Modulators of cystic fibrosis transmembrane conductance regulator
The present invention features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.
1. A compound of formula Ib-iii:
or a pharmaceutically acceptable salt thereof, wherein:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring;
and wherein, independently for each occurrence:
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a=CH 2 or ═O group;
R 3 is halo; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 groups taken together may form a=CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
n is 0, 1, 2 or 3;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
2. The compound or salt of claim 1 , wherein ring B is phenyl, pyridyl, pyridine-2(1H)-one, pyrazole, indole, aza-indole, thiophene, dihydrobenzofuran, or quinoline.
3. The compound or salt of claim 1 , wherein ring B is selected from
4. The compound or salt of claim 1 , wherein ring C is selected from indole, piperidine, azepane, azetadine, indoline, isoindoline, or pyrrolidine.
5. The compound or salt of claim 1 , wherein ring C is selected from
6. The compound or salt of claim 1 , wherein R 1 is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, pyrazole, or thiophene ring, or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR, wherein all rings are optionally substituted with one or more groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C3-C10 heteroaryl, and C3-C10 heterocycloalkyl.
7. The compound or salt of claim 1 , wherein R 1 is selected from CH 3 , Cl, F, CN, OCH 3 , CF 3 , CH 2 CH 3 , tBu, CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,
8. The compound or salt of claim 1 , wherein R 2 is selected from halo, OH, CN, azide, amino, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy or fluoroalkoxy, C3-C10 heterocyclic ring wherein up to 4 ring atoms are independently 0, S, N, or NR; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.
9. The compound or salt of claim 1 , wherein R 2 is selected from Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH 2 CH 2 CH 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , =O, CH 3 SO 2 , CH 3 SO 2 NH, CF 3 CONH, CH 3 CONH, CH 3 CON(CH 3 ), tBuOCONH, (CH 3 ) 2 CHOCONH, CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCF 3 , OCHF 2 , OC(CH 3 ) 3 , OCH 2 CH 2 tBu, NHCH(CH 3 )(CH 2 CH 2 CH 3 ), OCH(CH 3 ) 2 , NH(CH 2 ) 2 O(CH 2 ) 2 CH 3 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH 2 COOH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,
10. The compound or salt of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl or fluoroalkyl, C1-C6 alkoxy, or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR.
11. The compound or salt of claim 1 , wherein R 3 is selected from Cl, I, deuterium, F, CN, CH 3 , OH, OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , OCH(CH 3 ) 2 , CO 2 H, CO 2 NH 2 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CH 2 CONH 2 , CO 2 CH 3 , —CH 2 N(CH 3 ) 2 , CO 2 tBu, tBu, =CH 2 , =O,
12. A compound of formula Ib-iv:
or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, and wherein one nitrogen on Ring C is the point of attachment to the pyridine ring;
R 1 is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a=CH 2 or ═O group;
R 3 is halo; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 groups taken together may form a=CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl;
C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
13. A compound of formula Ib-v:
or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl;C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a=CH 2 or ═O group;
R 3 is halo; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl;
C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 groups taken together may form a=CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
n is 0, 1, 2 or 3;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
14. A compound of formula Ib-vi:
or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
R 1 is C6-C10 aryl or C3-C10 heteroaryl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkoxy or fluoroalkoxy; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 groups taken together may form a=CH 2 or ═O group;
R 3 is halo; CN; CO 2 R; C1-C6 alkyl or fluoroalkyl; C1-C6 alkenyl; C1-C6 alkynyl; C1-C6 alkoxy or fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 groups taken together may form a=CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C1-C6 alkyl; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
15. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
17. A pharmaceutical composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17 , further comprising one or more additional therapeutic agent(s).
19. The pharmaceutical composition of claim 18 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
20. The pharmaceutical composition of claim 18 , wherein at least one additional therapeutic agent is
or pharmaceutically acceptable salt thereof.
21. The pharmaceutical composition of claim 18 , wherein at least one additional therapeutic agent is
or pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition of claim 18 , wherein the additional therapeutic agents are
or
pharmaceutically acceptable salts thereof.
23. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound or salt of claim 1 .
24. The method of claim 23 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound or salt.
25. The method of claim 24 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
26. The method of claim 24 , wherein at least one additional therapeutic agent is
or a pharmaceutically acceptable salt thereof.
27. The method of claim 24 , wherein at least one additional therapeutic agent is
or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising the compound or salt of claim 15 and a pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , further comprising one or more additional therapeutic agent(s).
30. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
31. The pharmaceutical composition of claim 29 , wherein at least one additional therapeutic agent is
or pharmaceutically acceptable salt thereof.
32. The pharmaceutical composition of claim 29 , wherein at least one additional therapeutic agent is
or pharmaceutically acceptable salt thereof.
33. The pharmaceutical composition of claim 29 , wherein the additional therapeutic agents are
or
pharmaceutically acceptable salts thereof.
34. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound or salt of claim 15 .
35. The method of claim 34 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound or salt.
36. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
37. The method of claim 35 , wherein at least one additional therapeutic agent is
or a pharmaceutically acceptable salt thereof.
38. The method of claim 35 , wherein at least one additional therapeutic agent is
or a pharmaceutically acceptable salt thereof.