WO2011008931A2 - Composés arylpyrimidines et thérapie de combinaison comprenant ceux-ci pour traiter une mucoviscidose et des troubles apparentés - Google Patents

Composés arylpyrimidines et thérapie de combinaison comprenant ceux-ci pour traiter une mucoviscidose et des troubles apparentés Download PDF

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WO2011008931A2
WO2011008931A2 PCT/US2010/042103 US2010042103W WO2011008931A2 WO 2011008931 A2 WO2011008931 A2 WO 2011008931A2 US 2010042103 W US2010042103 W US 2010042103W WO 2011008931 A2 WO2011008931 A2 WO 2011008931A2
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alkyl
optionally substituted
cycloalkyl
aryl
pyrimidin
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PCT/US2010/042103
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English (en)
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WO2011008931A3 (fr
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Phoebe Chiang
Martin Mense
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Cystic Fibrosis Foundation Therapeutics, Inc.
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Publication of WO2011008931A2 publication Critical patent/WO2011008931A2/fr
Publication of WO2011008931A3 publication Critical patent/WO2011008931A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems

Definitions

  • the cystic fibrosis transmembrane regulator (CFTR), is a protein of
  • CFTR is a member or a class of related proteins which includes the multi-drug resistance (MDR) or P-glycoprotein, bovine adenyl cyclase, the yeast STE6 protein as well as several bacterial amino acid transport proteins. Proteins in this group, characteristically, are involved in pumping molecules into or out of cells. CFTR has been postulated to regulate the outward flow of anions from epithelial cells in response to phosphorylation by cyclic AMP- dependent protein kinase or protein kinase C.
  • MDR multi-drug resistance
  • P-glycoprotein bovine adenyl cyclase
  • yeast STE6 the yeast STE6 protein as well as several bacterial amino acid transport proteins. Proteins in this group, characteristically, are involved in pumping molecules into or out of cells.
  • CFTR has been postulated to regulate the outward flow of anions from epithelial cells in response to phosphorylation by cyclic AMP- dependent protein kin
  • Cystic fibrosis is a lethal hereditary autosomal recessive disease which is caused by mutations in the gene coding for the CFTR Cl ' -channel.
  • the most common disease-causing mutation is the deletion of the codon for phenylalanine 508 ( ⁇ F508) in the primary sequence of wild type CFTR.
  • ⁇ F508 phenylalanine 508
  • the gene product from this mutant gene is a CFTR Cl " -channel that is poorly processed within the cell: most of the mutant protein is incorrectly or incompletely folded and becomes targeted to endoplasmic reticulum-associated degradation (ERAD).
  • compositions comprising an arylpyrimidine compound that modulates the activity of a cystic fibrosis transmembrane regulator (CFTR) protein and a second compound that modulates the activity of a CFTR protein.
  • methods of treating a disorder associated with CFTR protein function by administering an arylpyrimidine compound that modulates the activity of a CFTR protein and a second compound that modulates the activity of a CFTR protein.
  • the invention contemplates various classes of CFTR modulators, and one particularly preferred embodiment is combination therapy involving an arylpyrimidine compound that has corrector activity for the CFTR protein. Another preferred embodiment is combination therapy involving a second compound that modulates the activity of a CFTR protein and has corrector activity for the CFTR protein.
  • the combination therapy provides, in certain instances, a synergistic effect. It is contemplated that, in certain preferred instances, a synergistic effect results from the differing mechanism by which the arylpyrimidine compound modulates the activity of the CFTR protein, compared to the mechanism by which the second compound modulates the activity of a CFTR protein.
  • one aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound; wherein Formulae I-IV are as described herein below.
  • the second CFTR-modulator compound is any one of Formulae V, VI, VII, VIII, or IX, wherein Formulae V-IX are as described herein below.
  • the pharmaceutical composition provides a synergistic increase in activity at a cystic fibrosis transmembrane regulator protein compared to the activity of the first CFTR-modulator compound alone and second CFTR-modulator compound alone towards the cystic fibrosis transmembrane regulator protein.
  • the method comprises administering to a subject in need thereof a
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound; wherein Formulae I-IV are as described herein below.
  • the second CFTR-modulator compound is any one of Formulae V, VI, VII, VIII, or IX, wherein Formulae V-IX are as described herein below.
  • Methods provided herein include methods of treating airway inflammation, cystic fibrosis, chronic obstructive pulmonary disease, dry eye disease, and Sjogren's syndrome.
  • one aspect of the invention provides a method of treating a disorder selected from the group consisting of airway inflammation and cystic fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound; wherein Formulae I-IV are as described herein below.
  • Another aspect of the invention provides a method of modulating the activity of one or more cystic fibrosis transmembrane regulator proteins.
  • the method comprises exposing said protein to a pharmaceutical composition described herein containing a therapeutically effective amount of a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound; wherein Formulae I-IV are as described herein below.
  • the method comprises exposing said protein to a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound; wherein Formulae I-IV are as described herein below.
  • the second CFTR-modulator compound is any one of Formulae V, VI, VII, VIII, or IX, as described herein below.
  • Figure 1 shows biological activity data for exemplary compounds from a FRT
  • Figure 2 shows biological activity data for exemplary compounds from a FRT Cell Ussing Chamber Assay described in Example 337.
  • Figure 3 shows biological activity data for exemplary compounds from a
  • Figure 4 shows biological activity data for exemplary compounds from a
  • Figure 5 shows biological activity data for exemplary compounds from a
  • Figure 6 shows biological activity data for exemplary compounds from a
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • aldehyde or "formyl” as used herein refers to the radical -CHO.
  • alkanoyl refers to a radical -O-CO-alkyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2 -Ci 2 alkenyl, C 2 -Cioalkenyl, and C 2 -C 6 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2- propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, etc.
  • alkoxy refers to an alkyl group attached to an oxygen
  • alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein as Ci-C ⁇ alkoxy, Ci-Cgalkoxy, and Ci-C ⁇ alkoxy, respectively.
  • Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.
  • exemplary "alkenoxy” groups include, but are not limited to vinyloxy, allyloxy, butenoxy, etc.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as CrC alkyl, Q-Qoalkyl, and CrC ⁇ alkyl, respectively.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl- 1 -propyl, 2- methyl-1-pentyl, 3-methyl-l -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • alkyl, alkenyl and alkynyl groups are optionally substituted or interrupted by at least one group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • the alkyl, alkenyl and alkynyl groups are not substituted or interrupted, i.e., they are unsubstituted.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-8, or 2-6 carbon atoms, referred to herein as C 2 -C 12 alkynyl, C 2- C 8 alkynyl, and C 2- C 6 alkynyl, respectively.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2- pentynyl, and 4-butyl-2-hexynyl, etc.
  • R a , R b and R c are each independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
  • the amide can be attached to another group through the carbon, the nitrogen, R b , R c , or R a .
  • the amide also may be cyclic, for example R b and R c , R a and R b , or R a and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10- membered ring or a 5- to 6-membered ring.
  • the term "carboxamido" refers to the structure -C(O)NRbRc.
  • R, R', and R" can each independently be selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone and nitro.
  • amine or "amino” as used herein refers to a radical of the form
  • Rd, R e , and R f are independently selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
  • the amino can be attached to the parent molecular group through the nitrogen, R d , R e or R f .
  • the amino also may be cyclic, for example any two of Rd, Re or Rf may be joined together or with the N to form a 3- to 12-membered ring, e.g., morpholino or piperidinyl.
  • the term amino also includes the corresponding quaternary ammonium salt of any amino group, e.g., -[N(Rd)(Re)(Rf)]+.
  • Exemplary amino groups include aminoalkyl groups, wherein at least one of R d , R e , or R f is an alkyl group.
  • aryl refers to refers to a mono-, bi-, or other multi- carbocyclic, aromatic ring system. Unless specified otherwise, the aromatic ring is optionally substituted at one or more ring positions with substituents selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl.
  • the aryl group is not substituted, i.e., it is unsubstituted.
  • arylalkyl refers to an aryl group having at least one alkyl substituent, e.g. -aryl-alkyl-.
  • exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms.
  • phenylalkyl includes phenylC 4 alkyl, benzyl, 1-phenylethyl, 2- phenylethyl, etc.
  • azido refers to the radical -N 3 .
  • R g; R h and R 1 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, and sulfonamide.
  • Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates, e.g., wherein at least one of R g Rh and Rj are independently selected from aryl or heteroaryl, such as phenyl and pyridinyl.
  • carbonyl refers to the radical -C(O)-.
  • R and R' may be the same or different.
  • R and R' may be selected from, for example, alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
  • cyano refers to the radical -CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
  • cycloalkyl refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8,
  • cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkyl groups are optionally substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be fuse
  • ether refers to a radical having the structure -RiO-R 1n -, where Ri and
  • R m can independently be alkyl, aryl, cycloalkyl, heterocyclyl, or ether.
  • the ether can be attached to the parent molecular group through Ri or R m .
  • Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups.
  • Ether also includes polyethers, e.g., where one or both of Ri and R m are ethers.
  • halo or halogen or “Hal” as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • heteroaryl refers to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings.
  • the heteroaryl ring is optionally substituted at one or more positions with such substituents as described above, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • substituents as described above, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl
  • heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazo
  • heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms. In certain embodiments, the heteroaryl group is not substituted, i.e., it is unsubstituted.
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
  • Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems.
  • a heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
  • Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, th
  • the heterocyclic ring is optionally substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • the heterocyclcyl group is not substituted, i.e., it is unsubstituted.
  • heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
  • heterocyclylalkoxy refers to a heterocyclyl attached to an alkoxy group.
  • heterocyclyloxyalkyl refers to a heterocyclyl attached to an oxygen
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • hydroxyalkyl refers to a hydroxy radical attached to an alkyl group.
  • nitro refers to the radical -NO2.
  • phenyl refers to a 6-membered carbocyclic aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring.
  • phenyl is optionally substituted with one or more substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • the phenyl group is not substituted, i.e., it is unsubstituted.
  • phosphate refers to the radical -OP(O)(OR aa )2 or its anions.
  • phosphanato refers to the radical - P(O)(OR aa )2 or its anions.
  • phosphinato refers to the radical -PR aa (O)(OR aa ) or its anion, where each R aa can be selected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
  • sulfate refers to the radical -OS(O)(OR aa )2 or its anions, where R aa is defined above.
  • sulfonamide or “sulfonamido” as used herein refers to a radical having the structure -N(R r )-S(O)2-R s - or -S(O)2-N(R r )R s , where R r , and R s can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl.
  • Exemplary sulfonamides include alkylsulfonamides (e.g., where R s is alkyl), arylsulfonamides (e.g., where R s is aryl), cycloalkyl sulfonamides (e.g., where R s is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R s is heterocyclyl), etc.
  • sulfonyl refers to a radical having the structure
  • R u S ⁇ 2 where R u can be alkyl, aryl, cycloalkyl, or heterocyclyl, e.g., alkylsulfonyl.
