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A defect in this APPLICATIONS 5 gene causes mutations in CFTR resulting in Cystic Fibrosis ( " CF " ) , the most common fatal genetic disease in humans. The present patent application is a continuation of U . S . Cystic Fibrosis affects approximately one in every 2 , 500 infants in the United States. Within the general United States application Ser . No . 15 / 162 ,887 , filed May 24 , 2016 , which population , up to 10 million people carry a single copy of the is a continuation of U . S . application Ser . No. 14 / 532, 791 , 10 defective gene without apparent ill effects . In contrast, filed Nov . 4 , 2014 , which is a continuation of U . S . applica - 10 individuals with two copies of the CF associated gene suffer tion Ser . No. 14 /058 ,839 , filed Oct. 21, 2013 , which is a from the debilitating and fatal effects of CF, including continuation of U . S . application Ser . No . 12 /829 ,879 , filed chronic lung disease . Jul. 2 , 2010 , which is a divisional of U . S . application Ser . In patients with cystic fibrosis , mutations in CFTR endog No . 11 /786 , 001 , filed Apr. 9 , 2007, which claims the benefit 15 enously expressed in respiratory epithelia leads to reduced of priority under 35 U . S . C . $ 119 to U . S . provisional patent apical anion secretion causing an imbalance in ion and fluid application No . 60 /790 ,459 , filed on Apr. 7 , 2006 , all of transport . The resulting decrease in anion transport contrib which are incorporated herein by reference . utes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause TECHNICAL FIELD OF THE INVENTION 20 death in CF patients . In addition to respiratory disease , CF patients typically suffer from gastrointestinal problems and The present invention relates to modulators of ATP pancreatic insufficiency that, if left untreated , results in Binding Cassette (“ ABC ” ) transporters or fragments thereof, death . In addition , the majority of males with cystic fibrosis including Cystic Fibrosis Transmembrane Conductance are infertile and fertility is decreased among females with Regulator ( “ CFTR ” ) , compositions thereof and methods 25 cystic fibrosis . In contrast to the severe effects of two copies therewith . The present invention also relates to methods of of the CF associated gene , individuals with a single copy of treating ABC transporter mediated diseases using such the CF associated gene exhibit increased resistance to chol era and to dehydration resulting from diarrhea — perhaps modulators. explaining the relatively high frequency of the CF gene BACKGROUND OF THE INVENTION 30 within the population . Sequence analysis of the CFTR gene of CF chromosomes ABC transporters are a family of membrane transporter has revealed a variety of disease causing mutations (Cutting , proteins that regulate the transport of a wide variety of G . R . et al . ( 1990 ) Nature 346 : 366 - 369 ; Dean , M . et al . pharmacological agents , potentially toxic drugs, and xeno ( 1990 ) Cell 61 : 863: 870 ; and Kerem , B - S . et al. ( 1989) biotics, as well as anions. ABC transporters are homologous 35 Science 245: 1073 - 1080 ; Kerem , B - S et al . ( 1990 ) Proc . membrane proteins that bind and use cellular adenosine Natl . Acad . Sci. USA 87 :8447 - 8451) . To date , > 1000 disease triphosphate ( ATP ) for their specific activities . Some of causing mutations in the CF gene have been identified these transporters were discovered as multidrug resistance ( http : // www . genet . sickkids .on .ca /cftr / ) . The most prevalent proteins ( like the MDR1- P glycoprotein , or the multidrug mutation is a deletion of phenylalanine at position 508 of the resistance protein , MRP1) , defending malignant cancer cells 40 CFTR amino acid sequence , and is commonly referred to as against chemotherapeutic agents . To date , 48 ABC Trans - AF508 -CFTR . This mutation occurs in approximately 70 % porters have been identified and grouped into 7 families of the cases of cystic fibrosis and is associated with a severe based on their sequence identity and function . disease . ABC transporters regulate a variety of important physi - The deletion of residue 508 in AF508 -CFTR prevents the ological roles within the body and provide defense against 45 nascent protein from folding correctly . This results in the harmful environmental compounds . Because of this, they inability of the mutant protein to exit the ER , and traffic to represent important potential drug targets for the treatment the plasma membrane . As a result , the number of channels of diseases associated with defects in the transporter, pre - present in the membrane is far less than observed in cells vention of drug transport out of the target cell , and inter - expressing wild - type CFTR . In addition to impaired traf vention in other diseases in which modulation of ABC 50 ficking , the mutation results in defective channel gating . transporter activity may be beneficial. Together , the reduced number of channels in the membrane One member of the ABC transporter family commonly and the defective gating lead to reduced anion transport associated with disease is the CAMP / ATP -mediated anion across epithelia leading to defective ion and fluid transport. channel , CFTR . CFTR is expressed in a variety of cells ( Quinton , P . M . ( 1990 ) , FASEB J . 4 : 2709 - 2727 ) . Studies types, including absorptive and secretory epithelia cells , 55 have shown , however, that the reduced numbers of AF508 where it regulates anion flux across the membrane , as well CFTR in the membrane are functional, albeit less than as the activity of other ion channels and proteins . In epithelia wild -type CFTR . (Dalemans et al. ( 1991 ), Nature Lond . 354 : cells , normal functioning of CFTR is critical for the main 526 - 528 ; Denning et al. , supra ; Pasyk and Foskett ( 1995 ) , J . tenance of electrolyte transport throughout the body, includ - Cell. Biochem . 270 : 12347 -50 ) . In addition to AF508 ing respiratory and digestive tissue. CFTR is composed of 60 CFTR , other disease causing mutations in CFTR that result approximately 1480 amino acids that encode a protein made in defective trafficking, synthesis , and / or channel gating up of a tandem repeat of transmembrane domains , each could be up - or down - regulated to alter anion secretion and containing six transmembrane helices and a nucleotide bind - modify disease progression and /or severity . ing domain . The two transmembrane domains are linked by Although CFTR transports a variety of molecules in a large , polar, regulatory (R )- domain with multiple phos- 65 addition to anions, it is clear that this role ( the transport of phorylation sites that regulate channel activity and cellular anions ) represents one element in an important mechanism trafficking . of transporting ions and water across the epithelium . The US 10 , 239 , 867 B2 other elements include the epithelial Na + channel , ENC, ABC transporters by the ER machinery has been shown to Na + / 2C1 - / K + co - transporter , Nat - K + - ATPase pump and be the underlying basis not only for CF disease , but for a the basolateral membrane K + channels , that are responsible wide range of other isolated and inherited diseases. The two for the uptake of chloride into the cell . ways that the ER machinery can malfunction is either by loss These elements work together to achieve directional 5 of coupling to ER export of the proteins leading to degra transport across the epithelium via their selective expression dation , or by the ER accumulation of these defectivel and localization within the cell . Chloride absorption takes misfolded proteins ( Aridor M , et al. , Nature Med ., 5 ( 7 ) , pp place by the coordinated activity of ENaC and CFTR present 745 - 751 ( 1999 ); Shastry, B . S ., et al. , Neurochem . Interna on the apicalmembrane and the Nat - K + - ATPase pump and tional, 43 , pp 1 - 7 (2003 ) ; Rutishauser , J . , et al. , Swiss Med Cl- channels expressed on the basolateral surface of the cell. 10 Wkly , 132, pp 211- 222 ( 2002 ) ; Morello , J P et al. , TIPS , 21 , Secondary active transport of chloride from the luminal side pp. 466 -469 ( 2000 ) ; Bross P ., et al. , Human Mut. , 14 , pp . leads to the accumulation of intracellular chloride , which 186 - 198 ( 1999 )] . The diseases associated with the first class can then passively leave the cell via Cl- channels , resulting of ER malfunction are Cystic fibrosis (due to misfolded in a vectorial transport . Arrangement of Na + / 2C1- 7K + co - AF508 -CFTR as discussed above ) , Hereditary emphysema transporter, Na K + - ATPase pump and the basolateral 15 (due to al- antitrypsin ; non Piz variants ) , Hereditary membrane K + channels on the basolateral surface and CFTR hemochromatosis , Coagulation -Fibrinolysis deficiencies , on the luminal side coordinate the secretion of chloride via such as Protein C deficiency, Type 1 hereditary angioedema, CFTR on the luminal side. Because water is probably never Lipid processing deficiencies, such as Familial hypercho actively transported itself , its flow across epithelia depends lesterolemia , Type 1 chylomicronemia , Abetalipoproteine on tiny transepithelial osmotic gradients generated by the 20 mia , Lysosomal storage diseases, such as I- cell disease / bulk flow of sodium and chloride . Pseudo - Hurler, Mucopolysaccharidoses (due to Lysosomal In addition to Cystic Fibrosis , modulation of CFTR activ processing enzymes) , Sandhof/ Tay - Sachs (due to ity may be beneficial for other diseases not directly caused B -Hexosaminidase ) , Crigler -Najjar type II (due to UDP by mutations in CFTR , such as secretory diseases and other glucuronyl- sialyc - transferase ) , Polyendocrinopathy /Hyper protein folding diseases mediated by CFTR . These include , 25 insulemia , Diabetes mellitus ( due to Insulin receptor ) , Laron but are not limited to , chronic obstructive pulmonary disease dwarfism (due to Growth hormone receptor ) , Myleoperoxi (COPD ), dry eye disease , and Sjögren ' s Syndrome. dase deficiency , Primary hypoparathyroidism (due to Pre COPD is characterized by airflow limitation that is pro - proparathyroid hormone ), Melanoma (due to Tyrosinase ) . gressive and not fully reversible . The airflow limitation is The diseases associated with the latter class of ER malfunc due to mucus hypersecretion , emphysema, and bronchiolitis . 30 tion are Glycanosis CDG type 1 , Hereditary emphysema Activators of mutant or wild - type CFTR offer a potential ( due to al- Antitrypsin (PiZ variant ) , Congenital hyperthy treatment of mucus hypersecretion and impaired mucocili - roidism , Osteogenesis imperfecta (due to Type I, II, IV ary clearance that is common in COPD . Specifically , procollagen ) , Hereditary hypofibrinogenemia (due to increasing anion secretion across CFTR may facilitate fluid Fibrinogen ) , ACT deficiency (due to al- Antichymotrypsin ) , transport into the airway surface liquid to hydrate the mucus 35 Diabetes insipidus (DI ) , Neurophyseal DI ( due to Vasopves and optimized periciliary fluid viscosity . This would lead to sin hormone /V2 - receptor ), Neprogenic DI ( due to Aqua enhanced mucociliary clearance and a reduction in the porin II ), Charcot- Marie Tooth syndrome (due to Peripheral symptoms associated with COPD . Dry eye disease is char- myelin protein 22 ) , Perlizaeus -Merzbacher disease , neuro acterized by a decrease in tear aqueous production and degenerative diseases such as Alzheimer ' s disease (due to abnormal tear film lipid , protein and mucin profiles. There 40 BAPP and presenilins) , Parkinson ' s disease , Amyotrophic are many causes of dry eye , some of which include age , lateral sclerosis , Progressive supranuclear plasy, Pick ' s dis Lasik eye surgery , arthritis , medications, chemical/ thermal ease , several polyglutamine neurological disorders such as burns, allergies, and diseases , such as Cystic Fibrosis and Huntington , Spinocerebullar ataxia type I , Spinal and bulbar Sjögrens ' s syndrome. Increasing anion secretion via CFTR muscular atrophy , Dentatorubal pallidoluysian , and Myo would enhance fluid transport from the corneal endothelial 45 tonic dystrophy , as well as Spongiform encephalopathies , cells and secretory glands surrounding the eye to increase such as Hereditary Creutzfeldt - Jakob disease ( due to Prion corneal hydration . This would help to alleviate the symp - protein processing defect ), Fabry disease ( due to lysosomal toms associated with dry eye disease . Sjögrens ' s syndrome a - galactosidase A ) and Straussler- Scheinker syndrome (due is an autoimmune disease in which the immune system to Prp processing defect ) . attacks moisture - producing glands throughout the body, 50 In addition to up - regulation of CFTR activity , reducing including the eye, mouth , skin , respiratory tissue , liver, anion secretion by CFTR modulators may be beneficial for vagina, and gut. Symptoms , include, dry eye , mouth , and the treatment of secretory diarrheas, in which epithelial vagina , as well as lung disease . The disease is also associ- water transport is dramatically increased as a result of ated with rheumatoid arthritis , systemic lupus , systemic secretagogue activated chloride transport. The mechanism sclerosis , and polymyositis /dermatomyositis . Defective pro - 55 involves elevation of cAMP and stimulation of CFTR . tein trafficking is believed to cause the disease , for which Although there are numerous causes of diarrhea , the treatment options are limited . Modulators of CFTR activity major consequences of diarrheal diseases, resulting from may hydrate the various organs afflicted by the disease and excessive chloride transport are common to all , and include help to elevate the associated symptoms. dehydration , acidosis , impaired growth and death . As discussed above , it is believed that the deletion of 60 Acute and chronic diarrheas represent a major medical residue 508 in AF508 -CFTR prevents the nascent protein problem in many areas of the world . Diarrhea is both a from folding correctly , resulting in the inability of this significant factor in malnutrition and the leading cause of mutant protein to exit the ER , and traffic to the plasma death ( 5, 000 ,000 deaths/ year ) in children less than five years membrane . As a result , insufficient amounts of the mature old . protein are present at the plasma membrane and chloride 65 Secretory diarrheas are also a dangerous condition in transport within epithelial tissues is significantly reduced . In patients of acquired immunodeficiency syndrome (AIDS ) fact , this cellular phenomenon of defective ER processing of and chronic inflammatory bowel disease ( IBD ) . 16 million US 10 , 239 , 867 B2 travelers to developing countries from industrialized nations lipid processing deficiencies, such as familial hypercholes every year develop diarrhea , with the severity and number of terolemia , Type 1 chylomicronemia , abetalipoproteinemia , cases of diarrhea varying depending on the country and area lysosomal storage diseases , such as I -cell disease /pseudo of travel. Hurler, mucopolysaccharidoses , Sandhof / Tay - Sachs, Cri Diarrhea in barn animals and pets such as cows, pigs and 5 gler- Najjar type II , polyendocrinopathy /hyperinsulemia , horses, sheep , goats , cats and dogs, also known as scours , is diabetes mellitus , laron dwarfism , myleoperoxidase defi a major cause of death in these animals . Diarrhea can result ciency, primary hypoparathyroidism , melanoma, glycanosis from any major transition , such as weaning or physical CDG type 1 , hereditary emphysema, congenital hyperthy movement, as well as in response to a variety of bacterial or r oidism , osteogenesis imperfecta , hereditary hypofibrino viral infections and generally occurs within the first few 10 genemia , ACT deficiency , diabetes insipidus, neurophysiol, hours of the animal' s life . nephrogenic , Charcot -Marie Tooth syndrome, Perlizaeus The most common diarrhea causing bacteria is entero Merzbacher disease , neurodegenerative diseases such as toxogenic E -coli ( ETEC ) having the K99 pilus antigen . Alzheimer ' s disease, Parkinson ' s disease , amyotrophic lat Common viral causes of diarrhea include rotavirus and eral sclerosis , progressive supranuclear plasy, Pick 's dis coronavirus. Other infectious agents include cryptospo - 15 ease, several polyglutamine neurological disorders such as ridium , giardia lamblia , and salmonella , among others . Huntington , spinocerebullar ataxia type I , spinal and bulbar Symptoms of rotaviral infection include excretion of muscular atrophy, dentatorubal pallidoluysian , and myo watery feces, dehydration and weakness . Coronavirus tonic dystrophy, as well as spongiform encephalopathies, causes a more severe illness in the newborn animals , and has such as hereditary Creutzfeldt - Jakob disease , Fabry disease , a higher mortality rate than rotaviral infection . Often , how - 20 Straussler- Scheinker syndrome, COPD , dry - eye disease , and ever , a young animal may be infected with more than one Sjögren ' s disease . virus or with a combination of viral and bacterial microor ganisms at one time. This dramatically increases the severity DETAILED DESCRIPTION OF THE of the disease . INVENTION Accordingly , there is a need for modulators of an ABC 25 transporter activity , and compositions thereof, that can be I. Definitions used to modulate the activity of the ABC transporter in the cell membrane of a mammal. As used herein , the following definitions shall apply There is a need for methods of treating ABC transporter unless otherwise indicated . mediated diseases using such modulators of ABC transporter 30 The term “ ABC - transporter " as used herein means an activity. ABC - transporter protein or a fragment thereof comprising at There is a need for methods of modulating an ABC least one binding domain , wherein said protein or fragment transporter activity in an ex vivo cell membrane of a thereof is present in vivo or in vitro . The term “ binding mammal. domain ” as used herein means a domain on the ABC There is a need for modulators of CFTR activity that can 35 transporter that can bind to a modulator. See, e . g ., Hwang , be used to modulate the activity of CFTR in the cell T . C . et al. , J . Gen . Physiol. (1998 ) : 111 ( 3 ) , 477 - 90 . membrane of a mammal. The term “ CFTR ” as used herein means cystic fibrosis There is a need for methods of treating CFTR -mediated transmembrane conductance regulator or a mutation thereof diseases using such modulators of CFTR activity . capable of regulator activity , including, but not limited to , There is a need for methods ofmodulating CFTR activity 40 AF508 CFTR and G551D CFTR ( see, e . g ., http : // www . gen in an ex vivo cell membrane of a mammal. et . sickkids . on . ca / cftr /, for CFTR mutations ) . The term “ modulating ” as used herein means increasing SUMMARY OF THE INVENTION or decreasing , e . g. activity , by a measurable amount. Com pounds that modulate ABC Transporter activity , such as It has now been found that compounds of this invention , 45 CFTR activity , by increasing the activity of the ABC Trans and pharmaceutically acceptable compositions thereof, are porter, e . g ., a CFTR anion channel, are called agonists . useful as modulators of ABC transporter activity , particu Compounds that modulate ABC Transporter activity , such as larly CTFR activity. These compounds have the general CFTR activity , by decreasing the activity of the ABC formula 1: Transporter, e . g . , CFTR anion channel, are called antago 50 nists . An agonist interacts with an ABC Transporter, such as CFTR anion channel, to increase the ability of the receptor to transduce an intracellular signal in response to endog enous ligand binding . An antagonist interacts with an ABC Transporter, such as CFTR , and competes with the endog N 55 enous ligand ( s ) or substrate ( s ) for binding site ( s ) on the n (R2 ) receptor to decrease the ability of the receptor to transduce Ri an intracellular signal in response to endogenous ligand binding. The phrase " treating or reducing the severity of an ABC or a pharmaceutically acceptable salt thereof , wherein Ri, 60 Transporter mediated disease ” refers both to treatments for R2, ring A , ring B , and n are defined below . diseases that are directly caused by ABC Transporter and / or These compounds and pharmaceutically acceptable com - CFTR activities and alleviation of symptoms of diseases not positions are useful for treating or lessening the severity of directly