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WO2013038378A1 - Dérivés pyridinamides - Google Patents

Dérivés pyridinamides Download PDF

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Publication number
WO2013038378A1
WO2013038378A1 PCT/IB2012/054816 IB2012054816W WO2013038378A1 WO 2013038378 A1 WO2013038378 A1 WO 2013038378A1 IB 2012054816 W IB2012054816 W IB 2012054816W WO 2013038378 A1 WO2013038378 A1 WO 2013038378A1
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Prior art keywords
alkyl
optionally substituted
heterocyclic group
halogen atoms
aryl
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PCT/IB2012/054816
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English (en)
Inventor
Darren Mark Legrand
Original Assignee
Novartis Ag
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Publication of WO2013038378A1 publication Critical patent/WO2013038378A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to pyridine amide derivatives, their preparation and use as pharmaceuticals.
  • Cystic fibrosis is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)- activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung.
  • CFTR CF transmembrane conductance regulator
  • PKA protein kinase A
  • Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both.
  • impair channel function e.g., gating or conductance mutations
  • the present invention discloses compounds which restore or enhance the function of mutant and/or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).
  • the invention provides compounds according to Formula I:
  • R c and R d together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl group optionally substituted by one or more Z substituents;
  • R 2 is C1-C 4 haloalkyl
  • R 3 is H or C-i-Ce alkyl optionally substituted by one or more halogen atoms
  • R 4a is selected from H; halogen; Ci-C 4 alkyl optionally substituted by one or more halogen atoms; C 2 -C 8 alkenyl; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl; -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl; Ci-Ce hydroxyalkyl; -(CH 2 ) m -NR 7 R 18 ; -(C 0 -C 4 alkyl)-C0 2 R 15 and -(C 0 -C 4 alkyl)-C(0)NR 7 R 18 ; R 4 is H, or Ci-C 8 alkyl optional substituted with one or more halogen;
  • R 5 is -(CH 2 ) m -NR 7 R 18 , -(CH 2 ) m -OR ' ; Ci-Ce alkoxy optionally substituted by one or more halogen atoms; -(C 0 -C 4 alkyl)-C0 2 R 15 ; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl and -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
  • R 6 is Ci-C 8 alkyl optionally substituted by one or more halogen atoms; C3-C10 cycloalkyi; -Ci-C 4 alkyl-C 3 -C 8 cycloalkyi; Ci-Ce alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl; or -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyi, cycloalkenyl, -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl and -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or R 6 is H
  • R 4 and R 6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system
  • R 5 and R 6 together with the carbon atom to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or
  • R 4 and R 5 and R 6 together with the carbon atom to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R is H, or C-i-Ce alkyl optional substituted with one or more halogen; m is 0, 1 , 2 or 3;
  • R 8 , R , R 3 and R 7 are each independently H, C C 8 alkyl optionally substituted by one or more halogen atoms, C 3 -Ci 0 cycloalkyl or -(C C 4 alkyl)-C 3 -C 8 cycloalkyl;
  • R 9 , R 0 , R 2 , R 4 , R 5 , R 6 and R 8 are each independently H;
  • R 8 and R 9 , R and R 2 , R 3 and R 4 , and R 7 and R 8 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
  • Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C C 6 alkyl optionally substituted by one or more OH groups or NH 2 groups, C C 6 alkyl optionally substituted by one or more halogen atoms, C C 6 alkoxy optionally substituted by one or more OH groups or C 1 -C4 alkoxy, NR 8 (S0 2 )R 21 , (S0 2 )NR 9 R 21 , (S0 2 )R 21 , NR 8 C(0)R 21 , C(0)NR 9 R 21 , NR 8 C(0)NR 9 R 21 , NR 8 C(0)OR 19 , NR 9 R 21 , C(0)OR 19 , C(0)R 19 , SR 9 , OR 19 , oxo, CN, N0 2 , halogen or a 3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S;
  • R 9 and R 2 are each independently H; C C 8 alkyl; C 3 -C 8 cycloalkyl; C 1 -C4 alkoxy-CrC 4 alkyl; (C 0 -C 4 alkyl)-aryl optionally substituted by one or more groups selected from Ci-C 6 alkyl, C C 6 alkoxy and halogen; (C 0 -C 4 alkyl)- 3- to 14-membered heterocyclic group, the heterocyclic group including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C C 6 alkyl and C(0)Ci-C 6 alkyl; (C 0 -C 4 alkyl)-0-aryl optionally substituted by one or more groups selected from Ci-C 6 alkyl, Ci-C 6 alkoxy and halogen; and (C 0 -C 4 alkyl)- 0-3- to 14- membered heterocyclic group, the hetero
  • R 9 and R 2 together with the nitrogen atom to which they attached form a 5- to 10- membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10- membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(0) 2 -aryl; S(0) 2 -Ci-C 6 alkyl; d-C 6 alkyl optionally substituted by one or more halogen atoms; C C 6 alkoxy optionally substituted by one or more OH groups or CrC 4 alkoxy; and C(0)OCrC 6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by Ci-C 6 alkyl, Ci-C 6 haloalkyl or Ci-C 6 alkoxy;
  • R 2 is CF 3 CF 2 -, (CF 3 ) 2 CH-, CH 3 -CF 2 -, CF 3 CF 2 -, CF 3 , CF 2 H-, CH 3 -CCI 2 -, CF 3 CFCCIH-, CBr 3 , CBr 2 H- CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 -, particularly R 2 is CF 3 .
  • R 3 is H or methyl.
  • R 4a is methyl, ethyl, isopropyl and trifluoromethyl.
  • R 4a is H.
  • R 4 is H or CrC 4 alkyl optionally substituted by one or more halogen atoms.
  • R 5 provides a heteroatom two carbons from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.