  • alkylsulfonyl refers to an alkyl group attached to a sulfonyl group.
  • sulfide refers to the radical having the structure R 2 S-, where R z can be alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, or ketone.
  • alkylsulfide refers to an alkyl group attached to a sulfur atom.
  • Exemplary sulfides include "thio,” which as used herein refers to an -SH radical.
  • thiocarbonyl or “thiocarboxy” as used herein refer to compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • pharmaceutically or “pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the invention can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated in the methods of the invention is desirably a mammal in whom modulation of cystic fibrosis transmembrane regulators is desired.
  • Modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. Modulators may be dual acting corrector/potentiator compounds. In one embodiment, a modulator is a corrector compound. In another
  • a modulator is a potentiator compound.
  • a therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the invention are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with cystic fibrosis transmembrane regulators.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R” or "S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or
  • diastereomers may be designated "(+)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • Geometric isomers can also exist in the compounds of the present invention.
  • ⁇ rr ⁇ r denotes a bond that may be a single, double or triple bond as described herein.
  • the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z' or "E” configuration wherein the terms "Z' and "E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Certain isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the, e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-C 8 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms
  • l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms
  • 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms
  • N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
  • di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl such as ⁇ -dimethylaminoethyl
  • carbamoyl-(C 1 -C 2 )alkyl N,N-di(C 1 -C 2 )alkylcarbamoy
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C 6 )alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl,
  • N-(C 1 -C 6 )alkoxycarbonylaminomethyl succinoyl, (Ci-C ⁇ Mkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 ,
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 - Cio)alkyl, (C 3 -C 7 )cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl-natural ⁇ -aminoacyl,— C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 ) Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (Ci-QOalkyl, carboxy(C 1 -C 6 )alkyl, amino(Ci- C 4 )alkyl or mono-
  • One aspect of the invention provides a pharmaceutical composition comprising a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR- modulator compound, wherein the structures of Formulae I-IV are as described below:
  • Formula I is represented by:
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N, where no more than two of X 2 -X 6 are N;
  • W is Ci-Cioalkyl or C 4 -Ciocycloalkyl, each of which are optionally substituted with one or two substituents independently selected from the group consisting of Ci-C 6 alkyl, C 3 - Ciocycloalkyl, -OCi-C 6 alkyl, -O-Ca-Ciocycloalkyl, -CF 3 , -OH, and fluoro;
  • R 1 and R 11 are independently hydrogen, Q-Qoalkyl, C 3 -C 10 cycloalkyl, C 3 - Cioheterocycloalkyl, aryl, heteroaryl, -Y-C 1 -C 1O aIlCyI, -Y-C 3 -C 1O CyClOaIlCyI, -Y-(CR 12 R 13 ) n -aryl, -Y-(CR 12 R 13 ) n -heteroaryl, -Y-aryl, -Y-heteroaryl, -Y-C 3 -C 10 heterocycloalkyl, -Y-(CR 12 R 13 ) n - C 3 -C 10 heterocycloalkyl, -CF 3 , -CN, -OCF 2 H, -OCH 2 F, -OCF 3 , halogen, -CONR 7 R 10 , -NR 7 R 10 , -NR 7 COR 8
  • R 2 and R 6 are independently hydrogen, F, Br, I, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, C 2 -
  • R 3 and R 5 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, C 1 -
  • R 4 is hydrogen, F, Cl, Br, I, -CF 3 , -CN, -OCHF 2 , -OCH 2 F, -OCF 3 , Ci-Cioalkyl,
  • any two adjacent variables selected from R 2 , R 3 , R 4 , R 5 , and R 6 are taken together to form a cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkylalkoxy, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, and sulfonyl;
  • R 7 and R 10 are independently hydrogen; or Ci-C 6 alkyl, C 3 -C 10 cycloalkyl, or
  • C 3 -C 10 heterocycloalkyl each of which are optionally substituted with one or two substituents independently selected from the group consisting of Q-Qalkyl, halogen, cyano, hydroxy, and alkoxy; or R 7 and R 10 are taken together to form a heterocyclyl group optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl; wherein the heterocyclyl is not imidazolyl;
  • Rg is alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • R 9 is alkyl, alkenyl, alkynyl, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • R 12 and R 13 each represent independently for each occurrence H, methyl, ethyl, n- propyl, isopropyl, or cyclopropyl; or R 12 and R 13 taken together with the atom to which they are attached form a C 3 -C 6 cycloalkyl group;
  • Y is O, S, S(O), or S(O) 2 ;
  • n 1, 2, or 3;
  • R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen
  • R 3 is not morpholino or pyridyl
  • R 4 is -CH 3 , -OCF 3 , -OCH 3 , F, Cl, -CONHnBu, -CONH-cyclopentyl, or -CONH-CH 2 -phenyl-3-Me, then W is not unsubstituted cyclohexyl or unsubstituted
  • X 2 is CR 2
  • X 3 is CR 3 or N
  • X 4 is CR 4
  • X 5 is CR 5
  • X 6 is CR 6 .
  • W is C 4 -Ciocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of Ci-C ⁇ alkyl and fluoro.
  • W is C 4 -Ciocycloalkyl optionally substituted with one or two CrC ⁇ alkyl substituents.
  • W is C 4 -Ciocycloalkyl optionally substituted with one or two trifluoromethyl groups.
  • W is cyclohexyl substituted with C 1 - C ⁇ alkyl. In certain embodiments, W is cyclohexyl optionally substituted with one or two trifluoromethyl groups. In certain embodiments, W is adamantyl. In certain embodiments, Y is O.
  • R 1 and R 11 are independently hydrogen, Ci-C ⁇ alkyl, C 3 - C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, -OCrCealkyl, -O-Q-Ciocycloalkyl, -0-C 3 - Cioheterocycloalkyl, -0-C(R 12 )(R 13 )-C 3 -C 1 oheterocycloalkyl, -O-aryl, -O-heteroaryl, -O- C(R 12 )(R 13 )-aryl, or -O-C(R 12 )(R 13 )-heteroaryl.
  • R 1 is methoxy, ethoxy, propoxy, t-butoxy, cyclobutoxy, cyclopropylmethoxy, morpholinyl, -O- tetrahydrofuranyl, -0-CH 2 - tetrahydrofuranyl, -O-tetrahydropyranyl, -0-CH 2 - tetrahydropyranyl, -O-oxetanyl, -O-CH 2 -oxetanyl, -N(CHs) 2 , phenoxy or benzyloxy; and R 11 is hydrogen or methyl.
  • R 1 and R 11 are independently hydrogen, C 1 - C 6 alkyl, -OCrC 6 alkyl, -O-Q-Ciocycloalkyl, or -O-Q-Cioheterocycloalkyl.
  • R 1 is methoxy, ethoxy, propoxy, -O-tetrahydrofuranyl, or -O-tetrahydropyranyl; and R 11 is hydrogen.
  • R 1 and R 11 are hydrogen.
  • R 2 and R 6 are hydrogen.
  • R 3 and R 5 are hydrogen or halogen.
  • R 4 is -CF 3 , -OCHF 2 , -OCH 2 F, -OCF 3 , Ci-C 6 alkyl,
  • R 4 is -CF 3 , -OCHF 2 , -OCH 2 F, -OCF 3 , Ci-Cealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, -OCi-C 6 alkyl, -OQ-Ciocycloalkyl, or -OQ-Cioheterocycloalkyl.
  • R 7 and R 10 are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 7 and R 1O are independently hydrogen, methyl, ethyl or propyl.
  • R 8 and R 9 are Ci-C ⁇ alkyl.
  • R 8 and R 9 are independently methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • the compound of Formula I is represented by Formula
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N, where no more than two of X 2 -X 6 are N;
  • W is Ci-Cioalkyl or C 4 -Ciocycloalkyl, each of which are optionally substituted with one or two substituents independently selected from the group consisting of Ci-C 6 alkyl, C 3 -
  • R 1 and R 11 are independently hydrogen, Q-Cealkyl, C 3 -Ciocycloalkyl, -OCi-C ⁇ alkyl, - O-C 3 -C 10 cycloalkyl,-CF 3 , -CN, -OCF 2 H, -OCH 2 F, -OCF 3 , halogen, -CONR 7 R 10 , -NR 7 R 10 , -NR 7 COR 8 , -NR 7 SO 2 R 9 , or -SO 2 R 9 ;
  • R 2 and R 6 are independently hydrogen, F, Br, I, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, C 2 - C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 heterocyclyl, -OCi-C 6 alkyl, -O-Q-Ciocycloalkyl, -NR 7 COR 8 , -NR 7 SO 2 R 9 , -CONR 7 R 10 , -SO 2 NR 7 R 10 , -CN, aryl, heteroaryl, -NR 7 R 10 , or -SO 2 R 9 ;
  • R 3 and R 5 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, C 1 - C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 heterocyclyl, -OCi-C 6 alkyl, -O-Q-Ciocycloalkyl,
  • R 4 is hydrogen, F, Cl, Br, I, -CF 3 , -CN, -OCHF 2 , -OCH 2 F, -OCF 3 , Q-Cealkyl,
  • any two adjacent variables selected from R 2 , R 3 , R 4 , R 5 , and R 6 can be taken together to form a cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl;
  • R 7 and R 10 are independently hydrogen; or alkyl or cycloalkyl, each of which are optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, and alkoxy, or
  • R 7 and R 10 can be taken together to form a heterocyclyl optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl; wherein the heterocyclyl is not imidazolyl;
  • R 8 is alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • R 9 is alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen
  • R 3 is not morpholino or pyridyl
  • R 4 is -CH 3 , -OCF 3 , -OCH 3 , F, Cl, -CONHnBu, -CONH-cyclopentyl, or -CONH-CH 2 -phenyl-3-Me, then W is not unsubstituted cyclohexyl or R 1 is not hydrogen.
  • at least one of R 1 and R 11 is selected from the group consisting of hydrogen, d-Qjalkyl, -O-Ci-C 6 alkyl, -O-Q-Ciocycloalkyl, -OCHF 2 , -OCH 2 F, -OCF 3> -CN, and -NR 7 R 1O .
  • At least one of R 1 and R 11 is selected from the group consisting of hydrogen, -CH 3 , -OCH 31 -O-CH 2 cyclopropyl, -O-isopropyl, -O-t-butyl, -O-cyclobutyl, and -N(CH 3 ) 2 .
  • at least one of R 2 and R 6 is selected from the group consisting of hydrogen, -NR 7 R 1O , F, -OCH 3 , -OCF 2 H, and -OCF 3 .
  • R 3 and R 5 is selected from the group consisting of hydrogen, F, -OCF 2 H, -OCFH 2 , -OCF 3 , -OtBu and -OiPr.
  • R 4 is selected from the group consisting of hydrogen, -OCH 3 , -OCF 3 , -OiPr, -OCF 2 H, -0-C 3 - Ciocycloalkyl, -SO 2 R 9 , -SO 2 NR 7 R 10 , -CONR 7 R 10 , and C 3 -C 10 heterocyclyl.
