Modulators of cystic fibrosis transmembrane conductance regulator
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.
1. A compound selected from compounds of Formula I:
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
X is selected from —O—, —S—, —SO—, and —SO 2 —;
each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and
each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —N(R Y1 ) 2 ; or two instances of R Y on the same atom may be taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on a first atom and the second of which is on an adjacent second atom, may be replaced with a pi bond between the first and second atom;
each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;
Ring B is selected from:
C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy),
C 3 -C 8 cycloalkyl,
5- to 10-membered heteroaryl, and
3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);
each Q is independently selected from:
C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:
halogen,
oxo,
C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and
C 3 -C 8 cycloalkyl,
C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:
halogen,
CN,
C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe),
C 1 -C 6 alkoxy,
C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and
C 3 -C 8 cycloalkyl,
C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:
halogen,
CN,
C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy),
C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:
halogen,
C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),
C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and
C 6 -C 10 aryl,
5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
halogen,
C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen),
C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and
3- to 10-membered heterocyclyl,
3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and
oxo;
each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;
each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);
Z is selected from
wherein Ring C is selected from C 6 -C 10 aryl and 5- to 10-membered heteroaryl;
R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;
R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;
each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl;
n is selected from 4, 5, 6, 7, and 8; and
m is selected from 0, 1, 2, and 3.
2. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein X is —O—.
3. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, and —OR Y1 .
4. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein —OR Y1 is —OH.
5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each Q is independently selected from:
C 3 -C 8 cycloalkyl,
C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.
6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each Q is independently selected from:
7. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R Y is independently selected from: hydrogen, fluorine,
8. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is selected from C 3 -C 8 cycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen.
9. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is selected from:
10. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein n is selected from 4, 5, and 6.
11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein —(Y) n — is a group selected from:
12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —N(R 2 ) 2 , and —CO 2 R 2 .
13. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.
14. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently selected from —CF 3 , —NH 2 , —NH(CH 2 CH 3 ), CO 2 H, and CH 2 OH.
15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Z is selected from
16. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the group:
is selected from:
17. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the group:
is selected from:
18. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z1 is selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).
19. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z1 is selected from hydrogen and —CF 3 .
20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z2 is hydroxy.
21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Z is selected from:
22. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein m is selected from 1 and 2.
23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
X is —O—;
each Y is independently selected from —C(R Y ) 2 —, —O—, and
each R Y is independently selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q);
Ring B is selected from C 3 -C 8 cycloalkyl groups:
each Q is independently selected from: C 3 -C 8 cycloalkyl and C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl,
each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen) and —NH 2 ;
Z is
R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen);
R Z2 is hydroxy;
n is selected from 5 and 6; and
m is 2.
24. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each Q is independently selected from:
25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R Y is independently selected from: hydrogen,
26. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is
27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein —(Y) n — is a group selected from:
28. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z1 is —CF 3 .
29. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein n is 5.
30. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein n is 6.
31. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is selected from:
Comp. No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.
32. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 31 , wherein the compound is selected from:
Comp. No.
Structure
5
11
14
36
37
47
49
50
52
59
61
63
64
pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.
33. A pharmaceutical composition comprising a compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier.
34. The pharmaceutical composition according to claim 33 , further comprising one or more additional therapeutic agent(s).
35. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 .
36. The method according to claim 35 , further comprising administering one or more additional therapeutic agent(s).
37. A compound of the formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.
38. A pharmaceutical composition comprising the compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 37 , and a pharmaceutically acceptable carrier.
39. The pharmaceutical composition according to claim 38 , further comprising one or more additional therapeutic agent(s).
40. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 37 .
41. The method according to claim 40 , further comprising administering one or more additional therapeutic agent(s).