WO2015143376A1 - Nouveaux composés destinés au traitement de la mucoviscidose - Google Patents

Nouveaux composés destinés au traitement de la mucoviscidose Download PDF

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WO2015143376A1
WO2015143376A1 PCT/US2015/021841 US2015021841W WO2015143376A1 WO 2015143376 A1 WO2015143376 A1 WO 2015143376A1 US 2015021841 W US2015021841 W US 2015021841W WO 2015143376 A1 WO2015143376 A1 WO 2015143376A1
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methyl
benzodioxol
difluoro
compound
group
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Xicheng Sun
Jian Qiu
Adam Stout
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Nivalis Therapeutics Inc
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Nivalis Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is directed to novel compounds, pharmaceutical compositions comprising such compounds, and the methods of making and using the same. These compounds are useful as modulators of Cystic Fibrosis Transmembrane Conductor Regulator (CFTR).
  • CFTR Cystic Fibrosis Transmembrane Conductor Regulator
  • the present invention also relates to methods of treating or lessening the severity of cystic fibrosis in a patient. These compounds may be used alone or in
  • Cystic fibrosis is one of the most common lethal genetic diseases in
  • CF cystic fibrosis transmembrane regulator
  • the present invention provides compounds that are modulators of the CFTR protein.
  • the present invention also provides methods for treating or lessening the severity of CF, alone or in combination with one or more secondary active agents. Also encompassed by the invention are pharmaceutical compositions comprising at least one compound and at least one pharmaceutically acceptable carrier. Also encompassed by the invention are pharmaceutical compositions comprising at least one compound for the treatment of cystic fibrosis.
  • compositions of the present invention can be prepared in any suitable pharmaceutically acceptable dosage form.
  • the methods of the invention encompass administration with one or more secondary active agents. Such administration can be sequential or in a combination composition.
  • Cystic fibrosis is a lethal genetic disease affecting 70,000 people worldwide, Approximately one in 3,500 children in the US is born with CF each year. It is a disease that affects all racial and ethnic groups, but is more common among Caucasians. An estimated 30,000 American adults and children have CF, and the median predicted age of survival is 36.8 years (CFF Registry Report 2011, Cystic Fibrosis Foundation, Bethesda, MD). CF is an autosomal recessive hereditary disease caused by a mutation in the gene for the cystic fibrosis transmembrane regulator (CFTR) protein.
  • CFTR cystic fibrosis transmembrane regulator
  • CFTR aids the regulation of epithelial salt and water transport in multiple organs, including the lung, pancreas, liver, and intestinal tract.
  • Clinical manifestations of CF include abnormal sweat electrolytes, chronic and progressive respiratory disease, exocrine pancreatic dysfunction, and infertility; however, it is lung disease that is the primary cause of morbidity and mortality.
  • the loss of CFTR mediated CI " secretion is believed to cause airway surface dehydration due to both a decrease in CFTR-mediated CI " and fluid secretion and a secondary increase in epithelial Na " channel (E aC) -mediated Na "1" and fluid absorption. This imbalance results in dehydration of the airway surface, and likely contributes to the deleterious cascade of mucus accumulation, infection, inflammation, and destruction that characterizes CF lung disease.
  • E aC epithelial Na " channel
  • CFTR activators act on their own to stimulate CFTR -mediated ion transport and include agents that increase cAMP levels, such as ⁇ - adrenergic agonists, adenylate cyclase activators, and phosphodiesterase inhibitors.
  • CFTR potentiators act in the presence of endogenous or pharmacological CFTR activators to increase the channel gating activity of cell-surface localized CFTR, resulting in enhanced ion transport.
  • CFTR correctors act by increasing the delivery and amount of functional CFTR protein to the cell surface, resulting in enhanced ion transport.
  • CFTR activators, potentiators, and correctors may be coadministered to maximize clinical efficacy or therapeutic window, if needed, CFTR antagonists act by decreasing CFTR-mediated ion transport and are being developed for the treatment of polycystic kidney disease and cholera-induced secretory diarrhea.
  • F508del-CFTR class II
  • F508del-CFTR class II
  • the lack of transport of chloride and accompanying water across the airway epithelium and excessive sodium reabsorption leads to dehydrated airway surface fluid, impaired mucociliary clearance, infection and inflammation.
  • the compounds of the present invention may provide a novel therapeutic strategy in cystic fibrosis (CF).
  • the present invention provides compounds that are modulators of CFTR.
  • compounds having the structure depicted below (Formula 1), or a pharmaceutically acceptable salt, stereoisomer, prodrug, metabolite thereof.
  • Ri is selected from
  • Ri groups taken together to form a 4-7 membered saturated, partially saturated, or aromatic ring with up to 3 ring atoms independently selected from O, NR 6 , and S and wherein the fused ring may optionally be substituted by one or more halogen or CrC 3 alkyl;
  • R 2 and R 3 each independently of one another are selected from the group consisting of
  • substituents are selected from cyano, hydroxyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, and halogen, a C3-C6 cycloalkyl group, in which a methylene unit in the cyclic moiety may optionally be replaced by a -NR 6 - group, an oxygen, or a sulphur atom, and optionally the cycloalkyl groups and heterocycloalkyl groups may be substituted by halogen; and
  • R 2 and R 3 cannot both be hydrogen
  • R 4 is selected from the group consisting of
  • oxygen atom wherein substitutions are selected from cyano, hydroxyl, and halogen;
  • Ring D is selected from an optionally substituted 5 or 6 membered ring which may be
  • n is selected from 0, 1, 2, and 3;
  • n is selected from 0, 1, 2, and 3.
  • two Ri groups are taken together to form a 4-7 membered saturated, partially saturated, or aromatic ring with up to 3 ring atoms independently selected from O, NR 6 , and S and wherein the fused ring may optionally be substituted by one or more halogen or Ci-C 3 alkyl.
  • the ring formed by two Ri groups taken together is an optionally substituted five membered ring wherein up to two atoms may be replaced by a heteroatom.
  • the fused ring system formed by two Ri groups taken together has the structure shown in formula 2.
  • R5 and R 6 are independently selected from hydrogen, halogen and C1-C3 alkyl.
  • both R5 and R 6 are fluorine.