  • R 3 and R 4 are taken together to form a heterocyclyl selected from the group consisting of benzodioxolyl, difluorobenzodioxolyl, dihydrobenzodioxinyl, and
  • X 2 -X 6 is N.
  • X 4 is N.
  • W is selected from the group consisting of cyclobutyl, cycloheptyl, cyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl, 1-methylcyclohexyl, cyclopentyl, isopropyl, and bicyclo[2,2,l]heptyl.
  • W is selected from the group consisting of cyclobutyl, cyclohexyl, cycloheptyl, A- methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl, cyclopentyl, and
  • the compound of Formula I is represented by Formula
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N;
  • W is cyclohexyl optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, and halogen;
  • R 1 is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OC 1 - C 6 alkyl, -O-Q-Ciocycloalkyl, -O-C 3 -C 10 heterocycloalkyl, or -O-(CH 2 ) n -C 3 - Cioheterocycloalkyl;
  • R 2 , R 5 , and R 6 are independently hydrogen, methyl, or ethyl
  • R 3 is hydrogen, halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, methyl, ethyl, methoxy, or ethoxy;
  • R 4 is hydrogen, F, Cl, Br, I, -CF 3 , -CN, -OCHF 2 , -OCH 2 F, -OCF 3 , CrCealkyl,
  • R 7 and R 10 are independently hydrogen; or CrC ⁇ alkyl, C 3 -C 10 cycloalkyl, or
  • C 3 -C 10 heterocycloalkyl each of which are optionally substituted with one or two substituents independently selected from the group consisting of halogen, methyl, ethyl, methoxy, or ethoxy;
  • Rg and R 9 are independently is methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, or benzyl, each of which is optionally substituted by halogen or methoxy;
  • R 11 is hydrogen or methyl
  • n 1, 2, or 3;
  • R 4 is -CH 3 , -OCF 3 , -OCH 3 , F, Cl, -CONHnBu, -CONH-cyclopentyl, or -CONH-CH 2 -phenyl-3-Me, then W is not unsubstituted cyclohexyl or R 1 is not hydrogen.
  • X 3 is CR 3 . In certain embodiments, X 3 is N. In certain embodiments, X 4 is CR 4 . In certain embodiments, X 4 is N. In certain embodiments, W is cyclohexyl optionally substituted with one or two substituents independently selected from the group consisting of methyl and ethyl.
  • R 1 is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCi-C ⁇ alkyl, -O-Q-Ciocycloalkyl, -0-C 3 - C 10 heterocycloalkyl, or -O-(CH 2 ) n -C 3 -C 10 heterocycloalkyl.
  • R 1 is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is -OCi-C ⁇ alkyl, -0-C 3 -Ciocycloalkyl, -O-Q-Cioheterocycloalkyl, or -O-(CH 2 ) n -C 3 - Cioheterocycloalkyl. In certain embodiments, R 1 is -0-(CH 2 ) n -C 3 -C 1 oheterocycloalkyl.
  • R 1 is -O-(CH 2 ) n -tetrahydrofuranyl, -O-(CH 2 ) n -tetrahydropyranyl, or -O- (CH 2 ) n -pyrrolidinyl, each of which is optionally substituted by methyl or ethyl.
  • R 3 is hydrogen, halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, methyl, ethyl, methoxy, or ethoxy.
  • R 4 is hydrogen, F, Cl, Br, I, -CF 3 , -CN, -OCHF 2 , -OCH 2 F, -OCF 3 , Ci-Cealkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 heterocyclyl, -OCi-C 6 alkyl,
  • R 4 is hydrogen, F, Cl, Br, I, -CF 3 , -CN, -OCHF 2 , -OCH 2 F, -OCF 3 , methyl, ethyl, methoxy, or ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl.
  • R 4 is -OCHF 2 , -OCH 2 F, -OCF 3 , methyl, ethyl, methoxy, or ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydofuranyl,
  • R 4 is morpholinyl.
  • R 4 is -OCHF 2 , -OCH 2 F, or -OCF 3 .
  • R 7 and R 1O are independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Formula II is represented by:
  • A is one of the following: W is Ci-Cioalkyl or C 4 -Ciocycloalkyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of Ci-C ⁇ alkyl, C 3 - Ciocycloalkyl, -OCi-C 6 alkyl, -O-Ca-Ciocycloalkyl, -CF 3 , -OH, and fluoro;
  • R 1 and R 4 are independently hydrogen, CrC ⁇ alkyl, C 3 -Ciocycloalkyl, -OCrC ⁇ alkyl, -O- C 3 -C 10 cycloalkyl, -O-Q-Cioheterocycloalkyl, -O-C(R 8 )(R 9 )-C 3 -C 10 heterocycloalkyl, -CF 3 , -CN, -OCF 2 H, -OCH 2 F, -OCF 3 , halogen, -CONR 5 R 6 , -NR 5 R 6 , -NR 5 COR 6 , -NR 5 SO 2 R 7 , or -SO 2 R 7 ;
  • R 2 is Ci-C 6 alkyl
  • R 3 is halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, Ci-C ⁇ alkyl, C 3 -C 10 cycloalkyl, C 3 - Cioheterocyclyl, -OCi-C 6 alkyl, -0-C 3 -Ciocycloalkyl, -O-Q-Cioheterocycloalkyl, -CONR 5 R 6 , -NR 5 COR 7 , -NR 7 SO 2 R 7 , -SO 2 NR 5 R 6 , -CN, aryl, heteroaryl, -NR 5 R 6 , or -SO 2 R 7 ;
  • R 5 and R 6 are each independently hydrogen; or alkyl or cycloalkyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, hydroxy, and alkoxy; or R 5 and R 6 are taken together to form a heterocyclyl that is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, and sulfonyl;
  • R 7 represents independently for each occurrence alkyl, alkenyl, alkynyl, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • Rg and R 9 represent independently hydrogen, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; or R 8 and R 9 taken together with the atom to which they are attached form a C 3 -C 6 cycloalkyl group.
  • A is . In certain embodiments, A is . In certain embodiments, R 1 and R 4 are independently hydrogen, Ci-C 6 alkyl, -OCi-C 6 alkyl, -O-Q-Ciocycloalkyl, -O-Q-Cioheterocycloalkyl, or -0-CH 2 -C 3 -
  • R 1 is methoxy, ethoxy, or propoxy; and R 4 is hydrogen, methoxy, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH ⁇ tetrahydrofuranyl, - O-CH 2 -tetrahydropyranyl, -O-pyrrolidinyl, -O-piperidinyl, or -O-azetidinyl.
  • R 1 and R 4 are independently hydrogen, CrC ⁇ alkyl, -Od-C 6 alkyl, -0-C 3 - Ciocycloalkyl, or -O-Cs-Cioheterocycloalkyl.
  • R 1 is methoxy, ethoxy, or propoxy; and R 4 is hydrogen.
  • R 3 is halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, d-C 6 alkyl, -Od-C 6 alkyl, or C 3 -C 8 cycloalkyl.
  • R 3 is halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, d-C 6 alkyl, or -OQ-C ⁇ alkyl.
  • W is C 4 -C 1 ocycloalkyl optionally substituted with one or two d-C 6 alkyl substituents. In certain embodiments, W is cyclohexyl substituted with d-C 6 alkyl.
  • Formula III is represented by:
  • B is heteroaryl or an unsaturated heterocyclyl
  • X is C(H) or N
  • W is d-doalkyl or C 4 -Ciocycloalkyl, each of which is optionally substituted with one or two substituents independently selected selected from the group consisting of d-C 6 alkyl, d-docycloalkyl, -Od-C 6 alkyl, -O-d-Ciocycloalkyl, -CF 3 , -OH, and fluoro;
  • R 1 and R 4 are independently hydrogen, d-C 6 alkyl, C 3 -C 10 cycloalkyl, -Od-C 6 alkyl, -O-
  • R 2 represents independently for each occurrence halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -CN, d-C ⁇ alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, -Od-C 6 alkyl, -0-C 3 - Ciocycloalkyl, -O-Ca-Cioheterocyclyl, -CONR 5 R 6 , -NR 5 COR 7 , -NR 7 SO 2 R 7 , -SO 2 NR 5 R 6 , -CN, aryl, heteroaryl, -NR 5 R 6 , or -SO 2 R 7 ;
  • R 3 is hydrogen, Ci-C 6 alkyl, or C 3 -C 6 cycloalkyl
  • R 5 and R 6 are independently hydrogen; or alkyl or cycloalkyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, hydroxy, nitro, and alkoxy; or
  • R 5 and R 6 are taken together to form a heterocyclyl that is optionally substituted by one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl;
  • R 7 represents independently for each occurrence alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkoxy, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl;
  • R 8 and R 9 each represent independently for each occurrence H, methyl, ethyl, or n- propyl, or isopropyl; or Rg and R 9 taken together with the atom to which they are attached form a C 3 -C 6 -cycloalkyl group;
  • n 1, 2, or 3;
  • n 0, 1, or 2.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is .
  • R 1 and R 4 are independently hydrogen, -OQ-Cealkyl, -O-Cs-Ciocycloalkyl, -0-C 3 -
  • Cioheterocycloalkyl or -O-CHi-Cs-Cioheterocycloalkyl.
  • R 1 is methoxy, t-butoxy, cyclobutoxy, cyclopropylmethoxy, -O-tetrahydrofuranyl, -O- tetrahydropyranyl, -O-CHi-tetrahydrofuranyl, -O-CHi-tetrahydropyranyl, -O-pyrrolidinyl- CO 2 CH 3 , -O-pyrrolidinyl-SOiCHs, or -O-phenyl-OCHs.
  • R 1 and R 4 are independently hydrogen, -OCi-C ⁇ alkyl, -O-Cs-Ciocycloalkyl, or -O-Cs-Cioheterocycloalkyl.
  • R 1 is methoxy, ethoxy, propoxy, -O-tetrahydrofuranyl, -O-pyrrolidinyl, or -O-phenyl-OCH 3 .
  • R 2 represents independently for each occurrence halogen, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, d-C 6 alkyl, C 3 -C 6 cycloalkyl, or -OCi-C 6 alkyl. In certain embodiments, R 2 represents independently for each occurrence halogen, -CF 3 , -OCF 3 , - OCHF 2 , -OCH 2 F, CrC ⁇ alkyl, or -OCi-C ⁇ alkyl. In certain embodiments, n is 0.