caused by ABC Transporter and / or CFTR anion a variety of diseases, disorders, or conditions, including , but channel activities . Examples of diseases whose symptoms not limited to , cystic fibrosis , hereditary emphysema, heredi - 65 may be affected by ABC Transporter and / or CFTR activity tary hemochromatosis , coagulation - fibrinolysis deficiencies, include , but are not limited to , Cystic fibrosis , Hereditary such as protein C deficiency , Type 1 hereditary angioedema , emphysema, Hereditary hemochromatosis , Coagulation - Fi US 10 , 239 , 867 B2 brinolysis deficiencies, such as Protein C deficiency , Type 1 cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl , hereditary angioedema, Lipid processing deficiencies , such (alkoxyaryl ) alkyl , ( sulfonylamino ) alkyl (such as ( alkyl as Familial hypercholesterolemia , Type 1 chylomicronemia , SO2- amino ) alkyl) , aminoalkyl, amidoalkyl , ( cycloaliphatic ) Abetalipoproteinemia , Lysosomal storage diseases , such as alkyl, or haloalkyl. I -cell disease /Pseudo -Hurler , Mucopolysaccharidoses, 5 As used herein , an “ alkenyl” group refers to an aliphatic Sandhof/ Tay - Sachs, Crigler- Najjar type II , Polyendocrin carbon group that contains 2 - 8 ( e . g . , 2 - 12 , 2 - 6 , or 2 - 4 ) opathy /Hyperinsulemia , Diabetes mellitus, Laron dwarfism , carbon atoms and at least one double bond . Like an alkyl Myleoperoxidase deficiency, Primary hypoparathyroidism , group , an alkenyl group can be straight or branched . Melanoma, Glycanosis CDG type 1 , Hereditary emphy - Examples of an alkenyl group include, but are not limited to sema, Congenital hyperthyroidism , Osteogenesis imper - 10 allyl, isoprenyl, 2 -butenyl , and 2 -hexenyl . An alkenyl group fecta , Hereditary hypofibrinogenemia , ACT deficiency , Dia - can be optionally substituted with one or more substituents betes insipidus (DI ) , Neurophysiol DI, Nephrogenic DI, such as halo , phospho , cycloaliphatic [ e . g. , cycloalkyl or Charcot- Marie Tooth syndrome, Perlizaeus -Merzbacher dis cycloalkenyl ], heterocycloaliphatic [ e . g ., heterocycloalkyl ease , neurodegenerative diseases such as Alzheimer 's dis or heterocycloalkenyl] , aryl, heteroaryl, alkoxy, aroyl, het ease, Parkinson ' s disease , Amyotrophic lateral sclerosis , 15 eroaroyl, acyl [ e. g ., (aliphatic )carbonyl , (cycloaliphatic )car Progressive supranuclear plasy , Pick ' s disease , several poly - bonyl, or (heterocycloaliphatic carbonyl] , nitro , cyano , glutamine neurological disorders such as Huntington , Spi amido [ e . g ., ( cycloalkylalkyl ) carbonylamino , arylcarbo nocerebullar ataxia type I, Spinal and bulbar muscular nylamino , aralkylcarbonylamino , (heterocycloalkyl ) carbo atrophy, Dentatorubal pallidoluysian , and Myotonic dystro - nylamino , (heterocycloalkylalkyl ) carbonylamino , het phy, as well as Spongiform encephalopathies, such as 20 eroarylcarbonylamino , heteroaralkylcarbonylamino Hereditary Creutzfeldt- Jakob disease , Fabry disease , alkylaminocarbonyl, cycloalkylaminocarbonyl , heterocy Straussler -Scheinker syndrome, COPD , dry -eye disease, and cloalkylaminocarbonyl, arylaminocarbonyl, or heteroary Sjogren ' s disease . laminocarbonyl] , amino [ e . g . , aliphaticamino , cycloaliphati For purposes of this invention , the chemical elements are camino , heterocycloaliphaticamino , or identified in accordance with the Periodic Table of the 25 aliphaticsulfonylamino ) , sulfonyl [ e . g . , alkyl- S0 - , Elements , CAS version , Handbook of Chemistry and Phys - cycloaliphatic - S02 – , or aryl -S02 – ) , sulfinyl, sulfanyl , ics, 75th Ed . Additionally , general principles of organic sulfoxy , urea, thiourea , sulfamoyl, sulfamide, oxo , carboxy , chemistry are described in “ Organic Chemistry " , Thomas carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, ary Sorrell , University Science Books , Sausolito : 1999 , and loxy , heteroaryloxy , aralkyloxy , heteroaralkoxy , alkoxycar “ March ' s Advanced Organic Chemistry ” , 5th Ed ., Ed . : 30 bonyl, alkylcarbonyloxy , or hydroxy. Without limitation , Smith , M . B . and March , J. , John Wiley & Sons, New York : some examples of substituted alkenyls include cyanoalk 2001, the entire contents of which are hereby incorporated enyl, alkoxyalkenyl , acylalkenyl, hydroxyalkenyl, aralk by reference . enyl , (alkoxyaryl ) alkenyl, ( sulfonylamino )alkenyl ( such as As described herein , compounds of the invention may (alkyl - SO2- amino )alkenyl ) , aminoalkenyl, amidoalkenyl, optionally be substituted with one or more substituents , such 35 (cycloaliphatic ) alkenyl, or haloalkenyl . as are illustrated generally above , or as exemplified by As used herein , an “ alkynyl" group refers to an aliphatic particular classes, subclasses , and species of the invention . carbon group that contains 2 - 8 ( e . g . , 2 - 12 , 2 - 6 , or 2 - 4 ) As used herein the term “ aliphatic ” encompasses the carbon atoms and has at least one triple bond . An alkynyl terms alkyl, alkenyl, alkynyl, each ofwhich being optionally group can be straight or branched . Examples of an alkynyl substituted as set forth below . 40 group include , but are not limited to , propargyl and butynyl. As used herein , an “ alkyl” group refers to a saturated An alkynyl group can be optionally substituted with one or aliphatic hydrocarbon group containing 1 - 12 ( e . g . , 1 - 8 , 1 - 6 , more substituents such as aroyl, heteroaroyl, alkoxy , or 1 - 4 ) carbon atoms. An alkyl group can be straight or cycloalkyloxy , heterocycloalkyloxy , aryloxy , heteroaryloxy , branched . Examples of alkyl groups include , but are not aralkyloxy , nitro , carboxy , cyano , halo , hydroxy, sulfo , mer limited to , methyl , ethyl, propyl, isopropyl, butyl, isobutyl, 45 capto , sulfanyl ?e . g ., aliphaticsulfanyl or cycloaliphaticsul sec -butyl , tert - butyl, n - pentyl, n -heptyl , or 2 - ethylhexyl. An fanyl] , sulfinyl [ e . g ., aliphaticsulfinyl or cycloaliphaticsulfi alkyl group can be substituted ( i. e ., optionally substituted ) nyl ], sulfonyl [ e . g ., aliphatic -SO2 - , aliphaticamino - S02 - , with one or more substituents such as halo , phospho , cycloa - or cycloaliphatic -S02 – ), amido [ e. g ., aminocarbonyl, alky liphatic [ e . g . , cycloalkyl or cycloalkenyl] , heterocycloali - laminocarbonyl, alkylcarbonylamino , cycloalkylaminocar phatic [e .g ., heterocycloalkyl or heterocycloalkenyl] , aryl, 50 bonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbo heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ e. g ., (aliphatic ) nylamino , arylaminocarbonyl, arylcarbonylamino , carbonyl , ( cycloaliphatic )carbonyl , or (heterocycloaliphatic ) aralkylcarbonylamino , (heterocycloalkyl ) carbonylamino , carbonyl ], nitro , cyano , amido [e . g. , (cycloalkylalkyl ) carbo - (cycloalkylalkyl ) carbonylamino , heteroaralkylcarbo nylamino , arylcarbonylamino , aralkylcarbonylamino , nylamino , heteroarylcarbonylamino or heteroarylaminocar ( heterocycloalkyl) carbonylamino , ( heterocycloalkylalkyl ) 55 bonyl] , urea, thiourea, sulfamoyl , sulfamide, alkoxycarbo carbonylamino , heteroarylcarbonylamino , heteroaralkylcar- nyl, alkylcarbonyloxy, cycloaliphatic , heterocycloaliphatic , bonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, heteroaryl, acyl [ e . g . , ( cycloaliphatic )carbonyl or ( het heterocycloalkylaminocarbonyl, arylaminocarbonyl, or het erocycloaliphatic ) carbonyl] , amino [ e . g . , aliphaticamino ) , eroarylaminocarbonyl] , amino [ e. g. , aliphaticamino , cycloa - sulfoxy, oxo , carboxy, carbamoyl, (cycloaliphatic )oxy , (het liphaticamino , or heterocycloaliphaticamino ) , sulfonyl ?e . g . , 60 erocycloaliphatic )oxy , or (heteroaryl ) alkoxy . aliphatic - S02 – ) , sulfinyl, sulfanyl , sulfoxy, urea, thiourea , As used herein , an “ amido ” encompasses both “ aminocar sulfamoyl, sulfamide , oxo , carboxy, carbamoyl, cycloali - bonyl” and “ carbonylamino ” . These terms when used alone phaticoxy , heterocycloaliphaticoxy, aryloxy , heteroaryloxy, or in connection with another group refer to an amido group aralkyloxy , heteroarylalkoxy , alkoxycarbonyl, alkylcarbo - such as — N ( R ) C ( O ) - R ' or C ( O ) - N ( R + ) 2 , when nyloxy, or hydroxy . Without limitation , some examples of 65 used terminally , and C ( O ) - N ( R ) or — N ( R ) C substituted alkyls include carboxyalkyl ( such as HOOC - ( 0 ) — when used internally, wherein R * and R¥ are defined alkyl, alkoxycarbonylalkyl , and alkylcarbonyloxyalkyl) , below . Examples of amido groups include alkylamido (such US 10 , 239 ,867 B2 10 as alkylcarbonylamino or alkylaminocarbonyl) , (heterocy - that is substituted with an aryl group . " Aliphatic , ” “ alkyl, ” cloaliphatic ) amido , (heteroaralkyl ) amido , (heteroaryl ) and “ aryl” are defined herein . An example of an araliphatic amido , (heterocycloalkyl ) alkylamido , arylamido , aralky - such as an aralkyl group is benzyl . lamido , ( cycloalkyl) alkylamido , or cycloalkylamido . As used herein , an “ aralkyl ” group refers to an alkyl group As used herein , an " amino " group refers to — NR R 5 ( e .g . , a C - 4 alkyl group ) that is substituted with an aryl wherein each of R * and R is independently hydrogen , group . Both “ alkyl” and “ aryl” have been defined above . An aliphatic , cycloaliphatic , ( cycloaliphatic ) aliphatic , aryl , ara example of an aralkyl group is benzyl. An aralkyl is option liphatic , heterocycloaliphatic , (heterocycloaliphatic ) ali ally substituted with one or more substituents such as phatic , heteroaryl, carboxy , sulfanyl, sulfinyl, sulfonyl, ( ali aliphatic ?e . g . , alkyl, alkenyl, or alkynyl, including carboxy phatic )carbonyl , ( cycloaliphatic )carbonyl , ( (cycloaliphatic ) 10 alkyl , hydroxyalkyl , or haloalkyl such as trifluoromethyl] , aliphatic )carbonyl , arylcarbonyl, ( araliphatic )carbonyl , cycloaliphatic [e . g. , cycloalkyl or cycloalkenyl] , ( cycloalky ( heterocycloaliphatic )carbonyl , ( heterocycloaliphatic )ali - l ) alkyl , heterocycloalkyl , (heterocycloalkyl ) alkyl, aryl, het phatic )carbonyl , ( heteroaryl) carbonyl, or (heteroaraliphatic ) eroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, ary carbonyl, each of which being defined herein and being loxy, heteroaryloxy , aralkyloxy, heteroaralkyloxy, aroyl, optionally substituted . Examples of amino groups include 15 heteroaroyl, nitro , carboxy, alkoxycarbonyl, alkylcarbony alkylamino , dialkylamino , or arylamino . When the term loxy, amido [ e . g ., aminocarbonyl, alkylcarbonylamino , " amino ” is not the terminal group (e . g. , alkylcarbo cycloalkylcarbonylamino , ( cycloalkylalkyl) carbonylamino , nylamino ), it is represented by — NR — R has the same arylcarbonylamino , aralkylcarbonylamino , (heterocy meaning as defined above . cloalkyl) carbonylamino , (heterocycloalkylalkyl ) carbo As used herein , an “ aryl ” group used alone or as part of 20 nylamino , heteroarylcarbonylamino , or heteroaralkylcarbo a larger moiety as in “ aralkyl” , “ aralkoxy " , or " aryloxy - nylamino ) , cyano , halo , hydroxy , acyl, mercapto , alkyl” refers to monocyclic ( e . g . , phenyl) ; bicyclic ( e . g ., alkylsulfanyl, sulfoxy , urea, thiourea, sulfamoyl, sulfamide , indenyl, naphthalenyl , tetrahydronaphthyl, tetrahydroinde - oxo , or carbamoyl. nyl) ; and tricyclic (e . g ., fluorenyl tetrahydrofluorenyl , or As used herein , a “ bicyclic ring system ” includes 8 - 12 tetrahydroanthracenyl, anthracenyl) ring systems in which 25 ( e . g . , 9 , 10 , or 11 ) membered structures that form two rings , the monocyclic ring system is aromatic or at least one of the wherein the two rings have at least one atom in common rings in a bicyclic or tricyclic ring system is aromatic . The (e . g ., 2 atoms in common ) . Bicyclic ring systems include bicyclic and tricyclic groups include benzofused 2 -3 mem - bicycloaliphatics (e . g. , bicycloalkyl or bicycloalkenyl) , bered carbocyclic rings. For example , a benzofused group bicycloheteroaliphatics, bicyclic aryls, and bicyclic het includes phenyl fused with two or more C4-8 carbocyclic 30 eroaryls . moieties . An aryl is optionally substituted with one or more As used herein , a “ carbocycle ” or “ cycloaliphatic ” group substituents including aliphatic [ e .g . , alkyl, alkenyl, or alky encompasses a " cycloalkyl” group and a " cycloalkenyl” nyl ]; cycloaliphatic ; ( cycloaliphatic )aliphatic ; heterocycloa group , each of which being optionally substituted as set forth liphatic ; (heterocycloaliphatic )aliphatic ; aryl; heteroaryl; below . alkoxy ; ( cycloaliphatic )oxy ; (heterocycloaliphatic ) oxy ; ary - 35 As used herein , a “ cycloalkyl” group refers to a saturated loxy ; heteroaryloxy ; (araliphatic ) oxy ; (heteroaraliphatic ) carbocyclic mono - or bicyclic ( fused or bridged ) ring of oxy ; aroyl ; heteroaroyl; amino ; oxo ( on a non - aromatic 3 - 10 ( e . g ., 5 - 10 ) carbon atoms. Examples of cycloalkyl carbocyclic ring of a benzofused bicyclic or tricyclic aryl) ; groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclo nitro ; carboxy ; amido ; acyl [ e . g . , ( aliphatic ) carbonyl; ( cy hexyl, cycloheptyl, adamantyl, norbomyl, cubyl , octahydro cloaliphatic )carbonyl ; (( cycloaliphatic )aliphatic )carbonyl ; 40 indenyl, decahydro -naphthyl , bicyclo [ 3 .2 .1 ] octyl, bicyclo ( araliphatic )carbonyl ; (heterocycloaliphatic ) carbonyl; ( het [ 2 . 2 . 2 ] octyl , bicyclo [ 3 . 3 . 1 ] nonyl, bicyclo [ 3 . 3 . 2 . ] decyl, erocycloaliphatic ) aliphatic ) carbonyl ; or (heteroaraliphatic ) bicyclo [ 2 . 2 . 2 ] octyl, adamantyl, or (( aminocarbonyl) cy carbonyl] ; sulfonyl [ e . g ., aliphatic -S02 — or amino - S02 – ) ; cloalkyl) cycloalkyl . sulfinyl [ e . g ., aliphatic - S ( O ) or cycloaliphatic - S ( O ) ) ; A “ cycloalkenyl” group , as used herein , refers to a non sulfanyl [ e .g . , aliphatic - s — ] ; cyano ; halo ; hydroxy ; mer - 45 aromatic carbocyclic ring of 3 - 10 ( e . g . , 4 - 8 ) carbon atoms capto ; sulfoxy ; urea ; thiourea ; sulfamoyl; sulfamide ; or having one or more double bonds. Examples of cycloalkenyl carbamoyl. Alternatively , an aryl can be unsubstituted groups include cyclopentenyl , 1 , 4 - cyclohexa - di -enyl , cyclo Non - limiting examples of substituted aryls include heptenyl, cyclooctenyl, hexahydro - indenyl , octahydro haloaryl [ e . g . , mono -, di (such as p , m -dihaloaryl ) , and naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [ 2 . 2 . 2 ]octe ( trihalo )aryl ] ; ( carboxy ) aryl [ e. g. , (alkoxycarbonyl ) aryl, 50 nyl , or bicyclo [ 3. 3 . 1 ]nonenyl . ( ( aralkyl) carbonyloxy) aryl, and (alkoxycarbonyl ) aryl ]; cycloalkyl or cycloalkenyl group can be optionally ( amido ) aryl [ e . g ., (aminocarbonyl ) aryl, (( ( alkylamino )alkyl ) substituted with one or more substituents such as phosphor , aminocarbonyl) aryl, ( alkylcarbonyl) aminoaryl, Carylamin - aliphatic [ e . g . , alkyl, alkenyl, or alkynyl] , cycloaliphatic , ocarbonyl) aryl , and ( ( (heteroaryl ) amino )carbonyl ) aryl ] ; (cycloaliphatic ) aliphatic , heterocycloaliphatic , (heterocy aminoaryl [ e . g . , ( ( alkylsulfonyl) amino ) aryl or ( (dialkyl ) am - 55 cloaliphatic ) aliphatic , aryl, heteroaryl, alkoxy , (cycloalipha ino )aryl ] ; (cyanoalkyl ) aryl; (alkoxy )aryl ; ( sulfamoyl) aryl tic ) oxy, (heterocycloaliphatic )oxy , aryloxy, heteroaryloxy , [ e . g . , ( aminosulfonyl) aryl] ; ( alkylsulfonyl ) aryl; ( cyano ) aryl; ( araliphatic ) oxy, (heteroaraliphatic ) oxy, aroyl, heteroaroyl, (hydroxyalkyl ) aryl; ( alkoxy )alkyl ) aryl; (hydroxy )aryl , amino , amido [ e . g . , ( aliphatic ) carbonylamino , ( cycloaliphat (( carboxy )alkyl ) aryl; ( (( dialkyl ) amino )alkyl ) aryl ; ( ni- ic )carbonylamino , ( (cycloaliphatic )aliphatic )carbo troalkyl) aryl ; (( ( alkylsulfonyl ) amino )alkyl ) aryl; (( heterocy - 60 nylamino , Caryl) carbonylamino , (araliphatic )carbo cloaliphatic ) carbonyl) aryl; (( alkylsulfonyl) alkyl) aryl ; (cya - nylamino , (heterocycloaliphatic ) carbonylamino , noalkyl) aryl; (hydroxyalkyl )aryl ; (alkylcarbonyl ) aryl; (( heterocycloaliphatic ) aliphatic )carbonylamino , (het alkylaryl; (trihaloalkyl ) aryl ; p -amino - m - alkoxycarbo eroaryl) carbonylamino , or (heteroaraliphatic ) carbo nylaryl; p - amino - m -cyanoaryl ; p -halo - m - aminoaryl; or ( m nylamino ), nitro , carboxy ( e .g ., HOOC - , alkoxycarbonyl, (heterocycloaliphatic ) - o - ( alkyl) ) aryl. 65 or alkylcarbonyloxy ), acyl [ e. g ., ( cycloaliphatic ) carbonyl, As used herein , an “ araliphatic ” such as an “ aralkyl” (( cycloaliphatic ) aliphatic ) carbonyl, ( araliphatic ) carbonyl, group refers to an aliphatic group ( e . g ., a C1- 4 alkyl group ) (heterocycloaliphatic ) carbonyl, (( heterocycloaliphatic ) ali US 10 , 239 ,867 B2 12 phatic )carbonyl , or (heteroaraliphatic )carbonyl ] , cyano , are azetidinyl, pyridyl, 1H - indazolyl, furyl, pyrrolyl, thienyl, halo , hydroxy, mercapto , sulfonyl [ e . g . , alkyl- SO2 - and thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, iso aryl- S0 , – ], sulfinyl [ e. g ., alkyl- S (O ) - ], sulfanyl [ e. g ., quinolinyl, benzthiazolyl , xanthene , thioxanthene, phenothi alkyl- s — ], sulfoxy, urea , thiourea , sulfamoyl, sulfamide, azine , dihydroindole , benzo [ 1, 3 ]dioxole , benzo [b ] furyl, oxo , or carbamoyl. 5 benzo [ b ] thiophenyl, indazolyl , benzimidazolyl, benzthiaz As used herein , the term " heterocycle ” or “ heterocycloa olyl, puryl, cinnolyl , quinolyl, quinazolyl, cinnolyl, phthala liphatic ” encompasses a heterocycloalkyl group and a het zyl , quinazolyl, quinoxalyl, isoquinolyl, 4H - quinolizyl , erocycloalkenyl group , each of which being optionally sub - benzo - 1 , 2 , 5 - thiadiazolyl, or 1 , 8 - naphthyridyl . stituted as set forth below . Without limitation , monocyclic heteroaryls include furyl , As used herein , a “ heterocycloalkyl” group refers to a 10 thiophenyl, 2H -pyrrolyl , pyrrolyl, oxazolyl, thazolyl, imi 3 - 10 membered mono - or bicylic ( fused or bridged ) ( e . g ., 5 . dazolyl , pyrazolyl, isoxazolyl, isothiazolyl, 1 , 3 , 4 -thiadiaz to 10 -membered mono - or bicyclic ) saturated ring structure , olyl, 2H - pyranyl, 4 - H - pranyl, pyridyl , pyridazyl, pyrimidyl , in which one or more of the ring atoms is a heteroatom ( e . g ., pyrazolyl, pyrazyl, or 1 , 3 , 5 - triazyl. Monocyclic heteroaryls N , O , S , or combinations thereof) . Examples of a heterocy - are numbered according to standard chemical nomenclature . cloalkyl group include piperidyl, piperazyl , tetrahydropyra - 15 Without limitation , bicyclic heteroaryls include indolizyl, nyl, tetrahydrofuryl, 1 , 4 -dioxolanyl , 1 ,4 - dithianyl, 1 , 3 - di- indolyl, isoindolyl, 3H - indolyl , indolinyl , benzo [ b ] furyl, oxolanyl, oxazolidyl, isoxazolidyl , morpholinyl, benzo [ b ] thiophenyl, quinolinyl, isoquinolinyl, indolizinyl , thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, isoindolyl, indolyl, benzo [b ] furyl, bexo [b ] thiophenyl, inda octahydrothiochromenyl, octahydroindolyl, octahydropy - zolyl, benzimidazyl , benzthiazolyl, purinyl , 4H - quinolizyl , rindinyl, decahydroquinolinyl, octahydrobenzo [ b ] thio - 20 quinolyl, isoquinolyl , cinnolyl, phthalazyl , quinazolyl, qui pheneyl, 2 - oxa - bicyclo [ 2 . 2 . 2 ] octyl, 1 - aza - bicyclo [ 2 . 2 . 2 ] oc - noxalyl, 1 , 8 -naphthyridyl , or pteridyl. Bicyclic heteroaryls tyl, 3 -aza -bicyclo [ 3 . 2 . 1 ]octyl , and 2 , 6 -dioxa -tricyclo a re numbered according to standard chemical nomenclature . [ 3. 3 . 