US2022227739A1PendingUtilityA1
Compounds, compositions, and methods for modulating cftr
Assignee: PROTEOSTASIS THERAPEUTICS INCPriority: Oct 6, 2015Filed: Aug 25, 2021Published: Jul 21, 2022
Est. expiryOct 6, 2035(~9.2 yrs left)· nominal 20-yr term from priority
A61P 11/00A61P 43/00A61K 31/675A61K 31/4985A61K 31/4375A61K 31/343A61K 31/4709C07D 487/04C07D 493/08C07D 417/04A61P 29/00C07D 413/14A61K 31/47C07D 405/14C07D 409/04C07D 409/14C07D 405/04A61K 45/06A61K 31/404C07D 413/04C07D 401/04C07D 471/04A61K 31/519A61K 31/443A61K 31/517
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Claims
Abstract
The present disclosure is directed to disclosed compounds that modulate, e.g., address underlying defects in cellular processing of CFTR activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by Formula I:
or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, wherein:
A is a 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms each selected from the group consisting of O, N, and S; wherein the bicyclic heteroaryl may optionally be substituted by one, two or three substituents each independently selected from R A1 :
X 1 is selected from the group consisting of N and C(R X1 );
X 2 is selected from the group consisting of N and C(R X2 );
X 3 is selected from the group consisting of N and C(R X3 );
wherein only one of X 1 , X 2 or X 3 can be N;
R 1 is selected from the group consisting of hydrogen; —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)—C(O)OH, —P(O)(OH) 2 , C 1-6 alkyl, and a 5-6 membered monocyclic heteroaryl having one, two, three, or four heteroatoms each selected from the group consisting of O, N, and S; wherein C 1-6 alkyl may optionally be substituted by one, two, or three substituents each selected independently from the group consisting of halogen, hydroxyl, C(O)OH, —P(O)(OH) 2 , and —C(O)OC 1-6 alkyl; and wherein said heteroaryl may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1-4 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl; wherein C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and phenyl; and wherein phenyl may optionally be substituted by one or more substituents each independently selected from R p ;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 0, 1, or 2), —NR a —C 1-6 alkyl, C 3-6 cycloalkoxy, —S(O) w —C 3-6 cycloalkyl (where w is 0, 1, or 2), —NR a —C 3-6 cycloalkyl, —O-phenyl, —S(O) w -phenyl (where w is 0, 1, or 2), —NR a -phenyl, C 8-12 benzocycloalkoxy, —NR a R b , —OC(O)NR a -phenyl, —NR a —C(O)—O— phenyl, —NR a —C(O)—C 1-6 alkyl-phenyl, —C 1-4 alkyl-NR a -phenyl, —NR a —C 1-6 alkyl-phenyl, and a 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclyloxy, heterocyclyl-NR a —, or heterocyclyl-S(O) w — moiety (where w is 0, 1, or 2) having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclyloxy, heterocyclyl-NR a —, or heterocyclyl-S(O) w — ring contains an —NH moiety, that nitrogen may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, and —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2); and wherein said heterocyclyloxy, heterocyclyl-NR a —, and heterocyclyl-S(O) w may optionally be substituted by one, two, three, or four substituents each independently selected from R f ; and wherein said phenyl moiety of —O-phenyl, —S(O) w -phenyl, —NR a -phenyl, —OC(O)NR a -phenyl, —NR a —C(O)—O-phenyl, —NR a —C(O)—C 1-6 alkyl-phenyl, —C 1-6 alkyl-NR a -phenyl and —NR a —C 1-6 alkyl-phenyl may optionally be substituted by one, two, or three substituents each independently selected from R p ; and wherein C 1-6 alkoxy, —S(O)—C 1-6 alkyl (where w is 0, 1, or 2), —NR a —C 1-6 alkyl, C 3-6 cycloalkoxy, —S(O) w —C 3-6 cycloalkyl (where w is 0, 1, or 2), and —NR a —C 3-6 cycloalkyl may optionally be substituted by one, two, or three substituents each independently selected from R gg ;
R ff is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , oxo, C 1-6 alkyl and C 1-6 alkoxy;
R gg is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl (optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy (optionally substituted by one, two or three fluorine atoms)), phenyl, a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclic ring contains an —NH moiety, that nitrogen may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, and —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2); and wherein phenyl may optionally be substituted by one, two, or three substituents each independently selected from R hh ; and wherein said 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclic ring may optionally be substituted by one, two, three, or four substituents each independently selected from R ii ;
