aminoformic acid methyl ester Methyl chloroformate (0.012 g, 0.150 nmol) was added to a solution of 3-(2-(4-(1-amino-2 methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one (0.025 g, 0.075 mmol), TEA (0.150 mmol, - 260 - 0.021 mL) and DMF (1 mL) and stirred at room temperature for 1 h. Then piperidine (0.074 ml, 0.750 mmol) was added and the reaction was stirred for another 30 min. The reaction mixture was filtered and purified by preparative HPLC (10-99 % CH 3

CN-H

2 0) to yield the product [2 methyl-2-[4-[(4-oxo- I H-quinolin-3 -yl)carbonylamino]phenyl]-propyl]aminofonnic acid methyl ester (323). 1H NMR (400 MHz, DMSO-d6) 5 12.94 (br s, IH), 12.44 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J= 8.2, 1.1 Hz, 1H), 7.82 (t, J= 8.3 Hz, IH), 7.76 (d, J= 7.7 Hz, 1H), 7.67 (d, J= 8.8 Hz, 2H), 7.54 (t, J = 8.1 Hz, IH), 7.35 (d, J= 8.7 Hz, 2H), 7.02 (t, J= 6.3 Hz, IH), 3.50 (s, 3H), 3.17 (d, J= 6.2 Hz, 2H), 1.23 (s, 6H); HPLC ret. time 2.93 min, 10-99'% CH 3 CN, 5 min run; ESI-MS 394.0 m/z (MH*). [00758] The table below lists other examples synthesized following the general scheme above. ~~ict Cditoroformut~ 119 Ethyl chloroformate 416 Propyl chloroformate 460 Butyl chloroformate 251 Isobutyl chloroformate 341 Neopentyl chiloroformate 28 2-methoxyethyl chloroformate 396 (tetrahydrofuran-3-yl)methyl chloroformate 1007591 Example 3: [007601 General Scheme: ,Nr1~I TFA 0 HN-[( 4 : HN-l'Il ' HNYO' < ~ ~ ~ OH H IEA. M.eOH 0 0 0 273 [00761] Specific example: -261- 0 HNc I TFA 0 HNC IO'v HN CHCI O lN OEA. MeOH H 273 273- 159 100762] 273-I; N-(1-Aminotetralin-7-yl)4-oxo-1H-quinoline-3-carboxamide To a solution of [7-[(4-oxo-1 H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid tert butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 rnL) was added TFA (2 mL). The reaction was stin-ed at room temperature for 30 min. More dichloromethane (10 mL) was added to the reaction mixture and the solution was washed with sat. NaHCO 3 solution (5 mL). A precipitate began to form in the organic layer so the combined organic layers were concentrated to yield N-(1-aminotetralin-7-yl)-4-oxo- I H-quinoline-3-carboxamide (273-I) (185 mg, 93 %). HPLC ret. time 1.94 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 334.5 m/z (MH+). [007631 159; [7-[(4-Oxo-IH-quinolin-3-yl)carbonylamino]tetralin-1 ylnaminoformic acid methyl ester To a solution of N-(l -aminotetralin-7-yl)-4-oxo- I H-quinoline-3-carboxamide (273-I) (65 mg, 0.20 mmol) and DIEA (52 ptL, 0.29 mmol) in methanol (1 mL) was added methyl chloroformate (22 [tL, 0.29 mmol). The reaction was stirred at room temperature for 1 h. LCMS analysis of the reaction mixture showed peaks corresponding to both the single and bis addition products. Piperidine (2 mL) was added and the reaction was stirred overnight after which only the single addition product was observed. The resulting solution was filtered and purified by HPLC (10-99 % CH 3 CN - H 2 0) to yield the product, [ 7

-[(

4 -oxo-IH-quinolin-3-yl)carbonylamino]tetralin-1 yl]aninoformic acid methyl ester (159) (27 mg, 35 %). HPLC ret. time 2.68 min, 10-99 %