  • both R5 and R 6 are hydrogen.
  • R 2 and R 3 are independently selected from the group consisting of an optionally substituted C -C alkyl group and an optionally substituted C -C alkyl group having one methylene unit replaced by an oxygen atom. Substitutions for the R 2 and R 3 groups are selected from cyano, hydroxyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, and halogen.
  • R 2 and R are independently selected from the group consisting of an optionally substituted CrC 3 alkyl group.
  • R 2 is methyl
  • R is methyl
  • both R 2 and R are methyl.
  • R 4 is selected from the group consisting of an optionally substituted C C 6 alkyl group and an optionally substituted C C 6 alkyl group having one methylene unit replaced by an oxygen atom. Substitutions for the R 4 group are selected from halogen, cyano, and hydroxyl.
  • R 4 is selected from the group consisting of an optionally substituted CrC 3 alkyl group.
  • R 4 is methyl
  • the B ring has the structure shown in Formula 3.
  • the D ring is an optionally substituted 5 membered ring.
  • the D ring is an optionally substituted 6 membered ring.
  • the D ring is an optionally substituted 5 membered ring with at least one heteroatom selected from N, O, and S.
  • the D ring is an optionally substituted 6 membered ring with at least one heteroatom selected from N, O, and S.
  • the fused C, D ring system has the structure shown in formula 4.
  • E, F and G are independently selected from the group consisting of CR x R y , N, NR Z , O,
  • R x and R y are independently selected from the group consisting of H, optionally
  • R z is selected from the group consisting of H, and optionally substituted C C 6 alkyl; bond a and bond b are independently selected from single or double bonds, provided that both are not double bonds.
  • the C, D ring system is selected from the group consistin of
  • the C, D ring system is selected from the group
  • compounds of Formula 1 are selected from the group consisting of
  • the compound of Formula 1 has a fused ring system formed by two R groups taken together with ring A having the structure shown in formula 2
  • R5 and R 6 are independently selected from hydrogen, halogen and Q-C3 alkyl, and wherein R 2 and R 3 are both methyl, and wherein the B ring has the structure shown in Formula 3,
  • the compound of Formula 1 has a fused ring system formed by two R groups taken together with ring A having the structure shown in Formula 2
  • R5 and R 6 are independently selected from hydrogen, halogen and CrC 3 alkyl, and wherein R 2 and R are both methyl, wherein the B ring has the structure shown in Formula 3,
  • the C, D ring system is selected from the group
  • the C, D ring system is selected from the group
  • the C, D ring system is selected from the group
  • the C, D ring system is selected from the group consisting of
  • compounds of Formula 1 are selected from the group consisting of
  • the C, D ring system is selected from the group consisting of
  • the C, D ring system is selected from the group
  • R 1; R 2 , R 3 , R4, Ring D, m and n are as defined above,
  • X is selected from the group consisting of CR 7 and N;
  • Y is selected from the group consisting of CR 7 and N;
  • R 7 is selected from the group consisting of H and halogen.
  • the C, D ring system of Formula 5 is selected from the group consisting of
  • the C, D ring system of Formula 5 is selected from the
  • compounds of Formula 5 are selected from the group consisting of
  • the compounds described herein may have asymmetric centers.
  • isomers arising from such asymmetry are included within the scope of the invention, unless indicated otherwise.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
  • the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • Alkenes can include either the E- or Z-geometry, where appropriate.
  • Example 1 The compounds of Example 1 (and Table 1 below) list representative compounds of Formula 1 and Formula 5.
  • the synthetic methods that can be used to prepare the compounds are described in Example 1, with reference to the synthetic scheme depicted before Example 1, and reference to intermediates described in Example 2. Coupling starting materials are also described in Example 2. Supporting mass spectrometry data and/or proton NMR data for each compound is included in Example 1. CFTR modulator activity was determined by the assay described in Example 3 and EC 50 values were obtained. The EC 50 values are shown as a range in Table 1 in the following manner: an EC 50 value ⁇ 100nM is designated the letter a and an EC 50 range of 100 ⁇ -1 ⁇ is designated the letter b.
  • acyl includes compounds and moieties that contain the acetyl radical (CH 3 CO-) or a carbonyl group to which a straight or branched chain lower alkyl residue is attached.
  • alkyl refers to a straight or branched chain
  • (CrC 6 ) alkyl is meant to include, but is not limited to methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, iert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl.
  • An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.
  • alkenyl refers to a straight or branched chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one double bond.
  • Examples of a (C 2 -C 8 ) alkenyl group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene.
  • An alkenyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.
  • alkynyl refers to a straight or branched chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond.
  • Examples of a (C 2 -C 8 ) alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1- heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, and 4-octyne.
  • An alkynyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.
  • alkoxy refers to an -O-alkyl group having the indicated number of carbon atoms.
  • a (CrC 6 ) alkoxy group includes -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-iert-butyl, -O-pentyl, -O- isopentyl, -O-neopentyl, -O-hexyl, -O-isohexyl, and -O-neohexyl.
  • aminoalkyl refers to an alkyl group (typically one to six carbon atoms) wherein one or more of the CrC 6 alkyl group' s hydrogen atoms is replaced with an amine of formula -N(R C ) 2 , wherein each occurrence of R c is independently - H or (Ci-C ) alkyl.
  • aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , t-butylaminomethyl,
  • aryl refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic aromatic ring system.
  • Examples of an aryl group include phenyl and naphthyl.
  • An aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • aryl groups include phenyl or aryl heterocycles such as, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • bioactivity indicates an effect on one or more cellular or extracellular process (e.g. , via binding, signaling, etc.) which can impact physiological or pathophysiological processes.
  • carbonyl includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carboxy or “carboxyl” means a -COOH group or carboxylic acid.
  • Acidic moiety as used herein is defined as a carboxylic acid or a carboxylic acid bioisostere. Bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. For a review of bioisosteres, see J. Med. Chem, 2011, 54, 2529-2591. Examples of “acidic moiety” include but are not limited to
  • Pharmacophore is defined as "a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity" (Gund, Prog. Mol. Subcell. Biol., 5: pp 117-143 (1977)).
  • C m - C n means “m” number of carbon atoms to "n” number of carbon atoms.