1 .09 . ? ] nonyl . A monocyclic heterocycloalkyl group can heteroaryl is optionally substituted with one or more be fused with a phenyl moiety to form structures, such as substituents such as aliphatic [ e. g ., alkyl, alkenyl, or alky tetrahydroisoquinoline , which would be categorized as het- 25 nyl] ; cycloaliphatic ; ( cycloaliphatic ) aliphatic ; heterocycloa eroaryls. liphatic ; (heterocycloaliphatic )aliphatic ; aryl; heteroaryl; A “ heterocycloalkenyl” group , as used herein , refers to a alkoxy ; ( cycloaliphatic )oxy ; ( heterocycloaliphatic ) oxy ; ary mono - or bicylic ( e . g ., 5 . to 10 -membered mono - or bicy - loxy ; heteroaryloxy ; (araliphatic ) oxy ; (heteroaraliphatic ) clic ) non -aromatic ring structure having one or more double oxy ; aroyl; heteroaroyl; amino ; oxo ( on a non -aromatic bonds, and wherein one or more of the ring atoms is a 30 carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroatom ( e . g ., N , O , or S ) . Monocyclic and bicyclic heteroaryl) ; carboxy ; amido ; acyl [ e . g ., aliphaticcarbonyl; heterocycloaliphatics are numbered according to standard (cycloaliphatic )carbonyl ; ( (cycloaliphatic )aliphatic )carbo chemical nomenclature. nyl; ( araliphatic ) carbonyl; (heterocycloaliphatic ) carbonyl; A heterocycloalkyl or heterocycloalkenyl group can be ( heterocycloaliphatic ) aliphatic ) carbonyl; or (heteroarali optionally substituted with one or more substituents such as 35 phatic ) carbonyl] ; sulfonyl [ e . g ., aliphaticsulfonyl or amino phosphor, aliphatic [ e . g ., alkyl, alkenyl , or alkynyl] , cycloa sulfonyl] ; sulfinyl [ e . g ., aliphaticsulfinyl] ; sulfanyl [ e . g ., liphatic , ( cycloaliphatic )aliphatic , heterocycloaliphatic , aliphaticsulfanyl] ; nitro ; cyano ; halo ; hydroxy ; mercapto ; (heterocycloaliphatic ) aliphatic , aryl, heteroaryl, alkoxy, ( cy - sulfoxy ; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. cloaliphatic )oxy , (heterocycloaliphatic )oxy , aryloxy , het- Alternatively, a heteroaryl can be unsubstituted . eroaryloxy, (araliphatic )oxy , (heteroaraliphatic )oxy , aroyl, 40 Non - limiting examples of substituted heteroaryls include heteroaroyl, amino , amido [ e. g ., (aliphatic )carbonylamino , (halo )heteroaryl [e .g ., mono - and di- ( halo )heteroaryl ] ; ( car ( cycloaliphatic ) carbonylamino , (( cycloaliphatic ) aliphatic ) boxy )heteroaryl [ e . g ., ( alkoxycarbonyl) heteroaryl ] ; cyano carbonylamino , (aryl ) carbonylamino , (araliphatic ) carbo heteroaryl; aminoheteroaryl [ e . g ., (( alkylsulfonyl) amino ) nylamino , (heterocycloaliphatic ) carbonylamino , ( (heterocy heteroaryl and ( ( dialkyl) amino )heteroaryl ] ; ( amido ) cloaliphatic ) aliphatic ) carbonylamino , (heteroaryl ) 45 heteroaryl [ e . g ., aminocarbonylheteroaryl, ( ( alkylcarbonyl) carbonylamino , or (heteroaraliphatic )carbonylamino ), nitro , amino )heteroaryl , ( (( ( alkyl ) amino )alkyl ) aminocarbonyl) carboxy [ e . g . , HOOC — , alkoxycarbonyl, or alkylcarbony - heteroaryl , ( ( (heteroaryl ) amino ) carbonyl) heteroaryl , loxy ], acyl [ e . g ., ( cycloaliphatic ) carbonyl, (( cycloaliphatic ) (( heterocycloaliphatic ) carbonyl )heteroaryl , and ( ( alkylcar aliphatic ) carbonyl, (araliphatic ) carbonyl, (heterocycloali - bonyl) amino )heteroaryl ] ; ( cyanoalkyl) heteroaryl; (alkoxy ) phatic )carbonyl , (( heterocycloaliphatic ) aliphatic )carbonyl , 50 heteroaryl; (sulfamoyl ) heteroaryl [e . g ., (aminosulfonyl ) het or (heteroaraliphatic ) carbonyl] , nitro , cyano , halo , hydroxy, eroaryl] ; ( sulfonyl) heteroaryl [ e . g ., ( alkylsulfonyl) mercapto , sulfonyl [ e. g ., alkylsulfonyl or arylsulfonyl] , heteroaryl] ; (hydroxyalkyl ) heteroaryl ; (alkoxyalkyl ) sulfinyl [ e . g ., alkylsulfinyl] , sulfanyl [ e . g ., alkylsulfanyl] , heteroaryl; (hydroxy )heteroaryl ; ( ( carboxy ) alkyl) heteroaryl ; sulfoxy, urea, thiourea , sulfamoyl, sulfamide , oxo , or car ( ( (dialkyl ) amino ) alkyl] heteroaryl ; (heterocycloaliphatic ) bamoyl. 55 heteroaryl; ( cycloaliphatic )heteroaryl ; (nitroalkyl ) het A “ heteroaryl” group , as used herein , refers to a mono eroaryl; (( ( alkylsulfonyl ) amino Jalkyl )heteroaryl ; ( ( alkylsul cyclic , bicyclic , or tricyclic ring system having 4 to 15 ring fonyl) alkyl) heteroaryl; ( cyanoalkyl) heteroaryl ; ( acyl) atoms wherein one ormore of the ring atoms is a heteroatom heteroaryl [ e . g . , (alkylcarbonyl ) heteroaryl ] ; (alkyl ) ( e . g . , N , O , S , or combinations thereof) and in which the heteroaryl, and ( haloalkyl) heteroaryl [ e . g ., monocyclic ring system is aromatic or at least one of the 60 trihaloalkylheteroaryl] . rings in the bicyclic or tricyclic ring systems is aromatic . A A " heteroaraliphatic ” ( such as a heteroaralkyl group ) as heteroaryl group includes a benzofused ring system having used herein , refers to an aliphatic group ( e . g ., a C1- 4 alkyl 2 to 3 rings. For example , a benzofused group includes group ) that is substituted with a heteroaryl group . “ Ali benzo fused with one or two 4 to 8 membered heterocy - phatic , ” “ alkyl, " and " heteroaryl ” have been defined above . cloaliphatic moieties ( e . g . , indolizyl , indolyl, isoindolyl, 65 A " heteroaralkyl” group , as used herein , refers to an alkyl 3H -indolyl , indolinyl, benzo [ b ] furyl, benzo [ b ]thiophenyl , group ( e . g ., a C -4 alkyl group ) that is substituted with a quinolinyl, or isoquinolinyl) . Some examples of heteroaryl heteroaryl group . Both “ alkyl” and “ heteroaryl ” have been US 10 , 239 , 867 B2 13 14 defined above . A heteroaralkyl is optionally substituted with As used herein , a “ sulfo ” group refers to S03H or one or more substituents such as alkyl ( including carboxy SO3R * when used terminally or - S ( O ) ; — when used alkyl, hydroxyalkyl , and haloalkyl such as trifluoromethyl) , internally . alkenyl, alkynyl, cycloalkyl, (cycloalkyl ) alkyl , heterocy As used herein , a “ sulfamide ” group refers to the structure cloalkyl, (heterocycloalkyl ) alkyl, aryl, heteroaryl, alkoxy , 5 — NR - S ( O ) 2 - NRÖR when used terminally and cycloalkyloxy , heterocycloalkyloxy, aryloxy , heteroaryloxy , — NRX _ S (O )2 - NRY — when used internally , wherein R ' , aralkyloxy , heteroaralkyloxy, aroyl, heteroaroyl, nitro , car R ' , and RZ have been defined above. boxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, As used herein , a “ sulfonamide ” group refers to the alkylcarbonylamino , cycloalkylcarbonylamino , ( cycloalky structure S ( O ) 2 - NR -* RY or NRX _ S (O ) 2 - R2 when lalkyl) carbonylamino , arylcarbonylamino , aralkylcarbo 10 used terminally ; or - S (O ) 2 - NR?— or NRX _ S (O ) 2 — nylamino , (heterocycloalkyl ) carbonylamino , (heterocy when used internally , wherein R *, R ’ , and R2 are defined above . cloalkylalkyl ) carbonylamino , heteroarylcarbonylamino , As used herein a " sulfanyl group refers to — S R when heteroaralkylcarbonylamino , cyano , halo , hydroxy , acyl, used terminally and S — when used internally , wherein R * mercapto , alkylsulfanyl, sulfoxy , urea , thiourea , sulfamoyl, 15 has been defined above . Examples of sulfanyls include sulfamide , oxo , or carbamoyl. aliphatic - S — , cycloaliphatic - s — , aryl - S — , or the like. As used herein , “ cyclic moiety ” and “ cyclic group ” refer As used herein a " sulfinyl” group refers to - S ( O ) - R * to mono -, bi- , and tricyclic ring systems including cycloa when used terminally and - S (O ) - when used internally , liphatic , heterocycloaliphatic , aryl, or heteroaryl, each of wherein R¥ has been defined above . Exemplary sulfinyl which has been previously defined . 20 groups include aliphatic - S ( O ) - , aryl- S ( O ) - , ( cycloali As used herein , a “ bridged bicyclic ring system ” refers to phatic (aliphatic ) )- S (O ) - , cycloalkyl- S (O ) - , heterocycloa a bicyclic heterocyclicaliphatic ring system or bicyclic l iphatic - S ( O ) - , heteroaryl - S ( O ) - , or the like. cycloaliphatic ring system in which the rings are bridged . As used herein , a " sulfonyl ” group refers to - S ( O ) 2 - R * Examples of bridged bicyclic ring systems include , but are when used terminally and - S ( O ) , — when used internally , not limited to , adamantanyl, norbornanyl, bicyclo [ 3 . 2 . 1 ] 25 wherein R has been defined above . Exemplary sulfonyl octyl, bicyclo [ 2 . 2 . 2 ] octyl, bicyclo [ 3 . 3 . 1 ]nonyl , bicyclo groups include aliphatic - S ( O ) 2 - , aryl- S ( O ) 2 - , ( cycloali [ 3 .2 .3 ]nonyl , 2 -oxabicyclo [ 2 .2 .2 ]octyl , 1 - azabicyclo [ 2 .2 . 2 ] phatic ( aliphatic )) - S ( O ) 2 - , cycloaliphatic -S ( O ) 2 , hetero octyl, 3 -azabicyclo [3 .2 .1 ]octyl , and 2 ,6 -dioxa - tricyclo cycloaliphatic -- ( 0 ) 2 heteroaryl- 2 , (cycloaliphatic [ 3 . 3 . 1 . 0 .3 , / Inonvl. A bridged bicyclic ring system can be ( amido (aliphatic ) ) ) - S ( O ) 2 - or the like . optionally substituted with one or more substituents such as 30 As used herein , a " sulfoxy ” group refers to 0 - 80 — alkyl ( including carboxyalkyl, hydroxyalkyl, and haloalkyl R * or - S0 – 0 - R " , when used terminally and O - S such as trifluoromethyl) , alkenyl, alkynyl, cycloalkyl, (cy ( 0 ) - or - S ( O ) 0 — when used internally , where R has cloalkyl ) alkyl, heterocycloalkyl, (heterocycloalkyl ) alkyl, been defined above . aryl, heteroaryl, alkoxy , cycloalkyloxy , heterocycloalky - 35 fluorineAs used chlorine herein , ,bromine a “ halogen or iodine ” or “. halo ” group refers to loxy , aryloxy , heteroaryloxy , aralkyloxy, heteroaralkyloxy, As used herein an " alkoxycarbonyl » which is enco aroyl, heteroaroyl, nitro , carboxy , alkoxycarbonyl, alkylcar - passed by the term carboxy , used alone or in connection with bonyloxy , aminocarbonyl, alkylcarbonylamino , cycloalkyl another group refers to a group such as alkyl- 0 _ C ( O ) - , carbonylamino , ( cycloalkylalkyl) carbonylamino , arylcarbo - As used herein , an “ alkoxyalkyl” refers to an alkyl group nylamino , aralkylcarbonylamino , (heterocycloalkyl ) 40 such as alkyl- O -alkyl - , wherein alkyl has been defined carbonylamino , (heterocycloalkylalkyl ) carbonylamino , above . heteroarylcarbonylamino , heteroaralkylcarbonylamino , As used herein , a " carbonyl” refer to - C ( O ) - , cyano, halo , hydroxy, acyl ,mercapto , alkylsulfanyl, sulfoxy, As used herein , an " oxo ” refers to = 0 . urea , thiourea , sulfamoyl, sulfamide , oxo , or carbamoyl. As used herein , the term “ phospho ” refers to phosphinates As used herein , an " acyl” group refers to a formyl group 45 and phosphonates . Examples of phosphinates and phospho or R * C ( O ) _ ( such as alkyl- C ( O ) - , also referred to as nates include — P ( O ) ( RP ) 2 , wherein RP is aliphatic , alkoxy, “ alkylcarbonyl” ) where R * and “ alkyl ” have been defined aryloxy , heteroaryloxy , ( cycloaliphatic ) oxy, ( heterocycloali previously . Acetyl and pivaloyl are examples of acyl groups . phatic oxy aryl, heteroaryl, cycloaliphatic or amino . As used herein , an “ aroyl ” or “ heteroaroyl” refers to an As used herein , an " aminoalkyl” refers to the structure aryl- C ( O ) - or a heteroaryl - C ( O ) — . The aryl and heteroaryl 50 (R $ ) 2N - alkyl- . portion of the aroyl or heteroaroyl is optionally substituted As used herein , a " cyanoalkyl” refers to the structure as previously defined . (NC ) -alkyl As used herein , an “ alkoxy ” group refers to an alkyl- 0 As used herein , a " urea ” group refers to the structure group where “ alkyl” has been defined previously . - NRY _ CO - NR 'R2 and a “ thiourea ” group refers to the As used herein , a " carbamoyl” group refers to a group 55 structure — NRY _ CS — NR ' R when used terminally and having the structure O CONR ' R or — NRY_ CO - NRY_ CO - NRY — or NRX CS - NRY — when used 0 - R2 , wherein R * and R ’ have been defined above and R2 internally , wherein R *, RY, and R2 have been defined above . can be aliphatic , aryl, araliphatic , heterocycloaliphatic , het- As used herein , a “ guanidine” group refers to the structure eroaryl, or heteroaraliphatic . - N = C ( N ( R + R ) ) N ( R ' R ) or — NRYC ( = NR NR * RY As used herein , a " carboxy” group refers to – COOH , 60 wherein R * and R have been defined above . - COOR , OC ( O ) H , OC ( O ) R " , when used as a termi- As used herein , the term “ amidino ” group refers to the nal group ; or — OC ( O ) - or C ( 0 ) 0 when used as an structure — C = (NRN ( R + R ) wherein R * and R¥ have internal group . been defined above . As used herein , a “ haloaliphatic " group refers to an In general, the term “ vicinal” refers to the placement of aliphatic group substituted with 1 - 3 halogen . For instance , 65 substituents on a group that includes two or more carbon the term haloalkyl includes the group CF3 . atoms, wherein the substituents are attached to adjacent As used herein , a “ mercapto ” group refers to — SH . carbon atoms. US 10 , 239 , 867 B2 15 16 In general, the term “ geminal ” refers to the placement of recognize, combinations of substituents envisioned by this substituents on a group that includes two or more carbon invention are those combinations that result in the formation atoms, wherein the substituents are attached to the same of stable or chemically feasible compounds. carbon atom . The phrase " stable or chemically feasible ,” as used herein , The terms " terminally ” and “ internally ” refer to the 5 refers to compounds that are not substantially altered when location of a group within a substituent. A group is terminal subjected to conditions to allow for their production , detec when the group is present at the end of the substituent not tion , and preferably their recovery, purification , and use for further bonded to the rest of the chemical structure . Car one or more of the purposes disclosed herein . In some boxyalkyl , i . e . , R ' O ( O ) C -alkyl is an example of a carboxy embodiments , a stable compound or chemically feasible group used terminally . A group is internalwhen the group is 10 compound is one that is not substantially altered when kept present in the middle of a substituent of the chemical at a temperature of 40° C . or less , in the absence ofmoisture structure . Alkylcarboxy ( e . g . , alkyl- C ( 0 ) 0 or alkyl- OC or other chemically reactive conditions, for at least a week . ( 0 ) ) and alkylcarboxyaryl ( e . g ., alkyl- C ( O ) O - aryl- or As used herein , an " effective amount" is defined as the alkyl- O (CO ) - aryl- ) are examples of carboxy groups used amount required to confer a therapeutic effect on the treated internally . 15 patient, and is typically determined based on age , surface As used herein , an “ aliphatic chain ” refers to a branched area , weight, and condition of the patient. The interrelation or straight aliphatic group ( e . g ., alkyl groups , alkenyl ship of dosages for animals and humans (based on milli groups , or alkynyl groups ). A straight aliphatic chain has the grams per meter squared of body surface ) is described by structure [CH , 1, – , where v is 1 - 12 . A branched aliphatic Freireich et al. , Cancer Chemother. Rep ., 50 : 219 ( 1966 ) . chain is a straight aliphatic chain that is substituted with one 20 Body surface area may be approximately determined from or more aliphatic groups. A branched aliphatic chain has the height and weight of the patient. See, e .g ., Scientific Tables , structure — [CQQ ], — where each Q is independently a Geigy Pharmaceuticals , Ardsley , N .Y ., 537 (1970 ). As used hydrogen or an aliphatic group ; however, shall be an herein , “ patient” refers to a mammal , including a human . aliphatic group in at least one instance . The term aliphatic Unless otherwise stated , structures depicted herein are chain includes alkyl chains, alkenyl chains, and alkynyl 25 also meant to include all isomeric ( e . g ., enantiomeric , diaste chains , where alkyl, alkenyl , and alkynyl are defined above . reomeric , and geometric (or conformational) ) forms of the The phrase " optionally substituted ” is used interchange structure ; for example , the R and S configurations for each ably with the phrase " substituted or unsubstituted .” As asymmetric center , ( Z ) and ( E ) double bond isomers, and ( Z ) described herein , compounds of the invention can optionally and ( E ) conformational isomers . Therefore , single stereo be substituted with one or more substituents , such as are 30 chemical isomers as well as enantiomeric , diastereomeric , illustrated generally above , or as exemplified by particular and geometric ( or conformational) mixtures of the present classes, subclasses, and species of the invention . As compounds are within the scope of the invention . Unless described herein , the variables R1, R2, and Rz, and other otherwise stated , all tautomeric forms of the compounds of variables contained in formulae described herein encompass the invention are within the scope of the invention . Addi specific groups, such as alkyl and aryl. Unless otherwise 35 tionally , unless otherwise stated , structures depicted herein noted , each of the specific groups for the variables R1, R2, are also meant to include compounds that differ only in the and Rz, and other variables contained therein can be option presence of one or more isotopically enriched atoms. For ally substituted with one or more substituents described example , compounds having the present structures except herein . Each substituent of a specific group is further option for the replacement of hydrogen by deuterium or tritium , or ally substituted with one to three of halo , cyano , oxo , alkoxy, 40 the replacement of a carbon by a 13C - or 14C - enriched hydroxy, amino , nitro , aryl, cycloaliphatic , heterocycloali - carbon are within the scope of this invention . Such com phatic , heteroaryl, haloalkyl, and alkyl. For instance , an pounds are useful, for example , as analytical tools or probes alkyl group can be substituted with alkylsulfanyl and the in biological assays, or as therapeutic agents . alkylsulfanyl can be optionally substituted with one to three Compounds of the present invention are useful modula of halo , cyano , oxo , alkoxy , hydroxy , amino , nitro , aryl , 45 tors of ABC transporters and are useful in the treatment of haloalkyl, and alkyl. As an additional example , the ABC transporter mediated diseases . cycloalkyl portion of a cycloalkyl carbonylamino can be optionally substituted with one to three of halo , cyano , II . Compounds alkoxy , hydroxy , nitro , haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent 50 A . Generic Compounds atoms, the two alkoxy groups can form a ring together with the atom ( s ) to which they are bound . The present invention relates to compounds of formula I In general , the term “ substituted ,” whether preceded by useful as modulators of ABC transporter activity : the term " optionally ” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a 55 specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indi cated , an optionally substituted group can have a substituent at each substitutable position of the group , and when more 60 than one position in any given structure can be substituted nR with more than one substituent selected from a specified group , the substituent can be either the same or different at every position . A ring substituent, such as a heterocy cloalkyl, can be bound to another ring , such as a cycloalkyl, 65 or a pharmaceutically acceptable salt thereof. to form a spiro - bicyclic ring system , e . g ., both rings share Riis - Z4R4, wherein each Z4 is independently a bond or one common atom . As one of ordinary skill in the art will an optionally substituted branched or straight C1-6 aliphatic US 10 , 239 ,867 B2 17 18 chain wherein up to two carbon units of Z4 are optionally atoms to which they are attached, form an optionally sub and independently replaced by CO , CS , stituted heterocycle . - CONR4 — — CONR4NR4 , C02 OCO — , n is 1 - 3 . - NR4C02 – , 0 , - NR “ CONR4 — , OCONR4 — , However, in several embodiments , when ring A is unsub _ NRANRA _ _ NRACO _ _ S _ _ SO _ _ SO — 5 stitutedhydrogen cyclopentyl , then ring, nB isis 1not , R ,2 -is ( tertbutyl 4 - chloro) indol , and- 5 - ylR ,, or18 - NR4 , SONR4 — , NR4S02 — , or ( 2 , 6 - dichlorophenyl( carbonyl ) ) - 3 -methyl - 1H - indol- 5 - yl; - NR4SO ,NR4 — . Each R4 is independently R4, halo , and when ring A is unsubstituted cyclopentyl , n is 0 , and R , - OH , — NH , - NO2, CN , or OCF3. Each R4 is is hydrogen , then ring B is not independently hydrogen , an optionally substituted aliphatic , an optionally substituted cycloaliphatic, an optionally sub - 1 stituted heterocycloaliphatic , an optionally substituted aryl, or an optionally substituted heteroaryl. R , is — ZPRs, wherein each ZP is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic 15 chain wherein up to two carbon units of ZP are optionally HN and independently replaced by C0 , CS — , - CONRB — — CONRBNRB , C02 OCO — , - NRBCO , – , 0 , - NRBCONRB , OCONRB , - NRNRB - , - NRBCO — , - S , - SO — , - 50 , – , 20 - NRB , SONRB NRPS02 — , or - NRPSO NRB — . Each R? is independently RB , halo , - OH , - NH2, - NO2, CN , CF3, or - OCF3. Each RB , or is independently hydrogen , an optionally substituted ali phatic , an optionally substituted cycloaliphatic , an option ally substituted heterocycloaliphatic , an optionally substi mo tuted aryl, or an optionally substituted heteroaryl. Alternatively , any two adjacent R , groups together with the atoms to which they are attached form an optionally sub - un20 stituted carbocycle or an optionally substituted heterocycle . OH . Ring A is an optionally substituted 3 -7 membered mono cyclic ring having 0 - 3 heteroatoms selected from N , O , and Ring B is a group having formula Ia : 35