  • R 4 is H, CrC 4 alkyl optionally substituted by one or more halogen atoms or not present;
  • R 5 is C-i-C 4 alkoxy optionally substituted by one or more halogen atoms; -(CH 2 ) m - NR 7 R 18 ; -(CH 2 ) m -OR ' ,or OH; m is 0, or 1 ;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms; CrC 4 alkoxy optionally substituted by one or more halogen atoms; OH ; CN ; halogen; -(C 0 -C 4 alkyl)- C 6 -C 14 aryl; or -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • R 2 is C 1 -C4 haloalkyl
  • R 3 is H
  • R 4 is H or Me
  • R 4a is H
  • R 5 is -(CH 2 ) m -NR 7 R 18 ; -(CH 2 ) m -OR ' ; or OH;
  • n 0, or 1 ;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • R 2 is C 1 -C4 haloalkyl
  • R 3 is H
  • R 4a is H
  • R 2 is C1-C4 haloalkyl
  • R 3 is H ;
  • R 4 is H or Me
  • R 4a is H ;
  • R 5 is -(CH 2 ) m -N R 7 R 18 ; -(CH 2 ) m -OR'; or OH ;
  • n 0, or 1 ;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N , O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • R 2 is C1-C4 haloalkyl
  • R 3 is H ;
  • R 4 is H or Me
  • R 4a is H ;
  • R 5 is -(CH 2 ) m -N R 7 R 18 ; -(CH 2 ) m -OR; or OH ;
  • n 0, or 1 ;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N , O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • R 2 is C1-C4 haloalkyl
  • R 3 is H ;
  • R 4 is H or Me
  • R 4a is H ;
  • R 5 is -N R 7 R 18 ; or OH ;
  • R 6 is C C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N , O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • R is C"i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 2 is C1-C4 haloalkyl
  • R 3 is H ;
  • R 4 is H or Me
  • R 4a is H ;
  • R 5 is -N R 7 R 18 ; or OH ;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Z is independently OH , d-C 4 alkyl optionally substituted by one or more OH groups or N H 2 groups, CrC 4 alkyl optionally substituted by one or more halogen atoms, CrC 4 alkoxy optionally substituted by one or more OH groups or d-C 4 alkoxy, N R 9 R 21 , C(0)OR 19 , C(0)R 19 , SR 9 , OR 19 , CN , N0 2 , or halogen;
  • R 9 and R 2 are each independently H ; C C 4 alkyl; C 3 -C 6 cycloalkyl; or d-C 4 alkoxy-Cr C 4 alkyl, wherein all alkyls are optionally substituted with halogens.
  • Z is independently OH, CrC 4 alkyl optionally substituted by one or more OH groups or NH 2 groups, CrC 4 alkyl optionally substituted by one or more halogen atoms, CrC 4 alkoxy optionally substituted by one or more OH groups or CrC 4 alkoxy, C(0)OR 19 , C(0)R 19 , OR 19 , CN, or halogen;
  • R 9 is H; d-C 4 alkyl; C 3 -C 6 cycloalkyl; or d-C 4 alkoxy-C-i-C 4 alkyl, wherein all alkyl are optionally substituted with halogens.
  • Z is independently, d-C 4 alkyl optionally substituted by one or more halogen atoms, C r C 4 alkoxy or halogen.
  • the compound of formula I is a substantially pure enantiomers with the R configuration.
  • the compound of formula I is a substantially pure enantiomers with the S configuration.
  • the compounds of Formula I include compounds of Formula II:
  • the compound is of formula II and R 3 is H or methyl.
  • the compound is of formula II and
  • the compound is of formula II and
  • R 3 is H
  • the compound is of formula II and
  • R 3 is H
  • the compound is of formula II and
  • R 3 is H
  • R 3 is H
  • the compound is of formula II and
  • R 3 is H
  • the compound of formula I or II, or pharmaceutically acceptable salts thereof is selected from:
  • Optionally substituted means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • “Optionally substituted by one or more Z groups” denotes that the relevant group may include one or more substituents, each independently selected from the groups included within the definition of Z. Thus, where there are two or more Z group substituents, these may be the same or different.
  • Halo or "halogen”, as used herein, may be fluorine, chlorine, bromine or iodine.
  • C-i-Ce-Alkyl denotes straight chain or branched alkyl having 1-8 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "Ci-C 4 -Alkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C-i-Ce-Alkoxy denotes straight chain or branched alkoxy having 1-8 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "C"i-C 4 -Alkoxy” will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • C 1 -C 4 -Haloalkyl denotes straight chain or branched alkyl having 1-4 carbon atoms with at least one hydrogen substituted with a halogen. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "C 1 -C 4 -Haloalkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF 3 CF 2 -, (CF 3 ) 2 CH-, CH 3 -CF 2 -, CF 3 CF 2 -, CF 3 , CF 2 H-, CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 -.
  • C-i-Ce-hydroxyalkyl denotes straight chain or branched alkyl having 1- 8 carbon atoms with at least one hydrogen substituted with a hydroxy group. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "C 1 -C 4 -hydroxyalkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with a hydroxy group.
  • 'C 2-8 alkenyl' refers to a linear or branched saturated hydrocarbon group containing from 2 to 8 carbon atoms that contains at least one carbon to carbon double bond. Examples of such groups include ethenyl, propenyl, butenyl and pentenyl. Unless a particular structure is specified, the terms butenyl and pentenyl etc. include all possible E and Z isomers.
  • the term 'C 3-8 cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkylene denotes a straight chain or branched saturated hydrocarbon chain containing between 1 and 8 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • Amino-C-i-Ce-alkyl and "amino-C-i-Cs-alkoxy” denote amino attached by a nitrogen atom to d-Ce-alkyl, e.g., NH 2 -(Ci-C 8 )-, or to Ci-C 8 -alkoxy, e.g., NH 2 -(Ci-C 8 )-0-. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • Ci-C 8 -alkyl denote Ci-C 8 -alkyl, as hereinbefore defined, attached by a carbon atom to an amino group.
  • the C-i-C 8 -alkyl groups in di(CrC 8 -alkyl)amino may be the same or different. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • Amino-(hydroxy)-C"i-C 8 -alkyl denotes amino attached by a nitrogen atom to C-i-C 8 -alkyl and hydroxy attached by an oxygen atom to the same CrC 8 -alkyl. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • Ci-C 8 -Alkylcarbonyl and "Ci-C 8 -alkoxycarbonyl”, as used herein, denote Ci-C 8 -alkyl or C"i-C 8 -alkoxy, respectively, as hereinbefore defined, attached by a carbon atom to a carbonyl group. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • C 3 -C 8 -Cycloalkylcarbonyl denotes C 3 -C 8 -cycloalkyl, as hereinbefore defined, attached by a carbon atom to a carbonyl group. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • C 7 -C 14 -Aralkyl denotes alkyl, e.g., Ci-C 4 -alkyl, as hereinbefore defined, substituted by a C 6 -Ci 0 -aromatic carbocyclic group, as herein defined. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly.
  • C 3 -C 15 -Cycloalkyl denotes a cycloalkyl having 3- to 15-ring carbon atoms that is saturated or partially saturated, such as a C 3 -C 8 -cycloalkyl.
  • Examples of C 3 -Ci 5 -cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl including indanyl and indenyl and bicyclodecyl. If a different number of carbon atoms is specified, such as C 6 , then the definition is to be amended accordingly.