  • Ci-C means one to six carbon atoms (C 1; C 2 , C 3 , C 4 , C 5 , or C 6 ).
  • C 2 -C 6 includes two to six carbon atoms (C 2 , C 3 , C 4 , C 5 , or C 6 ).
  • C 3 -C 6 includes three to six carbon atoms (C 3 , C 4 , C 5 , or C 6 ).
  • cycloalkyl refers to a 3- to 14-membered saturated or unsaturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Included in this class are cycloalkyl groups which are fused to a benzene ring.
  • Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3- cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, - 1,3,5-cycloheptatrienyl, cyclooctyl, cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl, - 1,3,5-cyclooctatrienyl, decahydronaphthalene, octahydronaphthalene, hexahydronaphthalene, octahydroinden
  • a cycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • haloalkyl refers to a CrC 6 alkyl group wherein from one or more of the CrC 6 alkyl group's hydrogen atom is replaced with a halogen atom, which can be the same or different.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, pentachloroethyl, and 1,1,1 -trifluoro-2-bromo-2-chloroethyl.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain alkyl, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, and S can be placed at any position of the heteroalkyl group.
  • Up to two heteroatoms can be consecutive, for example, -CH 2 -NH-OCH 3 .
  • a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
  • the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well.
  • a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH 2 SH.
  • a heteroalkyl group can be an oxyalkyl group.
  • (C 2 _Cs) oxyalkyl is meant to include, for example -CH 2 -0-CH (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH 2 CH 2 CH 2 CH 2 OH, - OCH 2 CH 2 OCH 2 CH 2 OH, - OCH 2 CH(OH)CH 2 OH, and the like.
  • heteroaryl refers to an aromatic heterocycle ring of
  • heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thienyl, benzothienyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl
  • heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • heterocycle refers to 3- to 14-membered ring systems which are either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized, including monocyclic, bicyclic, and tricyclic ring systems.
  • the bicyclic and tricyclic ring systems may encompass a heterocycle or heteroaryl fused to a benzene ring.
  • the heterocycle can be attached via any heteroatom or carbon atom, where chemically acceptable.
  • Heterocycles include heteroaryls as defined above.
  • heterocycles include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl, triazolyl,
  • a heterocycle group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
  • heterocycloalkyl by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of “heteroalkyl.” Additionally, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • hydroxyalkyl refers to an alkyl group having the indicated number of carbon atoms wherein one or more of the hydrogen atoms in the alkyl group is replaced with an -OH group.
  • hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH, and branched versions thereof.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • N-oxide or amine oxide
  • R N + -0 ⁇ a compound derived from a tertiary amine by the attachment of one oxygen atom to the nitrogen atom, R N + -0 ⁇ .
  • R N + -0 ⁇ the term includes the analogous derivatives of primary and secondary amines.
  • stereoisomer means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of a federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to such sterile liquids as water and oils.
  • a "pharmaceutically acceptable salt” or “salt” of a compound of the invention is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • a pharmaceutically acceptable salt can include, but is not limited to, acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Li, Na, and K, alkali earth metal salts such as Mg or Ca, or organic amine salts.
  • acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Li, Na, and K
  • a "pharmaceutical composition” is a formulation comprising the disclosed compounds or a combination thereof in a form suitable for administration to a subject.
  • a pharmaceutical composition of the invention is preferably formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, oral and parenteral, e.g. , intravenous, intradermal, subcutaneous, inhalation, topical, transdermal, transmucosal, and rectal administration.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • R d ' , R d " , and R d ' ' ' each independently refer to hydrogen, unsubstituted (Q-
  • R d ' and R d " are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5- , 6-, or 7-membered ring.
  • -NR d 'R d " can represent 1-pyrrolidinyl or 4- morpholinyl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being exemplary of the present invention.
  • An alkyl or heteroalkyl radical can be unsubstituted or monosubstituted. In some embodiments, an alkyl or heteroalkyl radical will be unsubstituted.
  • perfluoroalkoxy and perfluoro(C 1 -C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system.
  • R 6 ', R e " and R 6 '" are independently selected from hydrogen, unsubstituted
  • an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being exemplary in the present invention.
  • an aryl or heteroaryl group will be unsubstituted or monosubstituted.
  • an aryl or heteroaryl group will be unsubstituted.
  • Two of the substituents on adjacent atoms of an aryl or heteroaryl ring in an aryl or heteroaryl group as described herein may optionally be replaced with a substituent of the formula -T-C(0)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -0-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -J-(CH 2 ) r -K-, wherein J and K are independently -CH 2 -, -0-, -NH-, -S-, -S(O)-, - S(0) 2 -, -S(0) 2 NR '-, or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) r , where s and t are independently integers of from 0 to 3, and X is -0-, -NR f '-, -S-, -S(O)-, -S(0) 2 -, or - S(0) 2 NR a '-.
  • the substituent R f ' in -NR f '- and -S(0) 2 NR f '- is selected from hydrogen or unsubstituted (CrC 6 ) alkyl.
  • a "secondary active agent” is selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, a nutritional agent, or any agent known to treat CF.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the term "therapeutically effective amount” generally means the amount necessary to ameliorate at least one symptom of a disorder to be prevented, reduced, or treated as described herein.
  • the phrase "therapeutically effective amount” as it relates to the compounds of the present invention shall mean dosage that provides the specific pharmacological response for which the compound is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a compound that is administered to a particular subject in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
  • the phrase "therapeutically effective amount" as it relates to the secondary active agent of the present invention shall mean the dosage that provides the specific pharmacological response for which the secondary active agent is administered in a significant number of subjects in need of such treatment.
  • biological sample includes, but is not limited to, samples of blood
  • the invention encompasses pharmaceutical compositions comprising at least one compound of the invention described herein and at least one pharmaceutically acceptable carrier. Suitable carriers are described in "Remington: The Science and Practice, Twentieth Edition," published by Lippincott Williams & Wilkins, which is incorporated herein by reference. Pharmaceutical compositions according to the invention may also comprise one or more non-inventive compound active agents. [00107]
  • the pharmaceutical compositions of the invention can comprise novel compounds described herein, the pharmaceutical compositions can comprise known compounds which previously were not known to have CFTR modulatory activity, or a combination thereof.