  • R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, or methoxymethyl. In certain embodiments, R 3 is hydrogen, methyl, ethyl, or propyl. In certain embodiments, R 4 is hydrogen or methyl. In certain embodiments, W is C 4 -C 1 ocycloalkyl optionally substituted with one or two CrC ⁇ alkyl substituents. In certain embodiments, W is cyclohexyl substituted with CrC ⁇ alkyl. [0085] In certain embodiments, the first CFTR-modulator compound is selected from the group consisting of: N-((lS,4S)-4-methylcyclohexyl)-5-(4-(trifluoromethoxy)
  • phenyl)pyrimidin-2-amine N-(( lR,4R)-4-methylcyclohexyl)-5-(4- (trifluoromethoxy)phenyl)pyrimidin-2- amine ; 5 -(4-isopropoxyphenyl) -N- (( 1 S ,4S ) -4- (trifluoromethyl) cyclohexyl)pyrimidin-2-amine; 5-(4-isopropoxyphenyl)-4-methoxy-N- ((lS,4S)-4-methylcyclohexyl)pyrimidin-2-amine; N-cyclohexyl-5-(3- (trifluoromethoxy)phenyl)pyrimidin-2- amine; N-cyclohexyl-5-(2- (trifluoromethoxy)phenyl)pyrimidin-2- amine ; N- (4-(2- (cyclohexylamino)pyrimidin- 5 - yl)phenyl)is
  • Formula IV is represented by:
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N, where no more than two of X 2 -X 6 are N;
  • A is C 4 -Ciocycloalkyl, C 3 -Cioheterocycloalkyl, or phenyl, each of which is optionally substituted with one, two, or three substituents independently, for each occurrence, selected from the group consisting of F, Cl, -CF 3 , -OCi-C ⁇ alkyl, -OH, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxycarbonyl, C 3 -C 5 cycloalkyl, aryl, -C(O)-aryl, -C(O)-heteroaralkyl, -C(O)-Ci-C 6 alkyl, and -C(O)N(H)(Ci- C 6 alkyl);
  • Ri and Ri 2 are each independently hydrogen, CN, Ci-C ⁇ alkyl, -OCi-C ⁇ alkyl, C 3 - locycloalkyl, -OQ-iocycloalkyl, -OCF 3 , -OCF 2 H, -OCH 2 F, halogen, -NR 7 Ri 0 , -NR 7 COR 8 , -NR 7 SO 2 R 9 , or -SO 2 R 9 , where if R i2 is -OCF 2 H, then R 4 is not methyl;
  • R 2 is hydrogen, halogen, -CN, -OCi-Ci 0 alkyl, -Oaryl, -CF 3 , -OCHF 2 , -OCH 2 F, -NR 7 Ri 0 , -CO 2 Rn, or -SO 2 NR 7 Ri 0 ;
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , -OH, -OCF 3 , -OCHF 2 , -OCH 2 F, Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, -OCi-Ci 0 alkyl, -OQ-Ciocycloalkyl, -NR 7 COR 8 , -NR 7 SO 2 R 9 , -CONR 7 Ri 0 , -SO 2 NR 7 Ri 0 , -CN, aryl, -Oaryl, heteroaryl, -NR 7 Ri 0 , or -SO 2 R 9 ;
  • R 4 is hydrogen, halogen, Ci-C 3 alkyl, -OCi-C 6 alkyl, -O-aryl, -OH, -OCHF 2 , -OCH 2 F, -CN, heteroaryl, -NR 7 Ri 0 , or -SO 2 NR 7 Ri 0 ;
  • R 6 is hydrogen, halogen, -CN, -OCi-Ci 0 alkyl, -Oaryl, -CF 3 , -OCHF 2 , -OCH 2 F, -NR 7 Ri 0 , or -SO 2 NR 7 Ri 0 ;
  • any two adjacent variables selected from R 2 , R 3 , R 4 , R 5 , and R 6 can be taken together to form a cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted by one, two, or three substituents independently, for each occurrence, selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl, where R 3 and R 4 cannot be taken together to form a dioxolanyl when L is a bond and A is cyclohexyl;
  • R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen; and if R 4 is -OCH 3 , then R 3 and R 5 are not -OCH 3 ;
  • R 7 and Ri 0 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or two substituents independently, for each occurrence, selected from the group consisting of halogen, cyano, hydroxy, nitro, and alkoxy; or R 7 and R 10 are taken together to form a heterocyclyl optionally substituted by one, two, or three substituents independently, for each occurrence, selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl, where the heterocyclyl is not dihydro-2H-benzo[b] [ 1 ,4]dioxepinyl;
  • R 8 is alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen, or hydroxyl;
  • R 9 represents independently for each occurrence alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, or hydroxyl;
  • R 11 is alkyl, alkenyl, alkynyl, amido, aryl, cycloalkyl, haloalkyl, heteroaryl,
  • heterocyclyl or hydrogen.
  • R 1 and R 12 are independently hydrogen or methyl.
  • at least one of R 2 and R 6 is selected from the group consisting of F, Cl, -CF 3 , -OCH 3 , and -OCF 3 .
  • R 2 and R 6 is independently hydrogen, F, Cl, -CF 3 , -OCH 3 , or -OCF 3 .
  • At least one of R 3 and R 5 is selected from the group consisting of F, Cl, -OH, -OCH 3 -OiPr, -Osec-butyl, -OCF 3 , -Ophenyl, -Ocyclohexyl, -SO 2 Me, pyrrolidinylsulfonyl, morpholinylsulfonyl, -CON(H)-cyclopropyl, 5-methyl- 1,3,4- oxadiazolyl, -NHSO 2 cyclopropyl, and -NHCOcyclopropyl.
  • R 4 is selected from the group consisting of -NH 2 , -NMe 2 , -Ophenyl, -OCH 3 , and -OCF 3 . In certain embodiments, R 4 is selected from the group consisting of -NH 2 , -NMe 2 , -Ophenyl, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , Cl, and F.
  • R 2 is hydrogen, -CN, -OCi-Cioalkyl, -Oaryl, -CF 3 , -OCHF 2 , -OCH 2 F, -NR 7 R 10 , -CO 2 R 11 , or -SO 2 NR 7 R 10 .
  • R 3 and R 4 are taken together to form a heterocyclyl selected from the group consisting of dioxanyl, oxazolyl, pyrazinyl, and thiazolyl.
  • R 4 is hydrogen.
  • R 4 is hydrogen or fluoro.
  • A is C 4 -C 1 ocycloalkyl.
  • A is selected from the group consisting of cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4- methylcyclohexyl, 4-ethylcyclohexyl, 4-phenylcyclohexyl, 4,4-difluorocyclohexyl, 4,4- dimethylcyclohexyl, cycloheptyl, bicyclo[2.2.1]heptan-2-yl, adamantanyl, and 1,2,3,4- tetrahydronaphthalenyl.
  • A is cis-4-methylcyclohexyl, cis-4- ethylcyclohexyl; cis-4-trifluoromethylcyclohexyl; 4,4-dimethylcyclohexyl; or 4,4- difluorocyclohexyl.
  • A is cis-4-methylcyclohexyl.
  • R 5 and R 4 cannot be taken together to form a dioxolanyl when L is a bond and A is cyclohexyl.
  • R 2 is fluoro or chloro. In certain embodiments, R 2 is fluoro. In certain embodiments, X 2 is CR 2 , X3 is CR3, X 4 is CR 4 , X5 is CR5, and Xe is CR 6 . In certain embodiments, L is a bond.
  • X 2 is CR 2
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • X 5 is
  • X 3 is N, L is a bond, and A is cyclohexyl, then R 2 is not methoxy.
  • L is a bond.
  • A is C 4 -Ciocycloalkyl optionally substituted with one, two, or three substituents independently, for each occurrence, selected from the group consisting of F and Ci-C ⁇ alkyl.
  • R 1 and R 12 are each independently hydrogen and CrC ⁇ alkyl.
  • R 2 is hydrogen, -OCi-Cioalkyl, or -CF 3 .
  • R 6 is hydrogen, halogen, or -OCi-Cioalkyl.
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , -OH, -OCF 3 , Ci-C 8 alkyl, C 3 -C 8 cycloalkyl, -OCi-Ci 0 alkyl, -(XVCiocycloalkyl, -NR 7 COR 8 , -NR 7 SO 2 R 9 , -CONR 7 R 10 , -SO 2 NR 7 R 10 , -CN, aryl, -Oaryl, heteroaryl, -NR 7 R 10 , or -SO 2 Rg.
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , - OCF 3 , or -OCi-Cioalkyl.
  • R 4 is halogen, Ci-C 3 alkyl, -OC 1 - C ⁇ alkyl, -O-aryl, -OH, -NR 7 R 10 , or -SO 2 NR 7 R 10 .
  • R 4 is hydrogen, wherein at least one of R 2 , R 3 , R 5 , and R 6 is not hydrogen.
  • R 8 is cycloalkyl.
  • R 9 represents independently for each occurrence alkyl or cycloalkyl.
  • R 11 is alkyl.
  • the compound of Formula IV is represented by IV-A:
  • A is C 4 -Ci 0 cycloalkyl optionally substituted with one, two, or three substituents independently, for each occurrence, selected from the group consisting of F and Q-C ⁇ alkyl;
  • R 1 and R 12 are each independently hydrogen or Ci-C ⁇ alkyl
  • R 2 is hydrogen, -OCi-Ci 0 alkyl, or -CF 3 ;
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , -OH, -OCF 3 , Ci-C 8 alkyl,
  • R 4 is hydrogen, halogen, Ci-C 3 alkyl, -OCi-C 6 alkyl, -O-aryl, -OH, -NR 7 Ri 0 , or -SO 2 NR 7 Ri 0 ;
  • Re is hydrogen, halogen, or -OCi-Ci 0 alkyl
  • R 7 and Ri 0 each represent independently for each occurrence hydrogen, Ci-C ⁇ alkyl, or C 3 -C 8 cycloalkyl;
  • R 8 is C 3 -C 8 cycloalkyl
  • R 9 represents independently for each occurrence Ci-C ⁇ alkyl or C 3 -C 8 cycloalkyl; and Rn is Ci-C 6 alkyl.
  • Ri and Ri 2 are hydrogen or methyl.
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , -OCF 3 , or -OCi- Cioalkyl.
  • R 4 is hydrogen, halogen, or Ci-C 3 alkyl.
  • R 6 is hydrogen or halogen.
  • Ri is hydrogen, methyl or ethyl
  • R 2 is -O-methyl, -O-ethyl, -O-propyl, or -CF 3 ;
  • R 3 and R 5 are each independently hydrogen, halogen, -CF 3 , -OCF 3 , or -OCi-Ci 0 alkyl;
  • R 4 is hydrogen, halogen, or Ci-C 3 alkyl; and
  • R 6 is hydrogen, halogen, or Q-Qalkyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is methyl.
  • R 2 is -O-methyl.
  • R 3 is hydrogen or halogen.
  • R 5 is halogen.
  • R 4 is hydrogen or methyl.
  • R 6 is hydrogen or methyl.