la B . Specific Compounds R3 40 1. R , Group Riis Z4R4, wherein each Z4 is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic chain wherein up to two carbon units of Z4 are optionally and independently replaced by CO , CS — , mm 45 CONR4 — CONRANR4 — CO , OCO — , - NR4C0 4 , 0 % , - NRACONRA OCONR4 — , - NR4NRXM , NR “ CO , S - , - SO — , - S02 – , — NR4 — — SO , NR4 — — NRASO , — , or or a pharmaceutically acceptable salt thereof, wherein p is - NR4SO NR4 — . Each R4 is independently R4, halo , 0 - 3 and each Rz and R ' z is independently ZºR . , where 0 – OH , — NH2, — NO2, CN , or — OCF3. Each R4 is each Zº is independently a bond or an optionally substituted 50 independently hydrogen , an optionally substituted aliphatic , branched or straight C1-6 aliphatic chain wherein up to two an optionally substituted cycloaliphatic , an optionally sub carbon units of Zº are optionally and independently replaced stituted heterocycloaliphatic , an optionally substituted aryl, by CO — , CS — , - CONRCS , CONR NRCG , or an optionally substituted heteroaryl. - C02 - , - OCO — , - NRCC0 , - , - 0 , - NRCCO In several embodiments , R , is -- Z4R4, wherein each 24 NRC - OCONRC — , - NR NRC NRCO , » is independently a bond or an optionally substituted - S , SO , SO , — — NRC— , SO ,NRC , branched or straight C1- 6 aliphatic chain and each R4 is - NRC80 , — , or — NRCSO ,NRC — Each Rg is indepen - hydrogen . dently RC, halo , OH , NH2, - NO2, CN , or OCF3F . . In other embodiments , R , is -- Z4R4, wherein each Z4 is Each RC is independently hydrogen , an optionally substi- 6 a bond and each R , is hydrogen . tuted aliphatic , an optionally substituted cycloaliphatic , an Each R is independently ZPR5, wherein each zB is optionally substituted heterocycloaliphatic , an optionally independently a bond or an optionally substituted branched substituted aryl, or an optionally substituted heteroaryl. or straight C1- 6 aliphatic chain wherein up to two carbon Alternatively, any two adjacent R3 groups together with the units of ZB are optionally and independently replaced by atoms to which they are attached form an optionally sub - 65 CO , CS , CONRB , CONRBNRB , stituted carbocycle or an optionally substituted heterocycle . CO , OCO — NRPCO , — , 0 , NRP Furthermore, R '; and an adjacent R3 group, together with the CONRB — , OCONRB - , - NR NRB — , - NRPCO - , US 10 ,239 , 867 B2 19 20 S , SO , SO2 , NRB , SONRB , Each of Z1, Z2, Z3, Z4, and Zg is independently a bond , - NRBS0 , - , or NRBSO NRB — Each R? is indepen - CR , R ' , - , - C ( O ) - , - NR , — , or O — ; each R , is dently RB , halo , OH , - NH2, - NO2, CN , CF3, or independently ZPR3, wherein each Zº is independently a bind or an optionally substituted branched or straight C1- 6 - OCF3. Each RP is independently hydrogen , an optionally 5 aliphatic chain wherein up to two carbon units of ZP are substituted aliphatic , an optionally substituted cycloali - 5 optionally and independently replaced by CO — , - CS , phatic, an optionally substituted heterocycloaliphatic , an CONR ” — , - CO2 - , - OCO — . — NR ” CO — , - 04 , optionally substituted aryl, or an optionally substituted het NRDCONRD , OCONRD , NR NRD , eroaryl. Alternatively , any two adjacent R2 groups together - NRDCO . S . - SO . SO , — . - NRD , with the atoms to which they are attached form an optionally SO , NR ” , NRPS0 , - , or - NRPSONRD — . Each substituted carbocycle or an optionally substituted hetero - 10 R is independently RP , halo , OH , NH ,, - NO ,, CN , cycle , or an optionally substituted heteroaryl . CF3, or - OCF3. Each RD is independently hydrogen , an In several embodiments , R2 is an optionally substituted optionally substituted cycloaliphatic , an optionally substi aliphatic . For example , R2 is an optionally substituted tuted heterocycloaliphatic , an optionally substituted aryl, or branched or straight C1- 6 aliphatic chain . In other examples, an optionally substituted heteroaryl. Each R ' , is indepen R is an optionally substituted branched or straight C1- 6 alkyl 15 dently hydrogen , optionally substituted C1- 6 aliphatic , chain , an optionally substituted branched or straight Coco hydroxy , halo , cyano , nitro , or combinations thereof. Alter alkenyl chain , or an optionally substituted branched or natively , any two adjacent R , groups together with the atoms straight C2- 6 alkynyl chain . In alternative embodiments , R2 to which they are attached form an optionally substituted 3 - 7 is a branched or straight C1- 6 aliphatic chain that is option membered carbocyclic ring , such as an optionally substi ally substituted with 1 - 3 of halo , hydroxy , cyano , cycloali - 20 tuted cyclobutyl ring , or any two R , and R ', groups together with the atom or atoms to which they are attached form an phatic , heterocycloaliphatic , aryl, heteroaryl, or combina optionally substituted 3 - 7 membered carbocyclic ring or a tions thereof. For example , R , is a branched or straight C1- 6 heterocarbocyclic ring . alkyl that is optionally substituted with 1 - 3 of halo , hydroxyPAY , . In several other examples , two adjacent R2 groups form an cyano , cycloaliphatic , heterocycloaliphatic , aryl, heteroaryl?, 25 optionally substituted carbocycle . For example , two adja or combinations thereof. In still other examples , R2 is a 25 cent R2 groups form an optionally substituted 5 - 7 membered methyl, ethyl, propyl, butyl, isopropyl, or tert- butyl , each of carbocycle that is optionally substituted with 1 - 3 of halo , which is optionally substituted with 1 - 3 of halo , hydroxy, hydroxy , cyano , oxo , cyano , alkoxy , alkyl , or combinations cyano, aryl, heteroaryl, cycloaliphatic , or heterocycloali thereof. In another example , two adjacent R2 groups form a phatic . In still other examples , R , is a methyl, ethyl, propyl, 5 - 6 membered carbocycle that is optionally substituted with butyl, isopropyl, or tert -butyl , each of which is unsubsti - * 1 - 3 of halo , hydroxy , cyano , oxo , cyano , alkoxy , alkyl, or tuted . combinations thereof . In still another example , two adjacent In several other embodiments , R , is an optionally substi - R , groups form an unsubstituted 5 - 7 membered carbocycle . tuted branched or straight C1- 5 alkoxy . For example , R2 is a In alternative examples , two adjacent R2 groups form an C1- 5 alkoxy that is optionally substituted with 1 - 3 of optionally substituted heterocycle . For instance, two adja hydroxy , aryl, heteroaryl, cycloaliphatic , heterocycloali - 35 cent R2 groups form an optionally substituted 5 - 7 membered phatic , or combinations thereof. In other examples , R is a heterocycle having 1 - 3 heteroatoms independently selected methoxy , ethoxy, propoxy , butoxy , or pentoxy , each of from N , O , and S . In several examples, two adjacent R , which is optionally substituted with 1 - 3 of hydroxy , arvl. groups form an optionally substituted 5 - 6 membered het heteroaryl, cycloaliphatic , heterocycloaliphatic , or combina erocycle having 1- 2 oxygen atoms. In other examples, two tions thereof. 40 adjacent R2 groups form an unsubstituted 5 - 7 membered In other embodiments . R . is hydroxy . halo , or cyano . heterocycle having 1 - 2 oxygen atoms. In other embodi In several embodiments , R2 is ZPRs , and zB is inde ments , two adjacent R2 groups form a ring selected from : pendently a bond or an optionally substituted branched or straight C1- 4 aliphatic chain wherein up to two carbon units of zB are optionally and independently replaced by 45 XA1 - C (O ) , 0 , - S — , - S (O ) 2 - , or — NH — , and R , is RP , halo , OH , - NH2, — NO2, CN , CF3, or - OCF3, and RB is hydrogen or aryl. In several embodiments , two adjacent R2 groups form an optionally substituted carbocycle or an optionally substi- 50 tuted heterocycle . For example , two adjacent R2 groups form an optionally substituted carbocycle or an optionally sub XA2 stituted heterocycle , either of which is fused to the phenyl of formula I , wherein the carbocycle or heterocycle has for mula Ib :

