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US 2014/0371238 A1Published application
Compounds and methods for the treatment of cystic fibrosis
AssigneeFlatley Discovery Lab, LLC
InventorsMichael P. Zawistoski, Yevgen Barsukov, Bridget M. Cole, Richard A. Nugent
Life of this patent
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Abstract
The invention relates to a compound of Formula I and methods of treating cystic fibrosis comprising the step of administering a therapeutically effective amount of a compound of Formula I or IA to a patient in need thereof:
Claims21
A compound of Formula I or an ester or prodrug thereof:
- wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;
- each X is independently selected from —CR100, —N—, —COR100, —CN(R100)(R101), —CSR100—C—C(O)NR100, and —CN(R100)C(O)R101;
- A1 is absent, —[C(R100)(R101)]— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101), —N[C(R100)(R101)]m—, —N(R100)C(O)—, —N(R100)C(S)—, —N(R100)S(O)—, —N(R101)C(O)N(R100)— or —N(R100)S(O)2—, —N(R100)S(O)2N(R100)(R101);
- wherein m is 0, 1, 2, 3, 4, 5, 6 or 7;
- wherein each R100 and R101 is hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl, heterocycle, substituted heterocycle, heteroaryl or substituted heteroaryl;
- alternatively two of R100 and R101 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
- A2 is absent, —[C(R100)(R101)]m— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101);
- each R1 is independently selected from hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR100, —SR100, —S(O)—, S(O)2—, —S(O)2N(R100)(R101), —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —CF3, —CN, —NO2, —N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
- alternatively two of R1 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted 3, 4, 5, 6 or 7 membered ring;
- Cy1 is absent, alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- wherein when Cy1 is phenyl and A1 is absent or C1-C4 alkyl, the phenyl group is substituted with a group selected from halogen, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR100, —SR100, —S(O)—, S(O)2—, —S(O)2N(R100)(R101) —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —CF3, —CN, —NO2, —N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
- wherein when Cy1 is cyclobutyl, cyclopentyl or furan, Cy2 is substituted with a group other than —OCF3, —CF3, —OCH3, —Cl or —F;
- and,
- Cy2 is alkyl, cycloalkyl, substituted cycloalkyl aryl, substituted aryl, heteroaryl or substituted heteroaryl.
11 more elements
A compound of Formula IA or an ester or prodrug thereof:
- wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;
- each X is independently selected from each X is independently selected from —CR100—, —N—, —COR100, —CN(R100)(R101), —CSR100, —C—C(O)NR100, and —CN(R100)C(O)R101;
- A1 is absent, —[C(R100)(R101)]m— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101), —N[C(R100)(R101)]m—, —N(R100)C(O)—, —N(R100)C(S)—, —N(R100)S(O)—, —N(R101)C(O)N(R100)— or —N(R100)S(O)2—, —N(R100)S(O)2N(R100)(R101);
- wherein m is 0, 1, 2, 3, 4, 5, 6 or 7;
- wherein each R100 and R101 is hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl;
- alternatively two of R100 and R101 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
- A2 is absent, —[C(R100)(R101)]m— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101);
- each R1 is independently selected from hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR100, —SR100, —S(O)—, —S(O)2—, —S(O)2N(R100)(R101) —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —CF3, —CN, —NO2, —N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
- alternatively two of R1 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted 3, 4, 5, 6 or 7 membered ring;
- Cy1 is absent, alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- Cy2 is alkyl, cycloalkyl, substituted cycloalkyl aryl, substituted aryl, heteroaryl or substituted heteroaryl.
8 more elements
A compound selected from Table 4:
- TABLE 4
A method of treating a disease or disorder mediated by cystic fibrosis transmembrane conductance regulator (CFTR) comprising the step of administering a therapeutically effective amount of a compound of Formula I or IA to a patient in need thereof:
- wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;
- each X is independently selected from each X is independently selected from —CR100-5-N—, —COR100, —CN(R100)(R101), —CSR100, —C—C(O)NR100, and —CN(R100)C(O)R101;
- A1 is absent, —[C(R100)(R101)]m— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101), —N[C(R100)(R101)]m—, —N(R100)C(O)—, —N(R100)C(S)—, —N(R100)S(O)—, —N(R101)C(O)N(R100)— or —N(R100)S(O)2—, —N(R100)S(O)2N(R100)(R101);
- wherein m is 0, 1, 2, 3, 4, 5, 6 or 7;
- wherein each R100 and R101 is hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl;
- alternatively two of R100 and R101 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
- A2 is absent, —[C(R100)(R101)]m— —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)— or —S(O)2—, —S(O)2N(R100)(R101);
- each R1 is independently selected from hydrogen, deuterium, halogen, alkyl, cycloalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR100, —SR100, —S(O)—, S(O)2—, —S(O)2N(R100)(R101), —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —CF3, —CN, —NO2, —N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
- alternatively two of R1 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted 3, 4, 5, 6 or 7 membered ring;
- Cy1 is absent, alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- Cy2 is alkyl, cycloalkyl, substituted cycloalkyl aryl, substituted aryl, heteroaryl or substituted heteroaryl.
8 more elements
Dependencies are inferred from the claim text.