  • compositions of the present invention can be employed in combination therapies, that is, the compounds and
  • compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired secondary active agents or medical procedures.
  • therapies secondary agents or procedures
  • the particular combination of therapies (secondary agents or procedures) to employ in a combination regimen will take into account compatibility of the desired agents and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, a compound of the present invention may be administered concurrently with a secondary agent used to treat the same disorder), or they may achieve different effects (such as control adverse effects).
  • the secondary active agent is selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, a nutritional agent, or any agent known to treat CF.
  • the secondary active agent is a GSNOR inhibitor.
  • the secondary active agent is a GSNOR inhibitor disclosed in WO2010/019903, U.S. Pat. No. 8,470,857, U.S. Pat. No.8,642,628,
  • the secondary active agent is a GSNOR inhibitor disclosed in WO2011/100433, U.S. Pat. No.US 8,481,590, WO2012/048181,
  • the secondary active agent is selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, genistein, Apigenin, cAMP/cGMP modulators such as rolipram, sildenafil, milrinone, tadalafil, aminone, isoproterenol, albuterol, and almeterol,
  • deoxyspergualin HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, terfenadine, enalapril, meclofenamic acid, carbaryl, suprofen, urosolic acid, zaprinast, benzo[c]quinolizinium derivatives that exhibit CFTR modulation activity, modulators of abc transporters, benzopyran derivatives that exhibit CFTR modulation activity, etc.
  • proteosome inhibitors such as epoxomicin, lactacystin, terfenadine, enalapril, meclofenamic acid, carbaryl, suprofen, urosolic acid, zaprinast, benzo[c]quinolizinium derivatives that exhibit CFTR modulation activity, modulators of abc transporters, benzopyran derivatives that exhibit CFTR modulation activity, etc.
  • the compounds of the invention can be utilized in any pharmaceutically acceptable dosage form, including, but not limited to injectable dosage forms, liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, dry powders, tablets, capsules, controlled release formulations, fast melt formulations, delayed release
  • the compounds of the invention described herein can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, intravenous, intra-arterial, intrathecal, intra-articular, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, tablets, sachets, and capsules; (c) into a dosage form selected from the group consisting of lyophilized formulations, dry powders, fast melt formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination thereof.
  • an inhalation formulation can be used to achieve high local concentrations.
  • Formulations suitable for inhalation include dry power or aerosolized or vaporized solutions, dispersions, or suspensions capable of being dispensed by an inhaler or nebulizer into the endobronchial or nasal cavity of infected patients to treat upper and lower respiratory bacterial infections.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can comprise one or more of the following components: (1) a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; (2) antibacterial agents such as benzyl alcohol or methyl parabens; (3) antioxidants such as ascorbic acid or sodium bisulfite; (4) chelating agents such as ethylenediaminetetraacetic acid; (5) buffers such as acetates, citrates, or phosphates; and (5) agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use may comprise sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the pharmaceutical composition should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol or sorbitol, and inorganic salts such as sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active reagent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating at least one compound of the invention into a sterile vehicle that contains a basic dispersion medium and any other required ingredients.
  • exemplary methods of preparation include vacuum drying and freeze-drying, both of which yield a powder of a compound of the invention plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed, for example, in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g. , a gas such as carbon dioxide, a nebulized liquid, or a dry powder from a suitable device.
  • a suitable propellant e.g. , a gas such as carbon dioxide, a nebulized liquid, or a dry powder from a suitable device.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active reagents are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the reagents can also be prepared in the form of suppositories (e.g. , with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the compounds of the invention are prepared with carriers that will protect against rapid elimination from the body.
  • a controlled release formulation can be used, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • suspensions of the compounds of the invention may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or liposomes.
  • Non-lipid polycationic amino polymers may also be used for delivery.
  • the suspension may also include suitable stabilizers or agents to increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the compound of the invention calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the compound of the invention and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active agent for the treatment of individuals.
  • compositions according to the invention comprising at least one compound of the invention can comprise one or more pharmaceutical excipients.
  • excipients include, but are not limited to binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • Exemplary excipients include: (1) binding agents which include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel PH101 and Avicel ® PH102, silicified microcrystalline cellulose (ProSolv SMCCTM), gum tragacanth and gelatin; (2) filling agents such as various starches, lactose, lactose
  • disintegrating agents such as alginic acid, Primogel, corn starch, lightly crosslinked polyvinyl pyrrolidone, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof;
  • lubricants including agents that act on the flowability of a powder to be compressed, include magnesium stearate, colloidal silicon dioxide, such as Aerosil 200, talc, stearic acid, calcium stearate, and silica gel; (5) glidants such as colloidal silicon dioxide; (6) preservatives, such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkon
  • Avicel PH101 and Avicel PHI 02 lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL21 ; dibasic calcium phosphate such as Emcompress ; mannitol; starch; sorbitol; sucrose; and glucose; (8) sweetening agents, including any natural or artificial sweetener, such as sucrose, saccharin sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame; (9) flavoring agents, such as peppermint, methyl salicylate, orange flavoring, Magnasweet (trademark of MAFCO), bubble gum flavor, fruit flavors, and the like; and (10) effervescent agents, including effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL21
  • dibasic calcium phosphate such as Em
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • the present invention provides pharmaceutical compositions that are useful in treating or lessening the severity of cystic fibrosis in a patient by administering to said patient an effective amount of a compound of the present invention alone or in combination with one or more secondary active agents (e.g. GSNOR inhibitor).
  • GSNOR inhibitor a secondary active agent
  • the secondary active agent is a GSNOR inhibitor disclosed in WO2010/019903, U.S. Pat. No. 8,470,857, U.S. Pat. No.8,642,628,
  • the secondary active agent is a GSNOR inhibitor disclosed in WO2011/100433, U.S. Pat. No.US 8,481,590, WO2012/048181,
  • the secondary active agent is selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, a nutritional agent, or any agent known to treat CF..
  • the secondary active agent is selected from
  • gentamicin curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP modulators such as rolipram, sildenafil, milrinone, tadalafil, aminone, isoproterenol, albuterol, and almeterol,
  • deoxyspergualin HSP 90 inhibitors
  • HSP 70 inhibitors proteosome inhibitors such as epoxomicin, lactacystin, abc transporters, benzo[c]quinolizinium derivatives, benzopyran derivatives, etc.