R hh is independently selected for each occurrence from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, S(O) w —C 1-3 alkyl, —S(O) w —NR a R b , —NR a —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), a 5-6 membered monocyclic heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-7 membered heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein C 1-6 alkoxy and S(O) w —C 1-3 alkyl may optionally be substituted by one, two, or three halogens;
R ii is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , oxo, C 1-6 alkyl and C 1-6 alkoxy;
R A1 is independently for each occurrence selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, —NR a R b , —O—C(O)—NR a -phenyl, —NR a —C(O)-phenyl, and —NR a —C 1-4 alkyl-phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and —NR a R b ;
R X1 is selected from the group consisting of hydrogen, —C(O)OH, and C 1-6 alkyl; wherein C 1-6 alkyl may optionally be substituted by one, two or three halogens;
R X2 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and —C 1-6 alkoxy-phenyl; wherein phenyl may optionally be substituted by one or more substituents selected from R p ;
R X3 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, —C 1-6 alkoxy-phenyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, and phenyl; wherein C 1-6 alkyl and C 1-6 alkoxy may optionally be substituted by one, two, or three substituents selected from the group consisting of hydroxyl and halogen; and wherein phenyl may optionally be substituted by one or more substituents selected from R p ;
R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, —C(O)-phenyl, and —C(O)—C 1-6 alkyl; or
R a and R b taken together with the nitrogen to which they are attached form a heterocyclic ring; and
R p is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl, C 3-6 cycloalkoxy, —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), —S(O) w —NR a R b , and —NR a R b .
2 . The compound of claim 1 , wherein A is selected from the group consisting of:
wherein:
X 4 is independently for each occurrence selected from the group consisting of O, S, and N(R 4 );
X 5 is selected from the group consisting of N and C(R X5 );
R A1 is independently for each occurrence selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, —NR a R b , —OC(O)NR a R b , —NR a —C(O)-phenyl, and —O—C(O)—NR a -phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, —OC(O)NR a R b , —NR a —C(O)-phenyl, and —O—C(O)—NR a -phenyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NR a R b ;
R A2 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R A3 and R A4 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and NR a R b wherein C 1-6 alkyl and C 1-6 alkoxy may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NR a R b ;
R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, heterocycle, C 1-6 alkyl-S(O) 2 —, and phenyl-S(O) 2 —; wherein C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, and heterocycle may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and NR a R b ;
and R X5 is selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl.
3 . The compound of claim 1 or 2 , wherein R 1 is —C(O)OH.
4 . The compound of claims 1 or 2 , wherein R 1 is selected from the group consisting of:
wherein X is independently selected from the group consisting of O and S; R″ is hydrogen or C 1-4 alkyl; and each R 66 and R 77 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, and C 1-4 alkyl.
5 . The compound of claim 4 , wherein R 1 is selected from the group consisting of:
6 . The compound of any one of claims 1 - 5 , wherein R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, and halogen.
7 . The compound of claim 6 , wherein R 2 is methyl or ethyl.
8 . The compound of any one of claims 1 - 7 , wherein R 3 is C 3-6 cycloalkoxy; wherein C 3-6 cycloalkoxy may be optionally substituted by one or two substituents selected from R U .
9 . The compound of claim 8 , wherein R gg is selected from the group consisting of: C 1-6 alkyl,
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen and C 1-6 alkyl.
10 . The compound of claim 9 , wherein R gg is
11 . The compound of any one of claims 1 - 7 , wherein R 3 is C 1-6 alkoxy, wherein C 1-6 alkoxy may be optionally substituted by one, two or three substituents selected from R gg .
12 . The compound of claim 11 , wherein R gg is selected from the group consisting of: halogen, hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkyl (optionally substituted by one or two substituents independently selected from the group consisting of hydroxyl, C 1-3 alkyl and C 1-3 alkoxy), phenyl,
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 1-3 alkoxy and oxo; and wherein R N is selected from the group consisting of hydrogen and —S(O) 2 —C 1-3 alkyl; and wherein phenyl may be optionally substituted by on one two substituents selected from R hh .