XA3

- 25 US 10, 239, 867 B2 21 | 22 -continued -continued XA4 XA12 &

10 XA5 XA13 WWW HA

SS e

XA6 XA14

25

XAT XA15

30 UUN 35 XAS WWW XA16 & 41 ??&*4 XA XA17 45

? NH c 30 Med OHS XA10 Med XA10 XA18 .

s 55 www

XA11 XA19 www 09

65 US 10 , 239 , 867 B2 23 24 - continued -continued XA20 XA4 and mm

XA21 10 XA5

In alternative examples , two adjacent R2 groups form an optionally substituted carbocycle or an optionally substi XA6 tuted heterocycle , and a third R2 group is attached to any chemically feasible position on the phenyl of formula I . For instance , an optionally substituted carbocycle or an option ni ally substituted heterocycle , both of which is formed by two adjacent R2 groups ; a third R2 group ; and the phenyl of 25 N formula I form a group having formula Ic :

XAT

ZZ 30

I

21, Z2, Z3, Z4, and Zz has been defined above in formula XAS Ib , and R , has been defined above in formula I . In several embodiments , each R2 group is independently selected from hydrogen , halo , - OCH3, OH , CH2OH , 40 - CH3, and OCF3, and/ or two adjacent R2 groups together with the atoms to which they are attached form

XA1 45 XA9

50 N mum XA2 XA10 55 mun nin XA3 60 XA11

man 65 nes US 10 , 239 , 867 B2 25 26 -continued - continued XA20 XA12 wm and

} A21 10 ** XA13

In other embodiments , R2 is at least one selected from hydrogen , halo , methoxy, phenylmethoxy , hydroxy , XA14 20 hydroxymethyl, trifluoromethoxy , and methyl. In some embodiments , two adjacent R2 groups, together with the atoms to which they are attached , form

25 XA1

XA15 30 www XA2

| 35 Aut XA16 40 3 . Ring A Ring A is an optionally substituted 3 -7 membered mono cyclic ring having 0 - 3 heteroatoms selected from N , O , and XA17 In several embodiments , ring A is an optionally substi 45 tuted 3 - 7 membered monocyclic cycloaliphatic . For 4*&&& example , ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl , each of which is optionally substituted with 1 - 3 of halo , hydroxy, C1- 5 aliphatic , or combinations thereof. Meo OH 50 In other embodiments , ring A is an optionally substituted 3 - 7 membered monocyclic heterocycloaliphatic . For XA18 example , ring A is an optionally substituted 3 - 7 membered monocyclic heterocycloaliphatic having 1 - 2 heteroatoms WWW independently selected from N , O , and S . In other examples, 55 ring A is tetrahydrofuran - yl, tetrahydro - 2H -pyran - yl, pyr rolidone - yl, or piperidine -yl , each of which is optionally substituted . In still other examples, ring A is selected from XA19 60 XB1 (R8 ) q

r

\ US 10 ,239 , 867 B2 27 28 - continued -continued XB2 XB12 ( Rg) a

HN

XB3

10 XB13 (Re ) a

XB4 (R8 ) ? 15

XB14 Rela 20 XB5 (RS

25 XB15 V ( Rea XB6

30

XB16 XB7 35 T148) HNV mm 40 XB17 XB8 s Rela HN ( RS)

45 XB18 XB9 (Rg )q

50

XB10 XB19 HN 55

VUM

XB11 60 XB20 HN HN

65 and US 10 ,239 , 867 B2 29 30 - continued - continued XB21 XC4 (Re ) ? wa

Each R , is independently - ZFR9, wherein each Ze is 10 In several embodiments , ring A is independently a bond or an optionally substituted branched or straight C1- 5 aliphatic chain wherein up to two carbon units of Z are optionally and independently replaced by - C0 — , - CS , CONRE — , - C02 - , - OCO , 15 - NRECO2 - , 0 , - NRECONRE , COCONRE , _ NRENR? _ , NRECO — , - S , - SO — , - S02 , - NRE , SONRE , NRFS0 - or - NRESOQNRE — , each R , is independently RE , - OH , 4 . Ring B - NH2, - NO2, CN , CF3 , Oxo , or - OCF3. Each RF is 20 Ring B is a group having formula Ia : independently hydrogen , an optionally substituted cycloali phatic, an optionally substituted heterocycloaliphatic , an optionally substituted aryl, or an optionally substituted het eroaryl. 25 q is 0 - 5. In other embodiments , ring A is one selected from (R3 ) XC1 30 or a pharmaceutically acceptable salt thereof, wherein p is 0 -3 . Each Rz and R 'z is independently - ZºRo, where each Zº XC2 35 .is Eachindependently R . , a bond or an optionally substituted branched or straight C1- 6 aliphatic chain wherein up to two carbon units of Z© are optionally and independently replaced by _ CO , CS , CONR , CONR NRC , 4020 - 002 - , OCO , NRCO2 - , 0 , - NRCCO NRC , OCONRC — , NR NRC - , - NRCO , XC3 - S — — SO , S0 , — — NRC SO NRC — , - NRC80 , — , or NRCSO NRC — . Each Ro is indepen dently RC, halo , OH , - NH2, - NO2, CN , or — OCF3 . 15. Each RC is independently hydrogen , an optionally substi tuted aliphatic , an optionally substituted cycloaliphatic , an XC4o optionally substituted heterocycloaliphatic , an optionally substituted aryl, or an optionally substituted heteroaryl. Alternatively , any two adjacent Rz groups together with the atoms to which they are attached form an optionally sub 50 stituted carbocycle or an optionally substituted heterocycle , or R ' z and an adjacent Rz, i .e . , attached to the 2 position of min the indole of formula la , together with the atoms to which XC5 they are attached form an optionally substituted heterocycle . 55 In several embodiments , ring B is min R3 XC6 60 (R3 ) p , (R3 ) p ,

65 minn and US 10 , 239 ,867 B2 32 - continued formula Ia . In several other examples, Rz is attached to the R3 2 or 3 position of the indole of formula Ia , and Rz is independently an optionally substituted aliphatic . For instance, Rz is an optionally substituted acyl group . In several instances , Rz is an optionally substituted ( alkoxy ) carbonyl. In other instances , R , is (methoxy ) carbonyl, (R3 ) p , or ( ethoxy ) carbonyl, (propoxy carbonyl, or (butoxy ) carbonyl , each of which is optionally substituted with 1- 3 of halo , hydroxy, or combinations thereof. In other instances , R , is 10 an optionally substituted ( aliphatic carbonyl. For example , R2 is an optionally substituted ( alkyl) carbonyl that is option ally substituted with 1 - 3 of halo , hydroxy, or combinations thereof. In other examples, Rz is (methyl ) carbonyl , (ethyl ) (R20 ) carbonyl, (propyl ) carbonyl , or (butyl ) carbonyl , each of 15 which is optionally substituted with 1 - 3 of halo , hydroxy , or y (R3 ) p - 1 combinations thereof. In several embodiments , Rz is an optionally substituted mu (cycloaliphatic )carbonyl or an optionally substituted (het erocycloaliphatic ) carbonyl. In several examples , R , is an 20 optionally substituted (C3 -7 cycloaliphatic )carbonyl . For example , R , is a ( cyclopropyl) carbonyl, ( cyclobutyl) carbo wherein q is 0 - 3 and each R20 is - ZºR21 , where each ZG nyl, (cyclopentyl ) carbonyl, (cyclohexyl ) carbonyl , or ( cyclo is independently a bond or an optionally substituted heptyl) carbonyl , each of which is optionally substituted with branched or straight C1- 5 aliphatic chain wherein up to two aliphatic , halo , hydroxy , nitro , cyano , or combinations carbon units of Zº are optionally and independently replaced 25 thereof. In several alternative examples , Rz is an optionally by — CO , - CS - CONRG - CO , — OCO , substituted (heterocycloaliphatic ) carbonyl . For example , Rz - NRCO , – , 0 , OCONR - , - NRNRO - , is an optionally substituted (heterocycloaliphatic carbonyl - NRCO , S , SO , SO , — , - NRG , having 1 -3 heteroatoms independently selected from N , O , - SONRG - NRCSO2 , orNR SO NRG — . Each and S . In other examples , R , is an optionally substituted R21 is independently RG, halo , OH , NH2, - NO2,| 30 (heterocycloaliphatic )carbonyl having 1- 3 heteroatoms - CN , or OCF3. Each R is independently hydrogen , an independently selected from N and O . In still other optionally substituted aliphatic , an optionally substituted examples, Rz is an optionally substituted 4 - 7 membered cycloaliphatic , an optionally substituted heterocycloali monocyclic (heterocycloaliphatic ) carbonyl having 1- 3 het phatic , an optionally substituted aryl, or an optionally sub eroatoms independently selected from N and O . Alterna stituted heteroaryl. 35 tively , Rz is (piperidine - 1 -yl , carbonyl, (pyrrolidine - 1 -yl ) For example , ring B is carbonyl , or (morpholine - 4 -yl ) carbonyl , (piperazine - 1 -yl ) carbonyl, each of which is optionally substituted with 1 -3 of halo , hydroxy , cyano , nitro , or aliphatic . In still other instances , Rz is optionally substituted ( ali 40 phatic ) amido such as ( aliphatic ( amino ( carbonyl) ) that is attached to the 2 or 3 position on the indole ring of formula Ia . In some embodiments , Rz is an optionally substituted (R3 ) p (R3 ) (alkyl ( amino ) ) carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia . In other embodiments , R2 45 is an optionally substituted straight or branched ( aliphatic ( amino ) ) carbonyl that is attached to the 2 or 3 position on the indole ring of formula Ia . In several examples , Rz is (N , N dimethylamino )) carbonyl , (methyl ( amino )) carbonyl, ( ethyl (amino ) ) carbonyl , (propyl ( amino ) carbonyl, (prop - 2 -yl 50 (amino ) )carbonyl , (dimethyl ( but - 2 -yl ( amino ) )) carbonyl , (R3 ) p , ( tertbutyl( amino ) carbonyl, (butyl ( amino ) )carbonyl , each of (R3 )p , or which is optionally substituted with 1 - 3 of halo , hydroxy , cycloaliphatic , heterocycloaliphatic , aryl, heteroaryl, or combinations thereof. 55 In other embodiments , Rz is an optionally substituted (alkoxy ) carbonyl. For example , Rz is methoxy( ) carbonyl, ( ethoxy )carbonyl , (propoxy ) carbonyl, or ( butoxy ) carbonyl, (R20 )a . each of which is optionally substituted with 1- 3 of halo , hydroxy , or combinations thereof. In several instances , R , is 60 an optionally substituted straight or branched C1- aliphatic . For example , Rz is an optionally substituted straight or NA branched C - , alkyl. In other examples , R , is independently an optionally substituted methyl, ethyl, propyl, butyl, iso propyl, or tertbutyl, each of which is optionally substituted 65 with 1 - 3 of halo , hydroxy, cyano , nitro , or combination In several embodiments , R ' z is hydrogen and R3 is thereof. In other embodiments , Rz is an optionally substi attached to the 2 , 3 , 4 , 5 , 6 , or 7 position of the indole of tuted C3- 6 cycloaliphatic . Exemplary embodiments include US 10 , 239 , 867 B2 33 34 cyclopropyl, 1- methyl -cycloprop - 1 - yl , etc . In other - continued examples, p is 2 and the two R , substituents are attached to the indole of formula Ia at the 2 , 4 - or 2 , 6 - or 2 , 7 -positions . Exemplary embodiments include 6 - F , 3 - (optionally substi tuted C1- 6 aliphatic or C3- 6 cycloaliphatic ); 7 -OMe - 2 - (- ( op - 5 tionally substituted C1- 6 aliphatic or C3- 6 cycloaliphatic ) ), 4F - 2- (optionally substituted C1- 6 aliphatic or C3- 6 cycloali min phatic ); 7 -CN - 2 - (optionally substituted C - aliphatic or C3- 6 PHAY F cycloaliphatic ); 7 -Me - 2 - ( optionally substituted C1- 6 ali phatic or C3- 6 cycloaliphatic ) and 7 -0Me - 2 -( optionally sub n

stituted C1- 6 aliphatic or C3- 6 cycloaliphatic ) . In In several embodiments, Rz is hydrogen . In several > instances , Rz is an optionally substituted straight or Ham H .to branched C1- 6 aliphatic . In other embodiments , Rz is an 15 optionally substituted C3- 6 cycloaliphatic . NH In several embodiments , Rz is one selected from : — H , _ CHZ, CH ,OH , CH ,CHZ , CH ,CH , OH , Hanim Ha Ha CH2CH2CH3, — NH2, halo , - OCH3, CN , CF3, C (O )OCH CHz, - S (O )2CH3 , CH2NH2, C (O )NH2 , - NH K . K .X nh . 25 tym N BbOH . thx OH ?? for the NH OH HifiH to HR

AU Hf themm HEYNH HE- NH22 Hota tilNH tre IZ N OH , thi tha tets O to the OEt te ?? Hit NH tomm to top US 10 , 239 ,867 B2 35 36 - continued substituted with up to 4 OH substituents . In another embodiment, Rº is hydrogen , or C -, alkyl optionally sub N stituted with up to 4 — OH substituents . For example , in many embodiments , R 'z is independently 5 - ZºRo, where each Zº is independently a bond or an mu optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of Z© are optionally and independently replaced by - C ( O ) - , - C ( O )NRC , C ( O ) O - , - NR°C ( O ) O - , - O - , - NRCS ( O ) 2 - , or 10 — NRC — . Each Ro is independently RC, - OH , or — NH . ZZ Each RC is independently hydrogen , an optionally substi tuted cycloaliphatic , an optionally substituted heterocycloa liphatic , or an optionally substituted heteroaryl. In one embodiment, each R© is hydrogen , C1- 6 aliphatic , or C3 -6 15 cycloaliphatic , wherein either of the aliphatic or cycloali phatic is optionally substituted with up to 4 - OH substitu ents . In another embodiment, R is hydrogen , or C - , alkyl optionally substituted with up to 4 — OH substituents . uy In other embodiments , R ' z is hydrogen or NH 20 R31 R322 25 OH wherein Rz? is H or a C1- 2 aliphatic that is optionally substituted with 1 - 3 of halo , OH , or combinations thereof. 30 R32 is - L - R33 , wherein L is a bond , — CH , — , - CH20 , OH CH NHS( O ) 2 - , CH2C ( O ) - , - CH2NHC ( O ) - , or CH _ NH — ; and R33 is hydrogen , or C1- 2 aliphatic , cycloa liphatic , heterocycloaliphatic , or heteroaryl, each of which is optionally substituted with 1 of OH , - NH2, or — CN . For 35 example , in one embodiment, R31 is hydrogen and R32 is C1- 2 aliphatic optionally substituted with — OH , - NH2, or - CN . OH VW CO2H In several embodiments , R 'z is independently selected and from one of the following : - H , CH3, CH2CH3, 40 - C ( O )CH3 , - CH2CH2OH , - C ( O )OCH3 , In another embodiment, two adjacent Rz groups form

45 ut KHm

50 OH In several embodiments , R 'z is independently - ZºR6 , CH2OH where each Zº is independently a bond or an optionally substituted branched or straight C1- 6 aliphatic chain wherein CH up to two carbon units of Zº are optionally and indepen dently replaced by C0 — , CS — , CONRC , CONR NRC , C0 , - , - OCO — , - NR°C0 , - , - O - , - NR CONR , OCONRC , - NR NRC - , NRCO , S , SO , S0 , - , - NRC , - SO NRC — , - NRCS02 — , or NRCSO NRC — . Each 60 Ro is independently RC, halo , OH , - NH2, - NO2, CN , NHCOCH3, or - OCF3. Each R© is independently hydrogen , an option CO2H ally substituted aliphatic , an optionally substituted cycloa min liphatic , an optionally substituted heterocycloaliphatic , or an W optionally substituted heteroaryl. In one embodiment, each 65 NHMe, omeOMe, RC is hydrogen , C1- 6 aliphatic , or C3- 6 cycloaliphatic , OH OH wherein either of the aliphatic or cycloaliphatic is optionally US 10 , 239 ,867 B2 37 38 - continued - continued OH OH , NH OH , OH NN ?? ?? NH2, ??