  • kits comprising the compositions of the invention.
  • kits can comprise, for example, (1) at least one compound of the invention; and (2) at least one pharmaceutically acceptable carrier, such as a solvent or solution.
  • Additional kit components can optionally include, for example: (1) any of the pharmaceutically acceptable excipients identified herein, such as stabilizers, buffers, etc., (2) at least one container, vial, or similar apparatus for holding and/or mixing the kit
  • delivery apparatus such as an inhaler, nebulizer, syringe, etc.
  • diastereomers can be achieved by routine procedures known in the art.
  • the separation of enantiomers of a compound can be achieved by the use of chiral HPLC and related chromatographic techniques.
  • Diastereomers can be similarly separated. In some instances, however, diastereomers can simply be separated physically, such as, for example, by controlled precipitation or crystallization.
  • the process of the invention when carried out as prescribed herein, can be conveniently performed at temperatures that are routinely accessible in the art.
  • the process is performed at a temperature in the range of about 25°C to about 110°C.
  • the temperature is in the range of about 40°C to about 100°C.
  • the temperature is in the range of about 50°C to about 95°C.
  • the base is not nucleophilic.
  • the base is selected from carbonates, phosphates, hydroxides, alkoxides, salts of disilazanes, and tertiary amines.
  • the process of the invention when performed as described herein, can be substantially complete after several minutes to after several hours depending upon the nature and quantity of reactants and reaction temperature.
  • the determination of when the reaction is substantially complete can be conveniently evaluated by ordinary techniques known in the art such as, for example, HPLC, LCMS, TLC, and 1H NMR.
  • the invention encompasses methods of preventing or treating (e.g. , alleviating one or more symptoms of) cystic fibrosis through use of one or more of the disclosed compounds.
  • the methods comprise administering a therapeutically effective amount of a compound of the invention to a patient in need.
  • the compositions of the invention can also be used for prophylactic therapy.
  • the compositions of the invention can include one or more secondary active agents.
  • the method is a method of treating or lessening the severity of cystic fibrosis in a patient, comprising the step of administering to said patient an effective amount of a compound of the present invention and pharmaceutical compositions comprising such compounds.
  • the compound of the invention used in the methods of treatment according to the invention can be: (1) a compound described herein, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a prodrug thereof, a metabolite thereof; (2) a compound which was known prior to the present invention, but wherein it was not known that the compound is a CFTR modulator, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a prodrug thereof, a metabolite thereof; or (3) a compound which was known prior to the present invention, and wherein it was known that the compound is a CFTR modulator, but wherein it was not known that the compound is useful for the methods of treatment described herein, or a pharmaceutically acceptable salt, a stereoisomer, a prodrug, a metabolite, (4) a compound of the present invention in combination with one or more secondary agents.
  • the methods of the present invention can be compounds of the invention employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired secondary active agents or medical procedures.
  • the particular combination of therapies (secondary agents or procedures) to employ in a combination regimen will take into account compatibility of the desired agents and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, a compound of the present invention may be administered
  • the patient can be any animal, domestic, livestock, or wild, including, but not limited to cats, dogs, horses, pigs, and cattle, and preferably human patients. As used herein, the terms patient and subject may be used interchangeably.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. More specifically, “treating” includes reversing, attenuating, alleviating, minimizing, suppressing, or halting at least one deleterious symptom or effect of a disease (disorder) state, disease progression, disease causative agent (e.g. , bacteria or viruses), or other abnormal condition. Treatment is continued as long as symptoms and/or pathology ameliorate.
  • a disease disorder
  • disease causative agent e.g. , bacteria or viruses
  • the dosage i.e. , the therapeutically effective amount
  • modulation may be achieved, for example, by administering one or more of the disclosed compounds that up regulates CFTR function. These compounds may be administered alone or in combination with other agents as described in detail herein.
  • the present invention provides a method of treating a subject afflicted with a disorder ameliorated by CFTR modulation. Such a method comprises administering to a subject a therapeutically effective amount of a compound of the present invention alone or in combination with a secondary active agent.
  • the disorders can include pulmonary disorders associated with CFTR modulation in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury (e.g. , pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary fibros, pulmonary fibrosis, pulmonary fibrosis, pulmonary embolism, asthma, pneumolism, pneuma, pneumolism, pneuma, pneumomediastinum, pneumolism, pneuma, pneumomediastinum, pneumomediastinum, pneumomediastinum, pneumomediastinum, pneumomediastinum, pneumomediastinum, pneumomediastinum, pneumos
  • fibrosis/interstitial lung diseases cystic fibrosis, COPD, primary ciliary dyskinesia, chronic bronchitis, respiratory tract infections
  • cardiovascular disease and heart disease e.g., hypertension, ischemic coronary syndromes, atherosclerosis, heart failure, right ventricular hypertrophy, pulmonary artery dilation
  • diseases characterized by angiogenesis e.g., coronary artery disease
  • neurological disorders e.g., pancreatic diseases (e.g., pancreatitis, diabetes), inflammatory diseases (e.g.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • GTD gastroesophageal reflux disease
  • disorders of ocular fluid balance e.g. keratoconjunctivitis sicca, recurrent corneal erosions, corneal edema, glaucoma, retinal detachment and retinal ischemia
  • disorders of the salivary gland e.g. , xerostomia, salivary gland hypofunction
  • reproductive disorders e.g., infertility, amenorrhea
  • bone disorders e.g.
  • osteoporosis osteoporosis
  • proliferative cell disorders e.g. , lung carcinoma
  • disorders where there is risk of thrombosis occurring e.g., pulmonary embosis
  • disorders where there is risk of restenosis occurring e.g., diabetes mellitus, diabetes, neurological disorders, and liver injury
  • diseases where there is risk of apoptosis occurring e.g., heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, and liver injury
  • treatment of psoriasis e.g., heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, and liver injury.
  • the disorder is cystic fibrosis.
