MX2008004673A - Modulators of atp-binding cassette transporters - Google Patents

Abstract

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

Description

CONVEYOR MODULATORS WITH UNION CELLAR ATP CROSS REFERENCE TO RELATED REQUESTS The present application claims the low benefit U.S.C. § 119 of United States Provisional Application No. 60 / 724,736, filed on October 6, 2005, the full contents of the previous application are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION The present invention relates to modulators of ATP binding cassette transporters ("ABC") or fragments thereof, which include the cystic fibrosis transmembrane conductance regulator ("CFTR"), its compositions and methods who use them The present invention also relates to methods of treating diseases mediated by the ABC transporter by said modulators.

BACKGROUND OF THE INVENTION ABC transporters are a family of membrane transport proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind and use cellular adenosine trisphosphate (ATP) for their specific activities. Some of these transporters were discovered as proteins related to multidrug resistance (such as the glycoprotein MDR1-P or the protein related to multidrug resistance, MRP1), which defend malignant cancer cells against chemotherapeutic agents. To date, 48 ABC transporters have been identified and grouped into 7 families based on their sequence and function identity.

ABC transporters regulate a variety of important physiological functions within the body and provide defense against harmful environmental compounds. Because of this, these represent important potential targets of the drug for the treatment of diseases associated with defects in the transporter, the prevention of the transport of the drug out of the target cell and the intervention in other diseases in which the modulation of the activity of the drug. ABC transporter can be beneficial.

A member of the ABC transporter family commonly associated with diseases is the anion channel mediated by AMP / ATP, CFTR. CFTR is expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates the flow of ions through the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, the normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, which includes respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein composed of a tandem repeat of the transmembrane domains, each of which contains six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large regulatory (R) polar domain with multiple phosphorylation sites that regulate the activity of the channel and the cell circulation.

The gene encoding CFTR has been identified and sequenced (See Gregory, RJ et al (1990) Nature 347: 382-386; Rich, DP et al. (1990) Nature 347: 358-362), (Riordan, JR et al. al. (1989) Science 245: 1066-1073). A defect in this gene causes mutations in CFTR, which cause cystic fibrosis ("CF"), the most common fatal genetic disease of humans. Cystic fibrosis affects approximately one in 2,500 children in the United States. In the general population of the United States, up to 10 million people are carriers of a single copy of the defective gene without obvious effects of disease. Conversely, individuals with two copies of the gene associated with CF suffer from the debilitating and fatal effects of CF, which include chronic lung disease.

In patients with cystic fibrosis, mutations in CFTR expressed endogenously in the respiratory epithelium lead to the secretion of reduced apical anions, which causes an imbalance in the transport of ions and liquids. The resulting decrease in the transport of anions contributes to increased accumulation of mucus in the lung and accompanying microbial infections that ultimately cause death in patients with CF. In addition to respiratory disease, patients with CF typically suffer from gastrointestinal problems and pancreatic insufficiency, which if left untreated, results in death. In addition, most men with cystic fibrosis are infertile and fertility is reduced among women with cystic fibrosis. In contrast to the severe effects of the two copies of the gene associated with CF, individuals with a single copy of the gene associated with CF exhibit increased resistance to cholera and dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene in the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease-causing mutations (Cutting, GR et al (1990) Nature 346: 366-369; Dean, M. et al. (1990) Cell 61: 863: 870; and Kerem, BS et al. (1989) Science 245: 1073-1080; Kerem, BS et al. (1990) Proc. Nati, Acad. Sci. USA 87: 8447-8451). To date, > 1000 mutations that cause diseases in the CF gene (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is a phenylalanine deletion at position 508 of the CFTR amino acid sequence and is commonly referred to as? F508-CFTR. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with severe disease.

The deletion of residue 508 in? F508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit ER, and circulate through the plasma membrane. As a result, the number of channels present in the membrane is much smaller than that observed in cells expressing wild-type CFTR. In addition to the alteration of the circulation, the mutation produces a defective activation of the channels. Taken together, the reduced number of channels in the membrane and the defective activation leads to the reduction of anion transport through the epithelium leading to defective transport of ions and liquids (Quinton, PM (1990), FASEB J. 4 : 2709-2727). However, studies have shown that the reduced amounts of? F508-CFTR in the membrane are functional, although lower than in wild-type CFTR. (Dalemans et al. (1991), Nature Lond., 354: 526-528, Denning et al., Supra, Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to the? F508-CFTR, other mutations that cause disease in CFTR that produce defective circulation, synthesis and / or activation of the channel could be regulated by increase or decrease to alter the excretion of anions and modify the progression and / or severity of the disease.

While CFTR carries a variety of molecules in addition to anions, it is clear that this function (the transport of anions) represents an element in an important transport mechanism of ions and water through the epithelium. The other elements that include the epithelial Na + channel, ENaC, Na + / 2C1"/ K + cotransporter, Na + -K + -ATPase pump and the K + channels of the basolateral membrane, are responsible for the uptake of chloride in the cell.

These elements act together to obtain a directional transport through the epithelium by means of its selective expression and localization in the cell. The absorption of chloride occurs by the coordinated activity of ENaC and CFTR present in the apical membrane and the Na + -K + -ATPase pump and the Cl- channels expressed in the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to accumulation of intracellular chloride, which can then passively leave the cell through the channels of Cl ", which leads to vector transport, the Na + / 2C1 / K + cotransporter arrangement, Na + -K + -ATPase pump and the K + channels of the cell. The basolateral surface on the basolateral surface and the CFTR on the luminal side coordinate the secretion of chloride by means of CFTR on the luminal side. Because water is probably never actively transported by itself, its flow through the epithelium depends on the small transepithelial osmotic gradients generated by the gross flow of sodium and chloride.

In addition to cystic fibrosis, the modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's disease.

COPD is characterized by the limitation of air flow that is progressive and not completely reversible. The limitation of air flow is due to hypersecretion of mucus, emphysema and bronchiolitis. Mutant or wild-type CTFR activators offer potential treatment of mucus hypersecretion and defective mucociliary clearance that are common in COPD. Specifically, the increased secretion of anions through CFTR can facilitate the transport of fluids in the fluid of the airway surface to hydrate the mucus and optimize the viscosity of the periciliar fluid. This could lead to increased mucociliary clearance and reduced symptoms associated with COPD. Dry eye disease is characterized by a reduction in water production of tears and abnormal profiles of lipids, proteins, mucin from the tear film. There are many causes of dry eye, some of which include age, laser eye surgery, arthritis, medications, chemical / thermal burns, allergies and diseases, such as cystic fibrosis and Sjögren's syndrome. The increased secretion of anions by means of CFTR should improve the transport of fluids from the endothelial cells of the cornea and surrounding glands of the eye to increase the hydration of the cornea. This should help alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks the moisture-producing glands of the entire body, which include eyes, mouth, skin, respiratory tissue, liver, vagina, and intestine. Symptoms include, dry eye, mouth and vagina, in addition to lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymyositis / dermatomyositis. It is considered that the defective circulation of proteins causes the disease, so that the treatment options are limited. Modulators of CFTR activity can hydrate the various organs affected by the disease and help relieve associated symptoms.

As described above, it is considered that the deletion of residue 508 of the? F508-CFTR prevents the nascent protein from folding correctly, which results in the inability of this mutant protein to exit the ER, and circulate through the plasma membrane. As a result, insufficient amounts of mature protein are present in the plasma membrane and chloride transport in the epithelial tissue is significantly reduced. Indeed, it has been shown that this cellular phenomenon of defective ER processing of the ABC transporters by the ER machinery is the underlying basis not only of CF disease, but of a wide variety of other isolated and inherited diseases. The two ways in which the ER machinery can malfunction are due to loss of the ER export coupling of the proteins leading to degradation, or by accumulation in ER of these defective / misfolded proteins [Aridor M, et al. , Nature Med., 5 (7), pp 745-751 (1999); Shastry, B.S., et al. , Neurochem. International, 4_3, pp 1-7 (2003); Rutishauser, J., et al. , Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al. , TIPS, 21, pp. 466-46 (2000); Bross P., et al. , Human Mut. , 14, pp. 186-198 (1999)]. Diseases associated with the first class of ER malfunction are cystic fibrosis (due to the misfolded? F508-CFTR described above), hereditary emphysema (due to al-antitrypsin); non-Piz variants), hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, familial hypercholesterolemia, chylomicronemia type 1, Abetalipoproteinemia, lysosomal storage diseases, such as I / Pseudo-cell disease Hurler, mucopolysaccharidosis, (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to ß-hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialic-transferase), polyendocrinopathy / hyperinsulemia, diabetes mellitus (due to the insulin receptor), Laron dwarfism (due to the growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparatiroid hormone), melanoma (due to tyrosinase). Diseases associated with the last class of ER malfunction are type 1 CDG glycosis, hereditary emphysema, (due to al-antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to procollagen type I, II, IV), hypofibrinogenemia hereditary (due to fibrinogen), ACT deficiency (due to al-antiquimiotripsina), Diabetes insipidus (DI), neurohipofisaria DI (due to the hormone vasopressin / receptor of V2, nephrogenic DI (due to aquaporin II), Charcot-Marie Tooth syndrome (due to protein 22 of peripheral myelin), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to ßAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several neurological disorders of polyglutamine such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, paludoluisian dentatorubral atrophy, and myotonic dystrophy, in addition to encephalopathies spongiforms, such as Creutzfeldt-Jakob hereditary, (due to processing defects of prion protein), Fabry disease (due to lysosomal α-galactosidase A) and Straussler-Scheinker syndrome (due to the processing defect of Prp).

In addition to regulation for increased activity of CFTR, the reduction of anion secretion by CFTR regulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport are drastically increased as a result of transport of chloride activated by secretagogues. The mechanism involves the elevation of cAMP and the stimulation of the CFTR.

Although there are numerous causes of diarrhea, the main consequences of diarrheal diseases resulting from excessive chloride transport are common to all and include dehydration, acidosis, altered growth and death.

Acute and chronic diarrhea represent a major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths / year) of children under five years of age.

Secretory diarrheas are also a dangerous disease in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Each year 16 million travelers to developing countries from industrialized nations develop diarrhea, the severity and number of cases of diarrhea varies according to the country and area of travel.

Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as cattle diarrhea, is a major cause of death in these animals. Diarrhea may be the result of some major transition, such as weaning or physical movement, in addition to a response to a variety of bacterial or viral infections and generally occurs within the first hours of the animal's life.

The most common bacterium causing diarrhea is enterotoxigenic E-coli (ETEC) that has the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include, among others, cryptosporidium, giardia lamblia and salmonella.

Symptoms of rotaviral infection include excretion of watery stools, dehydration and weakness. Coronavirus causes a more severe disease in newborn animals and has a higher mortality rate than rotaviral infection. Often, however, a young animal can be infected with more than one virus or with a combination of viral and bacterial microorganisms at the same time. This drastically increases the severity of the disease.

Accordingly, there is a need for modulators of ABC transporter activity and compositions thereof that can be used to modulate the activity of the ABC transporter in the cellular membrane of a mammal.

Methods are needed to treat diseases mediated by the ABC transporter using these modulators of ABC transporter activity.

Methods are needed to modulate the activity of the ABC transporter in a cell membrane of an ex vivo mammal.

Methods are needed to modulate the activity of CFTR that can be used to modulate the activity of CFTR in the cellular membrane of a mammal.

Methods for treating diseases mediated by CFTR using such modulators of CFTR activity are needed.

Methods are needed to modulate the activity of CFTR in a cell membrane of an ex vivo mammal.

SYNTHESIS OF THE INVENTION It has now been found that the compounds of this invention, and their pharmaceutically acceptable compositions, are useful as modulators of the activity of the ABC transporter. These compounds have the general formula I: or one of its pharmaceutically acceptable salts, wherein R1, R2, R3, R4, X, and m are described generally and in the following classes and subclasses.