  • the compound of Formula IV is represented by IV-C:
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • X 5 is CR 5 or N
  • X 6 is CR 6 or N, where no more than two of X 2 -X 6 are N;
  • L is a bond or a Ci_ 2 alkylidene chain optionally substituted with one or two substituents independently, for each occurrence, selected from the group consisting of Ci-C 6 alkyl,
  • A is a C 4 -C 1 ocycloalkyl, optionally substituted with one, two, or three substituents independently, for each occurrence, selected from the group consisting of F, Cl, -CF 3 , -OC 1 - C 6 alkyl, Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl, C 3 -C 5 cycloalkyl, and aryl;
  • R 1 and R 12 are each independently selected from the group consisting of hydrogen, CN, Ci-C 6 alkyl, -OCi-C 6 alkyl, C 3 _i 0 cycloalkyl, -OC 3 _i 0 cycloalkyl, -OCF 3 , -OCF 2 H, -OCH 2 F, halogen, -NR 7 R 10 , -NR 7 COR 8 , -NR 7 SO 2 R 9 , and -SO 2 R 9 , where if R 12 is -OCF 2 H, R 4 is not methyl;
  • R 2 is independently selected from the group consisting of hydrogen, -CN, -OCi-C 6 alkyl, -Oaryl, -CF 3 , -OCHF 2 , -OCH 2 F, -NR 7 R 10 , -CO 2 R 11 , and -SO 2 NR 7 R 10 ;
  • R 3 and R 5 are each independently selected from the group consisting of hydrogen, halogen, -CF 3 , -OH, -OCF 3 , -OCHF 2 , -OCH 2 F, C 2 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 - Cgheterocyclyl, -OCi-Ci 0 alkyl, -OQ-Ciocycloalkyl, -NR 7 COR 8 , NR 7 SO 2 R 9 , -CONR 7 R 10 , -SO 2 NR 7 R 10 , -CN, aryl, -Oaryl, heteroaryl, -NR 7 R 10 , and -SO 2 R 9 ;
  • R 4 is selected from the group consisting of hydrogen, halogen, Ci-C 3 alkyl, -OC 2 - C 6 alkyl, -CN, -OCHF 2 , -OCH 2 F, -NR 7 R 10 , and -SO 2 NR 7 R 10 ;
  • Re is independently selected from the group consisting of hydrogen, halogen, -CN,
  • any two adjacent variables selected from R 2 , R 3 , R 4 , R 5 , and R 6 can be taken together to form a cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted by one, two, or three substituents independently, for each occurrence, selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl, where R 3 and R 4 cannot be taken together to form a dioxolanyl when L is a bond and A is cyclohexyl;
  • R 2 , R 3 , R 4 , R 5 , and R 6 is not hydrogen; and if R 4 is -CH 3 , then R 3 and R 5 are not both -OCH 3 ;
  • R 7 and Ri 0 are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or two substituents independently, for each occurrence, selected from the group consisting of halogen, cyano, hydroxy, nitro, and alkoxy, or R 7 and Ri 0 are taken together to form a heterocyclyl optionally substituted by one, two, or three substituents independently, for each occurrence, selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cyano, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonyl, where the heterocyclyl is not dihydro-2H-benzo[b][l,4]dioxepinyl;
  • Rg is selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen, and hydroxyl;
  • R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, amido, amino, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydroxyl;
  • Rn is selected from the group consisting of alkyl, alkenyl, alkynyl, amido, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen;
  • the compound of Formula IV is a compound selected from the group consisting of: bicyclo[2.2.1]hept-2-yl-[4-(5-chloro-2-methoxy-phenyl)-pyrimidin-2- yl]-amine; [4-(5-Chloro-2-methoxy-phenyl)-pyrimidin-2-yl]-(l,2,3,4-tetrahydro-naphthalen-2- yl)-amine; N-(3-(2-(cyclohexylamino)pyrimidin-4-yl)phenyl)-N-methylcyclopropane- carboxamide; N-(3-(2-(cyclohexylamino)pyrimidin-4-yl)phenyl)-N-methylcyclopropane- sulfonamide; N-cyclohexyl-4-(6-methylpyridin-3-yl)pyrimidin-2-amine; N-cyclohexyl-4-(
  • Scheme 1 illustrates reacting a dichloropyrimidine with an amine to form a chloropyrimidinylamino synthetic intermediate that is used in a subsequent Suzuki coupling reaction with an aryl boronic acid to form a 4-phenylpyrimidin-2-amine compound.
  • the first step in this sequence i.e., the amine coupling step, can be performed by reacting a 2,4-dichloropyrimidine compound and a desired amine in the presence of triethylamine in ethanol at about 75 0 C for about 8-48 hours.
  • the Suzuki coupling reaction can be performed according to standard, known Suzuki coupling conditions using a desired boronic acid or its pinacol ester.
  • This synthetic sequence is contemplated to be amenable to a variety of dichloropyrimidine compounds, aryl boronic acids, and/or aryl boronic esters, which are commercially available or can be readily prepared from commercially available materials.
  • Scheme 2 illustrates reacting a 2,4-dichloropyrimidine with an aryl boronic acid under Suzuki coupling conditions to form a 2-chloro-4-phenylpyrimidine synthetic
  • the first step in this sequence i.e., the Suzuki coupling reaction
  • the amine coupling step can be performed by reacting the 2-chloro-4- phenylpyrimidine synthetic intermediate with an amine in the presence of triethylamine in isopropanol at about 100 0 C for about 24-48 hours or heating in a microwave oven at 100 0 C for about 0.5-1 hours.
  • Scheme 3 illustrates reacting a 4-chloro-2-(methylthio)pyrimidine with an aryl boronic acid under Suzuki coupling conditions to form a 2-(methylthio)-4-phenylpyrimidine synthetic intermediate that can be reacted with an oxidant to form a methylsulfone that undergoes reaction with an amine to form the 4-phenylpyrimidin-2-amine product.
  • the first step in this sequence i.e., the Suzuki coupling reaction, can be performed according to standard, known Suzuki coupling conditions using a desired boronic acid or its pinacol ester.
  • the thiomethyl ether can be oxidized to the methylsulfone by reaction with meta- chloroperbenzoic acid (mCPBA) in dichloromethane at room temperature for about 12-24 hours.
  • mCPBA meta- chloroperbenzoic acid
  • Reaction of the methylsulfone intermediate with a desired amine R-NH 2 in the presence of triethylamine in isopropanol at about 100 0 C for about 24-48 hours or heating in a microwave oven at 100 0 C for about 0.5-1 hours provides the final 4-phenylpyrimidin-2-amine compound.
  • Scheme 4 illustrates a procedure for alkylating a phenolic hydroxylic group.
  • the procedure involves reacting the phenol with an alkyl halide (RX) in the presence of alkali metal base, such as potassium carbonate, in an organic solvent (such as acetone) at elevated temperature (such as ⁇ 70 0 C) for about 12-24 hours.
  • RX alkyl halide
  • organic solvent such as acetone
  • the second CFTR-modulator compound is any one of
  • Each R 1 is an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C 3-1O cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R 1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyridyl ring;
  • Each R 2 is hydrogen, an optionally substituted C 1-6 aliphatic, an optionally substituted C 3 _ 6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl;
  • Each R 3 and R' 3 together with the carbon atom to which they are attached form an optionally substituted C 3 _ 7 cycloaliphatic or an optionally substituted heterocycloaliphatic;
  • Each R 4 is an optionally substituted aryl or an optionally substituted heteroaryl
  • each n is 1, 2, 3 or 4.
  • one R 1 that is attached to 5- or 6- position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of R D ; wherein R D is -Z D R 9 ; wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -CO-, -CS-, -C0NR E -, -C0NR E NR E -, -CO 2 -, -OCO-, -NR E C0 2 -, -O-, -NR E C0NR E -, -0C0NR E -, -NR E NR E -, NR E C0-, -S-, -SO-, -SO 2 -, -NR E -, -S0 2 NR E -, -, -
  • each R 9 is independently R E , halo, -OH, -NH 2 , -NO 2 , -CN, -CF 3 , or -OCF 3 ; and each R E is independently hydrogen, an optionally substituted C 1 - S aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
  • one R 1 attached to the 5- or 6- position of the pyridyl ring is phenyl optionally substituted with 1, 2, or 3 of R D .
  • the one R 1 attached to the 5- or 6- position of the pyridyl ring is a phenyl optionally substituted with one R D , wherein R D is -Z D R 9 ; each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -O-, - NHC(O)-, -C(0)NR E -, -SO 2 -, -NHSO 2 -, -NHC(O)-, -NR E S0 2 -, -SO 2 NH-, -S0 2 NR E -, -NH-, or - C(O)O-.
  • one carbon unit of Z D is replaced by -O-, -NHC(O)-,
  • R 9 is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, H, or halo.
  • the one R 1 attached to the 5- or 6- position of the pyridyl ring is heteroaryl optionally substituted with 1, 2, or 3 of R D .
  • one R 1 attached to the 5- or 6- position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with one R D , wherein R D is -Z D R 9 ; each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -O-, -NHC(O)-, -C(O)NR > E-, -SO 2 -, -NHSO 2 -, -NHC(O)-, -NR E S0 2 -, -SO 2 NH-, -S0 2 NR E -, -
  • one carbon unit of Z D is replaced by -O-, - NHC(O)-,
  • R 9 is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, H, or halo.
  • R 1 that is attached to the 5- or 6- position of the pyridyl ring is:
  • Wi is -C(O)-, -SO 2 -, or -CH 2 -
  • D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy, and amino
  • R D is as defined above.
  • D is OH, an optionally substituted Ci_ 6 aliphatic, an optionally substituted C 3 -Cg cycloaliphatic, an optionally substituted alkoxy, or an optionally substituted amino.
  • said compound has formula V-A or formula V-B:
  • T is an optionally substituted Ci_ 2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by -CO-, -CS-, -COCO-, -SO 2 -, -B(OH)-, or -B(O(Ci -6 alkyl))-;
  • Each of Ri' and Ri" is hydrogen, an optionally substituted C 1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy;
  • R D1 is attached to carbon number 3" or 4"; each R D1 and R D2 is -Z D Rg, wherein each Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein up to two carbon units of Z D are optionally and independently replaced by -
  • R 9 is independently R E , ha , or -OCF 3 ; or R D1 and R D2 , taken together with atoms to whi
  • each R E is independently hydrogen, an optionally substituted C 1 - S aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
  • up to two methylene units of T are optionally substituted by -CO-, -CS-, -B(OH), or -B(O(C 1 -O alkyl).
  • T is an optionally substituted chain selected from the group consisting of -CH 2 - and -CH 2 CH 2 -.
  • T is optionally substituted by -Z E R 10 ; wherein each Z E is
  • each R F is independently hydrogen, an optionally substituted C 1 - S aliphatic group, an optionally substituted
  • T is optionally substituted by F, Cl, Ci- 6 alkyl, C 3 . 8 cycloalkyl, phenyl, naphthyl, -0-(C 1-6 alkyl), -0-(C 3-8 cycloalkyl), -O- phenyl, or C 3-8 spiroaliphatic.
  • T is selected from the group consisting of -CH 2 -, CH 2 CH 2 -, CF 2 -, C(CH 3 ), -C(O)-,
  • T is selected from the group consisting of -CH 2 -, -CF 2 -, and -C(CH 3 ) 2 -.
  • Z D is independently a bond or an optionally substituted branched or straight C 1-6 aliphatic chain wherein one carbon unit of Z D is optionally replaced by -CO-, -SO-, -SO 2 -, -COO-, -OCO-, -C0NR E -, -NR E C0-, NR E C0 2 -, -0-, -NR E S0 2 - , or -S0 2 NR E -.