  • Compounds of the invention are capable of treating and/or slowing the progression of cystic fibrosis. For approximately 90% of patients with CF, death results from progressive respiratory failure associated with impaired mucus clearance and excessive overgrowth of bacteria and fungi in the airways (Gibson et al., 2003, Proesmans et al., 2008). Compounds of the invention may positively modulate CFTR. Compounds of the invention are capable of treating and/or slowing the progression of CF. In this embodiment, appropriate amounts of compounds of the present invention are an amount sufficient to treat and/or slow the progression of CF and can be determined without undue experimentation by preclinical and/or clinical trials.
  • the therapeutically effective amount for the treatment of a subject afflicted with a CFTR mediated disorder is a bronchodilating effective amount; for cystic fibrosis, a therapeutically effective amount is an airway obstruction ameliorating effective amount or an amount effective in lessening the symptoms in the pancreas, GI tract, and/or liver caused by CF; for ARDS, a therapeutically effective amount is a hypoxemia ameliorating effective amount; for heart disease, a therapeutically effective amount is an angina relieving or angiogenesis inducing effective amount; for hypertension, a therapeutically effective amount is a blood pressure reducing effective amount; for ischemic coronary disorders, a therapeutic amount is a blood flow increasing effective amount; for atherosclerosis, a therapeutically effective amount is an endothelial dysfunction reversing effective amount; for glaucoma, a therapeutic amount is an ocular fluid balancing amount; for diseases characterized by angiogenesis,
  • the compounds of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer, prodrug, metabolite, or N-oxide thereof can be applied to various apparatus in circumstances when the presence of such compounds would be beneficial.
  • Such apparatus can be any device or container, for example, implantable devices in which a compound of the invention can be used to coat a surgical mesh or cardiovascular stent prior to implantation in a patient.
  • the compounds of the invention can also be applied to various apparatus for in vitro assay purposes or for culturing cells.
  • the compounds of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer, a prodrug, a metabolite, or an N-oxide thereof, can also be used as an agent for the development, isolation or purification of binding partners to compounds of the invention, such as antibodies, natural ligands, and the like. Those skilled in the art can readily determine related uses for the compounds of the present invention.
  • Example 1 lists representative novel analogs of Formula I and Formula 5 useful as modulators of CFTR.
  • An exemplary scheme below illustrates a general method of making the analogs of Example 1. Supporting mass spectrometry data and/or proton NMR data for each compound is also included in Example 1. Synthetic details for corresponding Intermediates and for starting materials are detailed in Example 2.
  • Scheme 1 illustrates a general method for preparing analogs described herein.
  • Conditions a or b a) microwave, 150°C, 30 min, b) 90-100 °C for 16 hours under N 2
  • Step 1 Synthesis of 2-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-2- methylpropanenitrile
  • Step 2 Synthesis of 2-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-2- methylpropanoic acid
  • Step 3 Synthesis of Intermediate 1 (N-(6-chloro-5-methylpyridin-2-yl)-2- (2,2-difluorobenzo[d][l,3]dioxol-5-yl)-2-methylpropanamide)
  • Step 1 Synthesis of 2-(benzo[d][l,3]dioxol-5-yl)-2-methylpropanenitrile.
  • Step 2 Synthesis of 2-(benzo[d][l,3]dioxol-5-yl)-2-methylpropanoic acid.
  • Step 3 Synthesis of 2-(benzo[d][l,3]dioxol-5-yl)-N-(6-chloro-5- methylpyridin-2-yl)-2-methylpropanamide (Intermediate 2).
  • Step 1 Synthesis of 2-bromo-N-(tert-butyl)-5-nitroaniline.
  • 2-bromo-5-nitroaniline 5.00 g, 23.0 mmol
  • tert-butyl 2,2,2- trichloroacetimidate (12.6 g, 57.6 mmol) in cyclohexane (30 mL)
  • BF 3 .Et 2 0 3.26 g, 23.0 mmol
  • Step 2 Synthesis of methyl (2-bromo-5-nitrophenyl)(tert- butyl)carbamate.
  • a solution of 2-bromo-N-(tert-butyl)-5-nitroaniline (2.60 g, 9.52 mmol) in methyl chloroformate (40 mL) was heated under reflux for 16 hours.
  • Aqueous work-up followed by silica gel column (PE/EtOAc, 10/1) gave the desired (1.40 g, yield: 44%) as a yellow solid.
  • Step 3 Synthesis of methyl 2,2-dimethyl-6-nitroindoline-l-carboxylate.
  • Step 5 Synthesis of methyl 6-bromo-2,2-dimethylindoline-l-carboxylate.
  • Step 6 Synthesis of 6-bromo-2,2-dimethylindoline (Intermediate 3). To a solution of methyl 6-bromo-2,2-dimethylindoline-l-carboxylate (150 mg, 0.528 mmol) in MeOH (4 mL) was added 20% aqueous NaOH (2 mL) at 15-20 °C. Then the mixture was heated at 60-70 °C for 20 hours. The mixture was concentrated and the residue was diluted with water (25 mL) and extracted with EtOAc (25 mL x2). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na 2 S0 4 and concentrated to give
  • YFP is a derivative of the green fluorescent protein (GFP). Its fluorescence is quenched in the presence of chloride at high concentrations. Its sensitivity to anions has been further improved by mutagenesis.
  • GFP green fluorescent protein
  • a convenient fluorescent probe is the halide- sensitive yellow fluorescent protein (HS-YFP).
  • HS-YFP halide- sensitive yellow fluorescent protein
  • the different sensitivity of the HS-YFP toward iodide and chloride allows one to perform assays measuring the transport of anions through the plasma membrane as changes in cell fluorescence.
  • the cells expressing HS-YFP are equilibrated in a physiological chloride-rich saline solution (e.g., Dulbecco's PBS).
  • Iodide influx quenches the cell fluorescence with a rate that depends on the halide permeability of cell membrane, and therefore, on the activity of anion channels or
  • F508del-CFTR correctors on a HTS assay platform.
  • Fischer Rat Thyroid (FRT) cells stably expressing YFP and F508del-CFTR and CFBE 41o- cells (CFBE) transiently transfected with YFP and F508del-CFTR were used for high throughput screening. Cells were incubated for 24-hrs in the presence of test compounds. The cells were washed to remove excess compound, stimulated with 20 ⁇ forskolin and 3 ⁇ of potentiator P3 in DPBS for 1-2 h, and the YFP signal quenching rate by iodide influx was then measured. The rate of fluorescence quenching is proportionally related to the total CFTR activities in the cell membrane.