CH

3 CN, 5 min run; ESI-MS 392.3 m/z (MH*). [00764] Another example: - 262 - 0 HN N HN0O H [007651 482; [7-[(4-Oxo-1H-quinolin-3-yl)carbonylaminoltetralin-1 yl]aminoformic acid ethyl ester [7-[(4-Oxo-1H-quinolin-3-yl)carbonylainino]tetralin-1-yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-I) and ethyl chloroformate. Overall yield (18 %). HPLC ret. time 2.84 min, 10-99 % CH 3 CN, 5 min run; ESI-MS 406.5 m/z (MH*). [00766] Set forth below is the characterizing data for compounds of the present invention prepared according to the above Examples. [00767] Table 2 1 444.3 3.19 23 457.5 3.56 45 308.1 3.18 2 350.1 3.8 24 398.3 3.13 46 490.1 1.89 3 455.3 3.75 25 397.1 2.38 47 375.3 3.33 4 350.3 2.81 26 348.1 .2.51 48 317.1 3.06 5 337.3 2.76 27 446.2 2.33 49 400.1 2.88 6 351.4 3 28 438.4 2.9 50 307.3 3.08 7 472.3 3.6 29 307.1 3.32 51 521.5 3.79 8 307.1 1.21 30 379.1 2.62 52 354.1 3.02 9 344.1 2.43 31 , 278.9 3.03 53 266.1 1.99 10 334.2 2.2 32 338.2 3 54 323.3 2.97 11 408.1 2.91 33 303.9 2.83 55 366.3 2.6 12 383.1 2.63 34 397.1 4.19 56 335.4 3.18 13 346.3 3.48 35 362.2 2.53 57 403.1 2.86 14 394.3 3.07 36 307.3 3.25 58 364.3 3.02 15 296.3 2.68 37 303.9 2.98 59 412.1 3.31 16 307.3 3.38 38 380.3 3.33 60 422.2 3.53 17 338.3 3.74 39 - 480.5 3.82 61 293.1 3.05 18 352.9 3.62 40 309.1 2.46 62 349.1 3.4 19 316.3 2.71 41 -321.1 1.88 63 376.1 2.89 20 371.3 3.53 42 460.0 3.71 64 321.1 2.31 21 421.1 2.66 43 457.5 3.6 65 381.5 1.85 22 332.2 2.21 44 336.1 2.95 66 345.1 3.32 -263- Cmd LC-MS LC-RT Cmd LC-MS LC-RT Cmd LC-MS LC-RT No. M+1 min No. M+1 min No. M+ min 67 332.3 3.17 109 404.5 3.17 151 360.0 3 68 398.1 2.85 110 303.9 2.75 152 322.3 2.31 69 322.5 2.37 _111 333.1 3 153 425,1 4.52 70 341.1 2.15 112 348.5 3.07 154 401.3 3.77 71 426.1 2.6 113 318.3 3.02 155 266.1 2.11 72 293.1 3.27 114 499.2 3.74 156 424.1 3.12 73 380.9 2.4 115 330.1 2.67 157 321.0 2.13 74 334.1 3.32 116 320.2 3.18 158 380.2 3.05 75 316.3 2.43 117 349.1 1.32 159 392.3 2.68 76 376.1 2.97 118 379.1 2.61 160 321.1 1.34 77 322.5 2.93 119 408.4 3.07 161 409.2 3.82 78 344.1 2.38 120 309.1 2.93 162 296.3 2.61 79 372,1 3.07 121 333.1 3.69 163 413.1 1.71 80 295.3 2.78 122 325.1 2.66 164 333.1 3.33 81 336.3 2.73 123 330.1 2.64 165 344.1 2.41 82 350.3 2.11 124 378.3 3.4 166 398.1 2.83 83 365.1 2:76 125 294.3 2.21 167 294.3 2.12 84 280.3 2.11 126 411.1 3.06 168 265.9 1.96 85 408.0 3.25 127 408.5 3.22 169 318 2.98 86 370.3 2.08 128 369.1 3.53 170 303 3.08 87 357.1 3.5 129 365.1 1.74 171 408.0 3.08 88 436.3 3.37 130 440.2 3.57 172 396.0 3.14 89 303.9 3.1 131 313.0 2.4 173 280.3 2.14 90 321.1 3.43 132 365.9 2.73 174 388,0 2.58 91 355.2 3.7 133 488.1 1.97 175 374.2 2.85 92 295.2 3.84 134 402.1 2.25 176 349.1 3.38 93 371.0 2.75 135 384.1 2.94 177 337.1 3.5 94 294.2 2.06 136 393.1 4.33 178 413.3 4 95 290.1 2.78 137 580.5 4.1 179 308.5 2.33 96 343.0 2-75 138 376.1 2-98 180 307.3 3.08 97 402.1 2.59 139 408.0 3.17 181 354.1 2.97 98 349.1 1.96 140 346.1 4 182 358.1 2.89 99 334.1 3.13 141 366.3 2.89 183 420.3 3.47 100 303.9 2.63 142 321.3 3.58 184 372.3 2.66 101 322.5 2.35 143 355.2 3.45 185 414.1 2.96 102 443.1 3.97 144 281.3 2.49 186 372.3 3.59 103 411.2 3.85 145 376.2 2.98 187 346.3 2.9 104 318.0 2.94 146 306.3 2.51 188 376.2 2.95 105 322.2 2.4 147 376.3 3.27 189 370.9 3.38 106 350.3 2.86 148 415.5 2.79 190 392.0 3.09 107 420.2 3.37 149 349.1 1.45 191 316.3 2.1 108 448.2 3.77 150 430.0 3.29 192 280.3 2.13 - 264 - Cmd LC-MS LC-RT Cmd LC-MS LC-RT Cmd LC-MS LC-RT No. M+1 min No. M+1 min No. M+1 min 193 326.3 3.02 235 308.4 212 277 358.1 2.89 194 290.1 2.98 236 333.1 3.35 278 408.1 3.09 195 280.3 2.14 237 410.3 2.96 279 386.1 2.88 196 434.5 3.38 238 489.4 2.78 280 316.3 2.06 197 334.1 3.15 239 379.0 2.62 281 293.1 3.22 198 283.1 3 240 370.9 3.65 282 307.1 1.22 199 354.1 2.96 241 316.3 2.61 283 370.1 3 200 335.5 2.49 242 348.3 3.08 284 305.3 2.57 201 303.9 3.08 243 363.0 2.44 285 376.1 2.88 202 404.0 3.19 244 358.1 3.48 286 319.1 3.35 203 394.3 3.42 245 425.1 3.69 287 411.2 4.15 204 349.3 3.32 246 292.9 3.2 288 413.3 3.8 205 455.5 3.74 247 432.1 3.23 289 297.3 3.25 206 386.1 3.5 248 336.3 2.46 290 382.1 3.19 207 390.3 2.71 249 365.0 2.54 291 371.0 3.57 208 429.7 3.89 250 352.3 2.53 292 391.1 3.69 209 294.1 2.39 251 436.2 3.38 293 330.3 3.05 210 385.2 3.72 252 368.9 3.17 294 303.9 2.67 211 351.3 3.53 253 424.1 3.25 295 334.3 2.26 212 360.9 2.45 254 340.1 3.08 296 365.3 3.6 213 408.0 3.3 255 526.5 3.89 297 358.3 3.26 214 358.1 2.7 256 306.1 2.4 298 .379.1 1.91 215 265.3 3.07 257 297.3 3.28 299 320.3 2.18 216 305.3 2.27 258 . 306.3 .2.05 300 348.2 2.4 217 305.3 2.41 259 360.3 3.46 301 346.3 2.26 218 413.2 3.98 260 336.3 2.33 - 302 370.1 2.28 219 266.9 2.48 261 368.1 3.08 303 362.2 2.51 220 409.0 3.35 262 352.3 2.7 304 513.2 3.66 221 379.1 2.68 263 372.9 3.69 305 370.1 2.98 222 324.3 3.27 264 353.1 3.42 306 384.1 3.11 223 386.1 3.14 265 354.9 3.4 307 374.0 3.05 224 466.3 3.08 266 405.3 4.05 308 304.1 2.71 225 393.1 2.75 267 357.1 3.43 309 316.3 2.83 226 306.1 3.6 268 400.3 6.01 310 320.1 3.73 227 381.1 2.24 269 393.0 2.75 311 344.9 3.43 228 371.1 2.84 270 329.3 3.02 312 400.1 2.86 229 311.1 2.93 271 336.5 2.75 313 358.1 2.8 230 318.1 2.81 272 524.1 1.87 314 335.1 3.52 231 471.3 3.41 273 434.5 3.17 315 293.1 2.9 232 363.1 2.57 274 493.5 3.46 316 378.5 2.84 233 348.5 2.75 275 427.1 3.93 317 333.2 2.91 234 372.3 3.2 276 414.3 2.81 318 522.1 1.8 - 265 - Cmd LC-MS LC-RT Cmd LC-MS LC-RT Cmd LC-MS LC-RT No. M+1 min No. M+1 min No. M+1 min 319 373.3 3.59 361 400.1 2.91 403 423.1 4.45 320 360.1 3.5 362 355.5 3.46 404 440.3 2.87 321 453.5 3.12 363 388.1 2.92 405 299.3 3,16 322 349.3 3.7 364 330.3 2.68 406 547.3 3.74 323 394.0 2.93 365 307.1 2.6 407 371.3 3.8 324_ _320.1 3.81 366 408.1 3.09 408 295.3 2.9 325 321.3 3.22 367 408.0 3.14 409 335.1 1.82 326 418.0 2.5 368 338.2 2.33 410 432.1 3.41 327 424.2 3.2 369 358.1 3.29 411 299.1 3.17 328 307.1 2.76 370 299.1 3.03 412 376.2 2.93 329 396.3 3.72 371 365.0 3.27 413 357.1 3.37 330 299.3 3.02 372 362.1 2.66 414 305.3 2.11 331 308.3 2.25 373 305.3 3.38 415 351.5 3.44 332 288.0 2.5 374 350.3 3.01 416 422.4 3.23 333 379.1 2.61 375 319.3 3.4 417 396.0 2.67 334 531.3 3.26 376 382.3 3.48 418 308.3 2.23 335 322.3 2.41 377 340.2 3.08 419 322.3 2.48 336 321.5 3.52 378 310.3 2.07 420 379.1 3.2 337 407.5 3.37 379 389.0 2.53 421. 419.2 3.82 338 318.3 2.73 380 309.3 3.02 422 333.1 2.48 339 329.0 2.75 381 360.2 3.18 423 376.3 3.02 340 399.1 2.6 382 393.1 2.84 424 374.0 3.06 341 450.4 3.56 383 332.3 3.2 425 306.1 3.53 342 422.3 3.41 384 376.1 2.87 426 371.3 2.95 343 403.3 2.73 385 393.9 3.32 427 420.3 3.3 344 384.1 3.07 386 334.3 -2.3 428 337.2 3.32 345 322.2 2.96 387 347.1 3.22 429 348.3 2.98 346 333.1 3.38 388 424.1 3.3 430 321.3 3.22 347 494.5 _1.97 389 355.3 3.65 431 280.3 2.09 348 384.1 3.12 390 350.3 2.44 432 382.1 3.22 349 405.3 _2.85 391 396.1 3.43 433 393.2 3.71 350 315.1 3.23 392 300.3 2.86 434 293.1 3.12 351 332.3 3.18 393 399.4 2.12 435 376.3 3.22 352 447.5 3.17 394 293.1 3.17 . 436 400.1 2.88 353 436.3 3.53 395 433.5 4.21 437 309.3 2.82 354 390.3 _2.36 396 464.4 2.97 438 427.5 3.87 355 370.9 3.37 397 341.3 3.45 439 295.3 2.8 356 335.0 1.81 398 434.3 3.1 440 395.3 3.61 357 346.3 3.08 399 335.0 1.75 441 425.0 2.67 358 338.2 3.15 400 351.3 2.11 442 412.3 3.35 359 482.1 1.74 401 368.1 3.09 443 317.3 2.45 360 331.3 3.07 402 342.1 2.96 444 379.2 3.42 - 266 - Cmd LC-MS LC-RT Cmd LC-MS LC-RT Cmd LC-MS LC-RT No. M+1 min No. M+1 min No. M+1 min 445 _ 305.5 _3.08 459 279.3 2.9 473 363.3 3.64 446 353.1 2.85 460 436.2 3.38 474 336.3 2.8 447 290.1 2.88 461 341.3 3.23 475 334.3 3.23 448 321.3 3.5 462 349.1 1.9 476 362.1 3.42 449 279.1 3.22 463 292.1 3.35 477 283.9 2.8 450 308.1 1.97 464 409.4 4.03 478 360.3 3.44 451 318.1 3.28 465 450.5 3.65 479 334.3 2.59 452 290-1 3.32 466 349.3 3.5 480 323.5 3.22 453 314.1 2.75 467 307.3 2.98 481 315.3 3.25 454 355.1 3.58 468 279.1 2.98 482 406.5 2.84 455 398.1 3.6 469 409.1 3.69 483 409.5 4.35 456 365.1 3.65 470 373.3 3.64 484 349.1 2.16 457 350.3 2.26 471 379.0 2.73 485 363.1 2.15 458 381.2 3.19 472 379.0, 2.67 NMR data for selected compounds is shown below.in Table 2-A: 1H NMR (300 MHz, CDCI 3 ) 6 12.53 (s. 1H), 11.44 (br d, J = 6.0 Hz, IH), 2 9.04 (d, J = 6.7 Hz, 1 H), 8.43 (d, J = .8 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33-7.21 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 3.79 (s. 3H), 1.36 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.94 (bs, 1H), 12.41 (s, 1H), 8.88 (s, IH), 8.34 (dd, J= 8, 1 Hz, IH), 7.82 (ddd, J= 8, 8, 1 Hz, 1H), 7.75 (d, J 5 = 8 Hz, 1H), 7.64 (dd, J= 7, 2 HZ, 2H), 7.54 (ddd, J= 8. 8, 1 Hz, 1H), 7.35 (dd, J = 7, 2 Hz, 2H), 4.66 (t, J= 5 Hz, 1H), 3.41 (d. J= 5 Hz, 2H), 1.23 (s, 6H). 