  • aryl or "C 6 -Ci 5 -Aromatic carbocyclic group” denotes an aromatic group having 6- to 15-ring carbon atoms.
  • C 6 -C 15 -aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzenetriyl, naphthyl, naphthylene, naphthalenetriyl or anthrylene. If a different number of carbon atoms is specified, such as C-io, then the definition is to be amended accordingly.
  • “4- to 8-Membered heterocyclyl”, “5- to 6- membered heterocyclyl”, “3- to 10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to 14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers, respectively, to 4- to 8-membered, 5- to 6- membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclic rings containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, which may be saturated, partially saturated or unsaturated (aromatic).
  • the heterocyclyl includes single ring groups, fused ring groups and bridged groups.
  • heterocyclyls include, but are not limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahyrofuran, tetrahydrothiophene, tetrahydrothiopyran,
  • a second aspect of the invention provides a compound of Formula I or II as defined anywhere herein for use as a pharmaceutical.
  • a further aspect of the invention provides a compound of Formula I or II for use in the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease or mucosal hydration.
  • an inflammatory or allergic condition particularly an inflammatory or obstructive airways disease or mucosal hydration.
  • Such conditions include, for example, cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).
  • a still further aspect of the present invention provides for the use of a compound of formula (I) or (II), as defined in any of the aforementioned embodiments, in free or pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease or mucosal hydration.
  • An embodiment of the present invention provides for the use of a compound of formula (I) or (II), as defined in any of the aforementioned embodiments, in free or
  • a medicament for the treatment of an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).
  • an inflammatory or allergic condition selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).
  • An embodiment of the present invention provides for the use of a compound of formula (I) or (II), as defined in any of the aforementioned embodiments, in free or
  • An embodiment of the present invention provides method for the prevention or treatment of a CFTR mediated condition or disease comprising administering an effective amount of at least one compound as described herein to a subject in need of such treatment.
  • CFTR mediated condition or disease are selected from cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002).
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their
  • co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
  • suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 %
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, i i c 13 C 14 C 15 N 18 F 31 p 32 p 35g 36 C
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 3 C, and 4 C , are present.
  • isotopically labeled compounds are useful in metabolic studies (with 4 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 8 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and
  • isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • deuterium in this context is regarded as a substituent of a compound of the formula (I) or (II).
  • concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium
  • Isotopically-labeled compounds of formula (I) or (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, de-DMSO.
  • co-crystals i.e. compounds of formula (I) or formula (II) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • co-crystals may be prepared from compounds of formula (I) or formula (II) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) or formula (II) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co- crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I) or formula (II).
  • a suitable halogenating reagent is trichloroisocyanuric acid, although a skilled person would know that other halogenating reagents might also work.
  • R is alkyloxy and R 4a is alkenyl, aryl or heteroaryl, compounds may be synthesiz
  • R , R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined for compounds of formula I and II, and B(OR x ) 2 refers to a boronic acid or boronate ester coupling agent.
  • a suitable palladium catalyst to use is [1 ,1 '-bis(di-tertbutylphospino)ferrocene] dichloropalladium(ll).
  • a skilled person would understand that other palladium catalysts may also be suitable.
  • the right hand side of the moiety is typically added via an amide formation reaction as shown below in general scheme 3.
  • Intermediate II HATU (2-(1 H-7-Azabenzotriazol-1-yl)-1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate Methanaminium) is a peptide coupling agent. A skilled person would understand that other coupling agents may also be suitable.
  • the amine intermediate II is either available commercially, or may be prepared according to known methods (published synthesis).
  • R 1 is methoxy
  • R 4a is hydrogen
  • Intermedate I may be synthesized according to the general scheme 4 Scheme 4
  • the starting materials are either commercially available compounds or are known compounds and can be prepared from procedures described in the organic chemistry art.
  • stereoisomers may be obtained in a conventional manner, e.g., by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g., optically active, starting materials.
  • the compounds of formula (I) or (II) can be prepared, e.g., using the reactions and techniques described below and in the Examples.
  • the reactions may be performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • agents of the invention are useful in the treatment of conditions which respond to the modulation of CFTR activity, particularly conditions benefiting from mucosal hydration such as cystic fibrosis.
  • Diseases mediated by modulation of CFTR activity include diseases associated with the regulation of fluid volumes across epithelial membranes.
  • the volume of airway surface liquid is a key regulator of mucociliary clearance and the maintenance of lung health.
  • the modulation of CFTR activity will promote fluid accumulation on the mucosal side of the airway epithelium thereby promoting mucus clearance and preventing the accumulation of mucus and sputum in respiratory tissues (including lung airways).
  • diseases include respiratory diseases, such as cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.
  • COPD chronic obstructive pulmonary disease
  • Diseases mediated by modulation of CFTR activity also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., Sjogren's Syndrome, xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
  • diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., Sjogren's Syndrome, xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
  • modulation of CFTR activity in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • Asthma includes intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome".)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvements in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular, other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • Dry eye disease is characterized by a decrease in tear aqueous production and abnormal tear film lipid, protein and mucin profiles.
  • causes of dry eye some of which include age, laser eye surgery, arthritis, medications, chemical/thermal burns, allergies and diseases, such as cystic fibrosis and Sjogren's Syndrome.
  • CFTR Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease.
  • Sjogren's Syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including eye, mouth, skin, respiratory tissue, liver, vagina and gut. Symptoms include dry eye, dry mouth and dry vagina, as well as lung disease. The disease is also associated rheumatoid arthritis, systemic lupus, systemic sclerosis and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs affected by the disease and help to alleviate the associated symptoms.
  • CFTR activity modulators as a treatment of a disease benefiting from mucosal hydration may be tested by determining the movement of chloride ions in a suitable cell-based assay.
  • a suitable cell-based assay For example single cells or confluent epithelia, endogenously expressing or engineered to overexpress CFTR can be used to assess channel function using electrophysiological techniques or ion flux studies. See methods described in: Hirsh et al., J Pharm Exp Ther (2004); Moody et al., Am J Physiol Cell Physiol (2005).
  • CFTR activity modulators including the compounds of formula (I), are also useful as co- therapeutic agents for use in combination with other drug substances, such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • drug substances such as antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of cystic fibrosis or obstructive or inflammatory airways diseases such as those mentioned hereinbefore, e.g., as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • the compounds of Formula (I) or (II) may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes as a further aspect a combination of a CFTR activity modulator with osmotic agents (hypertonic saline, dextran, mannitol, Xylitol), ENaC blockers, an anti-inflammatory, bronchodilatory, antihistamine, anti-tussive, antibiotic and/or DNase drug substance, wherein the CFTR activity modulator and the further drug substance may be in the same or different pharmaceutical composition.
