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 of Formula I:
and a deuterated derivative thereof, or a pharmaceutically acceptable salt of the foregoing, wherein:
X is selected from —N(R X1 )— and
Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl and oxo;
R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, —OR X2 , and —N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl;
each R X2 is independently selected from H and C 1 -C 6 alkyl;
each Y is independently selected from —C(R Y ) 2 —,—O—,—CO—,—NR YN —, and
wherein each R YN is independently selected from H, C 1 -C 4 alkyl, and CO 2 R YN1 , wherein each R YN1 is independently selected from C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;
each R Y is independently selected from hydrogen, hydroxy, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C 1 -C 6 alkoxy, and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 ,—COR Y1 ,—CON(R Y1 ) 2 , and —N(R Y1 ) 2 ;
or two R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 7-membered heterocyclyl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;
each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two 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 fluoroalkyl, C 1 -C 6 alkyl (optionally substituted with a group selected from hydroxy, C 6 -C 10 aryl, and 5- to 6-membered heteroaryl), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), 3- to 6-membered heterocyclyl, —B(OR 2 ) 2 , —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), C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl and C 1 -C 6 fluoroalkoxy);
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 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and 5- to 6-membered heteroaryl;
R Z2 is selected from hydrogen, halogen, hydroxy, NH 2 , NH(CO) (C 1 -C 6 alkyl), and C 1 -C 6 alkoxy (optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl),
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, and C 6 -C 10 aryl; or two 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 —N(R X1 )—.
3. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein X is
4. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein X is selected from:
5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
each R Y is independently selected from hydrogen, hydroxy, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C 1 -C 6 alkoxy, and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, —CO 2 R Y1 , and —CON(R Y1 ) 2 ;
or two R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 7-membered heterocyclyl;
or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl.
7. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each Q is independently selected from C 6 -C 10 aryl.
8. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each Q is phenyl.
9. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
each R Y is independently selected from:
or two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyryl, and tetrahydrofuryl;
or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
10. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and 5- to 10-membered heteroaryl.
11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is selected from phenyl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and pyridyl.
12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring B is selected from:
13. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein n is selected from 4, 5, 6, and 7.
14. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein —(Y) n — is a group selected from:
15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently selected from halogen, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl (optionally substituted with a group selected from C 6 -C 10 aryl), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), 3- to 6-membered heterocyclyl, —B(OR 2 ) 2 , —SO 2 R 2 , —SR 2 , —SOR 2 , and —PO(R 2 ) 2 .
16. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 2 is independently selected from hydrogen and C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkoxy).
17. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein each R 1 is independently selected from —Br, —CF 3 , —NH 2 , —CH 3 , —CH(CH 3 ) 2 , —CN, —OH, —OCH 3 , —NH(CH 3 ), —NH(CH 2 CH 3 ), —CONH 2 , —CO 2 CH 3 , —SO 2 CH 3 , —SO 2 Ph, PO(CH 3 ) 2 , B(OH) 2 , phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopropyl, cyclohexyl, imidazolyl.
18. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Z is selected from
wherein Ring C is selected from C 6 -C 10 aryl.
19. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the group:
is selected from:
20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the group:
21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and 5- to 6-membered heteroaryl.
22. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z2 is selected from hydrogen, halogen, hydroxy, and C 1 -C 6 alkoxy (optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl).
23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl; and
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.
24. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
R Z1 is selected from hydrogen, CH 3 , CF 3 , CH 2 OH, phenyl, cyclopropyl, and tetrahydropyranyl; and
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.
25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R Z2 is hydroxy.
26. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Z is selected from:
27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein m is selected from 1 and 2.
28. A compound selected from:
Com-
pound
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
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the forgoing.
29. A compound according to claim 28 , wherein the compound is:
Comp. No.
Structure
4
19
32
138
163
173
176
177
178
enantiomer 1
182
enantiomer 1
192
193
205
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the forgoing.
30. A pharmaceutical composition comprising a compound, salt, or deuterated derivative according to claim 1 and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition according to claim 30 , further comprising one or more additional therapeutic agent(s).
32. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, salt, or deuterated derivative according to claim 1 .
33. The method according to claim 32 , further comprising administering one or more additional therapeutic agent(s).
34. A compound according to claim 1 , wherein the compound is:
Compound
No.
Structure
4
5
19
41
52
60
70
163
173
175
188
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the forgoing.
35. A compound according to claim 34 , wherein Compound 4 is substantially amorphous Compound 4.
36. A compound according to claim 34 , wherein Compound 5 is substantially crystalline Compound 5 Form A.
37. A compound according to claim 34 , wherein Compound 19 is substantially amorphous Compound 19.
38. A compound according to claim 34 , wherein Compound 41 is substantially crystalline Compound 41 Form A.
39. A compound according to claim 34 , wherein Compound 52 is substantially crystalline Compound 52 Form A.
40. A compound according to claim 34 , wherein Compound 60 is substantially amorphous Compound 60.
41. A compound according to claim 34 , wherein Compound 70 is substantially amorphous Compound 70.
42. A compound according to claim 34 , wherein Compound 163 is substantially crystalline Compound 163 Form A.
43. A compound according to claim 34 , wherein Compound 173 is substantially amorphous Compound 173.
44. A compound according to claim 34 , wherein Compound 173 is substantially crystalline Compound 173 Form A.
45. A compound according to claim 34 , wherein Compound 175 is substantially crystalline Compound 175 Form A.
46. A compound according to claim 34 , wherein Compound 188 is substantially crystalline Compound 188 dichloromethane solvate Form A.
47. A process for preparing a compound of Formula 7-7:
comprising converting a compound of Formula 7-6:
into a compound of Formula 7-7, wherein:
R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, —OR X2 , and —N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl;
each R X2 is independently selected from H and C 1 -C 6 alkyl;
each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, —NR YN —, and
wherein each R YN is independently selected from H, C 1 -C 4 alkyl, and CO 2 R YN1 , wherein each R YN1 is independently selected from C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;
each R Y is independently selected from hydrogen, hydroxy, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C 1 -C 6 alkoxy, and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —N(R Y1 ) 2 ;
or two R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 7-membered heterocyclyl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;
each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two 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 fluoroalkyl, C 1 -C 6 alkyl (optionally substituted with a group selected from hydroxy, C 6 -C 10 aryl, and 5- to 6-membered heteroaryl), —OR 2 , —N(R 2 ) 2 , —NO 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), 3- to 6-membered heterocyclyl, —B(OR 2 ) 2 , —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), C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl and C 1 -C 6 fluoroalkoxy);
m is selected from 0, 1, 2, and 3;
each of a and b is an integer independently selected from 0, 1, 2, and 3, provided that the sum of a and b is not greater than 4; and
PG 1 is selected from suitable oxygen protecting groups.
48. A compound of the formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.
49. A compound of the formula:
50. A pharmaceutical composition comprising the compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 48 , and a pharmaceutically acceptable carrier.
51. The pharmaceutical composition according to claim 50 , further comprising one or more additional therapeutic agent(s).
52. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 48 .
53. The method of claim 52 , further comprising administering one or more additional therapeutic agent(s).