1 H NMR (CD3OD, 300 MHz) 6 8.88 (s, I H), 8.42 (d, J = 8.5 Hz, I H), 8 7.94 (s, 1 H), 7.81 (t, J = 8.3 Hz, I H), 7.67 (d, J = 8.3 Hz, I H), 7.54 - 7.47 (m, 2H), 7.38 (d, J = 8.5 Hz, IH), 2.71 (q, J = 7.7 Hz, 2H), 1.30 (t, J= 7.4 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 13.02 (d, J = 6.4 Hz, 1H), 12.58 (s, 1H), 10 8.87 (d, J = 6.8 Hz, I H), 8.33 (dd, J = 8.1, 1.2 Hz, I H), 7.89-7.77 (m, 3H), 7.56 (t, J = 8.1 Hz, IH), 7.39 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1 H), 3.23 (m, 2H), 2.81 (m, 2H), 1.94 (m, 2H), 1.65 (m, 2H) H NMR (400 MHz, DMSO-d6) 6 13.05 (bs, I H), 12.68 (s, 1 H), 8.89 (s, 13 1 H), 8.35 (t, J = 2.5 Hz, 1 H), 8.32 (d, J = 1.1 Hz, 1 H), 7.85-7.76 (m, 3H), 7.58-7.54 (m, 2H), 1.47 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 1.32 (s, 9H), 3.64 (s, 3H), 7.36 (d, J = 14 8.4 Hz, 1H), 7.55 (m, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.83 (m, 1H), 8.33 (d, J = 7.0 Hz, 1 H), 8.69 (s, I H), 8.87 (d, J = 6.7 Hz, 1 H), 12.45 (s, I H), 12.97 (s. 1 H) - 267 - H NMR (400 MHz, DMSO-d6)6 13.20 (d. J 6.7 Hz, 1H), 12.68 (s, 1K) 8.96-8.85 (m, 4H), 8.35 (d, J = 7.9 Hz, 1H), 7.91-7-77 (m, 3H), 7.64-7.54 27 (mn, 3H), 6.82 (m, 1H), 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J = 5.6 Hz 1.3H), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2H), 3.02 (s, 1H), 2.62 (t, J = -.A5.2 Hz, 2H), 2.54 (t, J = 5.4 Hz, 1 H) H NMR (400 MHz, CDC1 3 ) 5 9.0 9 (s, 1 H), 8.62 (dd, J = 8.1 and 1.5 Hz, 29 1 H), 7.83-7.79 (m, 3H), 7.57 (d, J = 7.2 Hz, I H). 7.38 (t, J =7.6 Hz, 2H), 7.14 (t, J = 7.4 Hz, 2H), 5.05 (m, 1H), 1.69 (d, J =6.6 Hz, 6H) H NMR (400 MHz, DMSO-d6) 6 12.93 (d, J = 6.6 Hz, 1H), 12.74 (s, 1H), 32 11.27 (s, 1H), 8.91 (d, J = 6.7 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.38 (n, 1H), 6.40 (m, 1H) H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 12.47 (s, 1H), 11.08 (s, 1H), 8.90 (s, 1H), 8.35 (dd, J =8.1, 1.1 Hz, 1H), 8.20 (t, J =0.8 Hz, 1H), 33 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1 H), 7.30 (t, J = 2.7 Hz, I H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (m, 1H) H NMR (400 MHz, DMSO-d6) 6 13.01 (d, J = 6.7 Hz, 1H), 12.37 (s, 1H) 8.86 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1, 1.3 Hz, 1H), 7.82 (t, J = 8.3 35 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.36 (s, 1H),, 7.19 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.29 (m, 2H), 1.85 (m, 1H), 1.73-1.53 (m, 3H), 1.21 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.77 (s, 1H), 11.94 (s, 1H), 9.56 (s, 1H), 8.81 (s, 1H), 8.11 (dd, J = 8.2, 1.1 Hz, 1H), 7.89 (s, 1H), 7.79-7.75 43 (m, 1H), 7.70 (d, J = 7.7 Hz, I H), 7.49-7.45 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.93-6.87 (m, 3H), 4.07 (q, J = 7.0 Hz, 2H), 1.38 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 1.24 (d, J = 6.9 Hz, OH), 3.00 (m, 1H), 47 7.55 (m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.89 (s, 1H), 12.65 (s, 1H), 12.95 (s, 1H) H NMR (400 MHz, DMSO-d6) 6 12.81 (d, J = 6.7 Hz, 1H), 12.27 (s, 1H), 56 9.62 (s, 1H), 8.82 (d, J = 6.7 Hz, 1H), 8.32 (dd, J = 8.2, 1.3 Hz, 1H), 8.07 (s, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, IH), 6.58 (s, 1H), 2.62 (m, 4H), 1.71 (m, 4H) H NMR (400 MHz, DMSO-d6) 612.95 (d, J = 6.6 Hz, 1H), 12.39 (s, IH), 8.86 (d, J = 6.8 Hz, 1H), 8.33 (d, J =7.3 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 58 7.75 (d, J = 7.8 Hz, 1H), 7.54 (t, J 8.1 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 1.3 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 5.44 (br s, 2H) H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H), 12.41 (s, IH), 10.63 (s, 64 1H), 10.54 (s, 1H), 8.86 (s, IH), 8.33 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H) H NMR (400 MHz, DMSO-d6) 6 13.06 (d, J = 6.5 Hz, 1H), 12.51 (s, 1H), 69 8.88 (d, J = 6.6 Hz, 1H), 8.33 (dd, J = 8.1, 1.0 Hz, 1H), 7.85-7.74 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 3.03 (septet, J = 6.8 Hz, 1H), 1.20 (d, J = 6.7 Hz, 6H) -268- I H-NMR (CDCl3, 300 MHz) 6 8.84 (d, J = 6.6 Hz, I H), 8.31 (d, J = 6.2 76 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.44-7.13 (m, 8H), 6.78 (d, J = 7.5 Hz, 1H). H NMR (400 MHz, DMSO-d6) 6 6.40 (m, 1 H), 7.36 (t, J = 2.7 Hz, 1H), 77 7.43 (d, J = 11.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.80 (m, 2H), 8.36 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 6.8 Hz, 1 H), 8.91 (s, IH), 11.19 (s, 1H), 12.72 (s, 1H), 12.95 (s. 1H) H NMR (400 MHz, DMSO-d6) 5 12.96 (d, J = 6.6 Hz, 1 H), 12.42 (s, 1 H), 8.89 (d, J = 6.7 Hz, 1 H), 8.33 (dd, J = 8.1, 1.2 Hz, 1 H), 7.82 (t, J = 8.3 88 Hz, 1H), 7.76 (d. J = 7.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.67 (t, J = 6.3 Hz, 1H), 3.12 (d, J = 6.3 Hz, 2H), 1.35 (s, 9H), 1.22 (s, 6H) 1 H NMR (400 MHz, DMSO-d6) 6 11.98 (s, 1 H), 8.89 (s, 1 H), 8.34 (dd, J 90 = 8.2, 1.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.59 (dd, J = 7.8, 1.5 Hz, 1H), 7.55-7.51 (m, 1H), 7.42 (dd, J = 7.9, 1.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.19-7.14 (m, IH), 1.43 (s, 9H) 1H NMR (400 MHz, DMSO-d6) 6 12.58 (s, 1 H), 11.11 (s, I H), 8.89 (s, 96 1H), 8.35 (dd, J = 8.1, 1.1 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.83-7.74 (m, 2H), 7.56-7.51 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 1.8 Hz, 1H), 4.03 (d, J = 0.5 Hz, 2H) H NMR (400 MHz, DMSO-d6) 6 1.37 (s, 9H), 1.38 (s, 9H), 7.08 (s, 1H), 103 7.17 (s, 1H), 7.74 (m, 1H), 7.86 (m, 1H), 7.98 (dd, J = 9.2, 2.9 Hz, 1H), 8.90 (d, J = 6.7 Hz, 1H), 9.21 (s, 1H), 11.71 (s, 1H), 13.02.(d, J = 6.7 Hz, 1H) IH NMR (400 MHz, DMSO-d6) 6 12.93 (d, J = 6.6 Hz, 1H), 12.41 (s, 104 1H), 10.88 (s, 1H), 8.88 (d, J = 6.7 Hz, 1H), 8.36-8.34 (m, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.4, 1.9 Hz, 1H), 6.07-6.07 (m, 1H), 2.37 (s, 3H) H NMR (400 MHz, DMSO-d6) 6 12.52 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 107 8.2, 1.1 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.57 7.51 (m, 3H), 7.15 (d, J = 8.3 Hz, IH), 4.51 (s, 2H), 3.56 (t, J = 5.7 Hz, 2H), 2.75 (t, J = 5.5 Hz. 2H), 1.44 (s. 9H) H NMR (400 MHz, DMSO-d6) 6 12.97 (br s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.88 (s, 1H), 7.82 (t, J = 8.4 Hz, 1H), 109 7.75 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.43 (m, 1H), 7.31 (d, J =8.5 Hz, 1H), 4.01 (m, IH), 3.41 (m, 1H), 2.21 (s, 3H); 1.85 (m, 1H), 1.68-1.51 (m, 3H), 123 (s, 3H), 0.71 (t, J = 7.4 Hz, 3H) 1H NMR (400 MHz, DMSO-d6) 6 12.92 (d, J = 6.6 Hz, 1H), 12.46 (s, 113 1H), 10.72 (d, J = 1.5 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 8.35 (dd, J = 8.1, 1.2 Hz, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, S1H), 7.44 (d, J = 8.4 Hz, 1H), 7.07-7.04 (m, 2H), 2.25 (d, J = 0.9 Hz, 3H) 1H NMR (300 MHz, DMSO-d6): 6 12.65 (d, J = 6.9 Hz, 1H), 11.60 (s, 1H), 9.33 (s, 1H), 8.71 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.03 114 (d, J = 7.8 Hz, 1H), 7.66 (t, J =7.2 Hz, IH), 7.60 (d, J =8.1 Hz, 1H), 7.38 (t, J 7.8 Hz, 1H), 7,29 (t, J = 7.5 Hz, 1H), 7.12 (m, 2H), 6.97 (m, 3H), 3.97 (m, 2H), 1.45 (s, 9H), 1.06 (t, J = 6.6 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 12.94 (s, 1H), 12.33 (s, 1H), 9.49 (s, 126 1H), 8.88 (s, 1H), 8.35 (dd, J = 8.7, 0.5 Hz, 1H), 7.86-7,82 (m, 1H), 7.77 (d, J = 7.8 Hz, , 7.58-7.54 (m, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.98 (dd, J = 8.4, 2.2 Hz, 1H), 3.67 (s, 2H), 3.51-3.47 (m, - 269 - 2H), 3.44-3.41 (m, 2H), 3.36 (s, 3H), 1.33 (s, 6H) H NMR (400 MHz, DMSO-d6) 6 1.23 (t, J = 7.0 Hz, 3H), 1.32 (s, 9H), 127 4.10 (q, J = 7.0 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1 H), 7.54 (m, 3H), 7.76 (d, J = 7.9 Hz, I H), 7.82 (m, 1 H) 8.33 (d, J = 9.2 Hz, 1 H), 8.64 (s, 1 H), 8.87 (s, 1H), 12.45 (s, 1H), 12.99 (s, 1H) 1H-NMR (CD30D, 300 MHz) 6 8.83 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 129 7.80 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.55 (m, 2H), 7.22 (d, J = 8.1 Hz, 1 H), 3.76 (s, 3H, OMe), 2.62 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 1H NMR (300 MHz, DMSO-d6) 5 12.37 (s, 1H), 8.81 (s, 1H), 8.30 (d, J = 131 8.1 Hz, 1H), 7.77 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.09 (s, 1H), 6.74 (s, 1H), 6.32 (s, 1H), 5.47 (s, 2H). 1H-NMR (CDCl3, 300 MHz) 6 8.86 (d, J = 6.6 Hz, 1H), 8.32 (d, J = 6.2 135 Hz, 1 H), 8.07 (d, J = 7.9 Hz, 1 H), 7.47 - 7.24 (m, 6H), 6.95 - 6.83 (m, 3H), 5.95 (s, 2H). H NMR (400 MHz, DMSO-d6) 6 1.29 (s, 9H), 1.41 (s, 9H), 7.09 (d, J 136 2.4 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 8.4 Hz, 1 H), 8.36 (d, J = 9.5 Hz, 1 H), 8.93 (d, J = 6.8 Hz, 1H), 9.26 (s, IH), 12.66 (s, 1H), 13.04 (d, J = 6.6 Hz, 1H) H NMR (400 MHz, DMSO-d6) 6 12.96 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.85-7.75 (m, 141 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.96 (d, J = 6.8 Hz, 1H), 12.56 (s, 1H), 143- 9.44 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.34 (dd, J = 8.2, 1.3 Hz, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, IH), 7.00 (d, J = 13.3 Hz, 1H), 1.34 (s, 9H) I H-NMR (DMSO d6, 300 MHz) 6 8.86 (d, J = 6.9 Hz, 1H), 8.63 (s, 1H), 150 8.30 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.82-7.71 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (td, J = 1.2Hz, 1H).