  • osmotic agents hyperertonic saline, dextran, mannitol, Xylitol
  • ENaC blockers an anti-inflammatory, bronchodilatory, antihistamine, anti-tussive, antibiotic and/or DNase drug substance
  • the CFTR activity modulator and the further drug substance may be in the same or different pharmaceutical composition.
  • Suitable antibiotics include macrolide antibiotics, e.g., tobramycin (TOBITM).
  • Suitable DNase drug substances include dornase alfa (PulmozymeTM), a highly-purified solution of recombinant human deoxyribonuclease I (rhDNase), which selectively cleaves DNA.
  • rhDNase a highly-purified solution of recombinant human deoxyribonuclease I
  • Dornase alfa is used to treat cystic fibrosis.
  • CFTR activity modulators with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1 , CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC- 351125, SCH-55700 and SCH-D; Takeda antagonists, such as A/-[[4-[[[[6,7-dihydro-2-(4- methyl-phenyl)-5 -/-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro- A/,A/-dimethyl-2H-pyran-4-amin-ium chloride (TAK-770); and CCR-5 antagonists described in USP 6,166,037 (particularly claims 18 and
  • Suitable anti-inflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 1 1 , 14, 17, 19, 26, 34, 37, 39, 51 , 60, 67, 72, 73, 90, 99 and 101 ), WO 03/35668, WO 03/48181 , WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO
  • LTD4 antagonists such as montelukast and zafirlukast
  • PDE4 inhibitors such as cilomilast (Ariflo ® GlaxoSmithKline), Roflumilast (Byk Gulden),V-1 1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , USP 3,714,357, USP 5,171 ,744, WO 01/041 18, WO 02/00652, WO 02/51841 , WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285.
  • anticholinergic or antimuscarinic agents in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , USP 3,714,357, USP 5,171 ,744, WO 01/04
  • Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as those disclosed in USP
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299, WO
  • the invention includes as a further aspect a combination of a CFTR activity modulator with a CFTR corrector, wherein the CFTR activity modulator and the CFTR corrector may be in the same or different pharmaceutical composition.
  • Suitable CFTR correctors include VX-809
  • the invention also provides as a further aspect a method for the treatment of a condition responsive to modulation of CFTR activity, e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula (I) or (II), in free form or in the form of a pharmaceutically acceptable salt.
  • a condition responsive to modulation of CFTR activity e.g., diseases associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airways disease
  • the invention provides a compound of formula (I) or (II), in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to modulation of CFTR activity, particularly an obstructive airways disease, e.g., cystic fibrosis and COPD.
  • a condition responsive to modulation of CFTR activity particularly an obstructive airways disease, e.g., cystic fibrosis and COPD.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, e.g., in the form of a tablet or capsule; parenterally, e.g., intravenously; by inhalation, e.g., in the treatment of an obstructive airways disease; intranasally, e.g., in the treatment of allergic rhinitis; topically to the skin; or rectally.
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • compositions may contain a co-therapeutic agent, such as an anti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • a co-therapeutic agent such as an anti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, e.g., a hydro-fluoro-alkane (HFA) propellant, such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art, such as ethanol (up to 20% by weight), and/or one or more surfactants, such as oleic acid or sorbitan trioleate, and/or one or more bulking agents, such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, e.g., the compound of formula (I) or (II) having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g., magnesium stearate.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, e.g., the compound of formula (I) or (II) either dissolved, or suspended, in a vehicle containing water, a co-solvent, such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.
  • a compound of formula (I) or (II) in inhalable form e.g., in an aerosol or other atomisable composition or in inhalable particulate, e.g., micronised form
  • an inhalable medicament comprising a compound of formula (I) or (II) in inhalable form
  • Dosages of compounds of formula (I) or (II) employed in practicing the present invention will of course vary depending, e.g., on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.005-10 mg, while for oral administration suitable daily doses are of the order of 0.05-100 mg.
  • compositions of formula (I) or (II) and their pharmaceutically acceptable salts are useful as pharmaceuticals.
  • the compounds are suitable CFTR activity modulators and may be tested in the following assays.
  • CFTR activity can be quantified by measuring the transmembrane potential.
  • the means for measuring the transmembrane potential in a biological system can employ a number of methods including electrophysiological and optical fluorescence-based membrane potential assays.
  • the optical membrane potential assay utilises a negatively charged potentiometric dye, such as the FLIPR membrane potential dye (FMP) (see Baxter DF, Kirk M, Garcia AF, Raimondi A, Holmqvist MH, Flint KK, Bojanic D, Distefano PS, Curtis R, Xie Y. ⁇ novel membrane potential-sensitive fluorescent dye improves cell-based assays for ion channels.' J Biomol Screen. 2002 Feb;7(1 ):79-85) which when extracellular is bound to a quenching agent . Upon cellular depolarisation the negatively charged dye redistributes to the intracellular compartment, unbinding from the membrane impermeant quench agent, yielding an increase in fluorescence.
  • FLIPR membrane potential dye FLIPR membrane potential dye
  • This change in fluorescence is proportional to the change in transmembrane potential which can result from the activity of CFTR.
  • the changes in fluorescence can be monitored in real time by an appropriately equipped fluorescence detector such as the FLIPR (fluorometric imaging plate reader) in 96 or 384-well microtitre plates.
  • FLIPR fluorometric imaging plate reader
  • CHO cells stably expressing the F508-CFTR channel were used for membrane potential experiments.
  • Cells were maintained at 37 °C in 5% v/v C0 2 at 100% humidity in Modified Eagles medium (MEM) supplemenetd with 8% v/v foetal calf serum, 100 ⁇ g/ml methotrexate and 100U/ml penicillin/streptomycin.
  • MEM Modified Eagles medium
  • Cells were grown in 225 cm 2 tissue culture flasks.
  • For membrane potential assays cells were seeded into 96 well plates at 40,000 cells per well, allowed to adhere and then maintained at 26 °C for 48h to facilitate channel insertion.
  • the membrane potential screening assay utilised a low chloride ion containing extracellular solution ( ⁇ 5mM) combined with a double addition protocol.
  • the first addition was of buffer with or without test compound followed 5 minutes later by an addition of forskolin (1-20 ⁇ ) - this protocol favours maximum chloride efflux in response to AF508-CFTR activation.
  • the AF508-CFTR mediated chloride ion efflux leads to a membrane depolarisation which is optically monitored by the FMP dye.