  • R D1 is -Z D R 9 , wherein R 9 is halo, -OH, - NH 2 , -CN, -CF 3 , -OCF 3 , or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, C 3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C 6-1O aryl, and 5-10 membered heteroaryl.
  • R 9 is F, Cl, -OH, -CN, -CF 3 , or -OCF 3 .
  • R 9 is selected from the group consisting of C 1-6 straight or branched alkyl or C 2 - 6 straight or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of R E , oxo, halo, -OH, -NR E R E , -OR E , -C00R E , and -CONR E R E . In certain embodiments, R 9 is C 3 .
  • R 9 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 9 is a 3-8 membered heterocyclic with 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NR E , and S; wherein said heterocyclic is optionally substituted by 1 or 2 substituents independently selected from the group R E , oxo, halo, -OH, -NR E R E , -OR E , -C00R E , and -CONR E R E .
  • the compound of Formula V is one of the following:
  • Formula VI is represented by:
  • R 1 represents independently for each occurrence hydrogen, Q-Csalkyl, or halogen
  • R 2 is Ci-C 6 alkyl
  • R 3 is CO 2 H or CCfc-Ci-C ⁇ alkyl
  • n 1, 2, 3 or 4.
  • R 1 is F.
  • R 2 is methyl or ethyl.
  • R 3 is CO 2 H.
  • n is 1. In certain embodiments,
  • Formula VII or VIII is represented by:
  • each R x is independently hydrogen, halo, CF 3 , C 1 -C 4 alkyl, or -OC 1 -C 4 alkyl; provided that both R x are not simultaneously hydrogen; or
  • X is CH 2 , CF 2 , CH 2 -CH 2 , or CF 2 -CF 2 ;
  • ring A is 3-7 membered monocyclic cycloalkyl ring
  • R' is hydrogen or Ci-C 6 aliphatic, wherein up to two carbon units of said aliphatic are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR-, -CONRNR-, -CO 2 -, -OCO-, -NRCO 2 -, -O-, -NRCONR-, -0C0NR-, -NRNR-, -NRNRCO-, -NRCO-, -S-, -SO-, -O 2 -, -NR-, -SO 2 NR-, NRSO 2 -, or -NRSO 2 NR-;
  • R is hydrogen or Ci-C 6 aliphatic
  • Z is halo, CF 3 , or difluoromethylenedioxy
  • two RX taken together form ring (a) and X is CH 2 .
  • two R x taken together form ring (a) and X is CF 2 .
  • one R x is hydrogen and the other R x is halo, CF 3 , Ci-C 4 alkyl, or -OCi-C 4 alkyl. In certain embodiments, one R x is hydrogen and the other R x is 4-methoxy. In certain embodiments, ring A is cyclopropyl, cyclopentyl, or cyclohexyl. In certain embodiments, ring A is cyclopropyl or cyclopentyl. In certain embodiments, ring A is cyclopropyl. In certain embodiments, R' is hydrogen. In certain embodiments, R' is C 1-6 alkyl.
  • R AA and R BB taken together, form a pyrrolidinyl with an OH substituent.
  • Z is halo.
  • q is 0.
  • q is 1.
  • R is hydrogen.
  • the compound comprises one or more, and preferably all, of the following features: two R x taken together form ring (a); X is CH 2 ; ring A is cyclopropyl; R is hydrogen; q is 1; and Z is halo, CF 3 , or
  • the compound comprises R AA and R BB ,
  • the compound of Formula VII or VIII is one of the following:
  • Ht is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH, wherein said ring is optionally fused to a 6-membered monocyclic or 10-membered bicyclic, carbocyclic or heterocyclic, aromatic or non-aromatic ring, wherein Ht is optionally substituted with w occurrences of -WR W , wherein w is 0-5;
  • R N is H or R
  • R is hydrogen or C 1-6 aliphatic
  • ring A is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A is optionally substituted with q occurrences of -QR Q ;
  • ring B is optionally fused to 5-6 membered carbocyclic or heterocyclic, aromatic or non- aromatic ring;
  • each of x and q is independently 0-5;
  • each of Q, X, and W is independently a bond or is an optionally substituted C 1 -C 6 alkylidene chain wherein up to two methylene units of Q, W, or X are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO 2 -, -OCO-, -NR 5 CO 2 -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -SO 2 -, -NR'-, -SO 2 NR'-, NR 5 SO 2 -, or -NR 5 SO 2 NR'-;
  • each of R x , R Q , and R w is independently R', halo, -NO 2 , -CN, -CF 3 , or -OCF 3 ;
  • R' is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;
  • R 1 is oxo, R 6 or ((C 1 -C 4 )aliphatic) n -Y;
  • n 0 or 1;
  • Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
  • R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 :
  • R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to
  • R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 ,
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (CrC 6 )-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n -Z;
  • Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 - aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
  • R 8 is an amino protecting group.
  • R' is independently selected from hydrogen or an optionally substituted group selected from a C 1 -Cg aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms
  • each of Q, X, and W is independently a bond or is an optionally substituted C 1 - Ce alkylidene chain wherein up to two methylene units of Q, W, or X are optionally and independently replaced by -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO 2 -, -OCO-, -NR 5 CO 2 -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'NR'CO-, -NR'CO-, -S-, -SO-, -SO 2 -, -NR'-, -SO 2 NR'-, NR 5 SO 2 -, or - NR 5 SO 2 NR'-.
  • each of R x , R Q , and R w is independently R' , halo, -NO 2 , -CN,
  • each of R x , R Q , and R w is independently R', halo,
  • Q is independently a bond or is an optionally substituted d- ⁇ alkylidene chain wherein one or two non- adjacent methylene units are optionally and independently replaced by O, NR, S, SO 2 , COO, or CO, and R Q is R' or halogen.
  • each occurrence of QR Q is independently -Ci_ 3 alkyl, -OCCi.salkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, -Cl, -Br, or -COOR', -COR', -O(CH 2 ) 2 N(R)(R'), -0(CH 2 )N(R)(R'), -CON(R)(R'), -(CH 2 ) 2 OR ⁇ -(CH 2 )OR', optionally substituted phenyl, -N(R)(R'), -(CH 2 ) 2 N(R)(R'), or -(CH 2 )N(R)(R').
  • X is independently a bond or is an optionally substituted C 1-6 alkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by O, NR, S, SO 2 , COO, or CO, and R x is R' or halogen.
  • each occurrence of XR X is independently -Ci- 3 alkyl, -O(Ci. 3 alkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, -Cl, -Br, or -COOR', -COR',
  • W is independently a bond or is an optionally substituted C 1-6 alkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by O, NR, S, SO 2 , COO, or CO, and R w is R' or halogen.
  • each occurrence of WR W is independently -C ⁇ alkyl, -O(Ci_ 3 alkyl), -CF 3 , -OCF 3 , -SCF 3 , -F, -Cl, -Br, or -COOR', -COR', -O(CH 2 ) 2 N(R)(R'), -0(CH 2 )N(R)(R'), -CON(R)(R'), -(CH 2 ) 2 OR ⁇ -(CH 2 )OR', optionally substituted phenyl, - N(R)(R'), -(CH 2 ) 2 N(R)(R'), or -(CH 2 )N(R)(R').
  • R is hydrogen.
  • ring A is a 3-7 membered cycloalkyl ring.
  • ring A is a 3-7 membered ring containing 1 heteroatom selected from O, NH, or S.
  • ring A contains up two heteroatoms selected from O, S, or NH.
  • ring A is selected from:
  • Ht is a 5-membered heteroaromatic ring containing 1-4 nitrogen atoms, wherein Ht is optionally substituted with up to three substituents.
  • Ht is selected from one of the following rings:
  • each ring is linked to the remainder of the molecule through a carbon ring atom.
  • ring B is optionally substituted phenyl.
  • the compound of Formula IX is represented by:
  • Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH, wherein said ring is optionally fused to a phenyl or 6-membered heteroaromatic ring; ring B is optionally fused to 5-6 membered carbocyclic or heterocyclic, aromatic or non-aromatic ring; and X, R x , x, W, R w , and w are as defined above for Formula IX. [0125] In certain embodiments, m is 0, or m is 1, or m is 2, or m is 3. In certain embodiments, Htiis selected from:
  • each ring is linked to the remainder of the molecule through a carbon ring atom.
  • the compound of Formula IX is represented by:
  • R L is -OR', -SR', -SOR', -SO 2 R', or -N(R' ) 2 ; wherein ring A' is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A' is optionally substituted with q occurrences of -QR Q ; R' is as defined above for Formula IX; Xg is CH 2 or CF 2 ; and Ht 1 is a 5- membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH, wherein said ring is optionally fused to a phenyl ring.
  • the compound of Formula IX is represented by:
  • L is a bond, O, S, SO, SO 2 , C(O), NR', C 1-4 aliphatic, or CHR L ;
  • ⁇ w R L is QR , SR , _ S0R ' ; -SO 2 R', or -N(R') 2 ; wherein ring A' is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A' is optionally substituted with q occurrences of -QR Q ; R' is as defined above for Formula IX; X 9 is CH 2 or CF 2 ; X 1 is O, S, or NR; R is hydrogen or C 1-4 aliphatic; and each of X 2 and X 3 is independently selected from CH or N.
  • X 1 is S, X 2 is N, and X 3 is CH. In certain embodiments, X 1 is S, X 2 and X 3 both are N. In certain embodiments, X 1 is S, X 2 is CH, and X 3 is N. In certain embodiments, X 1 is O, X 2 is N, and X 3 is CH. In certain embodiments, X 1 is O, X 2 and X 3 both are N. In certain embodiments, X 1 is O, X 2 is CH, and X 3 is N. In certain embodiments, X 1 is NR, X 2 is N, and X 3 is CH. In certain embodiments, R is hydrogen. In certain embodiments, R is C 1-4 alkyl.
  • X 1 is NR, X 2 and X 3 both are N, wherein R is hydrogen or R is C 1-4 alkyl. In certain embodiments, X 1 is NR, X 2 is CH, and X 3 is N, wherein R is hydrogen or C 1-4 alkyl.
  • the compound of Formula IX is one of the following:
  • Another CFTR-modulator contemplated for use as the second CFTR-modulator compound is the following compound, or a pharmaceutically acceptable salt thereof:
  • Another CFTR-modulator contemplated for use as the second CFTR-modulator compound is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • Exemplary procedures for preparing this compound are described in International Application Publication No. WO 2007/134279, the contents of which are hereby incorporated by reference in its entirety.
  • the pharmaceutical composition provides a synergistic increase in activity at a cystic fibrosis transmembrane regulator protein compared to the activity of the first CFTR-modulator compound alone and second CFTR-modulator compound alone towards the cystic fibrosis transmembrane regulator protein.
  • the pharmaceutical composition achieves a ⁇ FSK of at least 70 ⁇ A/cm 2 in a FRT cell assay when the sum of the ⁇ FSK in a FRT cell assay for the first CFTR-modulator compound and second CFTR-modulator compound is less than 40 ⁇ A/cm 2 .