10 LOH,

H .

CONHMe, HO from me 20 NHCO2tBu , * NHSO Et, w wenn ?? OEt man OH 25 Win OH tityOH nh CONMe2,

NHCOMe, xyOH .to NH OH OH NH , NHSO Me , CO2H , ? " ? OH IZ OH th N NH and tretOH OH mi Y NHSO2Me, OH

NHCOMe, NHCO Me, 60 OH 5 . n Term NH , 65 n is 1 -3 . OH In several embodiments , n is 1 . In other embodiments , n is 2 . In still other embodiments , n is 3 . US 10 , 239 ,867 B2 39 C . Exemplary Compounds of the Present Invention Exemplary compounds of the present invention include , but are not limited to , those illustrated in Table 1 below . TABLE 1 gicaExemplary compounds of the present invention . DigestN

H US 10 , 239 , 867 B2 41 TABLE 1 -continued Exemplary compounds of the present invention .

Ho

geotIZ ???NH

?

AgrotN ow 10

setit 11

N OH OL01 TO US 10 , 239 , 867 B2 43 44 TABLE 1 -continued Exemplary compounds of the present invention .

xquatNH

=O

O= TH

0203N + 14

NH aquestaNH questF 15

16

2

17 US 10 , 239 , 867 B2 45 46 TABLE 1 - continued Exemplary compounds of the present invention .

18

19

XaletN it 30

NH x2404H 22 quotaNH 23

guatNH US 10 , 239 , 867 B2 47 48 TABLE 1 -continued Exemplary compounds of the present invention .

NH

25

gratN 26 LottoN

LU

967 28

QuoteOH 29 ??? N US 10 , 239 , 867 B2 49 50 TABLE 1 -continued Exemplary compounds of the present invention .

30

H 31

AquaN 32

NH

33

34

???? , 35 20 US 10 , 239 , 867 B2 5 ) TABLE 1 - continued Exemplary compounds of the present invention .

36 xat

NH ogrost 38

39 guestN scat .40

41 quosoN US 10, 239 , 867 B2 53 54 TABLE 1 - continued Exemplary compounds of the present invention .

HN

43

F

EN ogida 45 ????N US 10 , 239 , 867 B2 55 56 TABLE 1- continued Exemplary compounds of the present invention . giost 46 47

NH

48

Xezet 49 OEZ

H

N

zich 52 OlcottN NI US 10 , 239 , 867 B2 57 58 TABLE 1 -continued Exemplary compounds of the present invention .

54

NH

55

xoxoF

56

57 F4F ?????IZ US 10 , 239 ,867 B2 59 60 TABLE 1 - continued Exemplary compounds of the present invention .

58

59

quaNH postex 60 coroa 61 US 10 , 239 , 867 B2 61 62 TABLE 1 -continued Exemplary compounds of the present invention .

63

N paidat 64

IZ

65

St .66

etagoxHN US 10 , 239 , 867 B2 63 US10 ,239 ,867 B 64 TABLE 1 - continued Exemplary compounds of the present invention .

67 QuestN 68 H

borost 69

NH

????? 70

1

71 para 72 US 10 , 239 , 867 B2 65 66 TABLE 1- continued Exemplary compounds of the present invention . Domot 73 0604 74 HOH OH 75 grootC

76

00 77 Quat 78 QuestNH US 10 , 239 , 867 B2 67 68 TABLE 1 -continued Exemplary compounds of the present invention . 79 NH

NH

80 ogrosheH 81 82

Aquat 83

ON . H

HN US 10 , 239 , 867 B2 69 TABLE 1- continued Exemplary compounds of the present invention .

H 84

H .

H 85 NH

H H 86 N 2 IZ

87

N ogro 88

89 CofindtHN US 10, 239, 867 B2 11 TABLE 1 -continued Exemplary compounds of the present invention .

H

91

N ged 92

93 C US 10 , 239 , 867 B2 73 74 TABLE 1 -continued Exemplary compounds of the present invention . 94

95

OS- CEN questN loroN NH

100

? . Quest 101 Dicast " US 10 , 239 , 867 B2 75 TABLE 1 -continued Exemplary compounds of the present invention .

102 ?? 103 OzletN 104

??? 105 Comist 106 greitlette 107 US 10, 239, 867 B2 77 TABLE 1 - continued Exemplary compounds of the present invention .

108

HN "

?

109 Cauct? OH ? ? H ? 11 )

111

112 US 10 , 239 ,867 B2 79 80 TABLE 1 - continued Exemplary compounds of the present invention .

113

Xin 114 BuicySziastH 115

116

117

NH

118

HN US 10 , 239 , 867 B2 81 82 TABLE 1 -continued Exemplary compounds of the present invention . Quest 119 uith 120 121

H

122

HO 123

get 124 125

NH

126 OzostaZE US 10 , 239 , 867 B2 83 84 e TABLE 1 -continued US1020967 82 Exemplary compounds of the present invention . quos 127 128

LL giosts 129

130

N

Ozuci 131

DictZE 132

traiesti133

N US 10, 239 , 867 B2 85 86 TABLE 1 -continued Exemplary compounds of the present invention . ?? 134 135 H N

????? 136

L

137 H

138

H

139

H US 10 , 239 , 867 B2 87 88 theTABLE leading1 -continued US 10 .230 . 867 B2 - Exemplary compounds of the present invention .

140

141

142

143

L

N xat144 US 10 , 239 , 867 B2 89 US10 ,239 , 867 B2 90 e TABLE 1 - continued Exemplary compounds of the present invention .

145 IZ

Sect 146

Dzek 147 GuestIZ 148

giostyIZ NH

149

NH Olets 150

NH H

151

Borost 152 CoutNH US 10 , 239 , 867 B2 91 TABLE 1 -continued Exemplary compounds of the present invention . 153

H 154 giostIZ 155

Na Det 156 157

IZ

158

N US 10 , 239 , 867 B2 93 94 TABLE 1- continued Exemplary compounds of the present invention .

159

QuatN 160

N

161

162

F US 10, 239 , 867 B2 95 96 TABLE 1- continued Exemplary compounds of the present invention .

163

164

??????H -165 166

N US 10 , 239 ,867 B2 97 98 TABLE 1 -continued Exemplary compounds of the present invention . 167

NH

168

? .

Z

169 0 = S = 0 HN

Oct 170

IZ

Kuct 171 guastaNH 172

H US 10 , 239 , 867 B2 99 100 TABLE 1 -continued Exemplary compounds of the present invention . both 173 174

NH

Aquat 175 gios aquest 176 177

bota 178

H

xatN US 10, 239 , 867 B2 101 102 TABLE 1 - continued Exemplary compounds of the present invention . NH 179 ???

180 )

HN

181

LZ

0 182 ???N US 10 , 239 , 867 B2 103 104 TABLE 1 - continued Exemplary compounds of the present invention .

183

HN

184 withHN

F oft 185 186 giatH US 10 , 239 , 867 B2 105 106 TABLE 1 -continued Exemplary compounds of the present invention .

187

H 188

NH oglaste OH 189 HZ

N

190 tayoofestN . soike "191 H 192

NH N

Dicio 193

N ht US 10 , 239 , 867 B2 107 108 TABLE 1 -continued Exemplary compounds of the present invention . OH 194 H ? ?

IZ

195 oglasa 196 N

197

*???? 198

grostiN DO 199

EN US 10 , 239 , 867 B2 109 110 TABLE 1 - continued Exemplary compounds of the present invention .

200

NH

201

H

202 olehOH 203 tarafN? 204

qsadNH 205

N US 10 , 239 , 867 B2 111 112 TABLE 1 -continued Exemplary compounds of the present invention . 206

HNT

207

208

? .

209 N pusatN - 210

H US 10 , 239 , 867 B2 113 114 TABLETABLE levantana1 - continued OS10239 ,867 B2 Exemplary compounds of the present invention .

211 H

NH

212

N ograd 213

214

N

215

N

216 toolbatN US 10 , 239 , 867 B2 115 116 TABLE 1 -continued Exemplary compounds of the present invention . H 217

ZH

218

IZ 219 O = S = O

LZ ograf 220 ago? 221 222

OgulitNH 223 US 10 , 239 , 867 B2 117 118 TABLE 1 -continued Exemplary compounds of the present invention . 224 40 ZI + 225 226

NH Oziast 227

228

quote :229 para geces 230 231 que totH US 10 , 239 , 867 B2 119 120 TABLE 1 - continued Exemplary compounds of the present invention .

232

233

Xat 234

IZ

Ozzeriti 235

NH

236

LA

237

238 grasH US 10 , 239 , 867 B2 121 122 TABLE 1- continued Exemplary compounds of the present invention .

239 agiot

240

NH

241

NH

NH

242 Oy NH

Quat 243 SoftF US 10 , 239 , 867 B2 123 124 TABLE 1 - continued Exemplary compounds of the present invention .

244

N

245

N Beat 246 gicoNH 247 Qyt glosti248 249

NH

brostH 250 N esteNH US 10 , 239 , 867 B2 125 126 TABLE 1 -continued Exemplary compounds of the present invention . 251

guestNH 252 H

N

zit 253

NH drasti254 Boost H 255

N

256 H HI

NH Aqua 257 240pN 258 H US 10 , 239 , 867 B2 127 128 TABLE 1 - continued Exemplary compounds of the present invention .

259

ZZ

260

NH ??? 261

262

263 QuctN US 10 , 239 , 867 B2 129 130 TABLE 1 -continued Exemplary compounds of the present invention . 264

HN

+ 265 grat 266

glede 267 guest 268 giast - CEN 269

NH

270

NH US 10 , 239 , 867 B2 131 132 TABLE 1 -continued Exemplary compounds of the present invention .

271

HN

asoNH quot 272

273 .

AquatNH

2 274

O S equatHN US 10 , 239 ,867 B2 133 134 TABLE 1 -continued Exemplary compounds of the present invention . 275 OmSO

Ag5.N 84

276

ZIP

xezeroH 277 278 yostexIZ

279 US 10 , 239 , 867 B2 135 136 TABLE 1 - continued Exemplary compounds of the present invention .

280

xgloIZ 281 aquatN

282

O = S = 0 AgiatHN

283

HIV

IZ US 10 , 239 , 867 B2 137 138 TABLE 1 - continued Exemplary compounds of the present invention .

284

H 285 Hor

tara 286

287 O = S= 0 xatHOH US 10 , 239 , 867 B2 139 140 TABLE 1 -continued Exemplary compounds of the present invention .

H 288

NEC

289

H

ZI

290

F

NH

291 xogueraNH US 10 , 239 , 867 B2 141 142 TABLE 1 -continued Exemplary compounds of the present invention . 292 OSO ??

M 293

OSO

NH

294

NH squad 295 NEC Hy US 10, 239 , 867 B2 143 144 TABLE 1 -continued Exemplary compounds of the present invention . 296

297 ???? 298

N ??

?????? 299

IZ

8 300

IZ US 10 , 239 , 867 B2 145 146 TABLE 1 - continued Exemplary compounds of the present invention . xquat 301

302

Aqua OH 303

H F 304 x340 N +

H 305305

LZ US 10 , 239 , 867 B2 147 148 TABLE 1 -continued Exemplary compounds of the present invention . 306

HN

H

XOOHNH . III. Subgeneric Compounds of the Present -continued Invention 25 Another aspect of the present invention provides a com OH . pound that is useful for modulating ABC transporter activity . The compound has formula Ic:

30 Ic Another aspect of the present invention provides a com pound that is useful formodulating ABC transporter activity . The compound has formula Id : 35 n ( R ) Id

40 or a pharmaceutically acceptable salt thereof. Z R1, R2 , and ring Aare defined above in formula I , and ring nR B , Rz and p are defined in formula Ia . Furthermore , when RI ring A is unsubstituted cyclopentyl, n is 1 , R2 is 4 - chloro , and R , is hydrogen , then ring B is not 2 - (tertbutyl ) indol- 5 - 45 yl, or ( 2 , 6 - dichlorophenyl( carbonyl ) ) - 3 -methyl - 1H - indol- 5 - or a pharmaceutically acceptable salt thereof. yl; and when ring A is unsubstituted cyclopentyl , n is 0 , and R1, R2, and ring A are defined above in formula I , and ring R , is hydrogen , then ring B is not B , R3 and p are defined in formula Ia . However, when R , is H , n is 0 , ring A is an unsubstituted 50 cyclopentyl, and ring B is an indole - 5 -yl substituted with 1 - 2 of Rz, then each R , is independently — Z R , where each Zº is independently a bond or an unsubstituted branched or straight C1- 6 aliphatic chain wherein up to two carbon units of ZG are optionally and independently replaced by - CS - , HN 55 CONR NRG _ , CO , O?O , NRCO , 0 , - NR CONRGOCONRO - , - NR NRC - S - , - S0 , S02 — , - NRG , SO NRG , - NRCS02 - , or - NRCSO NRC — , each R12 is indepen dently RC, halo , OH , - NH2, - NO2, CN , or - OCF3 , 60 and each R is independently hydrogen , an unsubstituted aliphatic , an optionally substituted cycloaliphatic , an option ally substituted heterocycloaliphatic , an unsubstituted aryl, O or or an optionally substituted heteroaryl; or any two adjacent Rz groups together with the atomsto which they are attached 65 form an optionally substituted heterocycle . Furthermore , when R , is H , n is 1 , R , is 4 - chloro , ring A is an unsubsti tuted cyclopentyl , and ring B is an indole - 5 - yl substituted US 10 , 239 ,867 B2 149 with 1 - 2 of R3, then each Rz is independently - HR22 , 150 where each z is independently a bond or an unsubstituted IIb branched or straight C1- 3 aliphatic chain wherein up to two 22- 21 carbon units of ZH are optionally and independently replaced by CS — , - CONRHNRH, - C02 - , OCO — , - NR C02 , 0 , NRHCONRH — , - OCONRH — , 24- 25 NRHNRH — , S , SO — , - 80 , - , NRH — , SO NRH — , - NRHSO2 - , or - NRHSO NRH — , each R22 is independently RH , halo , OH , NH , NO2, 10 - CN , or OCF3, and each RH is independently hydrogen , a substituted C4 alkyl, an optionally substituted C2- 6 alkenyl, or a pharmaceutically acceptable salt thereof. an optionally substituted Coalkynyl, an optionally substi - R1, R2, and ring A , are defined above in formula I ; R2, R ' z , and p are defined above in formula Ia ; and Z . Z . , Z2, Za, and tuted C4 alkenyl , an optionally substituted C4 alkynyl, an 155 Z , are defined above in formula Ib . optionally substituted cycloaliphatic , an optionally substi Another aspect of the present invention provides a com tuted heterocycloaliphatic , an optionally substituted het - pound that is useful for modulating ABC transporter activity . eroaryl, an unsubstituted phenyl, or a mono - substituted The compound has formula IIc : phenyl, or any two adjacent R3 groups together with the atoms to which they are attached form an optionally sub IIC stituted heterocycle . (R2 ) n Another aspect of the present invention provides a com pound that is useful for modulating ABC transporter activity . The compound has formula II : 25 ? p (R3 ) 21 22- R' BE 30 or a pharmaceutically acceptable salt thereof. R1, R2 and n are defined above in formula I ; and R3, R 'z , and p are defined in formula Ia . 24 - 25 Another aspect of the present invention provides a com pound that is useful for modulating ABC transporter activity . Oogledp (R3 ) 35 The compound has formula IId : or a pharmaceutically acceptable salt thereof. Ild R1, R2, and ring A are defined above in formula I ; R3, R ' 3 , 40 and p are defined above in formula Ia ; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula Ib . Another aspect of the present invention provides a com pound that is useful for modulating ABC transporter activity . 45 (R3 ) o - 2 The compound has formula Ila : or a pharmaceutically acceptable salt thereof. Both R groups , together with the atoms to which they are IIa attached form a group selected from : 50 22mm 2 , XA1 - N R 24www 25 55 w Oggy p (Rg or a pharmaceutically acceptable salt thereof. .60 XA2 R1, R2, and ring A are defined above in formula I; Rz , R 's , and p are defined above in formula Ia ; and Z1, Z2, Z3, Z4, and Z , are defined above in formula Ib . Another aspect of the present invention provides a 65 compound that is useful for modulating ABC transporter activity . The compound has formula IIb : US 10, 239, 867 B2 151 152 -continued -continued XA3 XA11