IH-NMR (CD30D, 300 MHz) 6 8.91 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 8.3 157 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.57 (t, J =7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 6.0 Hz, 1H), 3.08 (s, 3H, NMe), 2.94 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 12.96 (s, 1H), 12.41 (s, 1 H), 8.88 (s, 1H), , 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.75 (d, J = 7.9 161 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), , 7.44 (s, 1H), 7.19 (s, 2H), 4.13 (t, J = 4.6 Hz, 2H), 3.79 (t, J = 4.6 Hz, 2H), 3.54 (q, J = 7.0 Hz, 2H), 1.36 (s, 9H), 1.15 (t, J =7.0 Hz, 3H) I H-NMR (300 MHz, DMSO-d6) 6 12.87 (d, J = 6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d, J = 6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.08 (dd, J = 163 8.4 Hz, J = 1.5 Hz, 1H), 7.75(m, 1H), 7.67 (d, J = 7.8 Hz, I H), 7.47-7.37 (m, 2H), 7.24 (d, J = 0.9 Hz, 1H), 7.15 (dd, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.02 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 4.07 (m, - 270 - 4H), 1.094 (t, J = 6.9 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 2.03 (s, 3H), 4.91 (s, 2H), 6.95 (m, 3H), 167 7.53 (m, 1H), 7.75 (d, J = 8.2 Hz, IH), 7.81 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.84 (s, 1H), 12.20 (s. 1H), 12.90 (s, 1H) 1H NMR (400 MHz, DMSO-d6) 6 12.94 (d, J = 5.3 Hz, 1H), 12.51 (s, 1H), 8.89 (d, J = 6.3 Hz, 1H), 8.36 (dd, J = 8.1, 1.1 Hz, 1H), 8.06 (t, J = 169 0.7 Hz, 1 H), 7.85-7.75 (m, 2H), 7.57-7.51 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 3.78 (s, 3H) 1H NMR (400 MHz, DMSO-d6) 6 12.86 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), - 8.65 (dd, J = 8.1, 1.6 Hz, 1H), 8.19 (dd, J = 8.2, 1.3 Hz, 1H), 7.80-7.71 178 (m, 2H), 7.48-7.44 (m, 2H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 2H), 7.04 7.00 (m, 1H), 6.80 (dd, J = 8.0, 1.3 Hz, 1H), 6.69 (dd, J =8.1, 1.4 Hz, IH), 1.45 (s, 9H) 1H NMR (400 MHz, DMSO-d6) 6 12.42 (s, 1H), 8,88 (s, 1H), 8.33 (dd, J 183 = 8.2, 1.1 Hz, IH), 8.06 (d. J = 2.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.38 (dd, J = 8.2, 2.1 Hz, IH), 7.08 (d, J = 8.3 Hz, 1H), 3.66 3.63 (m, 2H), 2.70 (t, J = 6.5 Hz, 2H), 1.86-1.80 (m, 2H), 1.51 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.93 (s, 1 H), 12.47 (s, 1 H), 10.72 (s, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, IH), 8.13 (d, J 1.6 Hz, IH), 186 7.82 (t, J = 8.2 Hz, 1H), 7.76 (d. J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, IH), 7.50 (d, J 8.4 Hz, 1 H), 7.05-7.02 (m, 2H), 3.19 (quintet, J = 8.2 Hz, 1H), 2.08 (m, 2H), 1.82-1.60 (m, 6H) 1H NMR (400 MHz, DMSO-d6) 6 12.63 (s, 1H), 8.91 (s, 1H), 8.87-8.87 187 (m, 1H), 8.36 (dd, J = 8.2, 1.2 Hz, IH), 7.85-7.75 (m, 3H), 7.64-7.53 (m, 3H), 6.71 (dd, J = 3.7, 0.5 Hz, IH), 2.67 (s, 3H) H NMR (400 MHz, DMSO-d6) 6 12.84 (s, 1H), 12.73 (d, J = 6.6 Hz, 1H), 11.39 (s, IH), 8.85 (d, J = 6.7 Hz, 1H), 8.61 (s, IH), 8.33 (d, J = 6.8 Hz, 188 1 H), 8.23 (s, 1 H), 7.80 (t, J = 8.4 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 8.1 Hz, 1H), 7.43 (m, IH), 6.54 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.97 (s, 1 H), 12.37 (s, 1 H), 8.87 (d, J 1.2 Hz, I H), 8.32 (d, J = 8.2 Hz, 1 H), 7.82 (dd, J = 8.2, 7.0 Hz, 1 H), 7.75 204 (d, J = 8.3 Hz, IH), 7.54 (t, J = 7.5 Hz, IH), 7.32-7.28 (m, 2H), 7.06 (d, J = 8.4 Hz, 1 H), 4.16 (t, J = 4.9 Hz, 2H), 1.78 (t, J = 4.9 Hz, 2H), 1.29 (s, 6H), H NMR (400 MHz, DMSO-d6) 6 12.92 (br s, 1 H), 12.50 (s, 1 H), 10.95 (s, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.17 (d, J = 1.5 Hz, IH), 207 7.82 (t, J = 8.3 Hz, I H), 7.76 (d, J = 7.7 Hz, 1 H), 7.55 (t, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.4 Hz, IH), 7.21 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.5, 1.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.72 (s. 2H), 1.20 (t, J = 7.1 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 215 1H), 8.34 (dd, J = 8.1, 1.1 Hz, IH), 7.83 (t, J = 8.3 Hz, IH), 7.75 (m, 3H), 7.55 (1, J = 8.1 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H) -271- H NMR (400 MHz, DMSO-d6) 6 12.99 (d, J = 6.6 Hz, IH), 12.07 (s, 1H), 220 8.93 (d, J = 6.8 Hz, 1H), 8.35 (d,.J = 7.1 Hz. 1 H), 8.27 (s, 1 H), 8.12 (s, 1 H), 7.85-7.77 (m, 2H), 7.54 (td, J = 7.5, 1.2 Hz, 1 H), 6.81 (s, 1 H), 1.37 (d, J = 3.9 Hz, 9H), 1.32 (d, J = 17.1 Hz, 9H) 1H NMR (CD3OD, 300 MHz) 6 B.79 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 225 7.75 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.5 (m, 2H), 7.29 (d, J = 8.3 Hz, 1H), 4.21 (q, J = 7.2, 2H), 3.17 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H). 1 H-NMR (CD30D, 300 MHz) 6 8.87 (s, I H), 8.45 (d, J= 8.25, 1 H), 8.27 232 (m, 1H), 7.83 (t, J= 6.88, 1H), 7.67 (d, J= 8.25, 1H), 7.54 (t, J= 7.15, 1 H), 7.39 (d, J= 6.05, 1H), 7.18 (d, J= 8.5, 1H), 2.77 (t, J= 6.87, 2H), 2.03 (s, 3H), 1.7 (q, 2H), 1.04 (t, J= 7.42, 3H) 1H NMR (400 MHz, DMSO-d6) 6 12.75 (d, J = 13.6 Hz, 1H), 8.87 (s, 233 1H), 8.32-8.28 (m, 2H), 7.76-7.70 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.49 7.45 (m, 1H), 7.18 (d, J.= 8.4 Hz, 1H), 4.11 (t, J = 8.3 Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H), 2.18 (s, 3H) 1H NMR (400 MHz, DMSO-d6) 6 12.49 (s, 1 H), 11.50 (s, 1 H), 8.90 (s, 234 1H), 8.36-8.34 (M, 2H), 7.97 (s, 1H), 7.85-7.81 (m, 1H), 7.77-7.75 (m, 1H), 7.56-7.50 (m, 2H), 6.59-6.58 (m, 1H) H NMR (400 MHz, DMSO-d6) 5 13.09 (d, J 6.5 Hz, 1 H), 12.75 (s, 1 H), 235 9.04 (s, 1H), 8.92 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 7.1 Hz, 1H), 8.34 (d,.J = 6.9 Hz, 1 H), 7.85 (t, J = 8.4 Hz, 1H), 7.78 (d, J =7.7 Hz, 1 H), 7.63-7.56 (m, 2H), 3.15 (m, 1.29 (d.J 6.9 Hz, 6H) H NMR (400 MHz, DMSO-d6) 6 12.93 (d, J = 6.4 Hz, 1H), 12.29 (s, 1H), 8.85 (d, 1 = 6.7 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1K ), 7.82 (t, J 8.3 Hz, 1H), 238 7.75 (d, J =7.9 Hz, 1), 7.54 (t, J = 8.1 Hz, 1H), 7.17 (m, 2H), 6.94 (i, 1H), 3.79 (in, 2K), 3.21-2.96 (mn, 4H), 1.91-1.76 (in, 4H), 1.52 (in, 2H), 1.43 (s, 9H) H NMR (400 MHz, DMSO-d6) 612.95 (d, J = 6.6 Hz, 1H), 12.65 (s, 1K), 242 8.87 (d, J = 6.8 Hz, 1K), 8.34 (dd, J =8.1, 1.1 Hz, 1K), 8.17 (s, 1H), 7.83 (t, J 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.54 (t, J= 8.1 Hz, 1H), 7.37 (s, 1H), 5.60 (s, 2H) 1 H-NMR (CD3OD, 300 MHz) 6 8.87 (s, 1 H), 8.45 (d, J= 8.25, 1K), 8.27 243 (in, 1H), 7.83 (t, J= 6.88, 1H), 7.67 (d, J=8.25, 1H), 7.54 (t, J= 7.15, 1H), 7.39 (d. J= 6.05, 1H), 7.18 (d, 1=8.5, 1H), 2.77 (t, = 6.87, 2H), 2.03'(s, 3H), 1.7 (q, 2H), 1.04 (t, J=7.42, 3H) NMR Shows regio isomer H NMR (400 MHz, DMSO-d6) 6 12.89 (s, 1H), 12.42 (s, 1H), 10.63 (s, 1H), 8.88J = 6.7 Hz, 1H) 8.3 (d, J8. = 8.2 Hz, 1H), 8.03 (d,H 1.6 244 Hz, 1H), 7.82 ( , J = 8.3 Hz, I H), 7.76 (d, J = 7.7 Hz, 1 K), 7.54 (t, J = 8.1 Hz, 1H), 7.29 (d, J 8.3 Hz, 1K), 7.02 (dd, J = 8.4, 1.8 Hz, 1H5I), 2.69 (t, J _______ = 5.3Hz, 2H), 2.61 (t J=5.H 2H),1.82 m,4H H NMR (400 MHz, DMSO-d6) 6 12.95 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 9.30(s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1,1.3 Hz, 1H) 248 7.85-7.81 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1 H), 7.49 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d,J = 8.3 Hz, 1H), 2.18 (s, 3H), 2.08 (s, 3H) K NMR (400 MHz, DMSO-d6) 5 0.86 (t, J = 7.4 Hz, 3), 1.29 (d, J 6.9 259 Hz, 3H), 1.67 (n, 2H), 2.88 (m, 1H), 7.03 (in, 2H), 7.53 (m, 2H), 7.80 (mH, 2H), 8.13 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.89 (s, 1H), 10.75 (s, 1H), 12.45 (s, 1K), 12.84 (s, 1H) -- 272 - H NMR (400 MHz, DMSO-d6) 6 13.23 (d, J = 6.6 Hz, 1 H), 12.20 (s, I H), 260 10.22 (br s, 2H), 8.88 (d, J = 6.8 Hz, 1H). 8.34 (d, J = 7.8 Hz, 1H), 7.86 7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J = 8.5, 2.4 Hz, 1H), 1.46 (s, 9H) 1 H-NMR (d6-DMSO, 300 MHz) 6 11.99 (s, 1 H, NH), 8.76 (s, J = 6.6 Hz, 261 1 H), 8.26 (d, J = 6.2 Hz, 1 H), 8.09 (d, J = 7.9 Hz, 1 H), 7.72 - 7.63 (m, 2H), 7.44 - 7.09 (m, 7H), 2.46 (s, 3H), 2.25 (s, 3H). 1H NMR (400 MHz, DMSO-d6) 5 13.00 (s, IH), 12.53 (s, 1H), 10.62 (s, 262 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.85-7.75 (m, 2H), 7.57 7.50 (m, 2H), 7.34-7.28 (m, 2H), 3.46 (s, 2H) H NMR (400 MHz, DMSO-d6) 6 12.94 (d, J = 6.6 Hz, 1H), 12.57 (s, 1H), 266 10.37 (s, 1 H), 8.88 (d, J = 6.8 Hz, 1H), 8.34-8.32 (m, IH), 7.99 (s, 1H), 7.85-7.81 (m, IH), 7.76 (d, J = 7.8 Hz, IH), 7.56-7.52 (m, IH), 7.38 (s, 1 H), 1.37 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 13.02 (s, IH), 12.62 (s, IH), 8.91 (s, 268 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 8.22 (d, J = 2.4 Hz, IH), 8.14 (dd, J = 8.8, 2.4 Hz, 1 H), 7.84 (t, J = 8.3 Hz, 1 H), 7.77 (d, J 7.8 Hz, I H), 7.65 7.54 (m, 4H), 1.52 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 1.38 (s, 9H), 4.01 (s, 2H), 7.35 (s, 2H), 271 7.55 (m, I H), 7.65 (s, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.83 (m, 1 H), 8.33 (d, J = 7.6 Hz, IH), 8.86 (d, J = 6.8 Hz, I H), 12.49 (s, 1 H), 13.13 (s, 1 H) 1 H-NMR (d6-Acetone, 300 MHz) 6 8.92 (d, J= 6.6 Hz, 1 H), 8.39 (d, J= 272 7.8 Hz, 1H), 7.94 (s, IH), 7.79 (s, 1H), 7.77 (s, 2H), 7.53 (m, 1H), 7.36 (s, 1 H), 3.94-3.88 (m, 5H), 3.64-3.59 (m, 3H), 3.30 (m, 4H). H NMR (400 MHz, DMSO-d6) 6 13.21 (d, J = 6.6 Hz, I H), 11.66 (s, I H), 10.95 (s, 1H), 9.00 (d, J = 6.5 Hz, 1H), 8.65 (d, J = 2.1 Hz, IH), 8.18 (dd, 274 J = 8.7, 2.2 Hz, I H), 7.97 (d, J = 8.8 Hz, 1 H), 7.57 (m, 2H), 7.31 (t, J = 2.7 Hz, I H), 6.40 (t, J = 2.0 Hz, 1 H), 3.19 (m, 4H), 1.67 (m, 4H), 1.46 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s, 1H), 275 8.43 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (m, 6H), 7.11 (d, J = 8.4 Hz, IH), 6.99 (dd, J = 8.4, 2.1 Hz, 1 H), 5.85 (s, 2H), 1.35 (s, 9H) 1 H NMR (CD30D, 300 MHz) 6 8.90 (s, 1 H), 8.51 (s, 1 H), 8.44 (d, J = 7.9 282 Hz, IH);'7.82 (t, J = 8.3 Hz, IH), 7.69 (d. J = 8.5 Hz, IH), 7.56 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 7.9 Hz, IH), 7.07 (d, J = 5.8 Hz, IH), 2.93 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H). 1 H-NMR (CDCI3, 300 MHz) 6 8.82 (d, J = 6.6 Hz, 1 H), 8.29 (d, J = 6.2 283 Hz, I H), 8.06 (d, J = 7.9 Hz, 1 H), 7.43 - 7.24 (m, 6H), 7.02 (m, 2H), 6.87 - 6.81 (dd, 2H), 3.76 (s, 3H). H NMR (400 MHz, DMSO-d6) 6 13.51 (s, IH), 13.28 (d, J = 6.6 Hz, IH), 11.72 (d, J = 2.2 Hz, 1 H), 9.42 (s, I H), 8.87 (d, J = 6.9 Hz, 1 H), 8.04 (d, J 287 = 7.4 Hz, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.3, 0.8 Hz, 1H), 7.01 (d, J = 13.7 Hz,-1H), 6.81 (dd, J = 8.1, 0.8 Hz, I H), 2.10 (m, 2H), 1.63-1.34 (m, 8H), 1.26 (s, 3H) -273 - H NMR (400 MHz, DMSO-d6) 5 13.16 (s, 1 H), 12.85 (s, 1 H), 8.98 (s, 288 1H), 8.43 (dd, J = 8.1, 1.1 Hz, IH), 8.34 (dd, J = 10.3, 3.1 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 8.1 Hz, IH), 7.03 (dd, J = 10.7, 3.2 Hz, 1 H), 4.06 (s, 3H), 1.42 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 1.98 (m, 4H), 3.15 (m, 4H), 7.04 (m, 295 2H), 7.17 (d, J = 7.8 Hz, 1H), 7.52 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.81 (m, 1H), 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 6.7 Hz, IH). 12.19 (s, 1H), 12.87 (s, 1H) 1H NMR (400 MHz, DMSO-d6) 6 12.93-12.88 (m, 1H), 12.18 (s, 1H), 299 8.83 (d. J = 6.8 Hz, I H), 8.38-8.31 (m, 1 H), 7.85-7.67 (m, 2H), 7.57-7.51 (m, 1 H), 6.94 (s. 1 H), 6.81-6.74 (m, 2H), 3.19-3.16 (m, 2H), 2.68-2.61 (m, 2H), 1.80-1.79 (m, 2H) H NMR (400 MHz, DMSO-d6) 6 13.23 (d, J = 6.6 Hz, 1 H), 12.59 (s, 1 H), 300 8.87 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88 (m, 2H), 1.30 (s, 6H) H NMR (400 MHz, DMSO-d6) 6 12.96 (d, J = 6.5 Hz, 1H), 12.47 (s, 0.4H), 12.43 (s, 0. 6H), 8.87 (dd, J = 6.7, 2.3 Hz, 1H), 8.33 (d, J = 8.1 Hz, 303 1H), 7.82 (t, J = 8.2 Hz, IH), 7.75 (d, J = 8.3 Hz, 1H), 7.62-7.52 (m, 3H), 7.17 (d, J = 8.3 Hz, 1 H), 4.66 (s, 0.8H), 4.60 (s, 1 .2H), 3.66 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.8 Hz, 1.2H), 2.72 (t, J = 5.9 Hz, 0.8H), 2.09 (m, 3H) 1H NMR (300 MHz, DMSO-d6) 6 11.70 (s, 1H), 8.74 (s, IH), 8.15 (s, 304 1H), 8.07 (m, 1H), 7.72 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.45-7.31 (m, 3H), 7.15-6.95 (m, 5H), 4.17 (d, J = 6.0 Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 1,40 (s, 9H), 1.09 (t, J = 6.9 Hz, 3H). 1H-NMR (CDCl3, 300 MHz) 5 8.81 (d, J = 6.6 Hz, 1H), 8.30 (d, J = 6.2 307 Hz, 1H), 8.02 (d, J = 7.9 Hz, IH), 7.44-7.26 (m, 9H), 6.79 (d, J = 7.5 Hz, 1H). I H-NMR (d6-Acetone, 300 MHz) 6 8.92 (bs, I H), 8.40 (d, J= 8.1 Hz, 1 H), 318 8.05 (bs, 1H), 7.94 (bs, 1H), 7.78 (bs, 2H), 7.52 (m, 1H), 7.36 (bs, 1H), 3.97 (t J = 7.2 Hz, 2H), 3.66 (t, J= 8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36 1.31 (m, 4H). H NMR (400 MHz, DMSO-d6) 6 12.90 (s, IH), 12.44 (s, 1H), 10.86 (s, 320 1H), 8.90 (s, 1H), 8.35 (dd, J = 8.2, 1.0 Hz, IH), 8.12 (t, J = 0.8 Hz, IH), 7.84-7.75 (m, 2H), 7.56-7.52 (m, IH), 7.37 (d, J = 8.3 Hz, 1H), 6.99 (dd, J = 8.4, 1.9 Hz, 1 H), 6.08-6.07 (m, I H), 1.35 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 2.93 (m, 4H), 3.72 (m, 4H), 7.10 (m, 321 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.51 (m, 6H), 7.74 (d, J = 8.2 Hz, 1H), 7.81 (m, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.88 (d, J 6.7 Hz, 1H), 12.69 (s, 1H), 12.86 (s, 1H) H NMR (400 MHz, DMSO-d6) 5 12.94 (br s, 1H), 12.44 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 323 7.7 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 6.3 Hz, 1H), 3.50 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 1,23 (s, 6H) H NMR (400 MHz, DMSO-d6) 6 13.02 (br s, 1H), 12.46 (s, IH), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.89 (s, 1H), 7.82 (t J = 8.3 Hz, 1H), 334 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.44 (m, 1H), 7.37 (d, J = 8.6 Hz, 1H), 3.85 (m, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.18-3.14 (m, 2H), 92.23 (s, 3H), 1.93 (t, J = 5.7 Hz, 2H), 1.79 (m, 2H), 1.53 (m, 2H), 1.43 (s, -274- 9H) H NMR (400 MHz, DMSO-d6) 6 12.19 (s, 1H), 9.35 (s, 1H), 8.22 (dd, J = 337 8.1, 1.1 Hz, IH), 8.08 (s, 1H), 7.74-7.70 (m, IH), 7.65 (d, J = 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.23 (s, 1H), 3.31 (s, 3H), 1.37 (s, 9H), 1.36 (s, 9H) 1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, IH), 12.34 (s, 1H), 10.96 (s, 351 1H), 8.91 (s, 1H), 8.48 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.84-7.76 (m, 2H), 7.53 (t, J = 7.4 Hz, 1 H), 7.39 (s, 1 H), 7.26 (t, J = 2.6 Hz, 1 H), 6.34 (s, I H), 2.89-2.84 (m, 2H), 1.29 (t, J = 7.4 Hz, 3H) 1H NMR (400 MHz, DMSO-d6) 6 11.90 (s, 1H), 9.30 (s, 1H), 8.88 (s, 353 1H), 8.34 (dd, J = 8.2, 1.1 Hz, 1H), 7.84-7.71 (m, 3H), 7.55-7.50 (m, 1H), 7.28-7.26 (m, IH), 7.20-7.17 (m, 1H), 1.47 (s, 9H), 1.38 (s, 9H) 1 H-NMR (CD30D, 300 MHz) 6 8.89 (s, 1 H), 8.59 (s. I H), 8.45 (d, J = 8.3 356 Hz, 1 H), 7.83 (t, J = 7.2 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.57 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 6.0 Hz, 1H), 3.09 (s, 3H, NMe), 2.91 (t, J = 7.4 Hz, 2H), 1.76 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 12.91 (d, J = 6.6 Hz, 1H), 12.45 (s, 1H), 10.73 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1 H), 8.35 (dd, J = 8.1, 1.3 357 Hz, IH), 8.13 (d, J = 1.6 Hz, 1H), 7.83 (t, J = 8.3 Hz, IH), 7.76 (d, J = 7.7 Hz, IH), 7.57-7.51 (m, 2H), 7.06-7.02 (m, 2H), 3.12 (septet, J = 6.6 Hz, IH), 1.31 (d, J = 6.9 Hz, 6H) 1 H-NMR (CDCl3, 300 MHz) 6 8.86 (d, J = 6.6 Hz, 1 H), 8.24 (d, J = 6.2 363 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.43 - 7.16 (m, 5H), 7.02 - 6.92 (m, 2H), 6.83 (d, J = 7.9 Hz, 2H), 3.87 (s, 3H). H NMR (400 MHz, DMSO-d6) 6 12.97 (d, J = 6.6 Hz, 1H), 12.36 (s, 1H), 8.86 (d, J = 6.7 Hz, 1 H), 8.33 (dd, J = 8.1, 1.0 Hz, IH), 7.83 (t, J = 8.3 368 Hz, 1H), 7.76 (d, J = 7.8 Hz, IH), 7.62 (s, IH), 7.55 (t, J = 8.1 Hz, IH), 7.25 (dd, J = 8.7, 2.2 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1H), 3.98 (t, J = 6.5 Hz, 2H), 1.78 (sextet, J = 6.9 Hz 2H), 1.02 (t, J = 7.4 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.93 (d, J = 6.2 Hz, IH), 12.35 (a. 1H), 375 8.86 (d, J = 6.7 Hz, 1 H), 8.33 (d, J = 6.