These compounds and compositions acceptable for pharmaceutical use are useful for treating or reducing the severity of a variety of diseases, disorders or pathologies, including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, deficiencies in lipid processing, such as familial hypercholesterolemia, chylomicronemia type 1, Abetalipoproteinemia, lysosomal storage diseases, such as I / Pseudo-Hurler cell disease, mucopolysaccharidosis, Sandhof / Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI) ), Neuropituitary DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various neurological disorders of the polyglutamine such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, Palladoluis dentatorubral atrophy, and myotonic dystrophy, in addition to spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjögren's disease.

DETAILED DESCRIPTION OF THE INVENTION 1 . General description of the invention: The present invention relates to a method of modulating the activity of the transporter ABC comprising the step of contacting said transporter ABC with the compounds of formula I: or one of its acceptable salts for pharmaceutical use, where: Each R1 is independently R ', halo, N02, or CN; Each R2 is independently -XR '; Each X is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of X are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR' -, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; each R 'is independently selected from hydrogen or an optionally substituted Ci-β aliphatic group, a monocyclic or bicyclic ring with 3-8 membered saturated, partially saturated or fully saturated bridge having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 member bicyclic or tricyclic ring system saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two presentations of R 'are taken together with the atom (s) to which they are attached to form a saturated, partially saturated or fully saturated monocyclic or bicyclic ring of 3-12 members having 0-4 selected heteroatoms independently between nitrogen, oxygen, or sulfur, each R 'group different from hydrogen is optionally substituted with 1-3 de-RW.

Each m is independently 0-4; Each R3 is independently H or Ci-β aliphatic group optionally substituted with -X-RA and where up to two methylene units of the aliphatic group R3 can be replaced with -CO-, -CH2S-, -CONR'-, -CONR'NR ' -, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR ' CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each RA is independently R ', halo, N02, or CN; Each R 4 is a (cycloaliphatic) alkyl, (heterocycloaliphatic) alkyl, aralkyl, or heteroaralkyl wherein the alkyl portion of R 4 is optionally substituted with R 5 and where up to two methylene units of the alkyl portion of R 4 can be replaced with -CO-, - CS-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ' -, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR ' -, and the cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl portions of R 4 are optionally substituted with 1-3 de-RW, or R 4 is RB, or R3 and R4 together with the nitrogen to which they are attached can form a 5- to 7-membered heterocycloaliphatic group optionally substituted with 1 to 3 R '; RB is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally fused with an aryl or heteroaryl, where RB is attached to the atom of the nitrogen atom of the core structure of the cycloaliphatic or heterocycloaliphatic ring, and RB is optionally substituted with 1- 3 of -WR; Each R5 is independently aryl, heteroaryl, Ci-β aralkyl, or Ci-β heteroaralkyl wherein the alkyl portion of R5 is optionally substituted with Rw and where up to two methylene units of the alkyl portion of R5 can be replaced with -CO-, - CS-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ' -, NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'- , and the aryl or heteroaryl portions of R5 are optionally substituted with 1-3 de-RW; Each is independently a bond or an optionally substituted C? -6 alkylidene chain C? -6 where up to two methylene units of W are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR '-, -NR'NR'-, -NR'NR'CO -, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Y Each Rw is independently R ', halo, N02, CN, CF3, -O (Ci-4 alkyl), -0CF3, or phenyl which is optionally substituted with 1-3 halo, haloalkyl, alkoxy or aliphatic; As long as the compounds do not include, in position 5 of the indole, the groups: -C (O) - (optionally substituted piperidinyl) -CH2- (optionally substituted phenyl), or -C (O) - (optionally substituted piperazinyl) - (C 4 alkyl) - (optionally substituted phenyl). 2. Compounds and definitions: The compounds of this invention include those described in general form above and are further illustrated with the classes, subclasses and species described herein. As used herein, the following definitions will apply unless otherwise indicated.

The term "ABC transporter" as used herein means an ABC transporter protein or fragment thereof, comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vitro. The term "binding domain" as used herein means a domain of the ABC transporter that can be attached to a modulator. See, for example, Hwang, T. C. et al. , J. Gen. Physiol. (1998): 111 (3), 477-90.

The term "CFTR" as used herein means a cystic fibrosis transmembrane conductance regulator or a mutation of this capable of regulating activity, which includes, but is not limited to,? F508 CFTR and G551D CFTR (See, for example, http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term "modular" as used herein means increasing or decreasing, for example the activity, in a measurable amount. Compounds that modulate the activity of the ABC transporter, such as CFTR activity, by increasing the activity of the ABC transporter, for example, a channel of CFTR anions, are called agonists. Compounds that modulate the activity of the ABC transporter, such as CFTR activity, by reducing the activity of the ABC transporter, eg, CFTR anion channel, are called antagonists. An agonist interacts with an ABC transporter, such as CFTR anion channel, to increase the ability of the receptor to transduce an intracellular signal in response to binding of the endogenous ligand. An antagonist interacts with an ABC transporter, such as CFTR, and competes with the endogenous ligand (s) or substrate (s) for receptor binding sites to reduce the ability of the receptor to transduce an intracellular signal in response to binding of the receptor. endogenous ligand.

The phrase "treating or reducing the severity of a disease mediated by an ABC transporter" refers to treatments for diseases that are caused directly by the activities of the ABC and / or CFTR transporter and alleviation of the symptoms of diseases not directly caused by the activities of the anion channel of the transporter ABC and / or CFTR. Examples of diseases whose symptoms may be affected by the activity of the ABC and / or CFTR transporter include, but are not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, deficiencies in lipid processing, such as familial hypercholesterolemia, type 1 chylomicronemia, Abetalipoproteinemia, lysosomal storage diseases, such as I / Pseudo-Hurler cell disease, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II , polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (ID), neurohypophyseal DI , Nephrogenic DI, Charcot-Ma syndrome Tooth disease, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several neurological disorders of polyglutamine such as Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, paludoluisal dentatorubral atrophy, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

For the purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, whose complete contents are hereby incorporated by reference.

As described herein, the compounds of the invention may optionally be substituted with one or more substituents, as generally illustrated above, or exemplified by the particular classes, subclasses and species of the invention.

As used herein the aliphatic term embraces the terms alkyl, alkenyl, and alkynyl.

The term "alkylidene chain" or "alkylidene" refers to a straight or branched carbon chain that may be completely saturated, for example, alkyl, or has one or more units of unsaturation, for example, alkenyl or alkynyl, and has two points of attachment to the rest of the molecule. The term "spirocycloalkylidene" refers to a carbocyclic ring that can be completely saturated or have one or more units of unsaturation and has two points of attachment of the same carbon atom of the ring to the rest of the molecule.

As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (eg, 1-6 or 1-4) carbon atoms. An alkyl group can be linear or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl and 2-ethylhexyl. An alkyl group may be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom (s) to which they are attached), aroyl, heteroaryl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl , cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, oxo, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino , heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino.

As used herein, an "alkenyl" group refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and at least one double bond. As an alkyl group, an alkenyl group can be linear or branched. Examples of the alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. An alkenyl group may be optionally substituted with one or more substituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups of the same atom or adjacent atoms may form a ring together with the atom (s) to which they are attached). bonded), aroyl, heteroaryl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, oxo, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, or heteroaralk lcarbonylamino.

As used herein, an "alkynyl" group refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be linear or branched. Examples of the alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group may be optionally substituted with one or more substituents, such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups of the same atom or adjacent atoms may form a ring together with the atom (s) to which they are attached), aroyl, heteroaryl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl , cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, oxo, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino , heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino , or heteroaralkylcarbonylamino.

As used herein, an "amino" group refers to -NRXRY where each Rx and R? is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, heteroaryl, or heteroaralkyl, each of which are defined herein and are optionally substituted. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-. Rx has the same meaning defined above.

As used herein, an "aryl" group used alone or as part of a larger residue as in an "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to phenyl, naphthyl or a benzofused group having 2 to 3 rings. For example, a benzofused group includes phenyl fused to one or two C4-β carbocyclic residues, for example, 1, 2, 3, 4-tetrahydronaphthyl, indanyl or fluorenyl. An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea , sulfamollo, sulfamide, oxo, or carbamoyl.

As used herein, an "aralkyl" group refers to an alkyl group (eg, a C? _4 alkyl group) that is substituted with an aryl group. The groups "alkyl" and "aryl" are defined herein. An example of an aralkyl group is benzyl. A "heteroaralkyl" group refers to an alkyl group that is substituted with a heteroaryl. The groups "alkyl" and "heteroaryl" are defined herein.

As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group.

As used herein, a group "cycloalkyl" refers to a saturated monocyclic or bicyclic carbocyclic ring (fused or bridged) of 3-10 (eg, 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cylyl, octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] Nonyl and bicyclo [3.3.2.] decyl and adamantyl. A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of the cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo [2.2.2] octenyl and bicyclo [3.3.1] nonenyl. A cycloalkyl or cycloalkenyl group may be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea , thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

An aliphatic bicyclic ring system encompasses bridged and fused cycloaliphatic ring systems which may be substituted with the substituents of a cycloaliphatic.

As used herein, the term "heterocycloaliphatic" encompasses a heterocycloalkyl group and a heterocycloalkenyl group.

As used herein, a "heterocycloalkyl" group refers to a saturated 3- to 10-membered mono- or bicyclic ring structure (fused or bridged) (eg, mono- or bicyclic 5-10 membered), wherein one or more of the ring atoms is a heteroatom, for example, N, O or S. Examples of a heterocycloalkyl group include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo [b] thiophenyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2,6-dioxa-tricyclo [3.3.1. O3'7] nonyl. A monocyclic heterocycloalkyl group may be fused to a phenyl residue such as tetrahydroisoquinoline. A "heterocycloalkenyl" group, as used herein, refers to a non-aromatic mono or bicyclic ring structure (e.g., mono- or bicyclic 5- to 10-membered) having one or more double bonds and where one or more of the ring atoms is a heteroatom, for example, N, O or S. A heterocycloalkyl or heterocycloalkenyl group may be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl , cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl (such as benzimidazolidinyl), (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms can form a ring together with the atom (s)) to which they are attached), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkyl carbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea , thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

A bicyclic heteroaliphatic ring system encompasses bridged and fused cycloheteroaliphatic ring systems which may be substituted with the substituents of a heterocycloaliphatic group.

A "heteroaryl group," as used herein, refers to a monocyclic, bicyclic or tricyclic ring structure having 4 to 15 ring atoms where one or more ring atoms is a heteroatom, eg, N, O or S and where one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes phenyl fused to one or two C4_8 heterocyclic residues, for example, indolinyl and tertahydroquinolinyl. Some of the heteroaryl examples are azetidinyl, pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole and benzo [1,3] dioxole. A heteroaryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea , thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. A "heteroaralkyl group", as used herein, refers to an alkyl group (eg, a C? _4 alkyl group) that is substituted with a heteroaryl group. The "alkyl" and "heteroaryl" have been defined above.

As used herein, "cyclic residue" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which was previously defined.

As used herein, an "acyl" group refers to a formyl or C-alkyl group (= 0) -, where "alkyl" has been previously defined. Examples of acyl groups are acetyl and pivaloyl.

As used herein, a group "Carbamoyl" refers to a group that has the structure -0-C0-NRxR? or -NRx-C0-0-Rz wherein Rx and R? "have been defined above and Rz may be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl.

As used herein, the "carboxy" and "sulfo" groups refer to -COOH or -COORx and -S03H or -S03Rx, respectively.

As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" has been previously defined.

As used herein, a "sulfoxy" group refers to -0-SO-Rx or -SO-0-Rx, where Rx has been defined above.

As used herein, a group "Sulfonyl" refers to -S (0) 2 -Rx, where Rx has been defined above.

As used herein a "sulfinyl" group refers to -S (0) -R x, where R x has been defined above.

As used herein a "sulfanyl" group refers to -S-Rx, where Rx has been defined above.

As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 allogen. For example, the term "haloalkyl" includes the group -CF3.

As used herein, a group "Sulfamoyl" refers to the structure -S (0) 2-NRxR? or -NRX-S (0) 2-Rz where RX, R ?, and Rz have been previously defined.

As used herein, a "sulfamide" group refers to the structure -NRX-S (0) 2 -NR? Rz where Rx, R ?, and Rz have been defined above.