13 . The compound of claim 12 , wherein R gg is selected from the group consisting of:
14 . The compound of claim 12 , wherein R hh is selected from the group consisting of: halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), —S(O) w —NR a R b , —NR a —S(O) w —C 1-3 alkyl,
wherein R a is hydrogen or methyl; and wherein C 1-3 alkoxy and S(O) w —C 1-3 alkyl may optionally be substituted by one, two, or three fluorine atoms.
15 . The compound of any one of claims 1 - 7 , wherein R 3 is monocyclic, spirocyclic, or bridged bicyclic heterocyclyloxy.
16 . The compound of claim 15 , wherein R 3 is selected from the group consisting of:
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 1-3 alkoxy and oxo; and wherein R N is selected from the group consisting of hydrogen and —S(O) 2 —C 1-3 alkyl.
17 . The compound of claim 16 , wherein R 3 is selected from the group consisting of:
18 . The compound of any one of claims 1 - 17 , wherein X 1 is C(R X1 ), X 2 is C(R X2 ), and X 3 is C(R X3 ).
19 . The compound of any one of claims 1 - 18 , wherein A is selected from the group consisting of:
20 . The compound of claim 19 , wherein A is selected from the group consisting of:
21 . The compound of claim 1 , represented by:
wherein
X is O or S;
R A1 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 1 is selected from the group consisting of —C(O)OH and a 5-6 membered monocyclic heteroaryl having one, two, three, or four heteroatoms each selected from the group consisting of O, N, and S; wherein said heteroaryl may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1-4 alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;
Y is O or S(O) w (where w is 0, 1 or 2);
R 25 and R 26 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
p is 0 or 1; and
B is a 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclic ring contains an —NH moiety, that nitrogen may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, and —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2); and wherein said heterocyclic ring may optionally be substituted by one, two, three, or four substituents each independently selected from hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, and oxo.
22 . The compound of claim 21 , wherein X is O.
23 . The compound of claim 21 or 22 , wherein R A1 is methyl.
24 . The compound of any one of claims 21 - 23 , wherein R 1 is —C(O)OH.
25 . The compound of any one of claims 21 - 24 , wherein p is 1.
26 . The compound of any one of claims 21 - 25 , represented by
27 . The compound of any one of claims 21 - 26 , wherein Y is O.
28 . The compound of any one of claims 15 - 27 , wherein R 2 is C 1-6 alkyl.
29 . A compound represented by Formula II, III, IV, or V:
and pharmaceutically acceptable salts thereof, wherein:
X 1 is selected from the group consisting of N and C(R X1 );
X 2 is selected from the group consisting of N and C(R X2 );
X 3 is selected from the group consisting of N and C(R X3 );
wherein only one of X 1 , X 2 or X 3 can be N;
R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl; wherein C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and phenyl; and wherein phenyl may optionally be substituted by one or more substituents each independently selected from R p ;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 0, 1, or 2), —NR a —C 1-6 alkyl, C3-cycloalkoxy, —S(O) w —C 3-6 cycloalkyl (where w is 0, 1, or 2), —NR a —C 3-6 cycloalkyl, —O-phenyl, —S(O) w -phenyl (where w is 0, 1, or 2), —NR a -phenyl, C 8-12 benzocycloalkoxy, —NR a R b , —OC(O)NR a -phenyl, —NR a —C(O)—O— phenyl, —NR a —C(O)—C 1-6 alkyl-phenyl, —C 1-6 alkyl-NR a -phenyl, —NR a —C 1-6 alkyl-phenyl, and a 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclyloxy, heterocyclyl-NR a —, or heterocyclyl-S(O) w — moiety (where w is 0, 1, or 2) having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclyloxy, heterocyclyl-NR a —, or heterocyclyl-S(O) w — ring contains an —NH moiety, that nitrogen may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, and —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2); and wherein said heterocyclyloxy, heterocyclyl-NR a —, and heterocyclyl-S(O) w may optionally be substituted by one, two, three, or four substituents each independently selected from R 1 ; and wherein said phenyl moiety of —O-phenyl, —S(O) w -phenyl, —NR a -phenyl, —OC(O)NR a -phenyl, —NR a —C(O)—O-phenyl, —NR a —C(O)—C 1-6 alkyl-phenyl, —C 1-6 alkyl-NR a -phenyl and —NR a —C 1-6 alkyl-phenyl may optionally be substituted by one, two, or three substituents each independently selected from R p ; and wherein C 1-6 alkoxy, —S(O) w —C 1-6 alkyl (where w is 0, 1, or 2), —NR a —C 1-6 alkyl, C 3-6 cycloalkoxy, —S(O) w —C 3-6 cycloalkyl (where w is 0, 1, or 2), and —NR a —C 3-6 cycloalkyl may optionally be substituted by one, two, or three substituents each independently selected from R gg ;