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, IH), 7.75 (d, J = 7.8 Hz, IH), 7.54 (t, J = 8.1 Hz, IH), 7.47-7.43 (m, 2H), 7.04 (d, J = 8.2 Hz, I H), 2.71 (m, 4H), 1.76 (m, 4H) H NMR (400 MHz, DMSO-d6) 5 12.98 (d, J = 6.6 Hz, 1H), 12.39 (s, 1H), 378 8.86 (d, J = 6.7 Hz, 1H), 8.33 (dd, J = 8.1, 1.2 Hz, IH), 7.83 (t, J = 8.3 Hz, 1 H), 7.77 (d, J = 7.7 Hz, IH), 7.69 (s, I H), 7.55 (t, J = 8.1 Hz, IH), 7.31 (dd, J = 8.8, 2.4 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 3.85 (s, 3H) 1H NMR (300 MHz, DMSO-d6) 6 12.79 (s, IH), 10.30 (s, 1H), 8.85 (s, 379 1H), 8.32 (d, J = 7.8 Hz, 1 H), 8.06 (s, 1 H), 7.93 (s, 1 H), 7.81 (t, J = 7.8 Hz, I H), 7.74 (d, J = 6.9 Hz, I H), 7.73 (s, 1 H), 7.53 (t, J = 6.9 Hz, 1 H), 2.09 (s, 3H). H NMR (400 MHz, DMSO-d6) 6 12.78 (br s, 1H), 11.82 (s, 1H), 10.86 (s, 381 1H), 8.83 (s, 1H), 8.28 (dd, J = 8.1, 1.0 Hz, IH), 7.75 (t, J = 8.3 Hz, IH), 7.69 (d, J = 7.7 Hz, 1H),, 7.49-7.43 (m, 3H), 7.23 (m, IH), 6.32 (m, 1H), 1.39 (s, 9H) -275- 1 H NMR (CD30D, 300 MHz) 6 8.83 (s, 1 H), 8.40 (d, J = 7.4 Hz, 1 H), 382 7.81 - 7.25 (m, 2H), 7.65 (d, J = 8.3 Hz, 1 H), 7.51 (d, J 8.2, 1 H), 7.24 (d, J = 8.3, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.17 (s, 3H), 1.60 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 1.27 (t, J = 7.5 Hz, 3H), 2.70 (q, J = 7.7 Hz, 2H), 7.05 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 383 7.76 (d, J = 7.7 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 8.13 (s, 1H), 8.35 (d, J = 6.9 Hz, 1 H), 8.89 (d, J = 6.7 Hz, 1 H), 10.73 (s, 1 H), 12.46 (s, 1 H), 12.91 (s, 1H) H NMR (400 MHz, DMSO-d6) 6 13.18 (d, J = 6.8 Hz, 1H), 12.72 (s, 1H), 386 8.88 (d, J = 6.8 Hz, IH), 8.34 (d. J = 8.1 Hz, IH), 8.09 (s, 1H), 7.86-7.79 (m, 2H), 7.58-7.50 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 3.51 (s, 2H), 1.36 (s, 6H) 1H NMR (300 MHz, MeOH) 6 8.78 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.16 393 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 6.9, Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 7.06 (m, 2H), 4.02 (m, 2H), 1.13 (t, J = 6.9, Hz, 3H); 1 H-NMR (CD30D, 300 MHz) 6 8.91 (s, 1 H), 8.51 (s, 1H), 8.42 (d, J = 8.3 399 Hz, I H), 7.84 (t, J = 7.2 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.56 (t, J 7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 3.48 (m, 1H), 3.09 (s, 3H, NMe), 1.39 (d, J = 6.8 Hz, 6H). H NMR (400 MHz, DMSO-d6) 6 12.81-12.79 (m, 2H), 10.96 (s, 1H), 8.87 412 (d, J = 6.7 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.83-7.73 (m, 3H), 7.53 (t, J = 8.1 Hz, 1H), 7.36 (m, 1H), 6.52 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.37 (t,. J = 7.1 Hz, 3H) H NMR (400 MHz, DMSO-d6) 6 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 415 8.43-8.41 (m, 1H), 7.94-7.88 (m, 2H), , 7.65-7.61 (m, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (dd, 1H), 4.08 (s, 3H), 1.35 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.91 (bs, 1H), 12.51 (s, 1H), 8.89 (s, 420 1H), 8.33 (dd, J= 8, 1Hz, 2H), 7.82 (ddd, J= 8, 8, 1 Hz, 1K), 7.75 (dd, J =8, 1Hz, 1H), 7.70 (d, J= 9 Hz, 2H), 7.54 (ddd, J 8, 8, 1 Hz, IH), 4.09 (q, J= 7 Hz, 2H), 1.51 (s, 6H), 1.13 (t, J= 7 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 12.91 ( br s, 1H), 12.48 (s, 1H), 10.81 (d, J = 1.8 Hz, 1H), 8.89 (s, IH), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.14 (d, J 423 1.6 Hz, 1 H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.5, 1.8 Hz, 1H), 3.62 (t, J 7.3 Hz, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.91 (t, J = 7.3 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H) 1H-NMR (DMSO d6, 300 MHz) 6 8.84 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 425. 7.78-7.70 (m, 21H), 7.61 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 2.85 (h, J = 6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). H NMR (400 MHz, DMSO-d6) 6 1.45 (s, 9H), 2.84 (t, J = 5.9 Hz, 2H), 3.69 (m, 2H), 4.54 (s, 1H), 6.94 (d, J = 7.5 Hz, IH), 7.22 (t, J = 7.9 Hz, 427 1H), 7.55 (m, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.24 (d. J = 8.0 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.91 (s, 1H), 12.36 (s, 1H), 12.99 (s, S1H) - 276 - 1H NMR (300 MHz, CD30D) 6 12.30 (s, 1H), 8.83 (s, 1H), 8.38 (d, J = 428 7.4 Hz, IH), 7.78 (app dt, J = 1.1, 7.1 Hz, IH), 7.64 (d, J = 8..3 Hz, IH), 7.53 (app t, J = 7.5 Hz, 1H), 7.21 (br d, J = 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 2.1, 8.4 Hz, IH), 1.38 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 13.13 (d, J = 6.8 Hz, 1H), 12.63 (s, 1H), 429 8.86 (d, J = 6.8 Hz, I H), 8.33 (d, J = 7.0 Hz, 1 H), 7.84 (t, J = 8.3 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 8.1 Hz, IH), 7.51 (s, IH), 7.30 (s, 1H), 6.77 (s, IH) H NMR (400 MHz, DMSO-d6) 6 12.87 (br s, 1H), 11.82 (s, 1H), 9.20 (s. 433 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.17 (s, IH), 7.10 (s, I H), 1.38 (s, 9H), 1.36 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.97 (d, J = 6.6 Hz, 1H),'12.08 (s, IH), 438 8.90 (d, J = 6.8 Hz, 1H), 8.35-8.34 (m, 1H), 8.03 (s, 1H), 7.85-7.81 (m, 1 H), 7.77-7.71 (m, 1 H), 7.58-7.44 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H) I H-NMR (d6-Acetone, 300 MHz) 6 11.90 (br s, 1 H), 8.93 (br s, I H), 8.42 441 (d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.79 (m, 2H), 7.57 (m, 1H), 7.36 (s. 1H), 3.13 (s, 3H). H NMR (400 MHz, DMSO-d6) 6 12.56 (s, IH), 12.17 (br d, J= 6 Hz, 1H), 444 8.89 (d, J= 6 Hz, 1H), 8.42 (dd, J= 9, 2 Hz, IH), 7.77 (d, J= 2 Hz, 1H), 7.68 (dd, J = 9, 2 Hz, 1 H), 7.60 (ddd, J = 9, 9, 2 Hz, 1 H), 7.46-7.40 (m, ' 3H), 3.47 (s, 3H), 1.35 (s, 9H). H NMR (400 MHz, DMSO-d6) 6 12.96 (br s, 1H), 12.42 (s, 1H), 8.88 (s, 448 1 H), 8.33 (dd, J = 8.2, 1.1 Hz, 1 H), 7.82 (t, J = 8.3 Hz, 1 H), 7.75 (d, J = 7.7 Hz, I H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1 H), 7.39 (d, J 8.7 Hz, 2H), 1.29 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 12.95 (d, J = 6.5 Hz, 1H), 12.38 (s, 1H), 453 8.86 (d, J = 6.8 Hz, IH), 8.33 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7'.8 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H) H NMR (400 MHz, DMSO-d6) 6 12.97 (d, J = 7.1 Hz, IH), 12.39 (s, IH), 458 8.88 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.9 Hz, IH), 7.83 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1 H), 7.55 (t, J = 7.6 Hz, IH), 7.47 (s, I H), 7.17 (s, 2H), 4.04 (t, J = 5.0 Hz, 2H), 3.82 (t, J = 5.0 Hz, 2H), 1.36 (s, 9H) 1 H-NMR (d6-DMSO, 300 MHz) 6 11.97 (s, 1 H), 8.7 (s, 1 H), 8.30 (d, J = 7.7 Hz, IH), 8.07 (d, J = 7.7 Hz, IH), 7.726 - 7.699 (m, 2H), 7.446 461 7.357 (m, 6H), 7.236 - 7.178 (m, 2H). 13C-NMR (dO-DMSO, 75 MHz) d 176.3, 163.7, 144.6, 139.6, 138.9, 136.3, 134.0, 133.4, 131.0, 129.8, 129.2, 128.4,128.1, 126.4, 126.0, 125.6, 124.7, 123.6, 119.6,111.2. I H-NMR (DMSO d6, 300 MHz) 6 8.83 (s, 1 H), 8.29 (d, J = 7.8 Hz, 1 H), 463 7.78-7.70 (m, 2H), 7.61 (d. J = 7.8 Hz, 2H), 7.51 (t, IH), 7.17 (d, J = 8.1 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz,1 H), 0.92 (t, J = 7.8 Hz, 3H). H NMR (400 MHz, DMSO-d6) 6 1.37 (s, 9H), 1.38 (s, 9H), 6.80 (dd,J = 464 8.1, 0.9 Hz, IH), 7.15 (m, 3H), 7.66 (t, J = 8.2 Hz, IH), 8.87 (d, J = 6.9 Hz, IH), 9.24 (s, 1H), 11.07 (s, IH), 13.23 (d, J = 6.5 Hz, IH), 13.65 (s, I H) -277 - H NMR (400 MHz, DMSO-d6) 6 12.94 (d, J = 6.0 Hz, 1H), 12.40 (s, 1H), 465 8.87 (d, J = 6.8 Hz, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 7.84-7.75 (m, 3H), 7.57-7.43 (m, 2H), 7.31 (d, J = 8.6 Hz, 1 H), 4.40 (d, J = 5.8 Hz, 2H), 1.44 (s, 9H), 1.38 (s, 9H) 1H-NMR (CD30D, 300 MHz) 6 8.87 (s, 1H), 8.44 (d, J= 8.25, 1H), 8.18 471 (m, IH), 7.79 (t, J= 6.88, 1H), 7.67 (d, J= 8.25, 1 H), 7.54 (t, J= 7.15, 1H), 7.23 (d, J= 6.05, 1H), 7.16 (d, J= 8.5, 1H), 3.73 (s, 3H), 2.75 (t, J= 6.87, 2H), 1.7 (q, 2H), 1.03 (t, J= 7.42, 3H) H NMR (400 MHz, DMSO-d6) 6 13.00 (d, J = 6.4 Hz, 1H), 12.91 (s, 11H), 476 10.72 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 8.2 Hz, 11H), 8.16 (s, IH), 7.85-7.75 (m, 2H), 7.56-7.54 (m, 1H), 7.44 (s, 1H), 1.35 (s, 9H) H NMR (400 MHz, DMSO-d6) 6 1.40 (s, 9H), 6.98 (d, J = 2.4 Hz, IH), 7.04 (dd, J = 8.6, 1.9 Hz, 1 H), 7.55 (t, J = 8.1 Hz, 1 H), 7.66 (d, J = 8.6 478 Hz, 1 H), 7.76 (d, J =7.7 Hz, 1H), 7.83 (, J = 8.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, IH), 8.35 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 6.7 Hz, IH), 10.74'(s, 1H), 12.44 (s, I1), 12.91 (s, 1H) 1H NMR (300 MHz, DMSO-d6) 6 12.90 (d, J = 6.3 Hz, 1 H), 12.21 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 11H), 7.79 (app dt, J = 484 12, 8.0 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 6.9, 8.1 Hz, IH), 7.05 (d, J = 8.3 Hz, 1 H), 6.94 (s with fine str, 1 H), I H), 6.90 (d with fine str, J = 8.4 Hz, 1 H), 2.81 (s, 3H), 1.34 (s, 9H) 1H NMR (300 MHz, CDC 3 ) 6 13.13 (br s, IH), 12.78 (s, 1H), 8.91 (br s, 485 1H), 8.42 (br s, IH), 8.37 (d, J = 8.1 Hz, 1 H), 7.72-7.58 (m, 2H); 7.47 7.31 (m, 3H), 3.34 (s, 6H), 1.46 (s, 9H) [00768] B) Assays for Detecting and Measuring AF508-CFTR Correction Properties of Compounds [007691 1) Membrane potential optical methods for assaying AF508-CFTR modulation properties of compounds [00770] The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See. Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. B. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (Se Gonzalez, J. B., K. Oades, et at. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Dru; Discov Today 4(9): 431-439). -278- [00771] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (V,) cause the negatively charged DiSBAC 2 (3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPRm 11, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates. [007721 Identification of Correction Compounds [007731 To identify small molecules that correct the trafficking defect associated with AF508-CFTR; a single-addition HTS assay format was developed. The cells were incubated in serum-free medium for 16 hrs at 37 *C in the presence or absence (negative control) of test compound. As a positive control, cells plated in 384-well plates were incubated for 16 hrs at 27 *C to "temperature-correct" AF508-CFTR. The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate AF508-CFTR, 10 ptM forskolin and the CFTR potentiator, genistein (20 [iM), were added along with CF-free medium to each well. The addition of CF-free medium promoted Cl efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes. [007741 Identification of Potentiator Conpounds [00775] To identify potentiators of AF508-CFTR, a double-addition HTS assay format was developed. During the first addition, a CF-free medium with 'or without test compound was added to each well. After 22 sec, a second addition of CF-free medium containing 2 - 10 pM forskolin was added to activate AF508-CFTR. The extracellular CF concentration following both additions was 28 mM, which promoted Cl efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes. Solutions Bath Solution #1: (in mM) NaCl 160, KCI 4.5, CaCl 2 2, MgCI 2 1, HEPES 10, pH 7.4 with NaOH. - 279 - Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts. CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20*C. DiSBAC 2 (3): Prepared as a 10 mM stock in DMSO and stored at -20*C. [00776] Cell Culture [007771 NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 *C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, I X NEAA, P-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For all optical assays, the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 *C before culturing at 27 "C for 24 hrs. for the potentiator assay. For the correction assays, the cells are cultured at 27 "C or 37 *C with and without compounds for 16 - 24 hoursB). Electrophysiological Assays for assaying AF508-CFTR modulation properties of compounds [007791 1.Ussing Chamber Assay [007801 Ussing chamber experiments were performed on polarized epithelial cells expressing AF508-CFTR to further characterize the AF508-CFTR modulators identified in the optical assays. FRT6F 5 084FTR epithelial cells grown on Costar Snapwell cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of . Bioengineering University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 KO/ cm 2 or more. The solutions were maintained at 27 *C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the flow of C1~ through AF508-CFTR expressed in the apical membrane. The Isc was digitally acquired using an MP1OOA-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA). [00781] Identification of Correction Compounds - 280 - [007821 Typical protocol utilized a basolateral to apical membrane Cl~ concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl~ concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate AF508-CFTR, forskolin (10 pM) and the PDE inhibitor, IBMX (100 pM), were applied followed by the addition of the CFTR potentiator, genistein (50 pM). [007831 As observed in other cell types, incubation at low temperatures of FRT cells stably expressing AF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 pM of the test compound for 24 hours at 37*C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated Isc in compound-treated cells was normalized to the 27*C and 37*C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated Isc compared to the 37*C controls. [007841 Identification of Potentiator Compounds [007851 Typical protocol utilized a basolateral to apical membrane C~ concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 Ig/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl- concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 pM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative AF508-CFTR potentiators was compared to that of the known potentiator, genistein. [007861 Solutions Basolateral solution (in mM): NaCi (135), CaCl 2 (1.2), MgC 2 (1.2), K 2 HP0 4 (2.4),