10 & A4 XA12 WWW TE

XA5 20 XA13

--

25

XA6 XA14 wwww 30

35 XA7 XA15 & 41 XA8 XA16 45 www? ???? OS

XA XA17

C 55 HN

Meo XA10 XA18 st 60 www

65 ww US 10 ,239 , 867 B2 153 154 - continued -continued XA19

A CONHMe

XA20 10 and . .. the time OEt COH VU tmOH from XA21 NH2 CONMe2 OH sau 20 1 kmin hoan

HCOMe 25 themOH to R ' z is independently selected from one of the following : - H , CHz, - CH2CH3, - C ( O ) CH , CH2CH2OH , - C ( O )OCHz , CN 30 OH

NHSO2Me _ C02H fra KK 35 for tomOH

?? OH

OH to 40 the CH2OH

OH win CH2OH COH

45 OH NHSO2Me, nn OH to$ 50 tres , NHCOCH3 COH HC

OH

NHCO Me , NHMe OMe 55 tmOH tm tas OH NH 60 OH N OH N to the OH

OH , 65 JASTRITIBAfoto tyOH OH US 10 , 239 ,867 B2 155 156 -continued -continued

?? NH OH ?? 10 OH

HO FreniNHCO2tBu te to CNHSOEt 15 OH IZ

tree them .20 His the OH

25 Tikmn tota ZI www 30

M OH

w 35 tritOH .40 ty. the NH S IZ 45 OH

n trit and 50tet

CO H3, OH , tre 55 Han te to and each Rz is independently selected from — H , CHz, - CH2OH , CH2CH3 - CH2CH2OH , CH2CH2CH3, - NH - NH2, halo , OCH3, CN , CF3, - C ( O ) OCH' CH3CH39, 60 S (O )2CH3 , CH2NH2, C (O )NH2 ,

NH

65 R . Kmin . t . . * OH the OH , US 10 , 239 ,867 B2 157 158 -continued US10239367 82 -continued 145 tytty NH

ni OH

ty ". I OH If theOH semperor -OH and tely- NH to NH2 the to IV . Generic Synthetic Schemes N 25 win NH The compounds of formulae (I , Ic , Id , II , IIa , IIb , IIc , and til til Ild ) may be readily synthesized from commercially avail able or known starting materials by known methods. Exem vy plary synthetic routes to produce compounds of formulae (I , Ic , Id , II, IIa , IIb , IIc , and Ild ) are provided below in Schemes 1 -22 below . Preparation of the compounds of the invention is achieved by the coupling of a ring B amine with a ring A carboxylic OEt 35 acid as illustrated in Scheme 1.

O , Scheme 1 : 40 (R2 ) n (R2 ) n QuyoQHOH c , 45 na

50 (R2 )n

sob 55 ge

a) SOC12, DMF (cat . ) , DCM ; b ) R1 -N B ) , pyr. ; c ) R1 - N 60 HATU , TEA , DCM /DMF .

Referring to Scheme 1 , the acid la may be converted to NH 65 the corresponding acid chloride 1b using thionyl chloride in the presence of a catalystic amount of dimethylformamide . Reaction of the acid chloride with the amine US 10 , 239 ,867 B2 159 160 159 tetrakis (triphenylphosphine ) palladium ( 0 ) provides the ester 3b . Reduction of 3b with lithium aluminum hydride pro vides the alcohol 3c which is converted to the halide 3d with thionyl chloride. Reaction of 3d with sodium cyanide pro provides compounds of the invention I . Alternatively , the 5 vides the nitrile 2a . acid la may be directly coupled to the amine using known Other methods of producing the nitrile 2a are illustrated in coupling reagents such as , for example , HATU in the schemes 4 and 5 below . presence of triethylamine . Preparation of the acids la may be achieved as illustrated 10 in Scheme 2 . Scheme 4

Scheme 2 : CN

he Rn( Rn( N CI 4a 2a ( R2 ) 20

ons oorOH

b 25 (R2 ) (R2n OH 3c 3d (R2 ) n a ) TosMIC ; b ) NaBH4, THF ; c) SOCl2 ; d) NaCN 2b Scheme 5 a ) NaOH , BTEAC ; b ) NaOH , A 30 Br Olof ooa Referring to Scheme 2 , the nitrile 2a reacts with a suitable bromochloroalkane in the presence of sodium hydroxide and a phase transfer catalyst such as butyltriethylammonium 35 (R2 ) (R2 ) n chloride to provide the intermediate 2b . Hydrolysis of the 5a nitrile of 2b provides the acid la . In some instances, isola tion of the intermediate 2b is unnecessary . NC The phenylacetonitriles 2a are commercially available or may be prepared as illustrated in Scheme 3 . 40 (R2 ) n 2a Scheme 3 a ) NBS , AIBN , CCl4 ; b ) NaCN, EtOH CO2Me b 45 Preparation of (R2 ) ( R )

3a 50 R - 4B OH 50 components is illustrated in the schemes that follow . A (R2 ) n (R2 ) n number ofmethods for preparing ring B compounds wherein 55 30 3d ring B is an indole have been reported . See for example Angew . Chem . 2005 , 44 , 606 ; J . Am . Chem . Soc . 2005 , 127 , CN 5342 , ) ; J . Comb . Chem . 2005 , 7 , 130 ; Tetrahedron 2006 , 62 , 3439 ; J. Chem . Soc. Perkin Trans. 1, 2000 , 1045 . (R2 ) n 60 One method for preparing 2a a ) Pd (PPh3 )4 , CO ,MOH ; b ) LiAlH4, THF ; c ) SOCl2; d ) NaCN | 65 Referring to Scheme 3 , reaction of an aryl bromide 3a with carbon monoxide in the presence of methanol and is illustrated in Scheme 6 . US 10 , 239 ,867 B2 161 162 -continued Scheme 6 (R3p -1 NH2 R3 ONV NH2 ?? N H2N ZE (R3 ) p - 1 10 ( R3) p- 1 (R3 ) p - 1 6f 68 N -NH , by NH a ) NaNO2, HCl, SnCl2 ; b ) NaOH , R3CH2C ( O )R3 , EtOH ; c ) H3PO4, toluene; (R3 ) p -1 15 d ) H2, Pd - C , EtOH

ON Referring to Scheme 6 , a nitroaniline 6a is converted to 20 the hydrazine 6b using nitrous acid in the presence of HC1

?? , and stannous chloride . Reaction of 6b with an aldehyde or R3 ketone CH3C (O ) Rz provides the hydrazone 6c which on treatment with phosphoric acid in toluene leads to a mixture - 25 of nitro indoles 6d and 6e . Catalytic hydrogenation in the presence of palladium on carbon provides a mixture of the H (R3 ) p - 1 amino indoles 6f and 6g which may be separated using know 6d be methods such as, for example , chromatography . An alternative method is illustrated in scheme 7 .

Scheme 7

- R3 C NH2 R3 (R3 ) p -1 (R3 ) p - 1 N (R3 ) p - 1 Ta - (R3 ) p - 1 - - - R3

(R3 )p - 1 ON 7d - (R3 ) p -1 (R3 ) p - 1 R3 R3 ON H?N A

(R3 ) p -1 (R3 ) p -1 (R3 )p - 1

R3 NH - ON V NH , ON IZ ON ZT 7g 7h a ) R3& COCI , Et3N , CH2Cl2 ; b ) n -BuLi , THF ; c )- NaBH4, AcOH??? ; d ) KNO3, H2SO4 ; e ) DDQ , 1 , 4 -dioxane ; f) NaNO2 , HCI??, SnCl2•2H20 , H20 ; g ) MeCOR3, EtOH ; h ) PPA i) Pd/ C , EtOH or H2, Raney Ni, EtOH or MeOH US 10 , 239 ,867 B2 163 164 - continued Scheme 8 - COMET separation

ON NO2 ON DI NO2 NO2 NO2 CO2H COMET 10

NO2 NO Rz R3 ON NO2 NO 15 COMET

p ( R3) NO , a ) HNO3, H2SO4; b ) Me2NCHOMe) 2, DMF ; c ) H2, Raney Ni, EtOH 20 R3

HN Y Scheme 9 25 COEt Br by a ) HNO3, H2SO4; b ) SOCI2; EtOH ; c ) DMA, DMF; d ) Raney Ni, H2, MeOH NH2 plk p( R ) NH2 30 Br Scheme 11 (R3 ) p - 1 COMET O?N R?INH, 35 ? TMS

(R3 ) p - 1 40 _ C02Et

ON DIR ANH , ON “ NO2 ( R3 ) p - 1 EtO2C O?N p ( R3) CHO H?NH N 45 a ) NBS , DMF; b ) KNO3, H2SO4; c )HCFC - TMS, Pd (PPh3 ) 2Cl2, Cul, Et3N , toluene, H20 ; d ) Cul, DMF ; e )H2 , Raney Ni, MeOH HN ZI a ) DMA , DMF; b ) Raney Ni, H2, MOH 50

Scheme 10 NO2 Scheme 12 - CO2H CO2H Ss55 + NO2 R3 O2N NO , 60 CO2H COH _ N . Rz ON ON - NO2 'NO2 65 R3 US 10 , 239 ,867 B2 165 166 - continued R3 Scheme 14

5 U2 ZT N R3 07( R3) p- 1 - (07R3 ) p - 1

HN IZ N a ) R32CH2COR3b , AcOH , EtOH ; b ) H3PO4, toluene; c ) H2, Pd / C , EtOH (R3 ) p - 1 SOR

RD avanceramenteScheme 13 (R3 ) p - 1 (R3 ) p -1 (R3 ) p - 1 'SO2R RD

(R3 ) p -1 (R3 ) p - 1 VRn (R3 ) p - 1 SOR

PG PG IZ. (R3 )p - 1 (R3 ) p - 1 (R3 ) p - 1 Ru Ru RD

ON N ON (R3 ) p -1 (R3 ) p - 1 Rv (R3 )p - 1 09 RD 22h RD ON H2N # 40 ON ZI H?N a ) NaBH3CN ; b ) When PG = SO2Ph : PhSO2C1, Et3N , DMAP , CH2Cl2 ; (R3 ) p - 1 (R3 ) p - 1 When PG = Ac: ACCI, NaHCO3, CH2Cl2 ; c ) When Rº = RCO : (RCO ) 20 , AICI3 , CH2Cl2 ; When Rº =21 Br : AcOH ; d ) HBr or HCl; e- ) KNO3, H2SO40722; f) MnO2, CH2Cl2 a ) NaBH3CN ; b ) RSO2C1, DMAP , Et3N , CH2Cl2; c ) RPC ( O )CI , AIC13, CH2Cl2; d ) or DDQ , 1 ,4 -dioxane ; g ) H2, Raney Ni, EtOH . NaBH4 , THF ; e ) HBr; f ) KNO3, H2SO2; g ) MnO2; g ) MnO2; g ) Raney Ni, H2, EtOH

Scheme 15 (R3 ) p - 1 (R3 ) p- 1 (R3 ) p - 1 DJOO2N IZ HON N (R3 ) p -1 (R3 ) p - 1

ON H?N a ) R3X ( X = Br, I ), zinc triflate, TBAI, DIEA , toluene; b ) H2, Raney Ni, EtOH or H2, Pd / C , EtOH or SnCl2. 2H2O , EtOH ; c ) CISO2NCO , DMF, CH3CN US 10 , 239 ,867 B2 167 168 - continued Scheme 16 O2N Br

? NH2 02 - R3 (R3 ) p - 1 Br N R3 (R3 ) p - 1 Rza R3 15 ONTIRR3 wa NN ' R (R3 )pul R3Riz 20 02N a ) when X = Cl, Br, I, or OTs : R '3X , K2CO3, DMF, or CH3CN ; b ) H2, Pd/ C , EtOH or R3 - SnCl2. 2H2O , EtOH or SnCl2•2H2O , DIEA , EtOH . NH (R3 ) p -1 25 H2N Scheme 17 ON LZ a 30 a ) Br2 , AcOH ; b ) RC ( O )C1 , Et3N , CH2Cl2 ; c ) HC = CR3a Pd (PPh3 ) 2Cl2 , Cul, Et3N ; d ) TBAF , THF or tBuOK, DMF or Pd( PPh3 ) 2Cl2 , NH2 Cul , DMF; e ) H2, Pd / C , EtOH or SnCl2, MeOH or HCO2NH4 , Pd / C , EtOH (R3 ) p - 1

Scheme 18

ON ON b

NH2 F NH2 F NH2 R3 R3 R3

O2N. Rz ON. HN

NH N

ON HON .

RDO RDO a ) Br2 , AcOH , CHCl3 ; b )R3 & C = CH , Cul , Et3N , Pd (PPh3 )2Cl2 ; c ) RCOCI, Et3N , CH2Cl2; d ) TBAF-, DMF ; e ) Raney Ni, H2, MeOH ; f) ROK , DMF US 10 , 239 ,867 B2 169 170 -continued Scheme 19 H2N (R3 ) p - 1 -BB

R' 3 (R3 ) p - 1 a) H2NR '3 ; b) X = Br: Br2, HOAc; X = I: NIS ; c) HC = CR3, Pd( PPh3 )2Cl2 , OzNa Br 10 Cul, Et3N ; d ) Cul, DMF or TBAF , THF; e ) H2, Pd / C , EtOH or SnCl2 ,MeOH or HCO2NH4, Pd/ C , EtOH - NH2 ( R3) p - 1 Scheme 21 O2N . ("R3 ) p - 1 (R3 ) p - 1

ANH2 (R3 ) p - 1 (R3 ) p - 1 ON ON - Rz NH NHR 3 (R3 ) p - 1 ON Br HN . X NHR 3 (R3 ) p - 1 TMS a ) Br2, AcOH ; b ) HC = CR3a, Pd( PPh3 ) 2Cl2 , Cul, Et3N ; c )Pd (PPh3 )2Cl2 , Cul, DMF; d ) H2, Pd / C , EtOH or SnCl2 , MeOH or HCO2NH4, VON Pd / C , EtOH NHR 3 (R3 ) p -1 O2N Scheme 20 O2N ((R3 R3))p = -1 km H?N . (R3 ) p - 1 ( R3) p- 1 (R3 ) p - 1 R 2

NH 50 a ) R ' 3NH2, DMSO ; b ) Br2 , ACOH ; c ) TMS - CECH , (R3 ) p -1 CuI, TEA, Pd (PPh3 )2Cl2 ; d ) Cul, DMSO ; e ) Raney Ni, H2, MOH

(R3 ) p - 1 O2N 55 Scheme 22 Br NH NHR' ; 60 (R ) ON . (R3 ) p - 1 . - R3 e

65 NHR 3 US 10 , 239 ,867 B2 171 172 - continued - continued HN - Rz (R3 ) p - 1 (R3 ) p - 1 R '3 HN a ) SnCl2, EtOH or Pd/ C , HCO2NH4 or H2, Pd / C , EtOH or Raney Ni, H?, EtOH - R3 10 (R3 ) p- 1 R3 a ) R3& C = CH , CuI, TEA , Pd (PPh3 ) 2Cl2 ; b ) TBAF , THF ; c ) Raney Ni, MeOH Scheme 25 15 OH

(R3 ) p - 1 " NH2 Scheme 23 20 Br Y PPhPPh3Br Br NO2 NH2 (R3 ) p - 1 (R3 ) p - 1 25 (R3 MNH2) p -1 Br PPh3Br

( R3) p - 1

OEt (R3 ) p - 1 ?N

(R3 ) p - 1 CO Et (R3 ) p - 1 IZ (R3 ) p -1 ON - R3f I CO2Et (R3 ) p - 1 Boc (R3 ) p - 1 R HN Rf CO Et ( R3) p - 1 (R3 ) p - 1 Boc a ) NaBH4 , NiCl2, MeOH ; b ) RC (O ) Cl; c ) Pd( PPhz ) Cl2 , HC = C - R3, Cul, Et3N ; d ) tBuOK , DMF ; e ) KNO3, H2SO4; f ) NaBH4, NiCl , MeOH R g COMET Scheme 24 (R3 ) p - 1 R O2N O2NA

(R3 ) p - 1 7H (R3 ) p -1 US 10 , 239 ,867 B2 173 174 -continued - continued HN ON

OH (R3 ) p - 1 (R3 ) p - 1 N a) R '3 - X ; (X = Br, I, or OTs) , base (K2CO3 or Cs2CO3, DMF or CH3CN ; b ) H2, Pd / C , EtOH or Pd/ C , HCO NH4 R10