  • the pharmaceutical composition has at least two fold greater activity at a cystic fibrosis
  • the pharmaceutical composition provides a synergistic increase in therapeutic efficacy in treating cystic fibrosis compared to the therapeutic efficacy of the first CFTR-modulator compound alone and second CFTR-modulator compound alone in treating cystic fibrosis.
  • compositions described herein may be formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • the invention further provides methods of modulating the activity of one or more cystic fibrosis transmembrane regulator proteins comprising exposing said protein to a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR- modulator compound, wherein Formulae I-IV are as described above.
  • the second CFTR-modulator compound is any one of Formulae V, VI, VII, VIII, or IX, wherein Formulae V-IX are as described above.
  • the invention further provides methods of treating a disease associated with expression or activity of one or more cystic fibrosis transmembrane regulator proteins in a patient comprising administering to the patient a therapeutically effective amount of a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR- modulator compound, wherein Formulae I-IV are as described above.
  • the second CFTR-modulator compound is any one of Formulae V, VI, VII, VIII, or IX, wherein Formulae V-IX are as described above.
  • the method involves administering a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, as further defined in the particular embodiments above, such as compound of Formula Ia.
  • the method involves administering a second CFTR-modulator compound of any one of Formulae V, VI, VII, VIII, or IX as further defined in the particular embodiments above, such as a compound of Formula IX-A.
  • compositions and methods are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation- cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I- cell disease/pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma
  • One embodiment of the invention provides a method of treating a disorder selected from the group consisting of cystic fibrosis and airway inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, and a second CFTR-modulator compound, wherein Formulae I-IV are as described above.
  • the method involves administering a first CFTR-modulator compound of any one of Formulae I, II, III, or IV, as further defined in the particular embodiments above, such as compound of Formula Ia.
  • the method involves administering a a second CFTR-modulator compound of any one of Formulae V, VI, VII, VIII, or IX as further defined in the particular embodiments above, such as a compound of Formula IX-A.
  • the method provides a synergistic increase in activity at a cystic fibrosis transmembrane regulator protein compared to the activity of the first CFTR- modulator compound alone and second CFTR-modulator compound alone towards the cystic fibrosis transmembrane regulator protein.
  • the first CFTR- modulator compound and second CFTR-modulator compound result a ⁇ FSK of at least 70 ⁇ A/cm 2 in a FRT cell assay when used in combination, whereas the sum of the ⁇ FSK in a FRT cell assay for the first CFTR-modulator compound and second CFTR-modulator compound is less than 40 ⁇ A/cm 2 .
  • the method achieves at least two fold greater activity at a cystic fibrosis transmembrane regulator protein compared to the sum of activity of the first CFTR-modulator compound administered alone and the second CFTR- modulator compound administered alone.
  • the method provides a synergistic increase in therapeutic efficacy in treating cystic fibrosis compared to the therapeutic efficacy observed by administration of the first CFTR-modulator compound alone and administration of the second CFTR-modulator compound alone.
  • the compounds of the invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • the compound of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous,
  • compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may bemixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • preformulation composition containing a homogeneous mixture of a compound of the invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • aqueous solution suitably flavored syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • kits for use by a consumer having, or at risk of having, a disease or condition associated with cystic fibrosis transmembrane regulators include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like).
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . .” etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, compounds of the invention may be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available (such as through Aldrich Chemicals Co. (Milwaukee, WI), Alfa Aesar (Ward Hill, MA), Maybridge Chemical Company, Ltd. (Cornwall, England), Ryan Scientific Inc. (Mt. Pleasant, SC), Combi- Blocks, Inc. (San Diego, CA), and Focus Synthesis LLC (San Diego, CA)) or are readily prepared by standard methods from known materials.
  • Scheme 1 illustrates a general procedure for preparing a compound of the present invention where R 1 is H, or -OCH 3 , or -NH 2 .
  • Compound IA can be prepared by amination of a desired 2-chloropyrimidine with a desired amine according to methods known in the art.
  • compound IA can be prepared by heating a mixture of a commercially available 2-chloropyrimidine and a desired amine R-NH 2 in the presence of triethylamine in ethanol at about 75 0 C for about 8-24 h.
  • Compound IB can be prepared from compound IA through coupling of a desired boronic acid under Suzuki conditions, where X may be selected from, for example, alkyl, alkoxy, amino, etc.
  • Scheme 2 illustrates a general procedure for preparing a compound of the present invention where R 1 is -NR 7 R 1O
  • Compound 2A can be prepared by amination of a commercially available 2,4-dichloro-5-bromo-pyrimidine with a desired amine R 7 R 1O NH 2 using methods well-known in the art.
  • compound 2A can be prepared by treating the pyrimidine in CH 3 CN with a desired amine at about -20 0 C to 45 0 C in the presence of triethylamine.
  • Compound 2A can be converted to compound 2B according to the methods described in Scheme 1.
  • Compound 2C can be prepared from compound 2B and a desired boronic acid via Suzuki coupling.
  • Example 1 for intermediates Ia and Ib A mixture of 5-bromo-2-chloropyrimidine (475 mg, 2.46 mmol), 4-(trifluoromethyl)cyclohexanamine (mixture of cis and trans isomers, 411 mg, 2.46 mmol) and triethylamine (2.00 mL, 14.4 mmol) in EtOH (2.00 ml) was stirred at 100 0 C in a microwave oven for Ih.
  • Scheme 3 illustrates a general procedure for preparing a compound of the present invention where R 1 is alkoxy or cycloalkoxy.
  • Compound 3A can be prepared from a commercially available 2,4-dichloro-5-bromo- pyrimidine and a desired alcohol using methods known in the art.
  • compound 3A can be prepared by treating the pyrimidine in THF with a desired alkoxide at about -20 0 C to 60 0 C for about 8-24 h.
  • the alkoxide can be generated from a corresponding alcohol and NaH in THF at about -20 0 C to 60 0 C for about 2-24 h or according to methods known in the art.
  • Compound 3A can be converted to compound 3C by amination followed by Suzuki coupling as described in Scheme 3 below. SCHEME 3
  • Example 4 using 5-bromo-N-((lR,4R)-4-methylcyclohexyl)pyrimidin-2-amine (Ib) (54.0 mg, 200 ⁇ mol) and 4-(trifluoromethoxy)phenylboronic acid (82.4 mg, 400 ⁇ mol) as starting materials.
  • Example 4 using 5-bromo-N-((lS,4S)-4-(trifluoromethyl)cyclohexyl)pyrimidin-2-amine (2a) (32.4 mg, 100 ⁇ mol) and 4-isopropoxyphenylboronic acid (36.0 mg, 200 ⁇ mol), Pd(PPh 3 ) 4 (5.80 mg, 5.00 ⁇ mol) as starting materials.
  • the crude product was purified by ISCO
  • Example 1 using 5-bromo-4-methoxy-N-((lS,4S)-4-methylcyclohexyl)pyrimidin-2-amine (3a) (90.0 mg, 300 ⁇ mol) and 4-isopropoxyphenylboronic acid (81.0 mg, 450 ⁇ mol) as starting materials.
  • Scheme 4 illustrates a general procedure for preparing compound 1C where R is Cs-Cioheterocycloalkyl, Ci-C 4 alkylC 3 - Cioheterocyclooalkyl, Ci-C 4 alkylaryl or C 1 -C 4 alkylheteroaryl.
  • Compound IA can be prepared from a commercially available 2,4-dichloro-5-bromo-pyrimidine and a desired C 3 - Cioheterocyclo alcohol or C 3 -C 1 oheterocycloalkylC 1 -C 4 alkyl alcohol or arylCi ⁇ alkyl alcohol or heteroarylCi-C 4 alkyl alcohol using methods well-known in the art.
  • compound IA can be prepared by treating 2,4-dichloro-5-bromo-pyrimidine in THF with a desired sodium alkoxide at about -20 0 C to 25 0 C for about 8-24 h.
  • the sodium alkoxide can be generated from a corresponding alcohol and NaH in THF at about -20 0 C to 60 0 C for about 2-24 h or according to methods known in the art.
  • Compound IA can be converted to compound IB by amination in the presence of a hindered organic base, such as triethylamine (TEA).
  • TAA triethylamine
  • Compound 1C can be prepared from compound IB and a desired boronic acid or its corresponding pinacol ester through Suzuki coupling conditions.
  • Step 3 Preparation of 5-(4-Isopropoxyphenyl)-N-((ls,4S)-4-methylcyclohexyl)-4-((R)- tetrahydrofuran-3-yloxy)pyrimidin-2-amine
  • Scheme 5 illustrates a general procedure for preparing compounds 2B, 2C, 2D and 2E, where W is a bond or Ci-C 4 alkyl.
  • Compounds 2B, 2C, 2D and 2E can be prepared from compound 2A based on functional group
  • compound 2B can be prepared by treating compound 2A with a desired chloroformate in CH 2 C1 2 /H 2 O at about 0°C-40°C in the presence of a base such as Na 2 CO 3 .
  • compound 2C can be prepared from compound 2A with a desired acid chloride or corresponding anhydride in CH 2 Cl 2 at about 0°C-40°C in the presence of a base such as Na 2 CO 3 or TEA
  • Compound 2D can be prepared by reacting compound 2A with a desired carbamoyl chloride or an isocyanate in CH 2 Cl 2 at about 0°C-40°C in the presence of a base such as Na 2 CO 3 or TEA
  • Compound 2E can be prepared from compound 2A with a desired sulfonyl chloride in CH 2 Cl 2 at about 0°C-40°C in the presence of a base such as Na 2 CO 3 or TEA.
  • Compound 2A can be prepared based on the procedures described above in
  • Step 1 Preparation of tert-Butyl 3-(5-bromo-2-chloropyrimidin-4-yloxy)pyrrolidine-l- carboxylate
  • Step 2 Preparation of tert-Butyl 3-(5-bromo-2-((ls,4s)-4-methylcyclohexylamino) pyrimidin-4-yloxy)pyrrolidine-l-carboxylate
  • Step 3 Preparation of tert-Butyl 3-(5-(2-methyl-2H-indazol-6-yl)-2-((ls,4s)-4- methylcyclohexylamino)pyrimidin-4-yloxy)pyrrolidine-l-carboxylate
  • Step 4 Preparation of 5-(2-Methyl-2H-indazol-6-yl)-N-((ls,4s)-4-methylcyclohexyl)-4- (pyrrolidin-3-yloxy)pyrimidin-2-amine
  • Step 1 Preparation of tert-Butyl 3-(5-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-((ls,4s)-4- methylcyclohexylamino)pyrimidin-4-yloxy)pyrrolidine-l-carboxylate
  • Step 2 Preparation of 5-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-N-((ls,4s)-4- methylcyclohexyl)-4-(pyrrolidin-3-yloxy)pyrimidin-2-amine
  • Step 3 Preparation of Methyl 3-(2-((ls,4s)-4-methylcyclohexylamino)-5-(2,3,4a,8a- tetrahydrobenzo[b][l,4]dioxin-6-yl)pyrimidin-4-yloxy)pyrrolidine-l-carboxylate
  • Scheme 6 illustrates a general procedure for preparing compound 3C.
