Pyridyl derivatives as CFTR modulators
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
1. A method of treating a condition, disease, or disorder in a patient implicated by CFTR, wherein the condition, disease, or disorder is selected from cystic fibrosis, hereditary emphysema COPD, and dry-eye disease, comprising the step of administering to said patient a compound of
or a pharmaceutically acceptable salt thereof, wherein:
R N is H, or alkyl;
A is an optionally substituted 3 membered monocyclic ring;
B is optionally fused to a 5-7 membered ring selected from the group consisting of cycloaliphatic, aryl, heterocyclic, and heteroaryl;
R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or
two R 1 on adjacent atoms, taken together, form
wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;
W is independently-a (C1-C6) alkylidene chain wherein up to two methylene units of W are independently replaced by —O—, —S—, —SO 2 —, or —NR′—;
R′ is independently H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocyclic;
R W is independently H, halo, CN, NO 2 , N(R) 2 , CF 3 , OCF 3 , OH, OR, C(O)R, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;
R 2 is halo, CN, NO 2 , CF 3 , OCF 3 , OR, OC(O)R, OC(O)N(R) 2 , SR, S(O)R, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, CO 2 R, C(O)N(R) 2 , N(R) 2 , NRC(O)R, NRCO 2 R, NRC(O)N(R) 2 , NRSO 2 R, B(OR) 2 , or NRSO 2 N(R) 2 ;
R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
n is 1 or 2;
w is an integer from 1 to 4 inclusive; and
x is an integer from 1 to 5 inclusive.
2. The method of claim 1 , wherein A is:
a wherein
R 3 is alkyl, alkaryl, aryl, or heteroaryl; and
q is an integer from 0 to 4 inclusive.
3. The method of claim 1 , wherein A is
4. The method of claim 1 , wherein R 1 is selected from the group consisting of chloro, methyl, OH, methoxy, thiomethyl, and trifluoromethoxy.
5. The method of claim 1 , wherein two R 1 on adjacent atoms, taken together, form
wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 .
6. The method of claim 1 , wherein J is CH 2 .
7. The method of claim 1 , wherein J is CF 2 .
8. The method of claim 1 , wherein W is an optionally substituted (C1-C6)alkylidene chain.
9. The method of claim 1 , wherein W is selected from the group consisting of —CH 2 —, —NH—, —O—, and —OCH 2 —.
10. The method of claim 1 , wherein R w is selected from the group consisting of H, OH, heterocyclic, aryl, phenyl, heteroaryl, pyridyl, alkoxy, cycloalkyl, and cyclohexyl.
11. The method of claim 1 , wherein —W—R w is acyclic.
12. The method of claim 1 , wherein —W(R w ) n is selected from the following:
—CH 3 , —CH 2 CH 3 , —CN, —CF 3 , —CONH 2 , —CH 2 CH(CH 3 ) 2 ,
13. The method of claim 1 , having formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
J is CH 2 or CF 2 ;
W is independently a (C1-C6)alkylidene chain optionally substituted with R 2 wherein up to two methylene units of W are independently replaced by —O—, or —NR′—;
R′ is independently H or alkyl;
R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;
R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;
R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
n is 1 or 2; and
w is an integer from 1 to 4 inclusive.
14. The method of claim 13 , wherein J is CH 2 .
15. The method of claim 13 , wherein J is CF 2 .
16. The method of claim 13 , wherein —W—R w is acyclic.
17. The method of claim 13 , wherein —W(R w ) n is selected from the following:
—F, —CH 3 , —CH 2 CH 3 , —CN, —CF 3 , —CONH 2 , —CH 2 CH(CH 3 ) 2 ,
18. The method of claim 1 , having formula Ib:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or
two R 1 on adjacent atoms, taken together, form
wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;
W is —NR′, or —CH 2 —;
R′ is independently H or alkyl;
R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;
R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;
R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
n is 1 or 2;
w is an integer from 1 to 4 inclusive; and
x is an integer from to 5 inclusive.
19. The method of claim 18 , wherein two R 1 on adjacent atoms, taken together, form
and J is CH 2 .
20. The method of claim 18 , wherein two R 1 on adjacent atoms, taken together, form
and J is CF 2 .
21. The method of claim 18 , wherein —W(R w ) n is selected from the following:
—CH 3 , —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,
22. The method of claim 1 , having formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, alkyl, OH, alkoxy, thioalkyl, trifluoromethoxy; or
two R 1 on adjacent atoms, taken together, form
wherein J is selected from the group consisting of CH 2 , CF 2 , or C(CH 3 ) 2 ;
W is —NR′, or —CH 2 —;
R′ is independently H or alkyl;
R W is independently H, halo, CN, N(R) 2 , CF 3 , OH, CO 2 R, C(O)N(R) 2 , —O(C1-C6)alkylidene-OR, —O(C1-C6)alkylidene-N(R) 2 , —O(C1-C6)alkylidene-heterocyclic, or an optionally substituted aliphatic, cycloaliphatic, aryl, aryloxy, heterocyclic, or heteroaryl, wherein, when substituted, R w is substituted with up to two R 2 ;
R 2 is halo, OR, CO 2 R, C(O)N(R) 2 , SO 2 N(R) 2 , B(OR) 2 , or N(R) 2 ;
R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
n is 1 or 2;
w is an integer from 1 to 4 inclusive; and
x is an integer from 1 to 5 inclusive.
23. The method of claim 22 , wherein two R 1 on adjacent atoms, taken together, form
and J is CH 2 .
24. The method of claim 22 , wherein two R 1 on adjacent atoms, taken together, form
and J is CF 2 .
25. The method of claim 22 , wherein —W(R w ) n is selected from the following:
—CH 3 , —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,
26. The method of claim 1 , wherein the compound is selected from
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