  • FMP dye made up as per manufacturers' instructions in low chloride extracellular solution detailed above, at 10x final concentration, and stored as 1 ml. aliquots at -20°C. lonWorks Quattro assay:
  • CFTR activity can also be quantified electrophysiologically using the whole-cell configuration of the patch clamp technique (Hamill et al Pflugers Acrhive 1981 ).
  • This assay directly measures the currents associated with chloride flow through CFTR channels whilst either maintaining or adjusting the transmembrane voltage.
  • This assay can use either single glass micropipettes or parallel planar arrays to measure CFTR activity from native or recombinant cell systems. Currents measured using parallel planar arrays can be quantified using an appropriately equipped instrument such as the lonWorks Quattro (Molecular Devices) or the Qpatch (Sophion).
  • the Quattro system can measure CFTR currents from either a single cell per recording well (HT configuration) or alternatively from a population of 64 cells per well (Population Patch Clamp PPC) (Finkel A, Wittel A, Yang N, Handran S, Hughes J, Costantin J. 'Population patch clamp improves data consistency and success rates in the measurement of ionic currents.' J Biomol Screen. 2006 Aug; 1 1 (5):488-96).
  • CHO cells stably expressing the AF508-CFTR channel were used for lonWorks Quattro experiments. Cells were maintained at 37 °C in 5% v/v C0 2 at 100% humidity in D-MEM supplemented with 10 % (v/v) FCS, 100 U/mL
  • Penicillin/Streptomycin 1 % (v/v) NEAA, 1 mg/ml Zeocin and 500 ug/ml Hygromycin B.
  • cells were grown in 225 cm 2 tissue culture flasks until near confluence and then cultured at 26 °C for 48-72h to facilitate channel insertion. Cells were removed from the flask and resuspended in either extracellular recording solution for immediate experimentation or alternatively in growth medium supplemented with 10% v/v DMSO and frozen to -80°C as 1-2 ml. aliquots for use at a later date.
  • Extracellular solution (ECS) : 145 mM NaCI, 4 mM CsCI, 5 mM D-glucose, 10 mM TES, 1 mM CaCI 2 , 1 mM MgCI 2 , pH 7.4 NaOH
  • Intracellular buffer 1 13 mM L-Aspartic acid, 113 mM CsOH, 27 mM CsCI, 1 mM NaCI, 1 mM MgCI 2 , 1 mM EGTA, 10 mM TES. pH 7.2 with CsOH. Filter sterilized before use.
  • Ion transport assay 1 13 mM L-Aspartic acid, 113 mM CsOH, 27 mM CsCI, 1 mM NaCI, 1 mM MgCI 2 , 1 mM EGTA, 10 mM TES. pH 7.2 with CsOH. Filter sterilized before use.
  • Ion transport assay 1 13 mM L-Aspartic acid, 113 mM CsOH, 27 mM CsCI, 1 mM NaCI, 1 mM MgCI 2 , 1 mM EGTA, 10 mM TES. pH 7.2 with CsOH. Filter sterilized before use.
  • CFTR function Another method to measure CFTR function is Ussings chamber short circuit current measurement.
  • Engineered or native epithelial cells are grown to confluent monolayer on a semi-permeable filter and sandwiched between two perspex blocks.
  • the flow of chloride ions via CFTR from one side of the epithelia to the other can be quantified by measuring the flow of current whilst maintaining the transepithelial potential at OmV. This is achieved using KCI filled agar-based electrodes to both clamp the cellular monolayer and measure the flow of currents.
  • FRT cells stably expressing AF508-CFTR were cultured on plastic in Coon's modified F- 12 medium supplemented with 32mM NaHC0 3 , 10% v/v fetal bovine serum, 2 mM L- glutamine, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 30 ⁇ g/mL hygromycin B as the growth medium.
  • the cells were grown as polarized epithelia on Snapwell permeable support inserts (500000 cells/insert in growth medium) and cultured for 7 to 9 days. The inserts were fed with fresh Coon's modified F-12 growth medium every 48 hours, and 24 hours prior to Ussing chamber experiment.
  • plates were incubated at 27°C for 48h before performing an Ussing chamber experiment.
  • Fischer Rat Thyroid (FRT) epithelial cells stably expressing human AF508-CFTR were used as monolayer cultures on permeable supports.
  • CI " current was measured using the short circuit current technique, under an imposed basolateral to apical CI " gradient in Ussing chambers.
  • FRT cells were cultured for 48h at 27°C to facilitate the insertion of AF508 CFTR into the plasma membrane.
  • Ussing chamber studies were likewise conducted at 27°C . Under these conditions, the effects of cumulative additions of test compounds on AF508 CFTR currents could be quantitated with both potency and efficacy endpoints.
  • Compounds were added to both the apical and basloalteral sides subsequent to addition of 10 ⁇ forskolin. Efficacy of compounds was compared to a known potentiator such as gensitein.
  • Basolateral Ringer solution 126 NaCI, 24 NaHC0 3 , 0.38 KH 2 P0 4 , 2.13 K 2 HP0 4 , 1 MgS0 4 , 1 CaCI 2 and 10 glucose.
  • Apical Ringer solution 140 Na-gluconate, 1 MgS0 4 , 2 CaCI 2 , 1 HCI, 10 glucose and 24 NaHC0 3 .
  • Compounds can also be tested for their ability to stimulate insertion of AF508 CFTR into the cell membrane using the above assays.
  • the protocols were identical other than cells were not cultured at low temperature (26 or 27°C) but instead incubated with test compounds for 12-24 h prior to assay.
  • Mass spectra were run on LCMS systems using electrospray ionization. These were either Agilent 1 100 HPLC/Micromass Platform Mass Spectrometer combinations or Waters Acquity UPLC with SQD Mass Spectrometer. [M+H] + refers to mono-isotopic molecular weights.
  • NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometers using ICON-NMR. Spectra were measured at 298K and were referenced using the solvent peak.
  • SCX-2 strong cation exchange e.g. Isolute® SCX-2 columns from Biotage
  • the various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.
  • organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism.
  • chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the preferred embodiments encompasses any tautomeric form of the drawn structure.
  • Example compounds of the present invention include:
  • Step 1 Methyl 3-(2,5-dimethyl-1 H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate 3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate B step 2) (1.9 g, 6.05 mmol) in 1.25 M HCI in MeOH (12.09 ml) was heated at 90°C for 10 hours using microwave radiation. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, dried using a phase separating column and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound;
  • Step 2 Methyl 3-(2,5-dimethyl-1 H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate
  • the mixture was diluted with EtOAc and washed with water, brine and dried using a phase separating column.