R ff is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , oxo, C 1-6 alkyl and C 1-6 alkoxy;
R gg is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl (optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy (optionally substituted by one, two or three fluorine atoms)), phenyl, a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein if said heterocyclic ring contains an —NH moiety, that nitrogen may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, and —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2); and wherein phenyl may optionally be substituted by one, two, or three substituents each independently selected from R hh ; and wherein said 4-10 membered monocyclic, bridged bicyclic, or spirocyclic heterocyclic ring may optionally be substituted by one, two, three, or four substituents each independently selected from R gg ;
R hh is independently selected for each occurrence from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, S(O) w —C 1-3 alkyl, —S(O) w —NR a R b , —NR a —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), a 5-6 membered monocyclic heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of O, N, and S, and a 4-7 membered heterocyclic ring having one or two heteroatoms each independently selected from the group consisting of O, N, and S; wherein C 1-6 alkoxy and S(O) w —C 1-3 alkyl may optionally be substituted by one, two, or three halogens;
R ii is independently selected for each occurrence from the group consisting of halogen, hydroxyl, —NR a R b , oxo, C 1-6 alkyl and C 1-6 alkoxy;
R A1 is independently for each occurrence selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, —NR a R b , —O—C(O)—NR a -phenyl, —NR a —C(O)-phenyl, and —NR a —C 1-4 alkyl-phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, phenyl, and —NR a R b ;
R X1 is selected from the group consisting of hydrogen, —C(O)OH, and C 1-6 alkyl; wherein C 1-6 alkyl may optionally be substituted by one, two or three halogens;
R X2 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and —C 1-6 alkox-phenyl; wherein phenyl may optionally be substituted by one or more substituents selected from R p ;
R X3 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, —C 1-6 alkoxy-phenyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, and phenyl; wherein C 1-6 alkyl and C 1-6 alkoxy may optionally be substituted by one, two, or three substituents selected from the group consisting of hydroxyl and halogen; and wherein phenyl may optionally be substituted by one or more substituents selected from R p ;
R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, phenyl, —C(O)-phenyl, and —C(O)—C 1-6 alkyl; or
R a and R b taken together with the nitrogen to which they are attached form a heterocyclic ring; and
R p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl, C 3-6 cycloalkoxy, —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), —S(O) w —NR a R b , and —NR a R b .
30 . The compound of claim 29 , wherein R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, and halogen.
31 . The compound of claim 15 , wherein R 2 is methyl or ethyl.
32 . The compound of any one of claims 29 - 31 , wherein R 3 is C 3-6 cycloalkoxy; wherein C 3-6 cycloalkoxy may be optionally substituted by one or two substituents selected from R gg .
33 . The compound of claim 32 , wherein R gg is selected from the group consisting of: C 1-6 alkyl,
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen and C 1-6 alkyl.
34 . The compound of claim 33 , wherein R gg is
35 . The compound of any one of claims 29 - 31 , wherein R 3 is C 1-6 alkoxy, wherein C 1-6 alkoxy may be optionally substituted by one, two or three substituents selected from R gg .
36 . The compound of claim 35 , wherein R gg is selected from the group consisting of: halogen, hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkyl (optionally substituted by one or two substituents independently selected from the group consisting of hydroxyl, C 1-3 alkyl and C 1-3 alkoxy), phenyl,
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 1-3 alkoxy and oxo; and wherein R N is selected from the group consisting of hydrogen and —S(O) 2 —C 1-3 alkyl; and wherein phenyl may be optionally substituted by on one two substituents selected from R hh .