As used herein, a group "carbonylamino" used alone or in connection with another group refers to an amido group such as -C (0) -NRx-, -NRx-C (0) -, and -C (0) -N (Rx) 2. For example, an alkylcarbonylamino includes alkyl-C (0) -NRx- and alkyl-NRx-C (0) -.

As used herein, a "urea" group refers to the structure -NRx-C0-NR? Rz and a group "thiourea" refers to the structure -NRx-CS-NR? Rz. Rx, R? and Rz have been defined above.

The phrase "optionally substituted" is used with the phrase "substituted or unsubstituted". As described herein, the compounds of the invention may optionally be substituted with one or more substituents, such as are generally illustrated above, or exemplified by particular classes, subclasses and species of the invention. As described herein, variables, such as R1, R2, R3, and R4, encompass specific groups, such as alkyl and aryl. Unless indicated otherwise, each of the specific groups for the variables described herein with respect to the formulas I, II, III, Illa, and IV may optionally be substituted with one or more substituents described in the present memory. Each substituent of a specific group is also optionally substituted with one to three halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl. For example, an alkyl group may be substituted with alkylsulfanyl and the alkylsulfanyl may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl and alkyl. As an additional example, an alkyl may be substituted with a (cycloalkyl) carbonylamino. The cycloalkyl portion of the (cycloalkyl) carbonylamino is optionally substituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro, haloalkyl and alkyl.

In general, the term "substituted" if preceded by the term "optionally" or not, refers to the replacement of the hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of the compounds and examples thereof. Unless indicated otherwise, an optionally substituted group may have a substituent at each substitutable position in the group, and when more than one position in a given structure may be substituted with more than one substituent selected from a specific group, the substituent may be substituted. It can be the same or different in each position. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, for example, both rings share a common atom. As will be recognized by those skilled in the art, combinations of the substituents provided for this invention are combinations that result in the formation of stable or chemically feasible compounds.

The phrase "stable or chemically feasible" as used herein, refers to compounds that are not substantially altered when subjected to the conditions to allow their production, detection and preferably their recovery, purification and use of one or more than the purposes described herein. In some embodiments, a stable or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

As used herein, an "effective amount" is defined as the effective amount necessary to confer a therapeutic effect on the treated patient and is usually determined based on the patient's age, surface area, weight and pathology. The interrelation of doses for animals and humans (on the basis of milligrams per square meter of body surface area) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). The body surface area can be determined approximately from the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).

As used herein, "patient" refers to a mammal, which includes a human being.

Unless indicated otherwise, the structures described herein mean that they also include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E) and conformation isomers (Z) and (E). Accordingly, the unique stereochemical isomers in addition to the enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, it is understood that the structures described herein include those compounds that differ only in the presence of one or more of the atoms enriched in isotopes. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon with a carbon enriched in 13C or 1C are within the scope of the invention. Such compounds are useful, for example, as tools or analytical tests in biological assays. 3. Description of examples of compounds: In some embodiments of the present invention, the compounds of formula II are provided: II or one of its acceptable salts for pharmaceutical use, where: Each R1, R2, R3, X, R ', and m are as defined above; Each AA and AB is independently aryl, heteroaryl or heterocycloaliphatic optionally substituted with 1-3 of -WR; Each Yi and Y2 is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of the C? -6 alkylidene chain are optionally independently replaced with -CO-, -CS-, -COCO- , -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each W is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of W are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR' -, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each R is independently R ', halo, N02, CN, CF3, -0 (C? -4 alkyl) or -0CF3; Y Each E is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of the C? _6 alkylidene chain are optionally independently replaced with -C (O) -, -CS-, - COCO-, CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02, -O-, -OCONR'-, -NR'NR'-, -NR'NR'CO- , -NR'CO-, -S-, -SO-, S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; With the proviso that the compound is not N- [1- [(3,5-difluorophenyl) methyl] -3 - [[(3-ethylphenyl) methyl] amino] -2-hydroxypropyl] -1-methyl-a- oxo-lH-indol-3-acetamide, 2- (lH-indol-3-yl) -N- (2-morpholino-l-phenylethyl) -2-oxoacetamide or N- (1,3-bis (benzylthio) propan-2-yl) -2- (lH-indol-3-yl) -2-oxoacetamide.

In some embodiments of the present invention, the compounds of formula III are provided: III one of its acceptable salts for pharmaceutical use, where; Each R1, R2, R3, X, R ', and m are as defined above; Each R 10 is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally substituted with 1-3 halo, haloalkyl, alkoxy, aliphatic, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-3 halo, alkoxy , haloalkyl, aliphatic; Y Each p is 0-3.

In some specific aspects, the compounds of formula III include the Illa structure: Il a Where each R1, R2, R3, X, R ', and m are as defined above; The Zz ring is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally substituted with 1-3 halo, haloalkyl, alkoxy, aliphatic, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-3 halo , alkoxy, haloalkyl, or aliphatic; Each RE is independently halo, haloalkyl, alkoxy, or aliphatic; Y Each d is independently 0 to 3.

In other embodiments of the present invention, the compounds of formula IV are provided: IV one of its acceptable salts for pharmaceutical use, where: Each R1, R2, R3, X, R ', and m are as defined above; Each R 11 is aryl or heteroaryl, each of which is optionally substituted with 1-3 halo, aliphatic, aryl, or heteroaryl; Y Each q is 0-34. Description of substituents In one embodiment, R is hydrogen. O, R is aliphatic Ci-Cß. Examples of R include Ci-Cß alkyl, for example, methyl, ethyl, propyl or butyl.

In one embodiment, R 'R is hydrogen.

In one embodiment, R 'is aliphatic groups Ci-Cβ, optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, where up to two methylene units of said aliphatic Ci-Ce groups is optionally replaced with -CO-, -CONH (C-alkyl) ? ~ C4) -, -C02-, -OCO-, -N (C C-C) alkyl, C02-, -O-, -N (Cx-C4 alkyl) CON (C alqu-C4 alkyl) -, -OCON (C C-C) alkyl-, -N (C C-C4 alkyl) CO-, -S-, -N (C?-C4 alkyl) -, -S02N (C?-C4 alkyl) -, N (alkyl) C? -C4) S02- or -N (C? -C4 alkyl) S02N (C? -C4 alkyl) -.

In one embodiment, R 'is a C?-C4 alkyl or C2-C4 alkenyl, optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, where up to two methylene units of said alkyl C? ~ C4 or C2-C4 alkenyl optionally replaced with -CO-, CONH (C? -C4 alkyl) -, -C02-, -OCO-, -N (C? -C4 alkyl) C02-, -O-, -N (C 1 -C 4 alkyl) CON (C 1 -C 4 alkyl) -, -OCON (C 1 -C 4 alkyl) -, -N (C 1 -C 4 alkyl) CO-, -S-, -N (C 1 -C 4 alkyl) ) -, -S02N (Ci-C4 alkyl) - N (C 1 -C 4 alkyl) S 0 2 -, or - N (C 1 -C 4 alkyl) S 0 2 N (C 1 -C 4 alkyl) - In one embodiment, R 'is a C1-C4 alkyl or C2-C4 alkenyl, optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3 or OCHF2.

In one embodiment, R 'is a 3-8 membered saturated, partially saturated or fully saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or Ci-Cß alkyl, where up to two methylene units of said Ci-Cß alkyl is optionally replaced with -CO-, -CONH (C 1 -C 4 alkyl) -, - C02-, -OCO-, -N (alkyl dC) C02-, -O-, -N (C 1 -C 4 alkyl) CON (C 1 -C 4 alkyl) -, -OCON (C 1 -C 4 alkyl) -, -N (alkyl C? -C) CO-, -S-, -N (C1-C4 alkyl) -, -S02N (Ci-C4 alkyl) -, N (C? -C4 alkyl) S02- or -N (C1 alkyl) -C4) S02N (C1-C4 alkyl) - In one embodiment, R 'is a cycloalkyl ring of 3-8 members independently selected from nitrogen, oxygen or sulfur, where R' is optionally substituted with up to 3 substituents selected from halo , CN, CF3, CHF2, OCF3, OCHF2, or Ci-Cß alkyl, wherein up to two methylene units of said Ci-Cß alkyl is optionally replaced with -CO-, CONH (C 1 -C 4 alkyl) -, -C0 2 -, -OCO-, -N (C 1 -C alkyl) C02-, -0-, -N (C 1 -C 4 alkyl) CON (C 1 -C 4 alkyl) -, -OCON (C 1 -C 4 alkyl) -, -N (C 1 -C 4 alkyl) CO-, -S- , -N (C 1 -C 4 alkyl) -, -S0 2 N (C 1 -C 4 alkyl) -, N (C 1 -C 4 alkyl) S 0 2 -, or - N (C 1 -C 4 alkyl) S 0 2 N (C 1 -C 4 alkyl) -. Exemplary embodiments include optionally substituted cyclopropyl, cyclopentyl or cyclohexyl.

In one embodiment, R 'is a saturated 3-8 membered monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, 0CF3, 0CHF2, or C? -C6 alkyl, where up to two methylene units of said C? -C6 alkyl is optionally replaced with -CO-, -CONH (C? -C4 alkyl) -, -C02-, -OCO-, -N (C? -C4 alkyl) C02-, -O-, -N (C? -C alkyl) CON (C1-C4 alkyl) -, -OCON (C1-C4 alkyl) -, -N (C 1 -C 4 alkyl) CO-, -S-, -N (C 1 -C 4 alkyl) -, -S0 2 N (C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) S 0 2 -, or -N (C 1 -C 4 alkyl) S02N (C 1 -C 4 alkyl) - Examples of embodiments include optionally substituted tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, etc.

In one embodiment, R 'is a saturated 3-8 membered monocyclic ring having 1 heteroatom selected from nitrogen, oxygen, or sulfur, where R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, 0CF3, OCHF2, or C1-C6 alkyl, where up to two methylene units of said Ci-Ce alkyl is optionally replaced with -CO-, CONH (C1-C4 alkyl) -, -C02-, -OCO-, -N (C? -C4 alkyl) C02-, -O-, -N (C? -C4 alkyl) CON (C1-C4 alkyl) - , -OCON (C1-C4 alkyl) -, -N (C? -C4 alkyl) CO-, -S-, -N (C1-C4 alkyl) -, -S02N (C1-C4 alkyl) -, N (alkyl) C! -C4) S02-, or -N (C1-C4 alkyl) S02N (C1-C4 alkyl) -.

In one embodiment, R 'is a bicyclic ring system 8-12 members saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where R 'is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C? -C6 alkyl, where up to two methylene units of said Ci-C? alkyl is optionally replaced with -CO-, -CONH (C4-C4 alkyl), -C02-, -OCO-, -N (Ci-C4 alkyl) C02-, -0-, -N (C 1 -C 4 alkyl) CON (C 1 -C 4 alkyl) - , -OCON (C1-C4 alkyl) -, -N (C? -C4 alkyl) C0-, -S-, -N (C1-C4 alkyl) -, -S02N (C1-C4 alkyl) -, N (alkyl) C? -C4) S02-, or -N (C1-C4 alkyl) S02N (C? -C4 alkyl) -.

In one embodiment, two presentations of R 'are taken together with the atom (s) to which they are attached to form an optionally substituted saturated, partially saturated or fully saturated monocyclic or bicyclic ring having 3-12 members having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R 'is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, 0CF3, 0CHF2, or C? -C6 alkyl, where up to two methylene units of said Ci-Cß alkyl is optionally replaced with -CO-, -CONH (C 1 -C 4 alkyl) -, -C02-, -OCO-, -N (C 1 -C 4 alkyl) C02-, -O-, -N ( C 1 -C 4 alkyl) CON (C 1 -C 4 alkyl) -, -OCON (C 1 -C 4 alkyl) -, -N (C 1 -C 4 alkyl) CO-, -S-, -N (C 1 -C 4 alkyl) -, -S02N (C? -C4 alkyl) -, N (C? -C4 alkyl) S02-, or -N (C1-C4 alkyl) S02N (C1-C4 alkyl) -.