  • the mixture was dry loaded onto silica and purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the title compound.
  • the compound was used in the next step without further purification;
  • step 2 A solution of methyl 3-(2,5-dimethyl-1 H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl) picolinate (step 2)(415 mg, 1.321 mmol) in 1 ,4-dioxane (13 ml) was treated with 2- methoxyethanol (2.187 ml, 27.7 mmol) and PPh 3 (693 mg, 2.64 mmol) and the solution stirred. DEAD (0.418 ml, 2.64 mmol) was added dropwise and the reaction mixture stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the resltuing oil was partitioned between EtOAc and water.
  • Step 4 3-(2,5-Dimethyl-1 H-pyrrol-1-yl)-6-(2-methoxyethoxy)-5-(trifluoromethyl)picolinic acid
  • step 4 3-(2,5-Dimethyl-1 H-pyrrol-1-yl)-6-(2-methoxyethoxy)-5-(trifluoromethyl)picolinic acid (step 4)(50 mg, 0.140 mmol) was dissolved in EtOH (930 ⁇ ) and water (465 ⁇ ).
  • Triethylamine (58.3 ⁇ , 0.419 mmol) was added followed by hydroxylamine (50% in water) (86 ⁇ , 1.395 mmol). The mixture was stirred at RT overnight and then treated with hydroxylamine hydrochloride (19.39 mg, 0.279 mmol). The mixture was heated at reflux for 4 hours and stirred at RT overnight. A further portion of hydroxylamine hydrochloride (10 mg) was added and stirring continued at reflux for 4 hours. The mixture was poured into water and extracted with EtOAc. The organic portion was separated and acidified to pH1 using 1 M HCI. The organic portion was separated and washed with brine and dried using a phase separating column. The solvent was removed under reduced pressure to afford the title compound;
  • Stee_6 (S)-3-Amino-6-(2-methoxyethoxy)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5- (trifluoromethyl)picolinamide
  • step 5 3-Amino-6-(2-methoxyethoxy)-5-(trifluoromethyl)picolinic acid (step 5) (179 mg, 0.639 mmol) and HATU (291 mg, 0.767 mmol) were dissolved NMP (2 ml).
  • Step 4 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was dissolved in water (300 ml). Sulfuric acid (4.60 ml, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517 mmol). The reaction mixture was stirred at RT for 18 hours.
  • Step 5 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.40 g, 4.68 mmol) was suspended in MeOH (15 ml); Sodium hydroxide (2.0 M aqueous solution) (14.04 ml, 28.1 mmol) was added and the suspension was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (100 ml) and then acidifed by the addition of 5.0M HCI(aq).
  • Step 1 6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester
  • Step 2 3-(2,5-Dimethvl-pvrrol-1-vl)-6-methoxv-5-trifluoromethyl-pvridine-2-carboxvlic acid
  • Step 1 Benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate
  • Step 2 Separation of Enantiomers of benzyl 3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate
  • Step 3 (S)-3-Amino-1 ,1 ,1-trifluoro-2-methylpropan-2-ol hydrochloride
  • racemic 3-Amino-1 ,1 ,1-trifluoro-2-methylpropan-2-ol can be resolved into separate enantiomers by recrystallistion with either (S)-Mandelic acid or L-tartaric acid in isopropanol or ethanol to afford (S)-3-Amino-1 , 1 , 1-trifluoro-2-methylpropan-2-ol: Route 2:
  • Step 1 (S)-3-Amino-1 ,1 ,1-trifluoro-2-methylpropan-2-ol L-tartrate salt
  • step 1 To a suspension of Isolute® SCX-2 (Si-propylsulfonic acid) (537 g, 222 mmol) in DCM (1.5 L) was added (S)-3-amino-1 , 1 ,1-trifluoro-2-methylpropan-2-ol L-tartrate salt (step 1 )(65 g, 222 mmol) pre-dissolved in warm MeOH (500 ml).
  • the silica suspension was stirred at RT for 30 min and the slurry was poured onto a large silica frit. The frit was washed with 10 % MeOH in DCM (3.5 litres) and the washings were discarded.
  • the plug was eluted with 7M NHa/MeOH (300 ml) in DCM (2 litres) followed by 2M NH 3 /MeOH (300 ml) in DCM (1 litre). The combined washings were concentrated under reduced pressure to afford the title compound.
  • R is -0-R a ;
  • R c and R d together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclyl group optionally substituted by one or more Z substituents;
  • R 2 is Ci-C 4 haloalkyl
  • R 3 is H or C-i-Ce alkyl optionally substituted by one or more halogen atoms
  • R 4a is selected from H; halogen; d-C 4 alkyl optionally substituted by one or more halogen atoms; C 2 -C 8 alkenyl; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl; -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclyl; C C 8 hydroxyalkyl; -(CH 2 ) m -NR 7 R 18 ; -(C 0 -C 4 alkyl)-C0 2 R 15 and -(C 0 -C 4 alkyl)-C(0)NR 7 R 18 ; R 4 is H, or CrC 8 alkyl optional substituted with one or more halogen;
  • R 5 is -(CH 2 )m-NR 7 R 18 , -(CH 2 ) m -OR ' ; C C 8 alkoxy optionally substituted by one or more halogen atoms; -(C 0 -C 4 alkyl)-C0 2 R 15 ; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl or -3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl and -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents;
  • R 6 is Ci-C 8 alkyl optionally substituted by one or more halogen atoms; C 3 -Ci 0 cycloalkyi; -C C 4 alkyl-C 3 -C 8 cycloalkyi; C C 8 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl; or -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, -(C 0 -C 4 alkyl)-C 6 -C 14 aryl and -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group are each optionally substituted by one or more Z substituents; or
  • R 6 is H, and R 5 is -(CH 2 ) m -NR 7 R 18 , -(CH 2 ) m -OR ' , d-C 8 alkoxy optionally substituted by one or more halogen atoms; -(C 0 -C 4 alkyl)-C 6 -C 14 aryl; -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S; or -(C 0 -C 4 alkyl)-C0 2 R 15 , wherein -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl and -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group groups are each optionally substituted by one or more Z substituents; or
  • R 4 and R 6 together with the carbon atoms to which they are bound form a 3 to 8 membered carbocyclic ring system
  • R 5 and R 6 together with the carbon atom to which they are bound a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents; or