37 . The compound of claim 36 , wherein R gg is selected from the group consisting of:
38 . The compound of claim 36 , wherein R hh is selected from the group consisting of: halogen, C 1-3 alkyl, C 1-3 alkox, cyano, —S(O) w —C 1-3 alkyl (where w is 0, 1, or 2), —S(O) w —NR a R b , —NR a —S(O) w —C 1-3 alkyl
wherein R a is hydrogen or methyl; and wherein C 1-3 alkoxy and S(O) w —C 1-3 alkyl may optionally be substituted by one, two, or three fluorine atoms.
39 . The compound of any one of claims 29 - 31 , wherein R 3 is monocyclic, spirocyclic, or bridged bicyclic heterocyclyloxy.
40 . The compound of claim 39 , wherein R 3 is selected from the group consisting of:
wherein R 11 , R 22 , R 33 and R 44 are independently selected for each occurrence from the group consisting of hydrogen, hydroxyl, C 1-6 alkyl, C 1-3 alkoxy and oxo; and wherein R N is selected from the group consisting of hydrogen and —S(O) 2 —C 1-3 alkyl.
41 . The compound of claim 40 , wherein R 3 is selected from the group consisting of:
42 . A compound selected from the group consisting of:
and a pharmaceutically acceptable salt or stereoisomer thereof.
43 . A pharmaceutical composition comprising a compound of any one of claims 1 to 42 and a pharmaceutically acceptable excipient.
44 . The pharmaceutical composition of claim 43 , wherein the composition further comprises at least one additional CFTR modulator.
45 . The pharmaceutical composition of claim 44 , wherein the composition further comprises two, three, four or more additional CFTR modulators.
46 . A method of enhancing cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof comprising administering to said subject an effective amount of a compound of any one of claims 1 to 42 .
47 . The method of claim 46 , wherein the cellular processing of a mutant CFTR is enhanced.
48 . The method of claim 47 , wherein the mutant CFTR is selected from the group consisting ΔF508, S549N, G542X, G551D, R117H, N1303K, W1282X, R553X, 621+1G>T, 1717-1G>A, 3849+10kbC>T, 2789+5G>A, 3120+1G>A, I507del, R1162X, 1898+1G>A, 3659delC, G85E, DI 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR.
49 . The method of claim 48 , wherein ΔF508 CFTR activity is enhanced.
50 . The method of any one of claims 46 - 49 , wherein the subject is suffering from a disease associated with decreased CFTR activity.
51 . The method of claim 50 , wherein the disease is selected from the group consisting of cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, A-β-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, Sjogren's syndrome, familial hypercholesterolemia, I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian, myotonic dystrophy, hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, and Straussler-Scheinker syndrome.
52 . The method of claim 51 , wherein the disease is cystic fibrosis.
53 . The method of any one of claims 46 - 52 , wherein the subject is a human patient.
54 . The method of any one of claims 46 - 53 , further comprising administering at least one or two additional CFTR modulators.
55 . The method of claim 54 , wherein one, two, three or four or more additional CFTR modulators are administered.
56 . The method of any one of claims 54 or 55 , wherein at least one CFTR modulator is an additional CFTR corrector or potentiator.
57 . The method of claim 56 , wherein at least one CFTR corrector or potentiator is independently selected from the group consisting of VX-152, VX-440, VX-770 (ivacaftor), VX-809 (lumacaftor) (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, VX-661 ((R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropane-1-carboxamide), VX-983, QBW251, GLPG2222, GLPG2851, GLPG2665, GLPG2737, FDL169, GLPG2451, GLPG1837, and genistein.
58 . The method of claim 57 , wherein the CFTR corrector is selected from the group consisting of VX-809, VX-661, VX-152, VX-440, GLPG2222 and VX-983 and the CFTR potentiator is selected from the group consisting of GLPG2451, GLPG1837, ivacaftor and genistein.
59 . A method of treating cystic fibrosis in a patient in need thereof, comprising administering an effective amount of compound of any one of claims 1 - 42 .Join the waitlist — get patent alerts
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