In various embodiments R3 is independently H or an aliphatic group C? -8 optionally substituted with -X-RA. In several examples, R3 is H.

In some embodiments, R 4 is (cycloaliphatic) alkyl, (heterocycloaliphatic) alkyl, aralkyl or heteroaralkyl wherein the alkyl portion of R 4 is substituted with R 5. In other embodiments, R 4 is an aralkyl or heteroaralkyl group optionally substituted with WRW.

In some embodiments, each R 4 is C 1 -8 aralkyl or C 1-8 heteroaralkyl where the alkyl portion of R 4 is optionally substituted with R 5 and where up to two methylene units of the alkyl portion of R 4 can be replaced with -CO-, -CS-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR '-, NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR' -, and the aryl or heteroaryl portions of R 4 are optionally substituted with 1-3 of -WR.

In some embodiments, R 4 is C 1-8 aralkyl or C 7 β -heteroaralkyl wherein the aryl or heteroaryl portions are optionally substituted with 1-3 of -WR. R 4 is a (C 1-4 alkyl) -aryl in which the aryl is optionally substituted with 1-3 of -WR. R 4 is a - (C 4 alkyl) aryl wherein the aryl is substituted with 1-2 substituents independently selected from alkoxy, halo, alkylcarbonylamino, aliphatic, and alkylcarbonyl. R 4 is a - (C 4 alkyl) -heteroaryl in which the heteroaryl is optionally substituted with 1-3 of -WRW. R 4 is a - (C 4 alkyl) -heteroaryl in which the heteroaryl is substituted with 1-2 substituents independently selected from alkoxy, halo, alkylcarbonylamino, aliphatic, alkylarylalkyl and alkylcarbonyl.

In some embodiments, R 4 is C a _ 8 aralkyl or Ci_ s heteroaralkyl wherein the aryl or heteroaryl portions are optionally substituted with 1-3 of -WR and where one or more non-adjacent methylene units of the C 1 -C alkyl portion -4 are optionally independently replaced with -O-, -NR'-, -S-, -S02-, -COO-, or -CO-. R4 aralkyl C? -8 or heteroalkyl C? _ In which the aryl or heteroaryl portions are optionally substituted with 1-3 of -WR and where one or two non-adjacent methylene units of the C1-4 alkyl portion are optionally substituted independent mode with O, NR ', or S.

In some embodiments, R4 is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally substituted with 1-3 -WRW. In several examples, R 4 is a monocyclic cycloaliphatic or a monocyclic heterocyclic aliphatic. In some examples, R 4 is cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl, each of which is optionally substituted with 1-3 of -WR. In various other examples, R 4 is cycloaliphatic and R 4 is substituted by optionally substituted aryl. More specific examples of R4 include cyclohexyl, cyclopentyl or cyclopropyl which is monosubstituted with an optionally substituted phenyl.

In other examples, R4 is piperidinyl or tetrahydropyrrolyl, each of which is optionally substituted with 1-3 of -WRW. In other examples, R4 is a bicyclic aliphatic or a bicyclic heteroaliphatic, each bicyclic aliphatic or bicyclic heteroaliphatic is optionally substituted with 1-3 of -WR. R4 is a bicyclic aliphatic optionally substituted with 1-3 of -WRW. R4 is nobornyl optionally substituted with 1-3 of -WR. Alternatively, R4 is tropane optionally substituted with 1-3 of -WR.

In some embodiments, R5 is an optionally substituted C1-4 aliphatic group.

In various embodiments, RB is a cycloaliphatic or a heterocycloaliphatic, each of which is optionally fused with an aryl or heteroaryl where RB is attached to the amino nitrogen atom of the core structure at any chemically viable position of the cycloaliphatic ring or heterocycloaliphatic and RB is optionally substituted with 1-3 of -WRW.

In various embodiments RB is where RB is optionally substituted with 1-3 -WR at any chemically viable position, where -WRW was defined above. For example, RB is In various alternative embodiments, RB is indolizinyl, indolyl, indolinyl, benzo [Jb] furyl, benzo [£ > ] thiophenyl, hydroindazolyl, benzimidazolyl, benzthiazolyl, purinyl or indenyl; each of which is optionally substituted with 1-3 alkoxy, aliphatic, halo, or alkylcarbonyl.

In other embodiments, W is a bond or is an optionally substituted C? -6 alkylidene chain where one or two non-adjacent methylene units are optionally independently replaced with -O-, -NR'-, -S-, -S02-, -COO-, or -CO-. In some embodiment, R is R 'or halo. In yet other embodiments, each presentation of WR is independently -alkyl C? -3, -O (C? -3 alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, or- COOR ', -COR', 0 (CH2) 2N (R ') (R'), -0 (CH2) N (R ') (R'), -CON (R ') (R'), - (CH2 2OR ', - (CH2) 0', an optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfonyl, an optionally substituted 5-membered heteroaryl ring, N (R'MR '), -CH2) 2N (R') ( R '), or - (CH2) N (R') (R '). W is a bond and R1 is halo or R '.

In some embodiments, m is 1 or 2.

In some embodiments, m is 0. O, m is 1. O, m is 2. In some embodiments, m is 3. In still other embodiments, m is 4.

In some embodiments, R2 is hydrogen. Or, R2 is an optionally substituted Ci-s aliphatic group. In some embodiments, R2 is optionally substituted C? -4 aliphatic.

In one embodiment of the present invention, each R1 is simultaneously hydrogen. In another embodiment, R2 and R3 are simultaneously hydrogen.

In another embodiment, R1 is X-RA, where X is -S02NR'-, and RA is R '.

In some embodiments, X is a bond or is an optionally substituted C 1-6 alkylidene chain where one or two non-adjacent methylene units are optionally independently replaced with -O-, - NR-, -S-, -S02 -, -COO-, or -CO-. In some embodiments, RA is R 'or halo. In still other embodiments, each presentation of XRA is independently -alkyl C? -3, -O (C1-3 alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, or -COOR ', -COR', -O (CH2) 2N (R) (R '), -0 (CH2) N (R) (R'), -CON (R) (R '), - (CH2) 2OR' , - (CH2) 0 ', optionally substituted phenyl, -N (R) (R'), - (CH2) 2N (R) (R '), or - (CH2) N (R) (R').

In some embodiments, R3 is hydrogen. In certain other embodiments, R 3 is a linear or branched C α _ 4 aliphatic group.

In some embodiments, Rw is selected from hydrogen, aliphatic, alkylcarbonylamino or alkoxy.

In some embodiments, each presentation of WRW is independently -alkyl C? -3, -O (C? _3 alkyl), -CF3, -OCF3, -SCF3, -F, -Cl, -Br, -S02NH2, - COOR ', -COR', -0 (CH2) 2N (R) (R '), -0 (CH2) N (R) (R'), -CON (R) (R '), - (CH2) 2OR ', - (CH2) 0', optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfonyl, optionally substituted 5-membered heteroaryl ring, -N (R) (R '), - (CH2) 2N (R) (R' ), or - (CH2) N (R) (R '). In other embodiments, -WR is selected from aliphatic, alkoxy or alkylcarbonylamino.

In various embodiments R10 of formula III is cycloaliphatic. Examples of R 10 include cyclohexyl, cyclopropyl, cyclopentyl or cyclobutyl, each of which is optionally substituted with 1-3 aliphatic, aryl, or heteroaryl. If R 10 is substituted with aliphatic, halo, aryl or heteroaryl, said aliphatic, halo, aryl, or heteroaryl may be optionally substituted with 1-3 alkoxy, halo, or aliphatic.

In other embodiments, R10 is heterocycloaliphatic. Examples of R 10 include tetrahydrofuryl, piperidinyl or pyrrolidinyl, each of which is optionally substituted with 1-3 aliphatic, halo, aryl, or heteroaryl. If R 10 is substituted with aliphatic, halo, aryl, or heteroaryl, said aliphatic, halo, aryl, or heteroaryl may be optionally substituted with 1-3 alkoxy, halo or aliphatic.

In other embodiments, R10, of formula III, is one selected from: In various embodiments, R 11 is optionally substituted aryl or heteroaryl. In various embodiments R 11 is optionally substituted with 1-3 substituents independently selected from halo, aliphatic, aryl, heteroaryl alkoxy. Yes »?? is substituted with an aliphatic, aryl, heteroaryl, or alkoxy, said aliphatic, aryl, heteroaryl or alkoxy may be optionally substituted with 1-3 alkoxy, aliphatic or halo.

In several additional embodiments, R11 is one selected from: In still other embodiments, R3 and R4 together form a 5- to 7-membered heterocycloaliphatic optionally substituted with 1-3 of -WR. In specific embodiments, R3 and R4 together form an optionally substituted piperidine or an optionally substituted piperazine.

Representative compounds of the invention include: . General Synthesis Schemes The compounds of formula I can be prepared by methods known in the art. The following schemes 1 and 2 illustrate an example of a synthesis method for the compounds of formula I.

Scheme 1: Scheme 2: The indole oxalylchlorides and starting indoloxalic acids are commercially available or prepared by known methods.

Examples of compounds of the present invention prepared according to Schemes 1 and 2 are mentioned in the Examples below.

. Uses, formulation and administration Acceptable compositions for pharmaceutical use As described above, the present invention provides compounds that are useful as modulators of ABC transporters and thus are useful for the treatment of diseases, disorders or pathologies such as cystic fibrosis, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, familial hypercholesterolemia, type 1 chylomicronemia, Abetalipoproteinemia, lysosomal storage diseases, such as I / Pseudo-Hurler cell disease, mucopolysaccharidosis, Sandhof / Tay-Sachs (Crigler-Najjar type II) , polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (ID), neurohypophyseal DI , Nephrogenic DI, s Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various neurological disorders of polyglutamine such as Huntington's disease, ataxia Spinocerebellar type I, spinal and bulbar muscular atrophy, Palladoluis dentatorubral atrophy, and myotonic dystrophy, in addition to spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome (due to protein processing defects) of prion), Fabry disease and Straussler-Scheinker syndrome.

Accordingly, in another aspect of the present invention, compositions acceptable for pharmaceutical use are provided, wherein these compositions comprise any of the compounds described herein, and optionally comprise a carrier, adjuvant or vehicle, acceptable for pharmaceutical use. In certain embodiments, these compositions optionally also comprise one or more additional therapeutic agents.

It will also be appreciated that some of the compounds of the present invention may exist in free form for treatment or when appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. In accordance with the present invention, a pharmaceutically acceptable derivative or prodrug includes, but is not limited to, salts, acceptable esters for pharmaceutical use, salts of said esters or any other adduct or derivative that after administration to a patient who it is capable of providing, directly or indirectly, a compound as described otherwise herein, or a metabolite or residue thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that are, within the scope of the medical standard, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity , irritation, allergic responses and the like, and in accordance with a reasonable risk / benefit ratio. An "acceptable salt for pharmaceutical use" means any non-toxic salt or salt of an ester of a compound of this invention which, after administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention or an active inhibitory metabolite or residue of this.

Salts acceptable for pharmaceutical use are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Acceptable salts for pharmaceutical use of the compounds of this invention include those derived from suitable inorganic and organic bases and acids. Examples of acceptable salts for pharmaceutical use, the addition salts of nontoxic acids are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods used in the art such as ion exchange. Other acceptable salts for pharmaceutical use include adipate salts, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate , hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 4) alkyl 4 salts. This invention also provides for quaternization of any of the basic nitrogen-containing groups of the compounds described herein. Water-soluble or liposoluble dispersible products can be obtained by said quaternization. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. The additional pharmaceutical acceptable salts for use include, when appropriate, nontoxic ammonium cations, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a carrier, adjuvant, or vehicle acceptable for pharmaceutical use, which, as used herein, includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives , solid binders, lubricants and the like, suitable for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams &; Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.