  • R 4 and R 5 and R 6 together with the carbon atom to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R is H, or C-i-Ce alkyl optional substituted with one or more halogen; m is 0, 1 , 2 or 3; R 8 , R , R 3 and R 7 are each independently H, CrC 8 alkyl optionally substituted by one or more halogen atoms, C 3 -Ci 0 cycloalkyl or -(C1-C4 alkyl)-C 3 -C 8 cycloalkyl; R 9 , R 0 , R 2 , R 4 , R 5 , R 6 and R 8 are each independently H; C C 8 alkyl optionally substituted by one or more halogen atoms; C 2 -C 8 alkenyl; C 2 -C 8 alkynyl; C 3 -C 10 cycloalkyl; C 5 -Ci 0 cycloalkenyl; -C C 4 alkyl-C 3 -C 8 cycloalkyl; -(C 0 -C 4 alkyl
  • R 8 and R 9 , R and R 2 , R 3 and R 4 , and R 7 and R 8 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclic group optionally substituted by one or more Z substituents;
  • Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C C 6 alkyl optionally substituted by one or more OH groups or NH 2 groups, C C 6 alkyl optionally substituted by one or more halogen atoms, C C 6 alkoxy optionally substituted by one or more OH groups or d-C 4 alkoxy, NR 8 (S0 2 )R 21 , (S0 2 )NR 9 R 21 , (S0 2 )R 21 , NR 8 C(0)R 21 , C(0)NR 9 R 21 ,
  • R 9 and R 2 together with the nitrogen atom to which they attached form a 5- to 10- membered heterocyclic group, the heterocyclic group including one or more further heteroatoms selected from N, O and S, the heterocyclic group being optionally substituted by one or more substituents selected from OH; halogen; aryl; 5- to 10- membered heterocyclic group including one or more heteroatoms selected from N, O and S; S(0) 2 -aryl; S(0) 2 -Ci-C 6 alkyl; Ci-C 6 alkyl optionally substituted by one or more halogen atoms; C C 6 alkoxy optionally substituted by one or more OH groups or C C 4 alkoxy; and C(0)OCrC 6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by Ci-C 6 alkyl, Ci-C 6 haloalkyl or Ci-C 6 alkoxy;
  • R c and R d together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclyl group optionally substituted by one to three substituents independently selected from halogen, C C 4 alkoxy and C C 4 alkyl optionally substituted with one or more halogen atoms.
  • Embodiment 3 The compound according to embodiment 1 or 2, wherein R a is selected from H, -(C 0 -C 2 alkyl)-phenyl, -(C 0 -C 2 alkyl)-3-pyridyl, -(C 0 -C 2 alkyl)-4-pyridyl,-(C 0 -C 2 alkyl)-5-pyrazolyl, -(C 0 -C 2 alkyl)-3-isoxazolyl, -(C 0 -C 2 alkyl)-5-isoxazolyl,-(C 0 -C 2 alkyl)-5- imidazolyl, -(C 0 -C 2 alkyl)-2-oxazolyl, C C 4 alkyl optionally substituted with one or more substituents selected from halogen atoms, OH, CrC 4 -alkoxy and NR c R d ; -(C 0 -C 4 alky
  • R c and R d together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclyl group optionally substituted by one to three substituents independently selected from halogen, CrC 4 alkoxy and C C 4 alkyl optionally substituted with one or more halogen atoms.
  • Embodiment 4 The compound according to any one of embodiments 1 to 3, wherein R a is selected from -(C 0 -C 2 alkyl)-phenyl, -(C 0 -C 2 alkyl))-3-pyridyl, -(C 0 -C 2 a I ky I ) )-4-py ri dy I , - (Co-C 2 alkyl))-5-pyrazolyl, -(C 0 -C 2 alkyl))-3-isoxazolyl, -(C 0 -C 2 alkyl))-5-isoxazolyl,-(C 0 -C 2 alkyl))-5-imidazolyl, -(C 0 -C 2 alkyl))-2-oxazolyl, C C 4 alkyl optionally substituted with one or more substituents selected from halogen atoms, OH, d-C 4 -alkoxy and NR
  • Embodiment 5 The compound according to any one of embodiments 1 to 4, wherein R a is selected from d-C 4 alkyl optionally substituted with one or more substituents selected from halogen atoms, OH, C C 4 -alkoxy and NR c R d .
  • Embodiment 6 The compound according to any one of embodiments 1 to 5, wherein R 2 is CF 3 CF 2 -, (CF 3 ) 2 CH-, CH 3 -CF 2 -, CF 3 CF 2 -, CF 3 , CF 2 H-, CH 3 -CCI 2 -, CF 3 CFCCIH-, CBr 3 , CBr 2 H-CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 -, particularly R 2 is CF 3 .
  • Embodiment 7 The compound according to any one of embodiments 1 to 6, wherein R 3 is H or methyl.
  • Embodiment 8 The compound according to any one of embodiments 1 to 7, wherein A R 4a is methyl, ethyl, isopropyl and trifluoromethyl.
  • Embodiment 9 The compound according to any one of embodiments 1 to 7, wherein R 4a is H.
  • Embodiment 10 The compound according to any one of embodiments 1 to 9, wherein R 4 is H or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 1 1 The compound according to any one of embodiments 1 to 10, wherein R 5 provides a heteroatom two carbons from the amide nitrogen, wherein the heteroatom is oxygen or nitrogen.
  • Embodiment 12 The compound according to any one of embodiments 1 to 1 1 , wherein R 4 is H, C"i-C 4 alkyl optionally substituted by one or more halogen atoms or not present; R 5 is C"i-C 4 alkoxy optionally substituted by one or more halogen atoms; -(CH 2 ) m - NR 7 R 18 ; -(CH 2 ) m -OR ' ,or OH;
  • n 0, or 1 ;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms; CrC 4 alkoxy optionally substituted by one or more halogen atoms; OH; CN; halogen; -(C 0 -C 4 alkyl)- C 6 -C 14 aryl; or -(C 0 -C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents; or
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 8 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 13 The compound according to any one of embodiments 1 to 12, wherein R 2 is C1 -C4 haloalkyl;
  • R 3 is H
  • R 4 is H or Me
  • R 4a is H
  • R 5 is -(CH 2 ) m -NR 7 R 18 ; -(CH 2 ) m -OR ' ; or OH;
  • n 0, or 1 ;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N , O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 14 The compound according to any one of embodiment 1 to 13, wherein R 2 is C1-C4 haloalkyl;
  • R 3 is H ;
  • R 4a is H ;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms; C C 4 alkoxy optionally substituted by one or more halogen atoms; -(C 0 -C 4 alkyl)-C 6 -Ci 4 aryl; or -(C 0 - C 4 alkyl)-3 to 14 membered heterocyclic group, wherein the heterocyclic group contains at least one heteroatom selected from N, O and S, wherein the aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents.