KHPO

4 (0.6), N-2-hydroxyethylpiperazine-N'-2 ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated to pH 7.4 with NaOH. Apical solution (in mM): Same as basolateral solution with NaCI replaced with Na Gluconate (135). -281- [00787] Cell Culture 1007881 Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FRTAF 5 08-CER) were used for Ussing chamber experiments for the putative AF508-CFTR modulators identified from our optical assays. The cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 *C and 5% CO 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 pug/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 *C for 16 - 48 hrs to correct for the AF508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 "C or 37 *C with and without the compounds for 24 hours. [00789] 2. Whole-cell recordings [007901 The macroscopic AF508-CFTR current (IAF5o8) in temperature- and test compound-corrected NIH3T3 cells stably expressing AF508-CFTR were monitored using the perforated-patch, whole-cell recording. Briefly, voltage-clamp recordings of IAF50s were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had a resistance of 5 - 6 MI when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for Cl~ (Ec) at room temperature was -28 mV. All recordings had a seal resistance > 20 GQ and a series resistance < 15 MO. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath contained <250 d of saline and was continuously perifused at a rate of 2 ml/min using a gravity-driven perfusion system. [00791] Identification of Correction Compounds [007921 To determine the activity of correction compounds for increasing the density of functional AF508-CFTR in the plasma membrane, we used the above-described perforated-patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 10 pM forskolin and 20 pM genistein were added to the cells. Under our recording conditions, the current density following - 282 - 2 4-hr incubation at 27*C was higher than that observed following 24-hr incubation at 37 *C. These results are consistent with the known effects of low-temperature incubation on the density of AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 pM of the test compound for 24 hours at 37"C and the current density was compared to the 27"C and 37 0 C controls (% activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 jM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37"C controls. [00793] Identification of Potentiator Compounds [00794] The ability of AF508-CFTR potentiators to increase the macroscopic AF508-CFTR Cl~ current (iAFso8) in NIH3T3 cells stably expressing AF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IAF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated Eci (-28 mV). [007951 Solutions Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl 2 (1), HEPES (10), and 240 jig/ml amphotericin-B (pH adjusted to 7.35 with CsOH). Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150), MgCl 2 (2), CaC 2 (2), HEPES (10) (pH adjusted to 7.35 with HC1). [00796] Cell Culture [00797] NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for whole-cell recordings. The cells are maintained at 37 *C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, (-ME, I X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 *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. -283 - [007981 3.Single-channel recordings [00799] The single-channel activities of temperature-corrected AF508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. Briefly, voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz. Patch pipettes were fabricated from Coming Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MQ when filled with the extracellular solution. The-AF508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After channel activity stabilized, the patch was perifused using a gravity driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1 - 2 sec. To maintain AF508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min). Currents produced by positive charge moving from the intra to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (V,) was maintained at 80 mV. [00800] Channel activity was analyzed from membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of AF508-CFTR activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (P() were determined from 120 sec of channel activity. The P. was determined using the Bio-Patch software or from the relationship P = I/i(N), where I = mean current, i= single-channel current amplitude, and N = number of active channels in patch. [008011 Solutions Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl 2 (5), MgC1 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base). -284- Intracellular solution (in mM): NMDG-Cl (150), MgC 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCI). [008021 Cell Culture [008031 NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 *C in 5% CO 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, I X NEAA, P-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 *C before use. [008041 Compounds of the invention are useful as modulators of ATP binding cassette transporters. Table 3 below illustrates the EC50 and relative efficacy of certain embodiments in Table 1. [00805] In Table 3 below, the following meanings apply: EC50: "+++" means <10 uM; "++" means between 1OuM to 25 uM; "+" means between 25 uM to 60uM. % Efficacy: "+" means < 25%; "++" means between 25% to 100%; "+++" means > 100%. Table3 1 +++ ++ 17 +++ ++ 34 +++ ++ 2 +++ ++ 18 +++ ++ 35 +++ ++ 3 +_ ++ 19 ++ + 36 +++ ++ 4 _++ .. ++ 20 +++ ++ 37 ++ ++ 5 ++ ++ 21 + + 38 +++ ++ -6 +++ +++ 22 ++ ++ 39 ++ ++ 7 + 23 +++ - 40 + ++ 8 +-I--i -1- 24 + + 41 ... ++ 9 __+ + 25 ++ ++ 42 +++ ++ 10 + ++ 26 +++ ++ 43 +++ ++ 11 +++ ++ 28 ++ ++ 44 ++ ++ 12 +++ ++ 29 ++ ++ 46 ++ ++ 13 ++ 30 _ .. +_ ++ 47 ++ ++ 14 +++- ++ 31 +++ ++ 48 + ++ 15 ++ ++ 32 +++ ++ 49 +++ ++ 16 +++ ++ 33 + ++ 50 +++ ++ -285- Cmpd EC50 % Activity Cmpd EC50 % Activity Cmpd EC50 % Activity #t__ (uM) # EUM) # (uM) 51 +++ ++ 95 ++ ++ 140 +++ ++ 52 +++ ++ 96 +++ ++ 141 ++ ++ 53 + + 97 +++ ++ 142 +++ ++ 54 + + 98 ++ ++ 143 +++ ++ 55 + + 99 +++ ++ 144 +++ ++ 56 +++ ++ 100 + + 145 +++ ++ 57 ++ +++ 101 .+++ ++ 146 + + 58 +++ ++ 102 ++ ++ 147 +++ ++ 59 +++ +++ 103 +++ +++ 148 +++ ++ 60 +++ . ++ 104 44+ ++ 149 ++ ++ 61 +++ ++ 105 ++ ++ 150 +++ ++ 62 +++ ++ 106 + + 151 +++ ++ 63 +++ ++ 107 ++ ++ 152 + + 64 + + 108 +++ ++ 153 ++ ++ 65 +++ ++ 109 ++ ++ 154 + + 66 ++ ++ 110 + + 155 + + 67 +++ ++ 111 +++ ++ 156 +++ ++ 68 +++ ++ 112 +++ ++ 157 +++ ++ 69 +++ ++ 113 +++ ++ 158 +++ ++ 70 ++ ++ 114 +.+ ++ 159 ++ ++ 71 +++ ++ 115 +++ ++ 160 +.+ ++ 72 +++ ++ 116 , -+++ ++ 161 +++ ++ .73 + + 117 +++ ++ 162 + + 74 + + 118 +++ ++ 163 ++ ++ 75 + + 119 +++ ++ 164 44+ ++ 76 +++ ++ 120 ++ ++ 165 + + 77 +++ ++ 122 + + 166 +++ ++ 78 + + 123 +++ ++ 167 ++ ++ 79 _+. ++ 124 ++ .+ _168 + + 80 .++ + 125 ++ ++ 169 ++ ++ 81 + + 126 +++ ++ 170 + + 82 -i-i-i ++ 127 +4+ 4+ 171 ... 4+ 83 +++ ++ 128 + + 172 +++ ++ 84 + + 129 ++ ++ 173 + + 85 +++ ++ 130 .+ ++ 174 ++ + 86 ++ ++ 131 +++ ++ 175 ++ ++ 87 +++ ++ 132 + + 176 +.+ ++ 88 +++ ++ 133 ++ ++ 177 +++ +++ 89 + + 134 +++ ++ 178 + ++ 90 +... + 135 +++ + 179 + + 91 ++ ++ 136 +++ ++ 180 +++ ++ 92 +++ ++ 137 +.++ ++ 181 + ++ 93 ++ ++ 138 +++ ++ 182 +++ ++ 94 +++ ++ 139 +++ ++ 183 +++ ++ -286- Cmpd EC50 A Cmpd EC50 Cmpd EC5O # (uM) % Activity # (uM) %Activity # (uM) % Activity 184 + + 228 +++ ++ 272 ++ ++ 185 + + 229 +++ ++ 273 +++ +++ 186 ++-+ ++ 230 ++ ++ 274 +++ ++ 187 +++ ++ 231 +++ ++ 275 ++ ++ 188 +++ ++ 232 ++ ++ 276 ++ ++ 189 +++ ++ 233 ++ + 277 +++ +++ 190 +++ ++ 234 ++-+ ++ 278 +++ ++ 191 + + 235 +++ ++ 279 +++ ++ 192 + + 236 ++ ++ 280 .+ + 193 ++ ++ 237 +++ ++ 281 +++ ++ 194 + + 238 +++ ++ 282 +++ ++ 195 + + 239 +++ ++ 283 +++ ++ 196 +++ ++ 240 +++ ++ 284 ++ ++ 197 + + 241 ++ ++ 285 +++ ++ 198 +++ " ++ 242 +++ ++ 286 +++ +++ 199 +++ ++ 243 ++ ++ 287 .+ ++ 200 ++ ++ 244 +++ ++ 288 +++ ++ 201 ++ + 245 +++ ++ 289 +++ ++ 202 .++ ++ 246 +++ ++ 290 +++ ++ 203 +++ ++- 247 +++ ++ 291 +++ ++ 204 +++ ++ 248 ++ ++ 292 +++ ++ 205 +++ ++ 249 ++ ++ 293 ++ +++ 206 +++ ++ 250 + + 294 ++ ++ 207 +++ ++ 251 +++ ++ 295 +++ ++ 208 +++ ++ 252 ++ ++ 296 ++ ++ 209 ++ ++ 253 +++ ++ 297 ++ ++ 210 ++ ++ 254 +++ ++ 298 +++ ++ 211 +++ ++ 255 +++ ++ 299 +++ ++ 212 + + 256 + + 300 +++. _ ++ 213 +++ ++ 257 +++ ++ 301 + + 214 ++ ++ 258 +++ ++ 302 ++ ++ 215 +++ ++ 259 +++ ++ 303 ++ .++ 218 +- + 260 ... -1-4 304_ 4-4- +4 217 ++ ++ 261 +++ ++ 305 +++ ++ 218 +++ ++ 262 +++ + 306 .. +++ 219 + + 263 ++ ++ 307 +++ ++ 220 ++ ++ 264 ++ ++ 308 ++ ++ 221 ++ ++ 265 +++- ++ 309 + + 222 ++ ++ 266 +++ ++ 310 +++ ++ 223 ... i- ++- 267 ++ ++ 311 ++ ++ 224 +++ ++ 268 ++ ++ 312 +++ ++ 225 +. ++___ 269 +++ ++ 313 +++ ++ 226 +++ ++ 270 +++ ++ 314 ++ ++ 227 + + 271 +++ ++ 315 +++ ++ -287- Cmpd EC5O , Ampd EC50 Cmpd EC50 # (uM) o Activity # (uM) % Activity # (uM) % Activity 316 ++ ++ 361 +++ .+ 405 +++ ++ 317 +++ ++ 362 +++ ++ 406 +++ ++ 318 ++ +4_ _ 363 +++ +++ 407 +++ ++ 319 +++ ++ 364 +++- ++ 408 +++ ++ 320 +++ ++ 365 ++ ++ 409 +++ ++ 321 +++ ++ 366 +++ ++ 410 +++ 322 +++ ++ 367 +++ ++ 411 +++ ++ 323 +++ ++ 368 +++ ++ 412 +++ ++ 324 +++ ++ 369 ++ + 413 +++ ++ 325 + ++ 370 +++ ++ 414 + + 326 ++ ++ 371 +++ +-+ 415 +++ ++ 327 +++ ++ 372 +++ ++ 416 +++ ++ 328 + + 373 ++.. ++ 417 +++ ++ 329 ++ ++ 374 + + 418 ++ ++ 330 +++ ++ 375 +++ ++ 419 + + 331 + + 376 + + 420 +++ ++ 332 +++ ++ 377 ++ ++ 421 +++ ++ 333 +++ ++ 378 ++ ++ 423 +++ ++ 334 ++ ++ 379 ++ ++ 424 +++ ++ 335 + + 380 +++ ++ 425 +++ ++ 336 +++ ++ 381 +++ ++ 426 +++ ++ 337 +++ ++ 382 ++ ++ 427 +++ ++ 338 ++ ++ 383 +++ ++ 428 +++ ++ 339 +++ ++ 384 +++ ++ 429 +++ ++ 340 +++ ++ 385 +++ ++ 430 ++ ++ 341 ++. ++ 386 .++ ++ 431 ++ ++ 342 _.+ ++ 387 +++ ++ 432 +++ ++ 343 ++ ++ 388 +++ ++ 433 +++ ++ 344 +++ ++ 389 +++ ++ 434 +++ ++ 345 +++ ++ 390 + + 435 +++ ++ 346 +++ ++ 391 .++ ++ 436 ++ ++ 347 4--a ++4 392 -+ +i .3 + + 348 +++ ++ 393 ++ ++ 438 +++ ++ 350 +++ ++ 394 + + 439 +.+ ++ 351 +++. ++__ 395 .++ ++ 440 +++ ++ 352 +++ ++ 396 ++ ++ 441 +++ ++ 353 +++ 4--f 39.7 4--H +4- 442 4- + 354 -H-- +- 398 ++ ++ 443 + + 355 +++ +- 399 +++ ++ 444 +++ ++ 356 + ++ 400 + + 445 +++ +++ 357 +++ ++ 401 ++ ++ 446 + + 358 +++ ++ 402 +++ + 447 ++ ++ 359 ++ ++ 403 +++ ++ 448 +++ ++ 360 +++ ++ 404 +++ ++ 449 +++ ++ -288 - Cmpd EC50 % Activity Cmpd EC50 % Activity Cmpd EC5 % Activity # (uM) # (uM) # (uM) 450 ++ ++ 462 +++ ++ 474 + + 451 +++ ++ 463 ++ ++ 476 +++ ++ 452 +++ ++ 464 +++ ++ 477 + + 453 +++ ++ 465 +++ ++ 478 +++ ++ 454 + + 466 +++ ++ 479 +++ ++ 455 +++ ++ 467 + + 480 + + 456 +++ ++ 468 + + 481 +++ ++ 457 + + 469 +++ ++ 482 ++ ++ 458 +++ ++ 470 +++ ++ 483 +++ ++ 459 +++ ++ 471 +++ ++ 484 +++ ++ 460 +++ ++ 472 +++ ++ 485 +++ ++ 461 +++ ++ 473 ++ ++ [008061 The foregoing embodiments are illustrative only of the principles of the invention, and various modifications and changes will readily occur to those skilled in the art. The invention is capable of being practiced and carried out in various ways and in other embodiments. It is also to be understood that the terminology employed herein is for the purpose of description and should not be regarded as limiting. [008071 The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required. [00808] Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia. - 289 -

Claims (72)

1. A compound of formula I: R 1 0 0 R 2 NAr NN R R R4 R5 or a pharmaceutically acceptable salt thereof, wherein: Ar' is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar has m substituents each independently selected from -WRw; W is a bond or is an optionally substituted CI-C 6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -S02-, -NR'-, -SO 2 NR'-, NR'S0 2 -, -NR'SO 2 NR'-; Rw is independently R', halo, N02, CN, CF 3 , or OCF 3 ; m is 0-5; each of R', R2, R, R4, and Rs is independently -X-Rx; X is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -C02-, -0CO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO 2 -, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-; RX is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; R6 is hydrogen, CF 3 , -OR', -SR', or an optionally substituted C1.8 aliphatic group; R7 is hydrogen or a CI.6 aliphatic group optionally substituted with -X-Rx; R' is independently selected from hydrogen or an optionally substituted group selected from a C1.C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated - 290 - bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that: i) when R', R 2, R', R', R', R' and R 7 are hydrogen, then Arl is not phenyl, 2 methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2 bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxylic acid phenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, 3 carboxylic-acid phenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3 ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl,

2-ethylphenyl, or 4-ethoxycarbonylphenyl; ii) when R', R2, R , R , R6 and R 7 are hydrogen, and R is methoxy, then Arl is not 2 fluorophenyl or 3-fluorophenyl; iii) when R , R3, R4, R , R6 and R7 are hydrogen, R is 1,2,3,4-tetrahydroisoquinolin-1-yl sulfonyl, then Arl is not 3-trifluoromethylphenyl; iv) when R', R2, R3, R4, R and R7 are hydrogen, R6 is methyl, then Arl is not phenyl; v) when R', R 4 , R, R 6 and R 7 are hydrogen, R 2 and R3, taken together, are methylenedioxy, then Arl is not 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4 carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazol-2-yl. vi) when R', R 4 , R', R 6 and R7 are hydrogen, R 2 and R, taken together, are methylenedioxy, then Ar' is not 4-substituted phenyl wherein said'substituent is -SO 2 NHRx, wherein RXX is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl; vii) when R', R2, R3, R4, R5, R6, and R7 are hydrogen, then Ar is not thiazol-2-yl, 1H 1,2,4-triazol-3-yl, or 1H-1,3,4-triazol-2-yl; viii) when R', R 2 , R 3 , Ri, R 6 , and R7 are hydrogen, and R 4 is CF 3 , OMe, chloro, SCF 3 , or OCF 3 , then Ar 1 is not 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1 methyl-1,2-(1H)-pyrazol-5-yl, pyridine-2-yl, phenyl, N-methyl-imidazol-2-yl, imidazol-2-yl, 5 methyl-imidazol-2-yl, 1,3-oxazol-2-yl, or 1,3,5-(1Hl)-triazol-2-yl; -291- ix) when R', R2, R 3, R', R', R 6 , and R 7 each is hydrogen, then Arl is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl,