Boylan, 1988-1999, Marcel Dekker, New York, whose contents are incorporated by reference herein, describe various carriers using in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Except to the extent that some means of the conventional carrier is incompatible with the compounds of the invention, such as by the production of some undesirable biological effect or by otherwise interacting in a detrimental way with any of the other component (s). ) of the composition acceptable for pharmaceutical use, its use is contemplated within the scope of this invention. Some examples of materials that can act as acceptable carriers for pharmaceutical use include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial mixtures of glyceride of vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polymers in polyethylene-polyoxypropylene block, wool grease, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such cocoa butter and suppository waxes, oils such as peanut oil, cotton oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid, pyrogen-free water; isotonic saline solution; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, in addition to other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, in addition to coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the criteria of the formulator.

Uses of compounds and compositions acceptable for pharmaceutical use In still another aspect, the present invention provides a method of treating a pathology, disease or disorder involved by the activity of the ABC transporter. In certain embodiments, the present invention provides a method of treating a pathology, disease or disorder involved with a deficiency of ABC transporter activity, the method comprising administering a composition according to a compound of formula (I) to a subject , preferably a mammal that needs it.

In preferred embodiments, the present invention provides a method of treating cystic fibrosis, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, deficiencies in lipid processing, such as familial hypercholesterolemia. , chylomicronemia type 1, Abetalipoproteinemia, lysosomal storage diseases, such as I / Pseudo-Hurler cell disease, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, deficiency of myeloperoxidase, primary hypoparathyroidism, melanoma, CDG type 1 glycosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (ID), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various neurological disorders of polyglutamine such as Huntington's disease, spinocerebellar ataxia type I, muscular atrophy spinal and bulbar, paludoluisian dentatorubral atrophy, and myotonic dystrophy, in addition to spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to processing defects of the prion protein), Fabry disease, Straussler-Scheinker syndrome, secretory diarrhea , polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formula (I), or their preferred embodiments as was exposed previously.

According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of formula (I), or one of its preferred embodiments as set forth above.

According to the invention an "effective amount" of the compound or composition acceptable for pharmaceutical use is the amount effective to treat or reduce the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as Protein C deficiency, hereditary angioedema type 1, deficiencies in lipid processing, such as familial hypercholesterolemia, chylomicronemia type 1, Abetalipoproteinemia, lysosomal storage diseases, such as, cell disease I / Pseudo-Hurler, mucopolysaccharidosis, Sandhof / Tay -Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycanosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency , diabetes insipidus (ID), DI neurohipof isaria, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various neurological polyglutamine disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal muscular and bulbar atrophy, paludoluisian dentatorubral atrophy, and myotonic dystrophy, in addition to spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome.

The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of effective administration to treat or reduce the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation deficiencies. -fibrinolysis, such as Protein C deficiency, hereditary angioedema type 1, deficiencies in lipid processing, such as familial hypercholesterolemia, type 1 chylomicronemia, Abetalipoproteinemia, lysosomal storage diseases, such as, cell disease I / Pseudo-Hurler, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glyconosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hypofibrinogenemia hereditary, ACT deficiency, d iabetes insipidus (ID), neuropituitary DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several neurological disorders of polyglutamine such as Huntington's disease, type I spinocerebellar ataxia, spinal and bulbar muscular atrophy, paludoluisal dentatorubral atrophy, and myotonic dystrophy, in addition to spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjögren's syndrome.

The amount needed will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like. The compounds of the invention are preferably formulated in a unit dosage form to facilitate administration and uniformity of dosage. The term "unit dose form" as used herein refers to a physically discrete unit of the agent appropriate for the treated patient. It will be understood, however, that the use of the total daily dose of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific level of effective dose for a particular patient or organism will depend on a variety of factors including the disorder treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound employed and similar factors known in the medical arts. The term "patient", as used herein, means an animal, for example, a mammal and more specifically a human being.

Acceptable compositions for pharmaceutical use of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally, as an oral or nasal spray or similar, according to the severity of the infection treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dose levels of from about 0.1 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, body weight of the subject per day, once or twice per day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, syrups and elixirs acceptable for pharmaceutical use. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polietilenglicloes and esters of sorbitan and their mixtures. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and perfuming agents.

Injectable preparations, e.g. sterile injectable or oleaginous suspensions, may be formulated according to the known art using suitable dispersing agents and humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a diluent or solvent for non-toxic parenteral use, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulation can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other injectable medium before use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be obtained by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn, may depend on the crystalline size and the crystalline form. Alternatively, the delayed absorption of a compound administered parenterally is obtained by dissolving or suspending the compound in an oily vehicle. The depot injectable forms are prepared by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. According to the ratio of the compound to the polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by capturing the compound in liposomes or microemulsions that are compatible with body tissues.

Rectal or vaginal administration compositions are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquids at body temperature and consequently melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, lozenges, powders and granules. In said solid dosage forms, the active compound is mixed with at least one inert excipient or carrier, acceptable for pharmaceutical use such as sodium citrate or dicalcium phosphate and / or to) fillers or expanders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch potato or cassava, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, pol solid ethylene glycols, sodium lauryl sulphate and their mixtures. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of similar type can also be used as fillers in soft and hard gelatin capsules by excipients such as lactose or sweetened milk in addition to high molecular weight polyethylene glycols, and the like. Solid dosage forms of tablets, dragees, capsules, lozenges and granules can be prepared with coatings and shells such as enteric coatings and other well-known coatings in the pharmaceutical formulation are. These may optionally contain opacifying agents and may also be of a composition that allows only the active component (s) to be released, or preferably, in a certain part of the intestinal tract, optionally, in a delayed form. Examples of included compositions that may be used include polymeric substances and waxes. Solid compositions of similar type can also be used as fillers in soft and hard gelatin capsules by excipients such as lactose or sweetened milk in addition to high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients indicated above. The solid dosage forms of tablets, dragees, capsules, lozenges and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other well-known coatings in the pharmaceutical formulation are. In said solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said dosage forms may also comprise, in normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. These may optionally contain opacifying agents and may also be of a composition that allows only the active component (s) to be released, or preferably, in a certain part of the intestinal tract, optionally, in a delayed form. Examples of included compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a vehicle acceptable for pharmaceutical use and also preservatives or necessary buffer solutions may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled release of a compound to the body. Said dosage forms are prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by the provision of a membrane that controls the rate or by the dispersion of the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as modulators of ABC transporters. Thus, without being bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of a disease, pathology or disorder wherein the hyperactivity or inactivity of the ABC transporters is involved in the disease, pathology or disorder. . When the hyperactivity or inactivity of the ABC transporters is involved in a particular disease, pathology or disorder, the disease, pathology or disorder may also be referred to as a "disease, pathology or disorder mediated by the ABC transporter". Accordingly, in another aspect, the present invention provides a method for treating or reducing the severity of a disease, pathology or disorder where hyperactivity or inactivity of an ABC transporter is involved in the disease state.

The activity of a compound used in this invention as modulator of an ABC transporter can be assayed according to the methods generally described in the art and in the Examples herein.

It will also be appreciated that the compounds and compositions acceptable for pharmaceutical use of the present invention can be employed in combination therapies, ie, the compounds and compositions acceptable for pharmaceutical use can be administered concurrently, pre-or post-treatment, to one or more desired medical or therapeutic procedures. The combination of particular therapies (therapies or procedures) used in a combination regimen will take into account the compatibility of the therapies and / or procedures and the therapeutic effect that is desired. It will also be appreciated that the therapies employed can obtain a desired effect for the same disorder (e.g., a compound of the invention may be administered concurrently with another agent used to treat the same disorder), or may obtain different effects (eg, control of some adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, disorder or pathology are known as "appropriate for the disease, disorder or condition treated." The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that should normally be administered in a composition comprising this therapeutic agent as a single active agent. Preferably, the amount of additional therapeutic agent in the presently described compositions will vary from about 50% to 100% of the amount normally present in a composition comprising this agent as a therapeutically active agent.

The compounds of this invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular transplants, stent and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention generally described above and in the classes and subclasses of the present specification, and a suitable vehicle for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention described generally above, and in the classes and subclasses of the present specification, and a suitable vehicle for coating said implantable device. . Suitable covers and general preparation of the coated implantable devices are described in US Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The covers are usually biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The covers can optionally also be covered with a suitable top layer of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to modulating the activity of the ABC transporter in a biological sample or a patient (eg, in vi tro or in vivo), said method comprising administering to the patient or contacting said biological sample with a compound of Formula I or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

The modulation of the activity of the ABC transporter in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of new modulators of ABC transporters.

In still another embodiment, there is provided a method of modulating the activity of an anionic channel in vi tro or in vivo, comprising the step of contacting said channel with a compound of formula (I). In preferred embodiments, the anion channel is a chloride channel or a bicarbonate channel. In other preferred embodiments, the anion channel is a chloride channel.

According to an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formula (I). The term "functional ABC transporter" as used herein means an ABC transporter that is capable of carrying out transport activity. In preferred embodiments, said functional ABC transporter is CFTR.

According to another preferred embodiment, the activity of the transporter ABC is measured by the transmembrane voltage potential. Means for measuring the voltage potential across a membrane in a biological sample can employ any of the methods known in the art, such as membrane potential optical assay or other electrophysiological methods.

The membrane potential optical test uses voltage sensitive FRET sensors described by González and Tsien (Ver, González, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4): 1272 -80, and González, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77) in combination with instrumentation to measure fluorescence changes such as Reader Voltage / ion probe (VIPR) (See, Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439 ).

These voltage sensitive assays are based on the change of fluorescence resonance energy transfer (FRET) between the membrane-sensitive voltage sensitive dye, DiSBAC2 (3) and a fluorescent phospholipid, CC2-DMPE, which is attached to the sheet externally of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause DiSBAC2 (3) with negative charge to redistribute through the plasma membrane and therefore change the amount of energy transfer of CC2-DMPE. Changes in fluorescence emission can be controlled by VIPR ™ II, which is an integrated liquid dispenser and a fluorescent detector designed to perform cell-based assays in 96- or 384-well microtiter plates.

In another aspect the present invention provides a kit for use to measure the activity of a transporter ABC or a fragment thereof in an in vitro or in vivo biological sample comprising (i) a composition comprising a compound of formula (I) or any of the foregoing embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring the activity of said ABC transporter or a fragment thereof. In one embodiment, the kit further comprises instructions for a)) contacting the additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound and c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I). In preferred embodiments, the kit is used to measure the density of CFTR.

For a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed in any way as a limitation of this invention. 6. Examples The syntheses of examples of compounds are described in the following Examples.

Example 1: N-Benzhydril-2- (lH-indol-3-yl) -2-oxo-ace amide N-Benzhydryl-2- (lH-indol-3-yl) -2-oxo-acetamide was synthesized following from scheme I above from (lH-indol-3-yl) -oxo-acetyl chloride and C, C -diphenyl-methylamine. Performance (52%). HPLC retention time 3.59 min, 10-99% CH3CN, run for 5 minutes; 1 H NMR (400 MHz, DMSO-d 6) d 12.26 (s, 1 H), 9.56 (d, J = 9.1 Hz, 1 H), 8.56 (d, J = 3.2 Hz, 1 H ), 8.22 (m, 1H), 7.54 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J = 9.1 Hz, 1H); ESI-MS 355.5 m / z (MH +).

Example 2: 2- (lH-Indol-3-yl) -2-oxo-N-phenethyl-acetamide 2- (lH-indol-3-yl) -2-oxo-N-phenethyl-acetamide was synthesized following scheme I above from (lH-indol-3-yl) -oxo-acetyl chloride and phenethylamine. Performance (61%). HPLC retention time 3.17 min, 10-99% CH3CN, run 5 minutes; X H NMR (400 MHz, DMSO-d 6) d 12.23 (s, 1 H), 8.79 (t, J = 5.9 Hz, 1 H), 8.67 (s, 1 H), 8.23 (m , 1H), 7.53 (m, 1H), 7.33-7.19 (m, 7H), 3.47 (m, 2H), 2.85 (t, J = 7.4 Hz, 2H); ESI-MS 293.3 m / z (MH +).