  • F508del-CFTR correctors accelerate YFP quenching by increasing the number of CFTR molecules in the plasma membrane.
  • Dose response curves and EC 50 for each compound were obtained by fitting the data to the Hill's equation (Jinliang Sui and et al, Assay Drug Dev. Technol. 2010 Dec; 8(6):656-68).
  • F508del CFTR potentiators on a HTS assay platform Fischer rat thyroid (FRT) cells stably expressing YFP and F508del-CFTR were incubated overnight at 27 °C to induce maturation of F508del-CFTR. Cells were then washed with PBS buffer, treated for one to two hours at room temperature with Forskolin (20 ⁇ ) plus varying concentrations of GSNOR inhibitor. Potentiator activity was measured as YFP quenching rate by iodide influx. Iodide enters the cells via active CFTR channels in the plasma membrane, and quenches the YFP fluorescence. The rate of fluorescence quenching is proportionally related to the total CFTR activities in the cell membranes. F508del-CFTR potentiator accelerates YFP quenching by increasing overall CFTR activities in the plasma membrane.
  • FRT Fischer rat thyroid
  • Example 4 Ussing chamber measurements of CFTR activity in AF508 HAE cell monolayers treated with compounds of the present invention
  • HAE Human Airway Epithelial cells are grown at an air/liquid interface to obtain short-circuit current measurements in Ussing chambers. Cells are thawed from liquid nitrogen storage, washed and plated as passage 1 onto 100 mm cell culture plates for expansion in BEGM culture medium (Randell, et al. Primary Epithelial Cell Models for Cystic Fibrosis Research. Methods Mol Biol 2011; 742 : 285-310). At 80-90% confluency, cells are trypsinized, washed, suspended in ALI medium (Randell, et al.), and counted twice for accuracy. The total number of cells seeded as passage 2 in ALI medium onto each collagen-coated Snapwell (Corning 3407) porous membrane insert should be between 150K and 250K, as per standard protocol.
  • HAE cells are maintained at 37 °C, 95% 0 2 in ALI medium at a liquid/liquid interface until a confluent monolayer is formed, generally 5-8 days after seeding. HAE cultures are then maintained at an air/liquid interface in ALI medium (2.5 mL basolateral) changed every 48 hours). The apical surfaces of the cultures are washed with PBS every other day or as needed to remove mucus accumulation. Cells are maintained under these conditions for no less than 21 days to obtain well-differentiated HAE cultures before compounds are added and subsequent short-circuit current experiments are performed.
  • HAE cells are washed apically with PBS 18-24 hours prior to addition of compounds.
  • Stock dilutions of compounds are made in sterile IX PBS (PBS concentration never exceeded 0.1%). Snapwells are treated in the basolateral compartment with 2.5 mL ALI containing the test compound at the final concentration.
  • To initiate treatment one 20 uL drop of basolateral medium containing compound is placed on the apical surface of the cultures. Cultures are treated for a total of 24 hours before Ussing chamber experiments are performed.
  • Chamber temperature is maintained at 37 C +/-1 C by a circulating water bath, and agar bridges are equilibrated in 5 mL bilateral Krebs-bicarbonate-Ringer buffer solution (KBR; 140 niM Na + , 120 niM CI " , 5.2 niM K + , 1.2 niM Ca 2+ ' 1.2 niM Mg 2+ ' 2.4 niM HP0 4 2 _' 0.4 mM U 2 Po4 , 25 mM HC0 3 " , and 5 mM glucose) (Fulcher et al., Novel Human Bronchial Epithelial Cell Lines for Cystic Fibrosis Research.
  • KBR bilateral Krebs-bicarbonate-Ringer buffer solution
  • KBR/KBR baseline is obtained.
  • KBR is then aspirated from the apical chamber, and replaced with 5 mL of a modified KBR buffer, high K + , low CI " solution (HKLC; 40 mM Na + , 100 mM K + , 4.5 mM CI " , 120 mM gluconate, 25 mM HC0 3 " , 2.4 mM HP0 4 2 _ 0.4 mM HP0 4 " , 1.1 mM Ca 2+ ' 1.2 mM Mg 2+ ' and 5.2 mM glucose) (at 37 ° C).
  • Newly modified baseline PD and I sc measurements are obtained and allowed to stabilize for approximately 10 minutes.
  • Ion channel agonists and inhibitors are added to Ussing chambers at 10 minute intervals or longer depending on the stability or trend of the I sc .
  • the following is a typical planned protocol for all chambers regardless of pretreatment condition:
  • ICM Intestinal current measurements
  • the murine large intestine (or colon) is removed by fine dissection, taking care to cut but not pull the intestine from its mesenteric attachment.
  • the murine intestine is prepared by seromusculature "stripping" to minimize the influence of the intrinsic neuromuscular system. Seromusculature stripping removes the serosa (visceral peritoneum) and the longitudinal/circular muscle layers of the intestinal wall, leaving the underlying mucosal elements, primarily the epithelium, lamina basement, and muscularis mucosae.
  • the intestinal section is kept inRPMI 1640 medium containing 2.5 mM NaHC0 3 and 10 ⁇ indomethacin.
  • Indomethacin reduces contribution of non-CFTR mediated CI- channels.
  • the tissue is then mounted into a tissue holder (slider), placed in the Us sing chambers with RPMI 1640 medium containing 2.5 mM NaHC0 3 and 10 ⁇ indomethacin added bilaterally with continuous aeration with 95 0 2 :5 C0 2 .
  • Voltage and current are monitored under open and closed circuit conditions, respectively, to measure transepithelial resistance (R T ).
  • the short circuit current (I sc ) is then monitored under voltage clamp conditions.
  • Measurements are performed under conditions of fluid resistance compensation, i..e, readings are monitored following 'blanking' for fluid resistance in a tissue holder without tissue present.Following stabilization of currentthe tissue is treated with amiloride (100 ⁇ , mucosal exposure) to block Na + absorption. The tissue is then stimulated with 10 ⁇ forskolin + 100 ⁇ IBMX (bilateral exposure) to raise intracellular cAMP. Tissues are then stimulated with carbachol (100 ⁇ , serosal exposure) to activate basolateral K + channels and augment CFTR- dependent CI " secretion.