4-methoxy-6-methyl-1,3,5-triazin-2-yl;

5-bromo-pyridin-2-yl, pyridin-2-yl, or 3,5-dichloro-pyridin-2-yl; x) when R', R2, R 3 , R 4 , R' and R 7 each is hydrogen, R 6 is hydroxy, then Arl is not 2,6 dichloro-4-aminosulfonyl-phenyl; xi) when R2 or R is an optionally substituted N-piperazyl, N-piperidyl, or N morpholinyl, then Ar' is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl; xii) when R 2 is optionally substituted cyclohexylamino, then Arl is not optionally substituted phenyl, pyridyl, or thiadiazolyl; xiii) Arl is not optionally substituted tetrazolyl; xiv) when R2, R4, R', R', and R7 each is hydrogen, and R' and R 3 both are simultaneously CF 3 , chloro, methyl, or methoxy, then Ar is not 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl; xv) when R , R4, R5, R , and R7 each is hydrogen, and Arl is thiazol-2-yl, then neither R2 nor R 3 is isopropyl, chloro, or CF 3 ; xvi) when Ar is 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then: S2 R45 73 a) when R', R , R , R , R 6 , and R7 each is hydrogen, then R2 is not methoxy; or b) when R 1 , R2, R, R, Ri, and R7 each is hydrogen, then R4 is not chloro; or c) when R', R 2 , R 3 , Ri, R 6 , and R 7 each is hydrogen, then R4 is not methoxy; or d) when when R', R 3 , R4, R 6 , and R7 each is hydrogen, and R 5 is ethyl, then R 2 is not chloro; e) when R , R2, R4, R , R6, and R7 each is hydrogen, then R is not chloro; xvi) when R1, R3, R4, Ri, R, and R7 each is hydrogen, and R 2 is CF 3 or OCF 3 , then Ar is not [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl; xvii) when R', R2, R4, R 5 , R6, and R7 each is hydrogen, and R3 is hydrogen or CF3, then Arl is not a phenyl substituted with -OCH 2 CH 2 Ph, -OCH 2 CH 2 (2-trifluoromethyl-phenyl), OCH 2 CH 2 -(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl; and xviii) the following two compounds are excluded: - 292 - NH 0NH IzCl Cl1 and 2. The compound according to claim 1, wherein Arl is selected from: (WRwV)m or (WlwAm a-i a-Ni; wherein ring A1 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or A1 and A2, together, is an 8-14 aromatic, bicyclic or tricyclic aryl ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 3. The compound according to claim 2, wherein A1 is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein said heteroatom is nitrogen. 4. The compound according to claim 2, wherein A1 is an optionally substituted phenyl. 5. The compound according to claim 2, wherein A2 is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound according to claim 2, wherein A2 is an optionally substituted 5 membered aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. - 293 -

7. The compound according to claim 2, wherein A 2 is a 5-membered aromatic ring having 1-2 nitrogen atoms.

8. The compound according to claim 2, wherein A 2 is selected from: H (WRW)m H(WR) H (WRW)m (WRW)m N ,, R) N O N H N NH i ii iii iv S (WRw)m (WRW)m N (WRW)m >/(WRW)m 0~ N H S=O v vi vii Viii 0 (WRw)m N (WRW)m ,>(WRW)m N (WRW)m S. 0 ix x xi xii H (WRW)m (WRW)m (WRw)m (WRW)m NH N xiii xiv xv xvi (WRW)m (WRW)m N H xvii xviii xix - 294 - m(RW) (WRW)m (WRW)m O F (WRw)m, N.H 0 NH \ NH aI xx xxi xxii xxiii (WRW)m 1 (WRW)m (WRw)m (WRW)m 'O X 0 F N N 0 H H F H xxiv xxv xxvi xxviii BOC N (WRW)m (WRW) (WRW)m N O H N WNwN H H H xxix xxx xxxi xxxii; wherein ring A 2 is fused to ring A 1 through two adjacent ring atoms.

9. The compound according to claim 1, wherein R 5 and R6 is hydrogen.

10. The compound according to claim 9, wherein R3 and R 4 are simultaneously hydrogen; R' is hydrogen or -OH; and R 2 is hydrogen or fluoro.

11. The compound according to claim 10, R7 is hydrogen.

12. The compound according to claim 1, wherein each occurrence of WRW is independently -C1-C3 alkyl, C1-C3 perhaloalkyl, -O(C1-C3 alkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, -Cl, -Br, or -COOR', -COR', -O(CH 2 ) 2 N(R')(R'), -O(CH 2 )N(R')(R'), -CON(R')(R'), -(CH 2 ) 2 0R', (CH 2 )OR', optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, -N(R')(R'), -(CH 2 ) 2 N(R')(R'), or -(CH2)N(R')(R'). - 295 -

13. The compound according to claim 12, wherein each occurrence of WRW is selected from halo, cyano, CF 3 , CHF 2 , OCHF 2 , Me, Et, CH(Me) 2 , CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, 0-fluorophenyl, 0-difluorophenyl, 0-methoxyphenyl, O-tolyl, 0-benzyl, SMe, SCF 3 , SCHF 2 , SEt, CH 2 CN, NH 2 , NHMe, N(Me) 2 , NHEt, N(Et) 2 , C(O)CH 3 , C(O)Ph, C(O)NH 2 , SPh, S0 2 -(amino-pyridyl), SO 2 NH 2 , SO 2 Ph, SO 2 NHPh, S0 2 -N-morpholino, S 0 2 -N-pyrrolidyl, N pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4 Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2yl, furan-2-yl, 4-methyl-4H [1,2,4]triazol-3-yl, 3-(4'-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph, NHSO 2 Me, 2-indolyl, 5-indolyl, -CH 2 CH 2 OH, -OCF 3 , 0-(2,3-dimethylphenyl), 5 methylfuryl, -S0 2 -N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO 2 C(Me) 3 , CO 2 C(Me) 3 , isopropenyl, n-butyl, 0-(2,4-dichlorophenyl), NHSO 2 PhMe, 0-(3-chloro-5-trifluoromethyl-2 pyridyl), phenylhydroxymethyl, 2,5-dimethylpyrrolyl, NHCOCH 2 C(Me) 3 , 0-(2-tert butyl)phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethyl phenyl, 4 dimethylaminophenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4 trifluoromethylphenyl, 4-cyanomethylphenyl, 4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4 isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2 methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6 dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF 3 -phenyl, 3 trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2 fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5-isopropyi-2-methoxyphenyl, 2 fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5 difluorophenyl, 3-chloro-4-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3 dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl, 4 methoxycarbonyl phenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3 methylphenyl, 4-methanesulfinyl-phenyl, 4-methanesulfonyl-phenyl, 4-N-(2-N,N dimethylaminoethyl)carbanoylphenyl, 5-acetyl-2-thienyl, 2-benzothienyl, 3-benzothienyl, furan 3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N'-phenylcarbonyl-N-piperazinyl, -NHCO 2 Et, NHCO 2 Me, N-pyrrolidinyl, -NHSO 2 (CH 2 ) 2 N-piperidine, -NHSO 2 (CH 2 ) 2 N-morpholine, NHSO 2 (CH 2 ) 2 N(Me) 2 , COCH 2 N(Me)COCH 2 NHMe, -CO 2 Et, 0-propyl, - 296 - CH 2 CH 2 NHCO 2 C(Me) 3 , hydroxy, aminomethyl, pentyl, adamantyl, cyclopentyl, ethoxyethyl, C(Me) 2 CH 2 OH, C(Me) 2 CO 2 Et, -CHOHMe, CH 2 CO 2 Et, -C(Me) 2 CH 2 NHCO 2 C(Me) 3 , O(CH 2 ) 2 OEt, O(CH 2 ) 2 0H, CO 2 Me, hydroxymethyl, , 1-methyl-i -cyclohexyl, 1-methyl-1 cyclooctyl, 1-methyl-i -cycloheptyl, C(Et) 2 C(Me) 3 , C(Et) 3 , CONHCH 2 CH(Me) 2 , 2-aminomethyl phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl, cyclohexyl, 4-methylpiperidinyl, -OCO 2 Me, C(Me) 2 CH 2 NHCO 2 CH 2 CH(Me) 2 , -C(Me) 2 CH 2 NHCO 2 CH 2 CH 2 CH 3 ,.C(Me) 2 CH 2 NHCO 2 Et, C(Me) 2 CH 2 NHCO 2 Me, -C(Me) 2 CH 2 NHCO 2 CH 2 C(Me) 3 , -CH 2 NHCOCF 3 , -CH 2 NHCO 2 C(Me) 3 , -C(Me) 2 CH 2 NHCO 2 (CH 2 ) 3 CH 3 , C(Me) 2 CH 2 NHCO 2 (CH 2 ) 2 OMe, C(OH) (CF 3 ) 2 , C(Me) 2 CH 2 NHCO 2 CH 2 -tetrahydrofuran-3-yl, C(Me) 2 CH 2 0(CH 2 ) 2 OMe, or 3-ethyl-2,6 dioxopiperidin-3-yl.

14. The compound according to claim 2, wherein said compound has formula IIA or formula IIB: R 0 0 A (W R W )m R 0 0( W w H W' AlA (WRW)m R 3 . N RN R4H R4H IIA IIB.

15. The compound according to claim 2, wherein said compound has formula IIIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE: 0 0 x x RX-Ye-(WRW)m N H IIIA 0 0 0 0 XX2 RX-X (WRW)m R - (WRw N~N 2 N H H IIIB IIIC - 297 - o 0 A 2 (WRW)m 0 0 X5 Rx- H RX- A 2 (WRW)m H H IID IIE wherein: each of XI, X 2 , X 3 , X 4 , and X 5 is independently selected from CH or N; and X 6 is 0, S, or NR'.

16. The compound according to claim 15, wherein XI, X 2 , X 3 , X 4 , and X 5 , taken together with WRw and m, is optionally substituted phenyl.

17. The compounds according to claim 15, wherein XI, X 2 , X 3 , X 4 , and X 5 taken together in compound of formula IIIA is an optionally substituted ring selected from: C1 F N CI OMe MeO N OMe C a-i a-ii a-ii a-iv a-v 0 MeO N N CF 3 N, CH 3 N OH 3 ~N N a-vi a-vii a-viii a-ix a-x CI N N CH 3 a-xi a-xii a-xiii a-xiv a-xv a-xvi F F F N O F N C H 3 -298- a-xvii a-xviii a-xix a-xx a-xxi N a-xxii a-xxiii a-xxiv a-xxv

18. The compound according to claim 15, wherein XI, X 2 , X 3 , X 4 , X 5 , or X 6 , taken together with ring A 2 in compounds of formula IIIB, formula IIIC, formula HID, or formula IIIE, is an optionally substituted ring selected from: H H ,N b-i b-ii b-iii b-iv b-v H X NN b-i b-ii b-iii b-ix b-x CH nmN N N \Jn-NN X b-vi b-vii b-viii b-ix b-x SS-N HO N OH 3 b-xi b-xii b-xiii b-xiv b-xv H N N N N N I: ,NII N: b-xvi b-xvii b-xviii b-xix b-xx OH 3 N - HN .- S N > N /,SQ I I,, H 0N b-xxI b-xxii b-xxifi b-xxiv b-xxv - 299 - N OH 3 OH 3 H NN ~N/C 3 N HH N0 C N -0 0 J bxxxi -x xi b-xxxiii bxi b-xxx H 3 C 0 N- HN\ HN o N0 bxxxi b-xxxvi b xxxii -xi QI F N H3 HN HN b-xxvi bxxxvi b-xL bxv b-ii 0l F \ N X &N\ N HH H H H b-xxxiii b-.xx~ i b-xLb-x b-xLi H \I X ~ ~ N \ N H H H H H 0 b-xLviii b-xLviii b-xLix b-L H H HH b-Li b-Lii b-Liii b-Liv NN b-Lv b-Lvi b-Lvii b-Lviii C N N~ N N HHHH b-Lix b-Lx b-Lxi b-Lxii .0- 0 \ NN N -N H\ H H HH b-Lxiii b-Lxiv b-Lxv b-Lxvi ~0 0 b-Lxvii b-Lxviii b-Lxix b-Lxx -301 - HN b-Lxxi b-Lxxii b-Lxxiii b-Lxxiv Y.-N N N\ H -~ H H0 b-Lxxv b-Lxxvi b-Lxxvii b-Lxxviii N \-ZNN N N H H o--<o b-Lxxix b-Lxxx b-Lxxxi b-Lxxxii N N N N 0- -0 NON H H b-Lxxxviii b-Lxxxix b-xC b-xCi -302- HN O - HN O HN O O 0 0 0 b-xCi b-xCii b-xCiii b-xCiv N NF 0:L NXN )aLO0 H H b-xCv b-xCvi b-xCvii b-xCviii F F -HO 0F OH b-xCix b-C b-Ci b-Ci.

19. The compound according to claim 15, wherein said compound has formula IVA, formula IVB, or formula IVC: O O (WR)m RX-XO H IVA AA xi'N I N"" ' N A 2 -(WRW)m RX-X- H (WRW)m RX-X_ NOX H H IVB IVC. -303-

20. The compound according to claim 19, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic 5-7 membered ring with 0-3 heteroatoms selected from 0, S, or N.

21. The compound according to claim 19, wherein said compound has formula VA-1: WRWs Ww4 R WR RX~+ I H WRW 2 H VA-i wherein each of WRW 2 and WRW 4 is independently selected from hydrogen, CN, CF 3 , halo, Cl-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-CIO heteroaryl or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from 0, S, or N, wherein said WRW 2 and WRw4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , SR', S(O)R', SO 2 R', -SCF 3 , halo, CN, -COOR', -COR', -O(CH 2 ) 2 N(R')(R'), -O(CH 2 )N(R')(R'), CON(R')(R'), -(CH2)2OR', -(CH 2 )OR', CH 2 CN, optionally substituted phenyl or phenoxy, N(R')(R'), -NR'C(O)OR', -NR'C(O)R', -(CH 2 ) 2 N(R')(R'), or -(CH 2 )N(R')(R'); and WRW 5 is selected from hydrogen, -OH, NH 2 , CN, CHF 2 , NHR', N(R') 2 , -NHC(O)R', -NHC(O)OR', NHSO 2 R', -OR', CH 2 OH, CH2N(R') 2 , C(O)OR', SO 2 NHR', SO 2 N(R') 2 , or CH 2 NHC(O)OR'. Or, WRW 4 and WRWs taken together form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, 0, or S, wherein said ring is optionally substituted with up to three WRW substituents.