Example 5: N, N-Dibenzyl-2- (lH-indol-3-yl) -2-oxo-acetamide N, N-dibenzyl-2- (lH-indol-3-yl) -2-oxo-acetamide was synthesized following scheme I above from (lH-indol-3-yl) -oxo-acetyl chloride and dibenzylamine . Performance (58%). HPLC retention time 3.52 min, 10-99% CH3CN, run 5 minutes; X H NMR (400 MHz, DMSO-d 6) d 12.36 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 3.3 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.54 (m, 1H), 7.43-7.39 (m, 2H), 7.35-7.22 (m, 10H), 4.54 (s, 2H), 4.41 (s, 2H); ESI-MS 369.3 m / z (MH +).

Example 10: 2- (l-Methyl-lH-indol-3-yl) -2-oxo-N-phenethyl-actamide 2- (l-Methyl-lH-indol-3-yl) -2-oxo-N-phenethyl-acetamide was synthesized following scheme II above from (l-methyl-lH-indol-3-yl) - oxo-acetic and phenethylamine. Performance (61%). HPLC retention time 3.38 min, 10-99% CH3CN, run 5 minutes; H NMR (400 MHz, DMSO-d6) d 8.80 (t, J = 5.9 Hz, 1H), 8.73 (s, 1H), 8.25 (m, 1H), 7.60 (m , 1H), 7.36-7.20 (m, 7H), 3.91 (s, 3H), 3.47 (m, 2H), 2.86 (t, J = 7.4 Hz, 2H); ESI-MS 307.3 m / z (MH +).

Example 12: N-Benzhydril-2- (l-methyl-lH-indol-3-yl) -2-oxo-acetamide N-benzhydryl-2- (l-methyl-lH-indol-3-yl) -2-oxo-acetamide was synthesized following Scheme II above from (l-methyl-lH-indol-3-yl) - oxo-acetic acid and C, C-diphenyl-methylamine. Performance (11%). HPLC retention time 3.79 min, 10-99% CH3CN, run for 5 minutes; X H NMR (400 MHz, DMSO-d 6) d 9.56 (d, J = 9.1 Hz, 1 H), 8.65 (s, 1 H), 8.24 (, 1 H), 7.61 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J = 9.1 Hz, 1H), 3.90 (s, 3H); ESI-MS 369.1 m / z (MH +).

Example 14 N-Benzyl-2- (lH-indol-3-yl) -N-methyl-2-oxo-acetamide N-benzyl-2- (lH-indol-3-yl) -N-methyl-2-oxo-acetamide was synthesized following scheme I above from (lH-indol-3-yl) -oxo-acetyl chloride and benzylmethylamine. Performance (54%). HPLC retention time 2.96 min, 10-99% CH3CN, run for 5 minutes; X H NMR (400 MHz, DMSO-d 6) d 12.35 (s, 1 H), 8.25 (s, 0.5 H), 8.13-8.11 (m, 1.5 H), 7.54 ( m, 1H), 7.44-7.23 (, 7H), 4.68 (s, 1H), 4.47 (s, 1H), 2.88 (s, 1.5H), 2.85 ( s, 1.5H); ESI-MS 293.3 m / z (MH +).

Example 15: N, N-Dibenzyl-2- (l-methyl-lH-indol-3-yl) -2-oxo-acetamide N, N-dibenzyl-2- (l-methyl-lH-indol-3-yl) -2-oxo-acetamide was synthesized following scheme II above from (l-methyl-lH-indol-3-yl) acid ) -oxo-acetic and dibenzylamine. Performance (70%). HPLC retention time 3.70 min, 10-99% CH3CN, run 5 minutes; * H NMR (400 MHz, DMSO-d6) d 8.28 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.43-7.25 (m, 12H), 4.55 (s, 2H), 4.40 (s, 2H), 3.93 (s, 3H); ESI-MS 383.3 m / z (MH +).

Example 18: N- (2,2-Diphenylethyl) -2- (lH-indol-3-yl) -2-oxo-acetamide N- (2, 2-Diphenylethyl) -2- (lH-indol-3-yl) -2-oxo-acetamide was synthesized following the scheme I above from (lH-indol-3-yl) -oxo chloride -acetyl and 2,2-diphenyl-ethylamine. Performance (48%). HPLC retention time 3.55 min, 10-99% CH3CN, run 5 minutes; X H NMR (400 MHz, DMSO-d 6) d 12.22 (s, 1 H), 8.70 (t, J = 5.9 Hz, 1 H), 8.50 (s, 1 H), 8.17 (m , 1H), 7.52 (m, 1H), 7.36-7.18 (m, 12H), 4.43 (t, J = 8.0 Hz, 1H), 3.90 (dd, J = 8.0, 6.0 Hz, 2H); ESI-MS 369.3 m / z (MH +).

Persons reasonably skilled in the chemical arts can use the above examples and schemes to synthesize the compounds of the present invention, which include the compounds of Table 1.

The data for the characterization of the compounds of the present invention prepared according to the previous Examples are set forth below.

Table 2 Examples of compounds of the formulas (I, II, III and IV) * obtained with a 3 minute HPLC method 7. Tests for the detection and measurement of the correction properties of? 508-CFTR Optical methods of membrane potential to examine the modulation properties of? F508-CFTR of the compounds The optical test of the membrane potential used voltage sensitive FRET sensors described by González and Tsien (Ver, González, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69 (4): 1272 -80, and González, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77) in combination with instrumentation to measure fluorescence changes such as the ion voltage / probe (VIPR) reader (VerL Gonzalez, JE, K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431- 439).

These voltage sensitive assays are based on the change of fluorescence resonance energy transfer (FRET) between the membrane-sensitive voltage sensitive dye, DiSBAC2 (3) and a fluorescent phospholipid, CC2-DMPE, which is attached to the sheet externally of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause DiSBAC2 (3) with negative charge to redistribute through the plasma membrane and therefore change the amount of energy transfer of CC2-DMPE. Changes in fluorescence emission can be controlled by VIPR ™ II, which is an integrated liquid dispenser and fluorescent detector designed to perform cell-based assays in 96- or 384-well microtiter plates.

Identification of correction compounds To identify small molecules that correct the circulation defect associated with? F508-CFTR; a simple addition HTS assay format was developed. The cells were incubated in a serum-free medium for 16 hours at 37 ° C in the presence or absence (negative control) of the test compound. As a positive control, the cells were incubated in 384-well plates for 16 hours at 27 ° C with "F508-CFTR" "correct temperature". The cells were subsequently washed 3X with Krebs Ringer solution and loaded with the voltage sensitive dyes. To activate? F508-CFTR, 10 μM of forskolin and the CFTR enhancer, genistein (20 μM), were added together with the Cl free medium "to each well.The addition of Cl free medium promoted the efflux of Cl" in response to the activation of? F508-CFTR and the resulting membrane depolarization was optically controlled using voltage sensitive dyes based on FRET.

Identification of enhancing compounds To identify? F508-CFTR enhancers, ase developed a double-addition HTS assay format. During the first addition, Cl free medium was added with or without test compound to each well After 22 seconds, a second addition of Cl free medium containing 2-10 μM of forskolin was added to activate F508. -CFTR. The extracellular concentration of Cl "after both additions was 28 mM, which promoted the efflux of Cl ~ in response to the activation of? F508-CFTR and the resulting membrane depolarization was optically controlled using voltage sensitive dyes based on FRET.

Solutions Bath solution # 1: (in mM) 160 NaCl, 4.5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, pH 7.4 with NaOH.

Chloride-free bath solution: chloride salts from bath solution # 1 are replaced with gluconate salts.

CC2-DMPE: Prepared as a standard solution of 10 mM in DMSO and stored at -20 ° C.

DiSBAC2 (3): Prepared as a standard solution of 10 mM in DMSO and stored at -20 ° C.

Cell culture NIH3T3 mouse fibroblasts stably expressing? F508-CFTR are used for optical measurements of the membrane potential. Cells are maintained at 37 ° C in 5% C02 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, ß-ME, 1 X pen / strep, and 25 mM of HEPES in 175 cm2 culture flasks. In all optical assays, cells were seeded at 30,000 / well in plates coated with 384-well gel matrix and cultured for 2 hours at 37 ° C before culturing at 27 ° C for 24 hours for the enhancer assay . In the correction assays, the cells were cultured at 27 ° C or 37 ° C with and without compounds for 16-24 hours.

Electrophysiological tests to examine the modulation properties of? F508-CFTR of the compounds 1. Trial with Ussing camera Ussing chamber experiments were performed on polarized epithelial cells expressing? F508-CFTR to further characterize the? F508-CFTR modulators identified in the optical assays. FRT? F508-CFTR epithelial cells cultured in Costar Snapwell cell culture inserts were mounted on a Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were short-circuited continuously using a voltage clamping system (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA ). The transepithelial resistance was measured by the application of a 2-mV pulse. Under these conditions, the FRT epithelia showed resistances of 4 KO / cm2 or more. The solutions were maintained at 27 ° C and bubbled with air. The contact potential of the electrode and the resistance of the fluid were corrected using a cell-free insert. Under these conditions, the current reflects the flow of Cl "through? F508-CFTR expressed on the apical membrane, ISc was digitally obtained using an MP100A-CE interface and AcqKnowledge computer program (v3.2.6; BIOPAC Systems, Santa Bárbara, CA).

Identification of correction compounds The typical protocol used a gradient of Cl concentration in the apical membrane.To establish this gradient, a normal Ringer's solution was used in the basolateral membrane, while the apical NaCl was replaced with equimolar sodium gluconate (titrated to pH 7). , 4 with NaOH) to give a gradient of large Cl concentration through the epithelium. All experiments were performed with intact monolayers. For total activation of? F508-CFTR, forskolin (10 μM) and the PDE inhibitor, IBMX (100 μM) were applied, followed by the addition of the CFTR enhancer, genistein (50 μM).

As observed in other cell types, incubation at low temperatures of FRT cells expressing stably F508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of the correction compounds, the cells were incubated with 10 μM of the test compound for 24 hours at 37 ° C and subsequently washed 3X before recording. Isc mediated by cAMP and genistein in cells treated with the compound was normalized in the controls at 27 ° C and 37 ° C and expressed as a percentage of activity. The preincubation of the cells with the correction compound significantly increased the Isc mediated by cAMP and genistein compared to the controls of 37 ° C.

Identification of enhancing compounds The typical protocol used a gradient of Cl concentration from the basolateral to the apical membrane.To establish this gradient, a normal ringer solution was used in the basolateral membrane and permeabilized with nystatin (360 μg / ml), while the aCl Apical was replaced with equimolar sodium gluconate (titrated at pH 7.4 with NaOH) to give a large Cl ~ concentration gradient across the epithelium All the experiments were performed 30 minutes after the permeabilization with nystatin Forskolin was added (10 μM) and all test compounds on both sides of the cell culture inserts The efficacy of the putative? F508-CFTR enhancers was compared with that of the known enhancer, genistein.

Solutions Basolateral solution (in mM): NaCl (135), CaCl 2 (1,2), MgCl 2 (1,2), K2HP04 (2,4), KHP04 (0,6), N-2-hydroxyethylpiperazine-N '- 2-ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated to pH 7.4 with NaOH.

Apical solution (in mM): Same as the basolateral solution with NaCl replaced with Na gluconate (135).

Cell culture Fisher rat epithelial cells (FRT) expressing? F508-CFTR (FRT? F508-CFTR) were used for the Ussing chamber experiments for the putative modulators? F508-CFTR identified from our optical assays. The cells were cultured in Costar Snapwell cell culture inserts and cultured for five days at 37 ° C and 5% C02 in Co-modified Ham's F-12 medium supplemented with 5% fetal sheep serum, 100 U / ml penicillin and 100 μg / ml streptomycin. Before using for the characterization of the potentiated activity of the compounds, the cells were incubated at 27 ° C for 16-48 hours to correct the? F508-CFTR. To determine the correction activity of the compounds, the cells were incubated at 27 ° C or 37 ° C with and without the compounds for 24 hours. 2. Full cell records The current of? F508-macroscopic CFTR (I? FSOT) in NIH3T3 cells that stably express? F508-CFTR corrected for temperature and test compounds was monitored using the whole cell patch with punched patch. Briefly, the I? FSOT voltage clamp records were performed at room temperature using a Axopatch 200B zonal clamp amplifier (Axon Instruments Inc., Foster City, CA). All records were obtained with a sampling frequency of 10 kHz and low pass filter at 1 kHz. the pipettes had a resistance of 5-6 MO when filled with the intracellular solution. Under these recording conditions, the investment potential calculated for Cl "(EC?) At room temperature was -28 mV All records showed a sealing strength >; 20 GO and a series resistor < 15 MO. Pulse generation, data acquisition and analysis were performed using a PC equipped with a Digidata 1320 A / D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The batch contained < 250 μl of saline and it was pre-perfused continuously at a rate of 2 ml / min using a gravity-operated perfusion system.