OH (R3 ) p - 1 Scheme 28 a ) PPh3 ,HBr ; b ) CI( 0 ) CCH CO2Et; c ) tBuOK ; d ) (Boc ) 20 , DMAP ; e ) KHMDS, R - X ; KHMDS , R - X ; f ) TFA ; g ) NaNO3, H2SO4; h ) LiAlH4, THF ; i) SnCl2, EtOH 15ON Y - R3 a (R3 ) p -1 20 Scheme 26 Ra LRb COMET 25 — R3 b (R3 ) p - 1 (R3 O2N . Ra Rb b 30 CO2H H N (R3 ) p -1 ZH 3p-1 Ra R3 02N Rb 35 (R3 ) p- 1 CA NRyRz (R3 ) p -1 a ) R3 X X = C1, Br , I ) , AIC13 , CH2Cl2 ; b ) Raney Ninon, H2, MeOH O2N . Rb 40 NRyRz ( R3) p - 1 H AT Scheme 29 Rb 45 O2N NRyZ (R3 ) p - 1 a) LiOH ; b ) EDC , HOBt, Et3N ,HNRyRz ; c) BHz — THF; d) if Rz = H , RC ( O )CI (ZERC ( O ) - ) or RSO2Cl ( Z = RSO2 - ) or RO ( CO )C1 ( R3) p -1 ( 2 = RO (CO ) - ) or (RO ) CO )) 20 (2 =DE Z = RO (CO ) - ) , Et3N , CH2Cl2 50 20 H2N

Scheme 27 55 (R3 ) p - 1 ON

Boc 60 (R3 ) p - 1 HON ON

(R3 ) p -1 NH bot(R3 ) p - 1 Riz :03 a ) HCI MOH ; PtO2, H2; b ) (Boc ) 20 , Et3N , THF 1970 US 10 ,239 , 867 B2 175 us 10296782 1 17676 Scheme 30

ON O2N . ON

HO2C RO2C OH

ON

0 = R3 NRyRz

NRyRz a ) NaOH or LiOH ; b ) ROH , HCl; c) NaBH4 or LiAlH4 or DIBAL - H , THF; d) HNRyRz , HATU , Et3N , ETOH or DMF; e) LiAlH4, THF or BHz•THF; f ) H2O2, H2O (Ry = Rz = H ) ; g ) H2, Pd / C

-continued Rb Scheme 31 Ra LOR 35 b . ON ON h Or Or Ra Rb NH 40 Rb OR Rb OH Ra Ra

45 Ra Rb Rb OH * Ra . - * - . H?N . - OR 50 Rb OR N Ra Rb Ra R3 a ) R , — X ; NaH ; R — X , NaH ; b ) PC15, CH2Cl2 ; c ) NaOH ; d ) NaNH2, DMSO ; O2N Br e ) CH2N2; f) Pd (PPh3 ) 4 , CuI, Et3N ; g ) RC (O )C1 , pyr, CH2Cl2 ; h ) 55 Pd (CH3CN ) 2Cl2 , CH3CN ; i) Raney Ni, H2, MeOH NH2 Rb Ra Scheme 32 OR 60 ON 09 (R2 ) n

- NH2 IZ US 10 , 239 ,867 B2 177 178 - continued177 Scheme 35 Rn( - 5 (R2 ) n OH

RI R3 NH Rn( 10 (R2 ) n ÖR, IZ. N - RO Rc 15 TZ a ) LiOH , THF /H20 ; b ) HNRyRz, HATU , TEA , DMF /CH2Cl2 RI R3

Scheme 33

OH

OR b ( R2 )n walioonRa i Ra Z

- stavea ) LiBH4, THFu / Hmo ) or LiAlHsana , THFna ; b ) R - umaLi, THF ZI OH - continued Scheme 34 40 (R2 ) n

ó RI R3 45 CH2R6 RiR3 oho oha(R2 ) 50 ( R ) RI R3 CH2R6 a ) NaBH3CN ; b ) RGCHO , NaHB ( OAc) 3 , TFA , DCE ; c ) chloranil or CDC13 , light or DDO RI R3

Scheme 36 NH2 chodoha60 (R2 ) n (R2 ) n R3 a ) NaNO2, ACOH /H20 ; b ) Zn , AcOHbhabhios O US 10 , 239 ,867 B2 179 180 - continued -continued

(R2 (R2 )

Ri R3 a ) NaH , DMF - THF ; R3 - X (X öhion = Cl, Br , I , or OTs ) blog

Scheme 37 (R2 ) n

(R2 ) n Ohoo : a ) NBS ; b ) Ar — B ( OR ) 2 , Pd -ohod FibreCat 1007 , K2CO3, EtOH Scheme 38 SOR (Rin

Ri R3 IZ

(R2 ) n

(R2 ) n Z R3 ZI ZH OH (R2 )

IZ

H ( R2 ) n

Z Ri R3 NH

(R2 ) n - N ? ?i K3 a ) RSO ,C1 , NaH , THF - DMF; b ) R2 - X ( X = Br , I , or OTS ) , NaH , TMFolid - DMF; c ) ethylene dioxide , InC13; d ) POC13, DMF ; e) H2N - OH , CH2Cly ; Ac20 US 10, 239, 867 B2 18118 182 Scheme 39

( R2 ) ( R2 ) RI R3 ? - K ! R3 ?

(R2 ) n ( R )

=2

R RI R3 OH

R - NRyRz a ) NaH , THF - DMF; epichlorohydrin ; b ) ROH ; c ) HNRyRz

Scheme 40

( R2 ) ( R2 )

| OH RI R3 OH

OH OTs

6)

( R2 ) ( R? ) ( R ) #1

RIR3 OH RIR3 OH RIRI OH CN N3 - NHR d -- - - ( R2 ) ( R? ) +7 ( R2)

- A-7 O R1R' OH ? RiR3 RIR3 OH - CO, H / NH NEN N- “a ) TsCI???, EtsN , CHCl) ; b ) NaCN , DMF ; c ) NaOH, MeOH; d) NaN3, NHCl??; e ) NaN , DMF; f) Pd / C , H2 , MeOH ( R = H ); h ) R°C ( 0 ) Ci ( Z??? = RYC( O ) ~ ) or RSOCI ( Z = RYSO) ~ ) or RYO( CO) C1 ( Z = RYO( CO) ~ ) or ( RYO( CO) )20 ( Z = RYO( CO) ~ ) , EtN , CHCl) US 10 , 239 ,867 B2 183 184 embodiments , these compositions optionally further com Scheme 41 prise one or more additional therapeutic agents . It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment , or ( R2 ) n where appropriate , as a pharmaceutically acceptable deriva tive or a prodrug thereof. According to the present invention , a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to , pharmaceutically acceptable RI R3 NH salts , esters , salts of such esters , or any other adduct or 10 derivative which upon administration to a patient in need is (R2 ) n capable of providing , directly or indirectly, a compound as otherwise described herein , or a metabolite or residue thereof . As used herein , the term “ pharmaceutically acceptable 15 salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity , irritation , allergic response and the like , and are commen surate with a reasonable benefit/ risk ratio . A “ pharmaceuti 20 cally acceptable salt” means any salt or salt of an ester of a (R2 othom ) compound of this invention that , upon administration to a recipient, is capable of providing , either directly or indi rectly , a compound of this invention or an inhibitorily active metabolite or residue thereof. R3 25 Pharmaceutically acceptable salts are well known in the art . For example , S . M . Berge , et al. describes pharmaceu tically acceptable salts in detail in J . Pharmaceutical Sci ences, 1977 , 66 , 1 - 19, incorporated herein by reference . Pharmaceutically acceptable salts of the compounds of this ( R2) n 30 invention include those derived from suitable inorganic and organic acids and bases . Examples of pharmaceutically acceptable , nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric RI R3 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 blog acid or malonic acid or by using other methods used in the NH2 art such as ion exchange. Other pharmaceutically acceptable salts include adipate , alginate , ascorbate , aspartate , benze ( R2 ) n 40 nesulfonate , benzoate , bisulfate , borate , butyrate , camphor ate , camphorsulfonate , citrate , cyclopentanepropionate , dig luconate , dodecylsulfate , ethanesulfonate , formate , fumarate , glucoheptonate , glycerophosphate , gluconate , RI R3 hemisulfate , heptanoate , hexanoate , hydroiodide , 2 -hy 45 droxy - ethanesulfonate , lactobionate , lactate , laurate , lauryl sulfate , malate, maleate , malonate , methanesulfonate , 2 - naphthalenesulfonate , nicotinate , nitrate , oleate , oxalate , NHZ palmitate , pamoate , pectinate , persulfate , 3 - phenylpropi a ) CICH CHO , NaHB (OAc )3 , CH2C1; CDC13, light ; b ) NaN3, Nal, DMF; c ) H2, Pd / C , onate , phosphate , picrate , pivalate , propionate , stearate , suc MeOH , AcOH ; d ) RC (O )CI (Z = RCO ) — ) or RSO2Cl (2 = RSO2 - ) or 50 cinate , sulfate , tartrate , thiocyanate , p - toluenesulfonate , RO( CO )CI ( Z = RO (CO ) — ) or (RO (CO ) O (2 = RO (CO ) — ) , Et3N , CH2Cl2 undecanoate , valerate salts , and the like . Salts derived from appropriate bases include alkali metal, alkaline earth metal, In the schemes above , the radical R employed therein is ammonium and N *C ( alkyl) . salts . This invention also a substituent, e . g . , RW as defined hereinabove . One of skill envisions the quaternization of any basic nitrogen -contain in the art will readily appreciate that synthetic routes suitable 55 ing groups of the compounds disclosed herein . Water or for various substituents of the present invention are such that oil- soluble or dispersible products may be obtained by such the reaction conditions and steps employed do not modify quaternization . Representative alkali or alkaline earth metal the intended substituents . salts include sodium , lithium , potassium , calcium , magne sium , and the like . Further pharmaceutically acceptable salts 60 include , when appropriate , nontoxic ammonium , quaternary V . Formulations , Administrations, and Uses ammonium , and amine cations formed using counterions such as halide, hydroxide, carboxylate , sulfate , phosphate , Accordingly , in another aspect of the present invention , nitrate , lower alkyl sulfonate and aryl sulfonate . pharmaceutically acceptable compositions are provided , As described above , the pharmaceutically acceptable wherein these compositions comprise any of the compounds 65 compositions of the present invention additionally comprise as described herein , and optionally comprise a pharmaceu - a pharmaceutically acceptable carrier, adjuvant, or vehicle , tically acceptable carrier , adjuvant or vehicle . In certain which , as used herein , includes any and all solvents , US 10 , 239 , 867 B2 185 186 diluents , or other liquid vehicle , dispersion or suspension Charcot- Marie Tooth syndrome, Perlizaeus- Merzbacher dis aids, surface active agents , isotonic agents , thickening or ease , neurodegenerative diseases such as Alzheimer' s dis emulsifying agents , preservatives , solid binders, lubricants ease, Parkinson ' s disease , Amyotrophic lateral sclerosis , and the like, as suited to the particular dosage form desired . Progressive supranuclear plasy , Pick ' s disease , several poly Remington ' s Pharmaceutical Sciences , Sixteenth Edition , E . 5 glutamine neurological disorders such as Huntington , Spi W . Martin (Mack Publishing Co . , Easton , Pa . , 1980 ) dis - nocerebullar ataxia type I , Spinal and bulbar muscular closes various carriers used in formulating pharmaceutically atrophy , Dentatorubal pallidoluysian , and Myotonic dystro acceptable compositions and known techniques for the phy , as well as Spongiform encephalopathies, such as preparation thereof. Except insofar as any conventional Hereditary Creutzfeldt -Jakob disease (due to Prion protein carrier medium is incompatible with the compounds of the 10 processing defect ) , Fabry disease , Straussler -Scheinker dis invention , such as by producing any undesirable biological ease , secretory diarrhea , polycystic kidney disease , chronic effect or otherwise interacting in a deleterious manner with obstructive pulmonary disease (COPD ) , dry eye disease , and any other component( s ) of the pharmaceutically acceptable Sjögren ' s Syndrome, comprising the step of administering composition , its use is contemplated to be within the scope to said mammal an effective amount of a composition of this invention . Some examples of materials which can 15 comprising a compound of formulae ( I, Ic , Id , II , IIa, IIb , IIc , serve as pharmaceutically acceptable carriers include, but and IId ) , or a preferred embodiment thereof as set forth are not limited to , ion exchangers , alumina , aluminum above . stearate , lecithin , serum proteins , such as human serum A ccording to an alternative preferred embodiment, the albumin , buffer substances such as phosphates, glycine , present invention provides a method of treating cystic fibro sorbic acid , or potassium sorbate , partial glyceride mixtures 20 sis comprising the step of administering to said mammal a of saturated vegetable fatty acids, water, salts or electrolytes , composition comprising the step of administering to said such as protamine sulfate , disodium hydrogen phosphate , mammal an effective amount of a composition comprising a potassium hydrogen phosphate , sodium chloride , zinc salts , compound of formulae ( I , Ic , Id , II , IIa , IIb , IIc , and Ild ) , or colloidal silica , magnesium trisilicate , polyvinyl pyrroli a preferred embodiment thereof as set forth above . done, polyacrylates , waxes, polyethylene -polyoxypropyl - 25 According to the invention an “ effective amount of the ene- block polymers , wool fat, sugars such as lactose , glu - compound or pharmaceutically acceptable composition is cose and sucrose ; starches such as corn starch and potato that amount effective for treating or lessening the severity of starch ; cellulose and its derivatives such as sodium car - one or more of Cystic fibrosis , Hereditary emphysema , boxymethyl cellulose , ethyl cellulose and cellulose acetate ; Hereditary hemochromatosis , Coagulation - Fibrinolysis powdered tragacanth ; malt ; gelatin ; talc ; excipients such as 30 deficiencies , such as Protein C deficiency , Type 1 hereditary cocoa butter and suppository waxes; oils such as peanut oil, angioedema, Lipid processing deficiencies, such as Familial cottonseed oil ; safflower oil; sesame oil ; olive oil ; corn oil hypercholesterolemia , Type 1 chylomicronemia , Abetalipo and soybean oil ; glycols ; such a propylene glycol or poly - proteinemia , Lysosomal storage diseases, such as l -cell ethylene glycol; esters such as ethyl oleate and ethyl laurate ; disease /Pseudo -Hurler , Mucopolysaccharidoses, Sandhof/ agar ; buffering agents such as magnesium hydroxide and 35 Tay - Sachs, Crigler- Najjar type II , Polyendocrinopathy /Hy aluminum hydroxide ; alginic acid ; pyrogen - free water ; iso - perinsulemia , Diabetes mellitus , Laron dwarfism , Myleop tonic saline ; Ringer ' s solution ; ethyl alcohol, and phosphate eroxidase deficiency, Primary hypoparathyroidism , buffer solutions, as well as other non - toxic compatible Melanoma, Glycanosis CDG type 1 , Hereditary emphy lubricants such as sodium lauryl sulfate and magnesium sema, Congenital hyperthyroidism , Osteogenesis imper stearate , as well as coloring agents , releasing agents, coating 40 fecta , Hereditary hypofibrinogenemia , ACT deficiency, Dia agents , sweetening , flavoring and perfuming agents , preser betes insipidus ( DI) , Neurophyseal DI, Neprogenic DI, vatives and antioxidants can also be present in the compo - Charcot- Marie Tooth syndrome, Perlizaeus- Merzbacher dis sition , according to the judgment of the formulator. ease, neurodegenerative diseases such as Alzheimer' s dis In yet another aspect, the present invention provides a ease, Parkinson ' s disease , Amyotrophic lateral sclerosis , method of treating a condition , disease , or disorder impli- 45 Progressive supranuclear plasy , Pick ' s disease , several poly cated by ABC transporter activity . In certain embodiments, glutamine neurological disorders such as Huntington , Spi the present invention provides a method of treating a con - nocerebullar ataxia type I , Spinal and bulbar muscular dition , disease , or disorder implicated by a deficiency of atrophy , Dentatorubal pallidoluysian , and Myotonic dystro ABC transporter activity , the method comprising adminis - phy, as well as Spongiform encephalopathies , such as tering a composition comprising a compound of formulae ( 1 , 50 Hereditary Creutzfeldt - Jakob disease , Fabry disease , Ic , Id , II , IIa , IIb , IIc , and Ild ) to a subject , preferably a Straussler - Scheinker disease , secretory diarrhea , polycystic mammal, in need thereof. kidney disease , chronic obstructive pulmonary disease In certain preferred embodiments , the present invention (COPD ) , dry eye disease , and Sjögren ' s Syndrome. provides a method of treating Cystic fibrosis , Hereditary The compounds and compositions , according to the emphysema, Hereditary hemochromatosis , Coagulation - Fi- 55 method of the present invention , may be administered using brinolysis deficiencies , such as Protein C deficiency, Type 1 any amount and any route of administration effective for hereditary angioedema , Lipid processing deficiencies, such treating or lessening the severity of one or more of Cystic as Familial hypercholesterolemia , Type 1 chylomicronemia , fibrosis , Hereditary emphysema, Hereditary hemochroma Abetalipoproteinemia , Lysosomal storage diseases , such as tosis , Coagulation - Fibrinolysis deficiencies , such as Protein I -cell disease /Pseudo -Hurler , Mucopolysaccharidoses, 60 C deficiency , Type 1 hereditary angioedema, Lipid process Sandhof/ Tay - Sachs, Crigler- Najjar type II , Polyendocrin ing deficiencies , such as Familial hypercholesterolemia , opathy /Hyperinsulemia , Diabetes mellitus , Laron dwarfism , Type 1 chylomicronemia , Abetalipoproteinemia , Lysosomal Myleoperoxidase deficiency , Primary hypoparathyroidism , storage diseases, such as I- cell disease /Pseudo -Hurler , Melanoma, Glycanosis CDG type 1 , Hereditary emphy - Mucopolysaccharidoses , Sandhof/ Tay -Sachs , Crigler - Najjar sema, Congenital hyperthyroidism , Osteogenesis imper - 65 type II, Polyendocrinopathy /Hyperinsulemia , Diabetes mel fecta , Hereditary hypofibrinogenemia , ACT deficiency , Dia - litus , Laron dwarfism , Myleoperoxidase deficiency , Primary betes insipidus (DI ) , Neurophyseal DI, Neprogenic DI, hypoparathyroidism , Melanoma, Glycanosis CDG type 1,