  • the cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transport protein which, in its active form, resides in the plasma membrane.
  • CFTR consists of two homologous halves which both contain six transmembrane domains (TM) and a nucleotide binding domain (NBD), and these two halves are covalently connected by a regulatory domain (R).
  • TM transmembrane domain
  • NBD nucleotide binding domain
  • R regulatory domain
  • CFTR As much as 50-80% of newly synthesized wildtype CFTR does not achieve a proper folding state and is eventually degraded as core-glycosylated folding intermediates following retrograde translocation from the endoplasmic reticulum (ER).
  • the remaining core-glycosylated CFTR (immature; band B; -150 kDa) attains a folded conformation which is competent to be exported via vesicle transport from the ER to the Golgi complex.
  • CFTR is further modified in the Golgi to achieve a complex-glycosylated form (mature; band C; -180-200 kDa) which is ultimately transported to the plasma membrane.
  • Trafficking efficiency of CFTR can be monitored by immunoblotting, since the mature "band C” form of CFTR can be distinguished from the immature "band B” form by their migration pattern on SDS polyacrylamide gel analysis (SDS-PAGE). The proportion of mature CFTR versus total CFTR can be used as a measure of trafficking efficiency. In the case of wild- type CFTR, the majority of detectable protein is found as the complex glycosylated "C-band" form with a lesser amount migrating as the immature "B-band.” For F508del-CFTR, very little translated protein properly advances through the protein folding and processing pathways within the cell.
  • CFTR C-band and B-band If using cells, add an appropriate number of cells to a tissue culture plate and grow in a cell-type appropriate growth media at the desired experimental temperature (generally 37 °C). Cells should generally be subconfluent and actively growing at initiation of the experiment. Cells are treated with a CFTR modulator or a control compound for a set amount of time, depending on the experiment. When the treatment with test compound is completed, cells are washed with an appropriate ice-cold buffer, and scraped into the desired amount of ice-cold buffer. Cells are harvested by centrifugation and can be lysed as described below for immediate analysis or stored as a cell pellet at -70°C for later use.
  • Laemmli sample buffer Laemmli sample buffer
  • heat samples to 70°C for 10 min.
  • Load a fixed amount of sample onto an SDS-PAGE gel system such as the NuPAGE® 3-8% Tris-Acetate Minigels or Novex® 6% Tris-Gycine Minigels and electrophorese using the appropriate running buffering solution, voltage, and time that is compatible with the type of gel being used and time required to separate the proteins according to their molecular size.
  • the proteins are transferred to membranes (e.g. PVDF or nitrocellulose) for using a wet or semi-dry apparatus designed for immunoblotting and an appropriate transfer buffer.
  • the membranes with transferred proteins bands are then blocked in a suitable blocking buffer such as Tris-buffered saline solution containing 0.1% Tween (TBS-T) and 5% non-fat milk or another protein blocking agent .
  • TBS-T Tris-buffered saline solution containing 0.1% Tween
  • An antibody specific for CFTR is then added to the solution and incubated with the membrane for the desired length of time. After incubation with the anti-CFTR antibodies, the membrane is thoroughly washed with buffer.
  • the membrane is incubated with a secondary detection antibody, which binds to the anti-CFTR antibody, and contains a conjugate such that the antibody complex can produce a signal that can be detected, for example a chemiluminescent signal.
  • a secondary detection antibody which binds to the anti-CFTR antibody, and contains a conjugate such that the antibody complex can produce a signal that can be detected, for example a chemiluminescent signal.
  • the relative amounts of CFTR C-band and B-band can then be visualized and analyzed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés, des compositions pharmaceutiques comprenant ces composés et les procédés pour les fabriquer et les utiliser. Ces composés sont utiles en tant que modulateurs du gène CFTR (Cystic Fibrosis Transmembrane Conductor Regulator). La présente invention concerne également des procédés de traitement ou de diminution de la sévérité de la mucoviscidose chez un patient. Ces composés peuvent être utilisés seuls ou associés à un ou plusieurs agents actifs secondaires.
PCT/US2015/021841 2014-03-21 2015-03-20 Nouveaux composés destinés au traitement de la mucoviscidose Ceased WO2015143376A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11459310B2 (en) 2020-10-22 2022-10-04 Landos Biopharma, Inc. LANCL ligands
WO2024184650A1 (fr) * 2023-03-08 2024-09-12 ThirtyFiveBio Limited Composés hétéroaryle bicycliques destinés à être utilisés en tant que modulateurs de gpr35

Citations (4)

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Publication number Priority date Publication date Assignee Title
US20050159457A1 (en) * 2000-10-06 2005-07-21 Wenxi Pan Aminopyridinyl-, aminoguanidinyl- and alkoxyguanidinyl-substituted phenyl acetamides as protease inhibitors
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US20110098311A1 (en) * 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorported Compositions for treatment of cystic fibrosis and other chronic diseases
US20140113882A1 (en) * 2012-09-28 2014-04-24 Cancer Research Technology Limited Azaquinazoline Inhibitors of Atypical Protein Kinase C

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050159457A1 (en) * 2000-10-06 2005-07-21 Wenxi Pan Aminopyridinyl-, aminoguanidinyl- and alkoxyguanidinyl-substituted phenyl acetamides as protease inhibitors
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US20110098311A1 (en) * 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorported Compositions for treatment of cystic fibrosis and other chronic diseases
US20140113882A1 (en) * 2012-09-28 2014-04-24 Cancer Research Technology Limited Azaquinazoline Inhibitors of Atypical Protein Kinase C

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11459310B2 (en) 2020-10-22 2022-10-04 Landos Biopharma, Inc. LANCL ligands
US12391673B2 (en) 2020-10-22 2025-08-19 Nimmune Biopharma, Inc. LANCL ligands
WO2024184650A1 (fr) * 2023-03-08 2024-09-12 ThirtyFiveBio Limited Composés hétéroaryle bicycliques destinés à être utilisés en tant que modulateurs de gpr35

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