  • Compound 3A can be prepared from a commercially available 2, 4-dichloro-5-bromo-pyrimidine and a desired aryl alcohol or heteroaryl alcohol using methods well-known in the art.
  • compound 3A can be prepared by treating 2,4-dichloro-5- bromo-pyrimidine with a desired aryl alcohol or heteroaryl alcohol in DMF at about -20 0 C to O 0 C for about 6-24 h.
  • Compound 3B can be prepared from compound 3A by amination according to methods well-known in the art.
  • Compound 3C can be prepared from compound 3B and a desired boronic acid or its corresponding pinacol ester through Suzuki coupling conditions.
  • Step 3 Preparation of 5-(4-Isopropoxyphenyl)-4-(3-methoxyphenoxy)-N-((ls,4s)-4- methylcyclohexyl)pyrimidin-2-amine
  • Step 3 Preparation of 4-(((R)-l,4-Dioxan-2-yl)methoxy)-5-bromo-N-((ls,45)-4- methylcyclohexyl)pyrimidin-2-amine
  • Step 4 Preparation of 4-(((R)-l,4-Dioxan-2-yl)methoxy)-5-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)-N-((ls,45)-4-methylcyclohexyl)pyrimidin-2-amine
  • Step 1 Preparation of 4-((R)-Tetrahydrofuran-3-yloxy)-5-bromo-N-(2,6- dimethylcyclohexyl)pyrimidin-2-amine
  • the compound 4-amino- 1-methylcyclohexanol hydrochloride can be prepared in two steps from tert-butyl 4-oxocyclohexylcarbamate as shown in Scheme 9 below.
  • Step 2 Preparation of 4-(4-((R)-Tetrahydrofuran-3-yloxy)-5-bromopyrimidin-2- ylamino)-l-methylcyclohexanol
  • Step 1-1 Preparation of 2-((ls,4s)-4-Hydroxycyclohexyl)isoindoline-l,3-dione (2)
  • Step 1-2 Preparation of 2-((ls,4s)-4-Methoxycyclohexyl)isoindoline-l,3-dione (3)
  • Step 1-3 Preparation of 4-Methoxycyclohexanamine hydrochloride (4)
  • Step 2 Preparation of 4-((R)-Tetrahydrofuran-3-yloxy)-5-bromo-N-Cis-4- methoxycyclohexyl)pyrimidin-2-amine
  • Step 3 Preparation of 4-((R)-Tetrahydrofuran-3-yloxy)-5-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-N-((ls,4S)-4-methoxycyclohexyl)pyrimidin-2-amine
  • Scheme 11 illustrates a general procedure for preparing compound 4C where R is aryl or heteroaryl.
  • Compound 4A can be prepared using methods well-known in the art. For example compound 4A can be prepared by reacting 2,4-dichloro-5-bromo-pyrimidine with a desired tri(n-butyl)aryltin or tri(n-butyl)heteroaryltin in DMF in the presence of catalytic amount of bis(triphenylphosphine)palladium (II) dichloride at about 70-80 0 C for about 18-24 h.
  • Compound 4A can be converted to compound 4C via amination, followed by Suzuki coupling as shown in Scheme 11.
  • Step 2 Preparation of 5-Bromo-4-(3,5-dimethylisoxazol-4-yl)-N-((ls,4s)-4- methylcyclohexyl)pyrimidin-2-amine
  • CTFR i.e., increase the surface expression of CFTR channels, and potentiate existing channels
  • FRT cell electrophysiological (Ussing chamber) assay FRT epithelial cell monolayers were grown on Snapwell filter inserts and optionally treated with reference corrector N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide. The cells were exposed to a test compound for 24 hours prior to the assay.
  • the inserts were transferred to a Navicyte Ussing recording chamber and superfused with a HEPES buffered physiological saline (HB-PS) with composition (in mM): NaCl, 137; KCl, 4.0; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • HEPES buffered physiological saline HB-PS
  • the mucosal solution was lOCF-PS (composition in mM: Na-gluconate, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Mannitol, 10; pH adjusted to 7.4 with N-methyl-D-glucamine) to create a transepithelial Cl ion gradient.
  • lOCF-PS composition in mM: Na-gluconate, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Mannitol, 10; pH adjusted to 7.4 with N-methyl-D-glucamine
  • Inserts were voltage clamped at 0 mV to measure the ISC.
  • 10CF-PS solution (5 ml) was added to the mucosal (top) side of the Snapwell filter and HB-PS solution (5 mL) was added to the serosal (bottom) side of the Snapwell filter insert to permeabilize the serosal membrane.
  • Solution additions and replacements in the Navicyte chambers were performed in a way to maintain a hydrostatic pressure gradient from mucosal to serosal sides of the filters by maintaining a solution level greater or equal in the mucosal chamber relative to the serosal chamber during solution changes.
  • agonists final concentrations: 10 ⁇ M forskolin, 100 ⁇ M 3-isobutyl-l-methylxanthine [IBMX] and 20 ⁇ M genistein
  • antagonist final concentration: 10 ⁇ M CFTRinh-172
  • 10 minute intervals for forskolin and IBMX were applied sequentially and cumulatively at 10 minute intervals for forskolin and IBMX, and at 15 minute intervals for genistein and CFTRinh-172, to both serosal and mucosal epithelial surfaces.
  • Agonists were prepared as 200X-1000X concentrated solutions in HP-PS and
  • EC 50 values are defined as the concentration of compound that gives a >25% increase in whole cell Cl " conductance (compared to DMSO at 37°C as a vehicle) at 10 ⁇ M.
  • the corrector efficacy was measured as a percentage change in agonist + compound vs.
  • FRT epithelial cell monolayers are grown on Snapwell filter inserts.
  • cells are incubated with the test compound for 24 hours at 37°C in the incubator.
  • all the test compounds are added to the regular growth medium (F12 Coon's, 10% FBS) and cells are bathed in the test compounds containing medium for 24 hours.
  • HEPES buffered physiological saline HB-PS
  • HB-PS HEPES buffered physiological saline
  • the mucosal solution may be lOCF-PS (composition in mM: Na-gluconate, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with N-methyl-D-glucamine) and is used to create a transepithelial Cl ion gradient.
  • a Physiologic Instruments VCC MC8-8S epithelial voltage clamp (Physiologic Instruments, Inc., San Diego, CA) is used to record the short circuit current.
  • the assay is typically carried out at 27°C.
  • a 10CF-PS solution (5 mL) is added to the mucosal (top) side of the Snapwell filter, and HB-PS solution (5 mL) is added to the serosal (bottom) side of the Snapwell filter insert. Inserts are voltage clamped at 0 mV to measure the short circuit current.
  • agonists final concentrations: 10 ⁇ M forskolin, 100 ⁇ M 3-isobutyl-l-methylxanthine [IBMX] and 20 ⁇ M genistein
  • antagonist final concentration: 20 ⁇ M CFTRinh-172
  • agonists final concentrations: 10 ⁇ M forskolin, 100 ⁇ M 3-isobutyl-l-methylxanthine [IBMX] and 20 ⁇ M genistein
  • antagonist final concentration: 20 ⁇ M CFTRinh-172
  • Agonists are added as 20Ox-IOOOx stock solution to the solutions bathing the serosal and mucosal sides. Transepithelial resistance is then monitored every 20 s with 10 mV voltage steps.
  • the hBE Chamber Assay was performed on test compounds according to the procedures used by ChanTest Corporation. A test compound is added to the culture medium bathing the serosal side of the cells. In situations where the activity of two compounds were evaluated together, both test compounds are added to the culture medium bathing the serosal side of the cells.
  • the primary CF hBE cells are fully differentiated and have been cultured for at least three weeks as air-liquid interface cultures before used for compound testing. In the air- liquid interface culture, no medium bathes the mucosal side of the cells, and, accordingly, the compounds are applied from only the serosal side of the cells.
  • Compound incubations are typically carried out for 48 hours at 37°C in the tissue culture incubator, and the compound-containing medium is replaced after 24 hours with fresh compound-containing medium.
  • the mucosal side of the cells is washed 24 hours prior to the Ussing Chamber Assay to wash off the mucus produced by the cells.
  • the cells are transferred from the incubator and mounted with the
  • HEPES buffered physiological saline HB-PS
  • HB-PS HEPES buffered physiological saline
  • Glucose 10; pH adjusted to 7.4 with NaOH.
  • the solution bathing the mucosal side is identical except that glucose is replaced by mannitol.
  • a Physiologic Instruments VCC MC8-8S epithelial voltage clamp (Physiologic Instruments, Inc., San Diego, CA) is used to record short circuit current.
  • the assay is typically carried out at 27°C.
  • HB-PS solution with mannitol (5 mL) is added to the mucosal (top) side of the
  • concentrations 10 ⁇ M forskolin, 100 ⁇ M 3-isobutyl-l-methylxanthine [IBMX] and 20 ⁇ M genistein) and antagonist (final concentration: 20 ⁇ M CFTRinh-172) are applied sequentially and cumulatively at 10-15 minute intervals for forskolin and IBMX (-15 minute intervals for genistein and CFTRinh-172) to both serosal and mucosal epithelial surfaces.
  • Agonists are added as 20Ox-IOOOx stock solution to the solutions bathing the serosal and mucosal sides. Transepithelial resistance is monitored every 20 s with 10 mV voltage steps.
  • Results The activity of exemplary compounds (i.e., Compound A, Compound B, Compound C, and Compound E (See Table 5 for chemical structures); and Compound G which is an acute potentiator having the chemical name N-(5-hydroxy-2,4-ditert-butyl-phenyl)- 4-oxo-lH-quinoline-3-carboxamide) was evaluated in the above ChanTest hBE Chamber Assay. The data are presented in Figures 3-6.

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Abstract

L'invention porte sur des compositions pharmaceutiques comprenant un composé arylpyrimidine qui module l'activité d'une protéine régulatrice transmembranaire de la mucoviscidose (CFTR) et un second composé qui module l'activité d'une protéine CFTR. L'invention porte également sur des procédés de traitement d'un trouble associé à une fonction protéine CFTR par l'administration d'un composé arylpyrimidine qui module l'activité d'une protéine CFTR et un second composé qui module l'activité d'une protéine CFTR. La thérapie de combinaison peut être utilisée pour traiter, par exemple, une inflammation des voies aériennes et une mucoviscidose.
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WO2020049189A1 (fr) 2018-09-09 2020-03-12 Qanatpharma Gmbh Utilisation de modulateurs du cftr pour traiter des affections cérébrovasculaires
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
WO2022053823A1 (fr) * 2020-09-11 2022-03-17 Cerevance, Inc. Dérivés de pyrimidine substitués servant de modulateur alpha 6 du récepteur de l'acétylcholinestérase nicotinique

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