22. The compound according to claim 21, wherein: each of WRW 2 and WRw4 is independently selected from hydrogen, CN, CF 3 , halo, Cl-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, or phenyl, wherein said WRW 2 and WRW 4 is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , -SCF 3 , halo, -COOR', -COR', -O(CH 2 ) 2 N(R')(R'), O(CH 2 )N(R')(R'), -CON(R')(R'), -(CH 2 ) 2 0R', -(CH 2 )OR', optionally substituted phenyl, N(R')(R'), -NC(O)OR', -NC(O)R', -(CH 2 ) 2 N(R')(R'), or -(CH 2 )N(R')(R'); and -304- WRW 5 is selected from hydrogen, -OH, NH 2 , CN, NHR', N(R') 2 , -NHC(O)R', NHC(O)OR', NHSO 2 R', -OR', CH 2 OH, C(O)OR', SO 2 NHR', or CH 2 NHC(O)O-(R').

23. The compound according to claim 22, wherein: WRW 2 is a phenyl ring optionally substituted with up to three substituents selected from OR', -CF 3 , -OCF 3 , SR', S(O)R', SO 2 R', -SCF 3 , halo, CN, -COOR', -COR', O(CH 2 ) 2 N(R')(R'), -O(CH 2 )N(R')(R'), -CON(R')(R'), -(CH 2 ) 2 0R', -(CH 2 )OR', CH 2 CN, optionally substituted phenyl or phenoxy, -N(R')(R'), -NR'C(O)OR', -NR'C(O)R', (CH 2 ) 2 N(R')(R'), or -(CH2)N(R')(R'); WRW4 is C1-C6 straight or branched alkyl; and WRE is OH.

24. The compound according to claim 22, wherein each of WRW and WRW4 is independently selected from CF 3 , halo, CN, or C1-C6 straight or branched alkyl.

25. The compound according claim 24, wherein each of WRW 2 and WRW 4 is independently selected from optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, t butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2-(ethoxycarbonyl)-ethyl, 1,1-dimethyl-3-(t butoxycarbonyl-amino) propyl, or n-pentyl.

26. The compound according claim 25, wherein each of WRW 2 and WRw 4 is C1-C6 straight or branched alkyl.

27. The compound according to claim 21, wherein WRWs is selected from hydrogen, CHF 2 , NH 2 , CN, NHR', N(R') 2 , CH 2 N(R') 2 , -NHC(O)R', -NHC(O)OR', -OR', C(O)OR', or SO 2 NHR'.

28. The compound according to claim 21, wherein WRW5 is selected from hydrogen, NH 2 , CN, CHF 2 , NH(Cl-C6 alkyl), N(C1-C6 alkyl) 2 , -NHC(O)(C1-C6 alkyl), -CH 2 NHC(O)O(CI-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -OH, -O(C1-C6 alkyl), C(O)O(C1-C6 alkyl), CH 2 O(C1-C6 alkyl), or SO2NH 2 . -305-

29. The compound according to claim 28, wherein WRws is selected from -OH, OMe, NH 2 , -NHMe, -N(Me) 2 , -CH 2 NH 2 , CH 2 OH, NHC(O)OMe, NHC(O)OEt, CN, CHF 2 , CH 2 NHC(O)O(t-butyl), -O-(ethoxyethyl), -O-(hydroxyethyl), -C(O)OMe, or -SO 2 NH 2 .

30. The compound according to claim 21, wherein said compound has one, preferably more, or more preferably all, of the following features: a. WRW2 is hydrogen; b. WRW4 is C1-C6 straight or branched alkyl or monocyclic or bicyclic aliphatic; and c. WRWS is selected from hydrogen, CN, CHF 2 , NH 2 , NH(Cl-C6 alkyl), N(C1-C6 alkyl) 2 , -NHC(O)(Cl-C6 alkyl), -NHC(O)O(CI-C6 alkyl), -CH 2 C(O)O(Cl-C6 alkyl), -OH, -O(C1-C6 alkyl), C(O)O(C1-C6 alkyl), or SO 2 NH 2 .

31. The compound according to claim 21, wherein said compound has one, preferably more, or more preferably all, of the following features: a. WR is halo, Cl-C6 alkyl, CF 3 , CN, or phenyl optionally substituted with up to 3 substituents selected from C1-C4 alkyl, -O(C1-C4 alkyl), or halo; b. WRw4 is CF3, halo, C1-C6 alkyl, orC6-C1O cycloaliphatic; and c. WRw is OH, NH 2 , NH(C1-C6 alkyl), or N(C1-C6 alkyl).

32. The compound according to claim 19, wherein said compound has formula V-A-2: (WRw)m N Y-Rw N H V-A-2 wherein: Y is CH 2 , C(O)O, C(O), or S(O) 2 ; and m is 0-4. -306-

33. The compound according to claim 19, wherein said compound has fonula V-A-3: (WRw)m Rx-X-- H H (~ QRG) V-A-3 wherein: Q is W; RQ is RW; m is 0-4; and n is 0-4.

34. The compound according to claim 19, wherein said compound has formula V-A-4: 0 0 RX-X-- H H V-A-4.

35. The compound according to claim 19, wherein said compound has formula V-A-5: (WRw)m 0 0 R N N(R')2 Rx-X+ , H N H V-A-5 wherein: m is 0-4.

36. The compound according to claim 19, wherein said compound has formula V-A-6: -307- (WRW)m 0 0 <1 I I N H B V-A-6 wherein: ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of -Q-RQ; Q is W; RQ is Rw; m is 0-4; and n is 0-4.

37. The compound according to claim 36, wherein ring B is a 5-7 membered monocyclic, heterocyclic ring having up to 2 heteroatoms selected from 0, S, or N, optionally substituted with up to n occurrences of -Q-RQ.

38. The compound according to claim 36, wherein ring B is a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroatoms selected from 0, S, or N, optionally substituted with up to n occurrences of -Q-RQ.

39. The compound according to claim 36, wherein ring B is selected from N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazin-1-yl, pyrrolidin-1-yl, or 4-methyl-piperidin-1-yI, benzimidazol-2-yl, 5-methyl-furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridine-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxy-pyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-yl, 5-cyano-thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin 2-yl.

40. The compound according to claim 19, wherein said compound has formula V-B-1: -308- (RWW)m RX-X H N) H V-B-i wherein: one of Qi and Q3 is N(WRw) and the other of Q, and Q3 is selected from 0, S, or N(WRw); Q2 is C(0), CH 2 -C(O), C(O)-CH 2 , CH 2 , CH 2 -CH 2 , CF 2 , or CF 2 -CF 2 ; and in is 0-3.

41. The compound according to claim 40, wherein Q3 is N(WRw), wherein WRW is hydrogen, C1-C6 aliphatic, C(O)C1-C6 aliphatic, or C(0)OC1-C6 aliphatic.

42. The compound according to claim 41, wherein Q2 is C(O), CH 2 , CH 2 -CH 2 , and Qi is 0.

43. The compound according to claim 19, wherein said compound has formula V-B-2: (RwW)m Rws RW 3 0 0 W ~ H V-B-2 wherein: RwI is hydrogen or C1-C6 aliphatic; each of Rw 3 is hydrogen or C1-C6 aliphatic; or both RW 3 taken together form a C3-C6 cycloalkyl or heterocyclic ring having up to two heteroatoms selected from 0, S, or NR', wherein said ring is optionally substituted with up to two WRw substituents; and m is 0-4. -309-

44. The compound according to claim 43, wherein WRWI is hydrogen, Cl-C6 aliphatic, C(O)Cl-C6 aliphatic, or C(O)OC1-C6 aliphatic.

45. The compound according to claim 43, wherein each Rw 3 is hydrogen, CI-C4 alkyl; or both RW 3 taken together form a C3-C6 cycloaliphatic ring or 5-7 membered heterocyclic ring having up to two heteroatoms selected from 0, S, or N, wherein said cycloaliphatic or W1 heterocyclic ring is optionally substituted with up to three substitutents selected from WR .46. The compound according to claim 19, wherein said compound has formula V-B-3: (RwW)m 1-3 0 0 Rwl NI N-Q 4 Rx-X Rw ON.. H V-B-3 wherein: Q4 is a bond, C(O), C(0)0, or S(O)2; R71 is hydrogen or C1-C6 aliphatic; and m is 0-4.

47. The compound according to claim 19, wherein said compound has formula V-B-4: 0 0 (WRw)m N -3 Rx~X+ N I H H V-B-4 wherein: m is 0-4.

48. The compound according to claim 19, wherein said compound has formula V-B-5: -310- (WRW)m 0 0 - '0' 5 RX-X I H N H V-B-5 wherein: ring A 2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A 2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRw; and m is 0-4.

49. The compound according to claim 48, wherein ring A 2 is selected from: H H N N "/N 'S aa bb cc dd ' NN 0 \>. \> ee ff gg; wherein said ring is optionally substituted.

50. The compound according to claim 19, wherein said compound has formula V-B-5-a: G5 N N RX-X H H H V-B-5-a wherein: G 4 is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted C1-C6 aliphatic, aryl-C 1-C6 alkyl, or a phenyl, wherein G 4 is optionally substituted with up to 4 WRw substituents; wherein up to two methylene units of said C 1-C6 aliphatic or C1-C6 alkyl is - 311 - optionally replaced with -CO-, -CONR'-, -C02-, -OCO-, -NR'CO 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-.; G 5 is hydrogen or an optionally substituted C1-C6 aliphatic; wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRw

51. The compound according to claim 50, wherein G 4 is hydrogen, and G 5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C 1-C6 alkyl, halo, cyano, or CF 3 , and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-.

52. The compound according to claim 50, wherein G 4 is hydrogen, and G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH2 C (O)OMe, (CH 2 ) 2 -NHC(O)O-tert-But, or cyclopentyl.

53. The compound according to claim 50, wherein Gs is hydrogen, and G 4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C02-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-.

54. The compound according to claim 50, wherein G5 is hydrogen, and G4 is halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C(0)NH(CH 2 ) 2 -NMe 2 )-phenyl, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec butylaminocarbonyl, ethyl, t-butyl, or piperidin- 1 -ylcarbonyl.

55. The compound according to claim 1, wherein said compound is selected from Table 1.

56. A compound having formula A-I: -312- NH 2 G2 I 0 G G 3 A-I; or a salt thereof; wherein: GI is hydrogen, R', C(O)R', C(S)R', S(O)R', S(0) 2 R', Si(CH 3 ) 2 R', P(O)(OR') 3 , P(S)(OR') 3 , or B(OR') 2 ; G2 is halo, CN, CF 3 , isopropyl, or phenyl wherein said isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WRW, wherein W and Rw are as defined above for formula I and embodiments thereof; G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from WRw, wherein W and Rw are as defined above for formula I and embodiments thereof; provided that when Gi is methoxy, G3 is tert-butyl, then G2 is not 2-amino-4-methoxy-5-tert butyl-phenyl.

57. The compound according to claim 56, wherein: GI is hydrogen; G 2 is halo or isopropyl, wherein said isopropyl is optionally substituted with up to 3 substituents independently selected from R'; and G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R'.

58. The compound according to claim 57, wherein: G1 is hydrogen; G2 is halo, preferably fluoro; and G3 is a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from methyl, ethyl, propyl, or butyl. -313-

59. The compound according to claim 56, wherein: G, is hydrogen; G 2 is CN, halo, or CF 3 ; and G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G 3 is optionally substituted with up to 3 substituents independently selected from R'.

60. The compound according to claim 56, wherein: Gi is hydrogen; G2 is phenyl is optionally substituted with up to 3 substituents independently selected from -OC 1-C4 alkyl, CF 3 , halo, or CN; and G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R'.

61. The compound according to claim 56, wherein G3 is selected from optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

62. The compound according to claim 56, wherein G 3 is C3-C8 branched aliphatic chain.

63. A compound having formula A-II: G 5 H 2 N N H A-II; or a salt thereof, wherein: G4 is hydrogen, halo, CN, CF 3 , CHF 2 , C11 2 F, optionally substituted C1-C6 aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4 WRW substituents; G5 is hydrogen or an optionally substituted C1-C6 aliphatic; provided that both, G4 and Gs, are not simultaneously hydrogen; wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRW. -314-

64. The compound according to claim 63, wherein G 4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with Cl-C6 alkyl, halo, cyano, or CF 3 , and wherein up to two methylene units of said Cl -C6 aliphatic or Cl-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C02-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -S0 2 NR'-, NR'S0 2 -, or -NR'S0 2 NR'-.

65. The compound according to claim 63, wherein G4 is hydrogen, and G 5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH 2 C(O)OMe, (CH 2 ) 2 -NHC(O)O-tert-But, or cyclopentyl.

66. The compound according to claim 63, wherein G5 is hydrogen, and G4 is halo, CI-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with Cl-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-. 62. The compound according to claim 63, wherein G5 is hydrogen, and G 4 is halo, CF 3 , ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH 2 ) 2 -NMe 2 , 2 methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec butylaminocarbonyl, ethyl, t-butyl, or piperidin- 1 -ylcarbonyl.

68. A pharmaceutical composition comprising a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.

69. The composition according to claim 68, wherein said composition comprises an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti infective agent, an anti-inflammatory agent, CFTR modulator, or a nutritional agent.

70. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of formula (I): - 315 - R 1 0 0 R2 N ,Ari N R6 R4 R'5 or a phanmaceutically acceptable salt thereof, wherein: ArI is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar' has m substituents each independently selected from -VWRw; W is a bond or is an optionally substituted C I-C 6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -C0 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO-, -NR'-, -SO 2 NR'-, NR'SO 2 -, -NR'SO 2 NR'-; Rw is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; m is 0-5; each of R', R 2 , R', R 4 , and R 5 is independently -X-Rx; X is a bond or is an optionally substituted CI-C 6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, CONR'-, -CONR'NR'-, -C0 2 -, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -SO 2 NR'-, NR'S0 2 -, or -NR'SO 2 NR'-; Rx is independently R', halo, NO 2 , CN, CF 3 , or OCF 3 ; R 6 is hydrogen, CF 3 , -OR', -SR', or an optionally substituted Ci-s aliphatic group; R 7 is hydrogen or a C1. 6 aliphatic group optionally substituted with -X-RX; R' is independently selected from hydrogen or an optionally substituted group selected from a C1.Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully saturated monocyclic ring hvi 0-3 ieteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated blcy4ic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R' are taken together with the atom(s) to which they are bound to form an -316- optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

71. The method according to claim 70, wherein said ABC transporter is CFTR.

72. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, 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, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, said method comprising the step of administering to said patient an effective amount of a compound of formula I according to claim 70,

73. 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 formula (1) according to claim 70; (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof. -317-

74. The kit of claim 73, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and 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 formula (I).

75. The kit of claim 74, wherein the kit is used to measure the density of CFTR. -318 -