Identification of correction compounds To determine the activity of correction compounds to increase the density of functional F508-CFTRs in the plasma membrane, we use the perforated patch registration techniques described above to measure the current density after 24 hours of treatment with the correction compounds. To fully activate F508-CFTR, 10 μM of forskolin and 20 μM of genistein were added to the cells. In our recording conditions, the current density after 24 hours of incubation at 27 ° C was higher than that observed after 24 hours of incubation at 37 ° C. These results are compatible with the known effects of incubation at low temperature on the density of? F508-CFTR in the plasma membrane. To determine the effects of the correction compounds on the CFTR current density, the cells were incubated with 10 μM of the test compound for 24 hours at 37 ° C and the current density was compared with the controls of 27 ° C and 37 ° C (% activity). Before registration, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 μM of correction compounds significantly increased the AMPc and genistein-dependent current compared to the controls at 37 ° C.

Identification of the enhancing compound We also investigated the ability of the? F508-CFTR enhancers to increase the macroscopic current? F508-CFTR Cl "(I? FSOT) in NIH3T3 cells that stably express? F508-CFTR by perforated patch registration techniques. The enhancers identified from the optical assays caused by a dose-dependent increase in I? FSOT with power and efficiency similar to that observed in the optical assays.In all the cells examined, the inversion potential before and during the application of the enhancer It was around -30 mV, which is the calculated EC (-28 mV).

Solutions Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl2 (1), HEPES (10), and 240 μg / ml amphotericin-B (pH adjusted to 7.35 with CsOH).

Extracellular solution (in mM):? netil-D-glucamine (NMDG) -Cl (150), MgCl 2 (2), CaCl 2 (2), HEPES (10) (pH adjusted to 7,35 with HCl).

Cell culture NIH3T3 mouse fibroblasts stably expressing? F508-CFTR are used for whole-cell logs. Cells are maintained at 37 ° C in 5% C02 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, ß-ME, 1 X pen / strep, and 25 mM of HEPES in 175 cm2 culture flasks. In all complete cell counts, 2,500-5,000 cells were seeded on glass coverslips coated with poly-L-lysine and cultured for 24-48 hours at 27 ° C before use to test the activity of the enhancers; and incubated with or without the correction compound at 37 ° C to measure the activity of correctors. 3. Single channel records The single channel activities of? F508-CFTR corrected for temperature stably expressed in NIH3T3 cells and the activities of enhancer compounds using membrane patch cleaved from the inside out were observed. Briefly, the voltage clamp records of the single channel activity were performed at room temperature with a Axopatch 200B zone clamp amplifier (Axon Instruments Inc.). All records were obtained with a sampling frequency of 10 kHz and a low pass filter at 400 Hz. The pipettes were manufactured from Corning Kovar Sealing # 7052 glass (World Precision Instruments, Inc., Sarasota, FL) and presented a resistance of 5-8 MO when filled with the intracellular solution. The? F508-CFTR was activated after excision, by the addition of 1 mM Mg-ATP and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA); Promega Corp. Madison, Wl). After stabilizing the channel activity, the patch was perfused using a gravity-operated perfusion system. The influx was placed adjacent to the patch, which produces the complete solution exchange within 1-2 seconds. In order to maintain CFTR? F508 activity during rapid perfusion, the non-specific phosphatase inhibitor F "(10 mM NaF) was added to the bath solution.In these recording conditions, the activity of the channel remained constant throughout. the duration of the patch registration (up to 60 minutes) The currents produced by the positive charges that move from the intracellular to the extracellular solutions (anions moving in the opposite direction) are shown as positive currents. Vp) was maintained at 80 mV.

The channel activity of the membrane patches containing < 2 active channels. The maximum number of simultaneous holes determined the number of active channels during the course of an experiment. To determine the single channel current amplitude, the recorded 120-second data of the CFTR? F508 activity was filtered "off-line" at 100 Hz and then used to construct amplitude histograms of total points that were adjusted to Multigaussian functions using the computer program Bio-Patch Analysis (Bio-Logic Comp.France). The total microscopic current and the open probability (P0) were determined from 120 seconds of channel activity. The P0 was determined using the Bio-Patch computer program or the P0 = I / i (N) ratio, where I = average current, i = single channel current amplitude and N = number of active channels in the patch.

Solutions Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl 2 (5), MgCl 2 (2), and HEPES (10) (pH adjusted to 7,35 with Tris base).

Intracellular solution (in mM): NMDG-C1 (150), MgCl2 (2), EGTA (5), TES (10), and base Tris (14) (pH adjusted to 7.35 with HCl).

Cell culture Fibroblasts from NIH3T3 mice that stably express F508-CFTR are used for the membrane cleaved zonal clamp records. Cells are maintained at 37 ° C in 5% C02 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 X NEAA, ß-ME, 1 X pen / strep, and 25 mM of HEPES in 175 cm2 culture flasks. In single-channel logs, 2,500-5,000 cells were seeded onto glass coverslips coated with poly-L-lysine and cultured for 24-48 hours at 27 ° C before use.

The compounds of the invention are useful as modulators of ATP binding cassette transporters. The following Table 3 illustrates the EC50 and the relative efficacy of certain embodiments of Table 1.

In the following Table 3, the following meanings apply: EC50: "+++" means < 1 uM; "++" means between luM to 5 uM; "+" means more than 5 uM.

Table 3 OTHER FORMS OF REALIZATION It is understood that while the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims (56)

1. A method of modulating the activity of the transporter ABC comprising the step of contacting said transporter ABC with a compound of formula (I): or its acceptable salt for pharmaceutical use, where: Each R1 is independently R ', halo, N02, or CN; Each R2 is independently -XR '; Each X is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of X are optionally independently replaced with -CO -, - CS-, -COCO-, -CONR'-, - CONR'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR '-, -NR'NR'CO- , -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each R 'is independently selected from hydrogen or an optionally substituted group selected from an aliphatic group C? -8, a monocyclic or bicyclic ring with a 3 to 8 membered bridge, saturated, partially saturated or fully saturated having 0-3 heteroatoms selected independently between nitrogen, oxygen, or sulfur, or a bicyclic or tricyclic ring of 8-12 members saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two presentations of R 'are taken together with the atom (s) to which they are attached to form a saturated, partially saturated or fully saturated monocyclic or bicyclic ring of 3-12 members having 0-4 selected heteroatoms independently between nitrogen, oxygen, or sulfur, each R 'group different from hydrogen is optionally substituted with 1-3 of -WR; Each m is independently 0-4; Each R3 is independently H or an aliphatic group C? _8 optionally substituted with -X-RA and where up to two methylene units of the aliphatic group R3 can be replaced with -CO-, -CH2S-, -CONR'-, -CONR'NR '-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR 'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each RA is independently R ', halo, N02, or CN; Each R4 is a (cycloaliphatic) alkyl, (heterocycloaliphatic) alkyl, aralkyl, or heteroaralkyl wherein the alkyl portion of R4 is optionally substituted with R5 and where up to two methylene units of the alkyl portion of R4 may be replaced with -CO-, - CS-, CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'- , -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'- , and the cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl portions of R4 are optionally substituted with 1-3 of -WR, or R4 is RB, or R3 and R4 together with the nitrogen to which they are attached can form a 5- to 7-membered heterocycloaliphatic ring optionally substituted with 1 to 3 R '; RB is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally fused with an aryl or heteroaryl wherein RB is attached to the nitrogen atom via the cycloaliphatic or heterocycloaliphatic ring, and RB is optionally substituted with 1-3 of -WRW; Each R5 is independently aryl, heteroaryl, C? _8 aralkyl or C? -8 heteroaralkyl where the alkyl portion of R5 is optionally substituted with Rw and where up to two methylene units of the alkyl portion of R5 can be replaced with -CO-, - CS-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ' -, NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR '-, -S02NR' -, -NR'S02-, or -NR'S02NR'- , and the aryl or heteroaryl portions of R5 are optionally substituted with 1-3 of -WR; Each W is independently a bond or is an optionally substituted Ci-β alkylidene chain where up to two methylene units of W are optionally independently replaced with -CO -, - CS-, -COCO-, -CONR'-, -CONR ' NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR '-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Y Each R is independently R ', halo, N02, CN, CF3, -0 (C1-4 alkyl), -0CF3, or phenyl which is optionally substituted with 1-3 halo, haloalkyl, alkoxy, or aliphatic; Provided the compounds do not include, in the 5-position of the, the groups: -C (O) - (optionally substituted piperidinyl) -CH 2 - (optionally substituted phenyl), or -C (0) - (optionally substituted piperazinyl) - (C 1-4 alkyl) - (optionally substituted phenyl).

2. The method according to claim 1, wherein each R4 is aralkyl Ci-β or heteroaralkyl C? _8 where the alkyl portion of R4 is optionally substituted with R5 and where up to two methylene units of the alkyl portion of R4 may be replaced with - CO-, -CS-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, - NR'NR '-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR' S02- or -NR 'S02NR'-, and the aryl or heteroaryl portions of R4 are optionally substituted with 1-3 of -WRW.

3. The method according to claim 1, wherein m is 1 or 2.

4. The method according to claim 1, wherein each occurrence of WR is independently -Calkyl -3.0 (C3-alkyl), -CF3, -0CF3, -SCF3, -F, -Cl, -Br, -S02NH2, -COOR ', -COR', -0 (CH2) 2N (R) (R '), -0 (CH2) N (R) (R'), -C0N (R) (R '), - (CH2) 2OR ', - (CH2) 0', optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfonyl, optionally substituted 5-membered heteroaryl ring, -N (R) (R '), - (CH2) 2N (R ) (R '), or - (CH2) N (R) (R').

5. The method according to claim 1, wherein m is 0.

6. The method according to claim 1, wherein m is 1.

7. The method according to claim 1, wherein m is 2.

8. The method according to claim 1, wherein R 4 is (cycloaliphatic) alkyl, (heterocycloaliphatic) alkyl, aralkyl or heteroaralkyl in which the alkyl portion of R 4 is substituted with R 5.

9. The method according to claim 8, wherein R5 is an optionally substituted C? _4 aliphatic group.

10. The method according to claim 8, wherein R 4 is an aralkyl or a heteroaralkyl optionally substituted with WRW.

11. The method according to claim 10, wherein W is a bond or is an optionally substituted C? -6 alkylidene chain where one or two adjacent methylene units are optionally independently replaced with -O-, -NR'-, -S -, -S02-, -COO-, or -CO-.

12. The method according to claim 11, wherein Rw is R 'or halo.

13. The method according to claim 12, wherein m is 1-4 and -WR is selected from aliphatic, alkoxy, or alkylcarbonylamino group.

14. The method according to claim 1, wherein R3 is H.

15. The method according to claim 1, wherein m is 1, 2, or 3, and each X is independently a bond or is an optionally substituted C 1 -6 alkylidene chain where one or two non-adjacent methylene units are optionally replaced independent with -0-, -NR-, -S-, -S02-, -COO- or -C0-.

16. The method according to claim 15, wherein R1 is R 'or halo.

17. The method according to claim 1, wherein m is 1-4, and each occurrence of -XR1 is independently -Calkyl -3, -0 (C? -3 alkyl), -CF3, -0CF3, -SCF3, -F, -Cl, -Br, -S02NH2, -COOR ', -COR', -0 (CH2) 2N (R ') (R'), -0 (CH2) N (R ') (R'), -C0N (R ') (R'), - (CH2) 2OR ', - (CH2) 0', optionally substituted phenyl, -N (R ') (R'), - (CH2) 2N (R ') ( R '), or - (CH2) N (R') (R ').