  • Embodiment 15 The compound according to any one of embodiments 1 to 14, wherein R 2 is C1-C4 haloalkyl;
  • R 3 is H ;
  • R 4 is H or Me
  • R 4a is H ;
  • R 5 is -(CH 2 ) m -N R 7 R 18 ; -(CH 2 ) m -OR'; or OH ;
  • n 0, or 1 ;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N , O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H ; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 16 The compound according to any one of embodiments 1 to 15, wherein R 2 is C1-C4 haloalkyl;
  • R 3 is H ;
  • R 5 is -(CH 2 ) m -NR 7 R 18 ; -(CH 2 ) m -OR; or OH;
  • n 0, or 1 ;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H; or CrC 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 17 The compound according to any one of embodiments 1 to 16, wherein R 2 is C1-C4 haloalkyl;
  • R 3 is H
  • R 4 is H or Me
  • R 4a is H
  • R 5 is -NR 7 R 18 ; or OH;
  • R 6 is C"i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 5 and R 6 together with the carbon atoms to which they are bound form a 5 to 6 membered heterocyclic ring system containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
  • R 7 and R 8 are each independently H; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 18 The compound according to any one of embodiments 1 to 17, wherein R is C-i-C 4 alkyl optionally substituted by one or more halogen atoms;
  • R 2 is C1-C4 haloalkyl
  • R 3 is H
  • R 4 is H or Me
  • R 4a is H
  • R 5 is -NR 7 R 18 ; or OH;
  • R 6 is C-i-C 4 alkyl optionally substituted by one or more halogen atoms
  • R 7 and R 8 are each independently H; or C C 4 alkyl optionally substituted by one or more halogen atoms.
  • Embodiment 19 The compound according to any one of any one of embodiments 1 to
  • Z is independently OH, d-C 4 alkyl optionally substituted by one or more OH groups or NH 2 groups, CrC 4 alkyl optionally substituted by one or more halogen atoms, CrC 4 alkoxy optionally substituted by one or more OH groups or C C 4 alkoxy, NR 9 R 21 , C(0)OR 19 , C(0)R 19 , SR 9 , OR 19 , CN, N0 2 , or halogen;
  • R 9 and R 2 are each independently H; d-C 4 alkyl; C 3 -C 6 cycloalkyl; or d-C 4 alkoxy-Cr C 4 alkyl, wherein all alkyls are optionally substituted with halogens.
  • Embodiment 20 The compound according to any one of any one of embodiments 1 to
  • Z is independently OH, d-C 4 alkyl optionally substituted by one or more OH groups or NH 2 groups, CrC 4 alkyl optionally substituted by one or more halogen atoms, CrC 4 alkoxy optionally substituted by one or more OH groups or d-C 4 alkoxy, C(0)OR 19 , C(0)R 19 , OR 19 , CN, or halogen;
  • R 9 is H; d-C 4 alkyl; C 3 -C 6 cycloalkyl; or d-C 4 alkoxy-C-i-C 4 alkyl, wherein all alkyl are optionally substituted with halogens.
  • Embodiment 21 The compound according to any one of any one of embodiments 1 to
  • Z is independently, d-C 4 alkyl optionally substituted by one or more halogen atoms, CrC 4 alkoxy or halogen.
  • Embodiment 22 The compound according to any one of embodiments 1 to 21 , wherein the compound is a substantially pure enantiomers with the R configuration.
  • Embodiment 23 The compound according to any one of embodiments 1 to 22, wherein the compound is a substantially pure enantiomers with the S configuration.
  • Embodiment 24 The compound according to any one of embodiments 1 to 23, wherein the compounds of Formula I include compounds of Formula II: 0
  • Embodiment 25 The compound according to embodiment 24, wherein
  • R 3 is H or methyl.
  • Embodiment 26 The compound according to embodiment 24 or 25, wherein
  • R 3 is H
  • Embodiment 27 The compound according to any one of embodiments 24 to 26, wherein R 3 is H;
  • Embodiment 28 The compound according to any one of embodiments 24 to 27, wherein R 3 is H;
  • R ,4 4 a a is H
  • Embodiment 29 The compound according to any one of embodiments 24 to 28, wherein R 3 is H;
  • Embodiment 34 The compound according to any one of embodiments 24 to 29, wherein R 3 is H;
  • R 4a is H
  • Embodiment 31 The compound according to any one of embodiments 24 to 30, wherein R 3 is H;
  • Embodiment 32 The compound according to embodiment 1 , or pharmaceutically acceptable salts thereof, selected from:
  • Embodiment 33 A compound according to any one of embodiments 1 to 32 for use as a pharmaceutical.
  • Embodiment 34 A compound according to any one of embodiments 1 to 32 for use in the treatment of an inflammatory or obstructive airways disease or mucosal hydration.
  • Embodiment 35 Use of a compound according to any one of embodiments 1 to 32 in the manufacture of a medicament for use in the treatment of an inflammatory or obstructive airways disease or mucosal hydration.
  • Embodiment 36 A pharmaceutical composition, comprising:
  • Embodiment 37 A pharmaceutical combination, comprising:
  • Embodiment 39 A method for the prevention or treatment of a CFTR mediated condition or disease, comprising:

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Abstract

La présente invention concerne des dérivés pyridinamides qui restaurent ou accroissent la fonction de CFTR mutant et/ou de type sauvage pour traiter une fibrose kystique, une dyskinésie ciliaire primitive, une bronchite chronique, une maladie pulmonaire obstructive chronique, l'asthme, des infections du tractus respiratoire, un carcinome du poumon, une sécheresse de la bouche et une kératoconjonctivite sèche ou une constipation (induite par IBS, IBD, opioïdes). L'invention concerne également des compositions pharmaceutiques comprenant de tels dérivés.
PCT/IB2012/054816 2011-09-16 2012-09-14 Dérivés pyridinamides WO2013038378A1 (fr)

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WO2016069891A1 (fr) 2014-10-31 2016-05-06 Abbvie Inc. Tétrahydropyrannes substitués et méthode d'utilisation associée
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WO2016193812A1 (fr) 2015-06-02 2016-12-08 Abbvie S.A.R.L. Pyridines substituées et méthode d'utilisation
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WO2017060874A1 (fr) 2015-10-09 2017-04-13 Abbvie S.Á.R.L Pyrazolo[3,4-b]pyridin-6-carboxamides n-sulfonylés et leur procédé d'utilisation
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US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
WO2017187321A1 (fr) 2016-04-26 2017-11-02 AbbVie S.à.r.l. Modulateurs de protéine régulatrice de conductance transmembranaire de la fibrose kystique
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