18. The method according to claim 16, wherein each R 'is independently aliphatic.

19. A method of modulating the activity of the transporter ABC comprising the step of contacting said transporter ABC with a compound of formula (Illa): Illa or one of its acceptable salts for pharmaceutical use, where: Each R1 is independently R ', halo, N02, or CN; Each R2 is independently -XR '; Each X is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of X are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR' -, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; each R 'is independently selected from hydrogen or an optionally substituted group selected from the C? -8 aliphatic group, a monocyclic or bicyclic ring with saturated, partially saturated or fully saturated 3-8 membered bridge having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bicyclic or tricyclic ring of 8-12 members saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two presentations of R 'are taken together with the atom (s) to which they are attached to form a monocyclic or bicyclic ring optionally substituted 3-12 membered, saturated, partially saturated or fully saturated having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R 'group different from hydrogen is optionally substituted with 1-3 of -WRW; Each m is independently 0-4; Each R3 is independently H or an aliphatic group C? _8 optionally substituted with -X-RA and where up to two methylene units of the aliphatic group R3 can be replaced with -CO-, -CH2S-, -CONR'-, -CONR'NR '-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR 'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each RA is independently R ', halo, N02, or CN; Each W is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of W are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR' -, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each R is independently R ', halo, N02, CN, CF3, -O (C? -4 alkyl), -0CF3, or phenyl which is optionally substituted with 1-3 halo, haloalkyl, alkoxy or aliphatic; The Zz ring is a cycloaliphatic or heterocycloaliphatic group, each of which is optionally substituted with 1-3 halo, haloalkyl, alkoxy, aliphatic, aryl, or heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1-3 halo , alkoxy, haloalkyl or aliphatic; Each RE is independently halo, haloalkyl, alkoxy, or aliphatic; and Each d is independently O to 3.

20. A method of modulating the activity of the transporter ABC comprising the step of contacting said transporter ABC with a compound of formula (II) II or one of its acceptable salts for pharmaceutical use, where: Each R1 is independently R ', halo, N02, or CN; Each R2 is independently -XR ', halo, N02, or CN; Each R is independently H or an aliphatic group Ci-β optionally substituted with -X-RA and where up to two methylene units of the aliphatic group R3 can be replaced with -CO-, -CH2S-, -CONR'-, -CONR'NR '-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR 'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-NR'S02NR'-; Each RA is independently R ', halo, N02, or CN; Each m is independently 0-4; Each X is independently a bond or is an optionally substituted C1-6 alkylidene chain where up to two methylene units of X are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR ' NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR '-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; each R 'is independently selected from hydrogen or an optionally substituted group selected from an aliphatic group C? _ß, a monocyclic or bicyclic ring with saturated, partially saturated or fully saturated 3-8 membered bridge having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bicyclic or tricyclic 8-12 member ring system saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two presentations of R 'are taken together with the atom (s) to which they are attached to form an optionally substituted, partially saturated or fully saturated 3- to 12-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R 'group different from hydrogen is optionally substituted with 1-3 of -WRW; Each AA and AB is independently aryl, heteroaryl, or heterocycloaliphatic optionally substituted with 1-3 of -WR; Each Yi and Y2 is independently a bond or is an optionally substituted C ?_6 alkylidene chain where up to two methylene units of the C?-6 alkylidene chain are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, - NR'NR'CO-, -NR'CO-, S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each W is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of W are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each Rw is independently R ', halo, N02, CN, CF3, -O (C1-4 alkyl) or -OCF3; Y Each E is independently a bond or is an alkylidene chain i-Ce where up to two methylene units of the alkylidene chain C? _6 are optionally independently replaced with -C (0) -, -CS-, -COCO-, CONR ' -, CONR'NR'-, -C02-, -OCO-, -NR'C02, -O-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO- , -S-, -SO-, S02-, -NR '-, -S02NR'-, -NR' S02-, or -NR'S02NR'-.

21. The method according to claim 20, wherein R2 is H.

22. The method according to claim 20, wherein one of Y1 and Y2 is a C? -C4 alkylidene chain where a methylene unit of the C1-C4 alkylidene chain is optionally replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR '-, -NR' NR '-, - NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-.

23. The method according to claim 22, wherein a methylene unit of the C 1 -C 4 alkylidene chain is replaced with -CO-, -CS-, -0-, -S-, -SO-, -S02-, or - NR'-.

24. The method according to claim 23, wherein a methylene unit of the C1-C4 alkylidene chain is replaced with -0-, -S-, or -NR'-.

25. The method according to claim 24, wherein a methylene unit of the C1-C4 alkylidene chain is replaced with -0- or -S-.

26. The method according to claim 22, wherein one of Y1 e? 2 is C? -C4 alkyl.

27. The method according to claim 20, wherein AA is an optionally substituted 6-membered aromatic ring having 1-3 heteroatoms or AA is an optionally substituted phenyl.

28. The method according to claim 27, wherein AA is phenyl.

29. The method according to claim 27, wherein AA is a pyridyl, pyrimidinyl, pyrazinyl, 1, 3, 5-triazinyl or 1, 2,4-triazinyl optionally substituted.

30. The method according to claim 20, wherein AA is an optionally substituted 5-membered aromatic ring having 1-3 heteroatoms, wherein said heteroatom is nitrogen, oxygen or sulfur.

31. The method according to claim 30, wherein AA is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms.

32. The method according to claim 1, wherein the compound is selected from:

33. A method of treating or reducing the severity of a disease mediated by the ABC transporter comprising administering a compound described in any of claims 1, 19, and 20 to a mammal.

34. The method according to claim 33, wherein the disease mediated by the ABC transporter is cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary angioedema type 1, familial hypercholesterolemia, chylomicronemia type 1, Abetalipoproteinemia, cell disease I / Pseudo-Hurler, mucopolysaccharidosis, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, CDG type 1 glycosis, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (ID), neurohypophyseal DI, nephrogenic DI, Charcot syndrome -Marie Tooth, Perlizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, Palladoluis dentatorubral atrophy, dystrophy myotonic, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye syndrome and Sjögren's disease.

35. A compound of formula (II): II or one of its acceptable salts for pharmaceutical use, where: Each R1 is independently R ', halo, NO2, or CN; Each R2 is independently -XR ', halo, NO2, or CN; Each R3 is independently H or a C1-8 aliphatic group optionally substituted with -X-RA and where up to two methylene units of the aliphatic group R3 can be replaced with -CO-, -CH2S-, -CONR'-, -CONR'NR '-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR 'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each m is independently 0-4; Each X is independently a bond or is an optionally substituted Ci-Ce alkylidene chain where up to two methylene units of X are optionally independently replaced with -C0 -, - CS-, -COCO-, -CONR'-, -CONR ' NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR'CONR'-, -OCONR'-, -NR'NR '-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each R 'is independently selected from hydrogen or an optionally substituted Ci-β aliphatic group, monocyclic or bicyclic ring with 3-8 membered saturated, partially saturated or fully saturated bridge having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 member bicyclic or tricyclic ring system saturated, partially saturated or fully saturated having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two presentations of R 'are taken together with the atom (s) which bind to form a saturated, partially saturated or fully saturated monocyclic or bicyclic ring of 3-12 members having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R 'group different from hydrogen is optionally substituted with 1-3 of -WR; Each RA is independently R ', halo, N02, or CN; Each AA and AB is independently aryl, heteroaryl, or heterocycloaliphatic optionally substituted with 1-3 of -WRW; Each Yi and Y2 is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of the C? _6 alkylidene chain are optionally independently replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR'-, - NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each W is independently a bond or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of W are optionally independently replaced with -C0 -, - CS-, -COCO-, -CONR'-, -CONR 'NR'-, -C02-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR' -, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR'-, -NR'S02-, or -NR'S02NR'-; Each R is independently R ', halo, N02, CN, CF, -0 (C? -4 alkyl) or -0CF3; Y Each E is bond independently or is an optionally substituted C? -6 alkylidene chain where up to two methylene units of the C? -6 alkylidene chain are optionally independently replaced with -C (O) -, -CS-, -COCO- , CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02, -O-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, - NR'CO-, -S-, -SO-, S02-, -NR'-, -S02NR'-, -NR'S02-, -NR'S02NR'-; provided that the compound is not N- [1 - [(3,5-difluorophenyl) methyl] -3 - [[(3-ethylphenyl) methyl] amino] -2-hydroxypropyl] -l-methyl-a-oxo-lH -indol-3-acetamide, 2- (1H-indol-3-yl) -N- (2-morpholino-l-phenylethyl) -2-oxoacetamide, or N- (1,3-bis (benzylthio) propan-2 -yl) -2- (lH-indol-3-yl) -2-oxoacetamide.

36. The compound according to claim 35, wherein R2 is H.

37. The compound according to claim 36, wherein one of Y1 and Y2 is a C? -C4 alkylidene chain where a methylene unit of the alkylidene chain C? C4 is optionally replaced with -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -C02-, -OCO-, -NR'C02-, -O-, -NR ' CONR'-, -OCONR '-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -S02-, -NR'-, -S02NR' -, -NR'S02- or -NR'S02NR'-.

38. The compound according to claim 37, wherein a methylene unit of the C1-C4 alkylidene chain is replaced with -CO-, -CS-, -O-, -S-, -SO-, -S02- or -NR ' -.

39. The compound according to claim 38, wherein a methylene unit of the C1-C alkylidene chain is replaced with -0-, -S- or -NR'-.

40. The compound according to claim 39, wherein a methylene unit of the C1-C4 alkylidene chain is replaced with -0- or -S-.

41. The compound according to claim 40, wherein one of Y1 and Y2 is a C1-C4 alkylidene chain.

42. The compound according to claim 35, wherein AA is an optionally substituted 6-membered aromatic ring having 1-3 heteroatoms or AA is an optionally substituted phenyl.

43. The compound according to claim 35, wherein AA is phenyl.

44. The compound according to claim 35, wherein AA is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl.

45. The compound according to claim 35, wherein AA is an optionally substituted 5-membered aromatic ring having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.

46. The compound according to claim 35, wherein m is 1, 2, or 3, and each X is independently a bond or an optionally substituted Ci-β alkylidene chain where one or two non-adjacent methylene units are optionally independently replaced. with -0-, -NR-, -S-, -S02-, -COO- or -C0-.

47. The compound according to claim 46, wherein R1 is R 'or halo.

48. The compound according to claim 35, wherein m is 1, 2, or 3, and each presentation of -XR1 is independently halo, -alkyl C? -3, -0 (C? -3 alkyl), -CF3 , -0CF3, -SCF3, -F, -Cl, -Br, -S02NH2, -COOR ', -COR', 0 (CH2) 2N (R) (R '), -0 (CH2) N (R) ( R '), -C0N (R) (R'), - (CH2) 2OR ', - (CH2) 0', optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfonyl, optionally substituted 5-membered heteroaryl ring, -N (R) (R '), - (CH2) 2N (R) (R') or - (CH2) N (R) (R ').

49. The compound according to claim 35, wherein R3 is H.

50. A compound selected from:

51. A pharmaceutical composition comprising: (i) a compound according to claim 35; Y (ii) an acceptable vehicle for pharmaceutical use.

52. The composition according to claim 51, further optionally comprises an additional agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator or a nutritional agent.

53. A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound according to claim 35.

54. The method according to claim 53, wherein the conveyor ABC is CFTR.

55. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: (i) a composition comprising a compound according to any of claims 1, 19, 20, and 35; (ii) instructions for: a) contacting the composition with the biological sample; b) Measurement of activity of said ABC transporter or fragment thereof.

56. The kit according to claim 55, wherein the kit is used to measure the density of CFTR. 146 CELLAR CONVEYOR MODULATORS WITH ATP UNION SUMMARY The present invention relates to modulators of ATP binding cassette transporters ("ABCs") or fragments thereof, including the transmembrane conductance regulator of cystic fibrosis ("CFTR"), its compositions and methods that they use them The present invention also relates to methods of treating diseases mediated by the ABC transporter by said modulators.